Arquivo da tag: Genética

New application of physics tools used in biology (Science Daily)


February 7, 2014

Source: DOE/Lawrence Livermore National Laboratory

Summary: A physicist and his colleagues have found a new application for the tools and mathematics typically used in physics to help solve problems in biology.

This DNA molecule is wrapped twice around a histone octamer, the major structural protein of chromosomes. New studies show they play a role in preserving biological memory when cells divide. Image courtesy of Memorial University of Newfoundland. Credit: Image courtesy of DOE/Lawrence Livermore National Laboratory

A Lawrence Livermore National Laboratory physicist and his colleagues have found a new application for the tools and mathematics typically used in physics to help solve problems in biology.

Specifically, the team used statistical mechanics and mathematical modeling to shed light on something known as epigenetic memory — how an organism can create a biological memory of some variable condition, such as quality of nutrition or temperature.

“The work highlights the interdisciplinary nature of modern molecular biology, in particular, how the tools and models from mathematics and physics can help clarify problems in biology,” said Ken Kim, a LLNL physicist and one of the authors of a paper appearing in the Feb. 7 issue ofPhysical Review Letters.

Not all characteristics of living organisms can be explained by their genes alone. Epigenetic processes react with great sensitivity to genes’ immediate biochemical surroundings — and further, they pass those reactions on to the next generation.

The team’s work on the dynamics of histone protein modification is central to epigenetics. Like genetic changes, epigenetic changes are preserved when a cell divides. Histone proteins were once thought to be static, structural components in chromosomes, but recent studies have shown that histones play an important dynamical role in the machinery responsible for epigenetic regulation.

When histones undergo chemical alterations (histone modification) as a result of some external stimulus, they trigger short-term biological memory of that stimulus within a cell, which can be passed down to its daughter cells. This memory also can be reversed after a few cell division cycles.

Epigenetic modifications are essential in the development and function of cells, but also play a key role in cancer, according to Jianhua Xing, a former LLNL postdoc and current professor at Virginia Tech. “For example, changes in the epigenome can lead to the activation or deactivation of signaling pathways that can lead to tumor formation,” Xing added.

The molecular mechanism underlying epigenetic memory involves complex interactions between histones, DNA and enzymes, which produce modification patterns that are recognized by the cell. To gain insight into such complex systems, the team constructed a mathematical model that captures the essential features of the histone-induced epigenetic memory. The model highlights the “engineering” challenge a cell must constantly face during molecular recognition. It is analogous to restoring a picture with missing parts. The molecular properties of a species have been evolutionarily selected to allow them to “reason” what the missing parts are based on incomplete information pattern inherited from the mother cell.

Story Source:

The above story is based on materials provided by DOE/Lawrence Livermore National Laboratory. The original article was written by Anne M Stark. Note: Materials may be edited for content and length.


Humanity’s forgotten return to Africa revealed in DNA (New Scientist)

20:00 03 February 2014 by Catherine Brahic

Call it humanity’s unexpected U-turn. One of the biggest events in the history of our species is the exodus out of Africa some 65,000 years ago, the start ofHomo sapiens‘ long march across the world. Now a study of southern African genes shows that, unexpectedly, another migration took western Eurasian DNA back to the very southern tip of the continent 3000 years ago.

According to conventional thinking, the Khoisan tribes of southern Africa, have lived in near-isolation from the rest of humanity for thousands of years. In fact, the study shows that some of their DNA matches most closely people from modern-day southern Europe, including Spain and Italy.

Because Eurasian people also carry traces of Neanderthal DNA, the finding also shows – for the first time – that genetic material from our extinct cousin may be widespread in African populations.

The Khoisan tribes of southern Africa are hunter-gatherers and pastoralists who speak unique click languages. Their extraordinarily diverse gene pool split from everyone else’s before the African exodus.

Ancient lineages

“These are very special, isolated populations, carrying what are probably the most ancient lineages in human populations today,” says David Reich of Harvard University. “For a lot of our genetic studies we had treated them as groups that had split from all other present-day humans before they had split from each other.”

So he and his colleagues were not expecting to find signs of western Eurasian genes in 32 individuals belonging to a variety of Khoisan tribes. “I think we were shocked,” says Reich.

The unexpected snippets of DNA most resembled sequences from southern Europeans, including Sardinians, Italians and people from the Basque region (see “Back to Africa – but from where?“). Dating methods suggested they made their way into the Khoisan DNA sometime between 900 and 1800 years ago – well before known European contact with southern Africa (see map).

Archaeological and linguistic studies of the region can make sense of the discovery. They suggest that a subset of the Khoisan, known as the Khoe-Kwadi speakers, arrived in southern Africa from east Africa around 2200 years ago. Khoe-Kwadi speakers were – and remain – pastoralists who make their living from herding cows and sheep. The suggestion is that they introduced herding to a region that was otherwise dominated by hunter-gatherers.

Khoe-Kwadi tribes

Reich and his team found that the proportion of Eurasian DNA was highest in Khoe-Kwadi tribes, who have up to 14 per cent of western Eurasian ancestry. What is more, when they looked at the east African tribes from which the Khoe-Kwadi descended, they found a much stronger proportion of Eurasian DNA – up to 50 per cent.

That result confirms a 2012 study by Luca Pagani of the Wellcome Trust Sanger Institute in Hinxton, UK, which found non-African genes in people living in Ethiopia. Both the 2012 study and this week’s new results show that the Eurasian genes made their way into east African genomes around 3000 years ago. About a millennium later, the ancestors of the Khoe-Kwadi headed south, carrying a weaker signal of the Eurasian DNA into southern Africa.

The cultural implications are complex and potentially uncomfortably close to European colonial themes. “I actually am not sure there’s any population that doesn’t have west Eurasian [DNA],” says Reich.

“These populations were always thought to be pristine hunter-gatherers who had not interacted with anyone for millennia,” says Reich’s collaborator, linguist Brigitte Pakendorf of the University of Lyon in France. “Well, no. Just like the rest of the world, Africa had population movements too. There was simply no writing, no Romans or Greeks to document it.”

Twist in tale

There’s one more twist to the tale. In 2010 a research team – including Reich – published the first draft genome of a Neanderthal. Comparisons with living humans revealed traces of Neanderthal DNA in all humans with one notable exception: sub-Saharan peoples like the Yoruba and Khoisan.

That made sense. After early humans migrated out of Africa around 60,000 years ago, they bumped into Neanderthals somewhere in what is now the Middle East. Some got rather cosy with each other. As their descendants spread across the world to Europe, Asia and eventually the Americas, they spread bits of Neanderthal DNA along with their own genes. But because those descendants did not move back into Africa until historical times, most of this continent remained a Neanderthal DNA-free zone.

Or so it seemed at the time. Now it appears that the Back to Africa migration 3000 years ago carried a weak Neanderthal genetic signal deep into the homeland. Indeed one of Reich’s analyses, published last month, found Neanderthal traces in Yoruba DNA (Nature, DOI: 10.1038/nature12886).

In other words, not only is western Eurasian DNA ancestry a global phenomenon, so is having a bit of Neanderthal living on inside you.

Journal reference: PNAS, DOI: 10.1073/pnas.1313787111

Back to Africa – but from where?

Reich and his colleagues found that DNA sequences in the Khoisan people most closely resemble some found in people who today live in southern Europe. That, however, does not mean the migration back to Africa started in Italy or Spain. More likely, the migration began in what is now the Middle East.

We know that southern Europeans can trace their ancestry to the Middle East. However, in the thousands of years since they – and the ancestors of the Khoisan – left the region, it has experienced several waves of immigration. These waves have had a significant effect on the genes of people living in the Middle East today, and and means southern Europeans are much closer to the original inhabitants of the Levant than modern-day Middle Easterners.

Neanderthals Leave Their Mark on Us (New York Times)

JAN. 29, 2014

A reconstruction of a Neanderthal skeleton, right, with a modern human skeleton in the background. Frank Franklin II/Associated Press

By Carl Zimmer

Ever since the discovery in 2010 that Neanderthals interbred with the ancestors of living humans, scientists have been trying to determine how their DNA affects people today. Now two new studies have traced the history of Neanderthal DNA, and have pinpointed a number of genes that may have medical importance today.

Among the findings, the studies have found clues to the evolution of skin and fertility, as well as susceptibility to diseases like diabetes. More broadly, they show how the legacy of Neanderthals has endured 30,000 years after their extinction.

“It’s something that everyone wanted to know,” said Laurent Excoffier, a geneticist at the University of Bern in Switzerland who was not involved in the research.

Neanderthals, who became extinct about 30,000 years ago, were among the closest relatives of modern humans. They shared a common ancestor with us that lived about 600,000 years ago.

In the 1990s, researchers began finding fragments of Neanderthal DNA in fossils. By 2010 they had reconstructed most of the Neanderthal genome. When they compared it with the genomes of five living humans, they found similarities to small portions of the DNA in the Europeans and Asians.

The researchers concluded that Neanderthals and modern humans must have interbred. Modern humans evolved in Africa and then expanded out into Asia and Europe, where Neanderthals lived. In a 2012 study, the researchers estimated that this interbreeding took place between 37,000 and 85,000 years ago.

Sir Paul A. Mellars, an archaeologist at the University of Cambridge and the University of Edinburgh, who was not involved in the research, said the archaeological evidence suggested the opportunity for modern humans to mate with Neanderthals would have been common once they expanded out of Africa. “They’d be bumping into Neanderthals at every street corner,” he joked.

The first draft of the Neanderthal genome was too rough to allow scientists to draw further conclusions. But recently, researchers sequenced a far more accurate genome from a Neanderthal toe bone.

Scientists at Harvard Medical School and the Max Planck Institute for Evolutionary Anthropology in Germany compared this high-quality Neanderthal genome to the genomes of 1,004 living people. They were able to identify specific segments of Neanderthal DNA from each person’s genome.

“It’s a personal map of Neanderthal ancestry,” said David Reich of Harvard Medical School, who led the research team. He and his colleagues published their results in the journal Nature.

Living humans do not have a lot of Neanderthal DNA, Dr. Reich and his colleagues found, but some Neanderthal genes have become very common. That’s because, with natural selection, useful genes survive as species evolve. “What this proves is that these genes were helpful for non-Africans in adapting to the environment,” Dr. Reich said.

In a separate study published in Science, Benjamin Vernot and Joshua M. Akey of the University of Washington came to a similar conclusion, using a different method.

Mr. Vernot and Dr. Akey looked for unusual mutations in the genomes of 379 Europeans and 286 Asians. The segments of DNA that contained these mutations turned out to be from Neanderthals.

Both studies suggest that Neanderthal genes involved in skin and hair were favored by natural selection in humans. Today, they are very common in living non-Africans.

The fact that two independent studies pinpointed these genes lends support to their importance, said Sriram Sankararaman of Harvard Medical School, a co-author on the Nature paper. “The two methods seem to be converging on the same results.”

It is possible, Dr. Akey speculated, that the genes developed to help Neanderthal skin adapt to the cold climate of Europe and Asia.

But Dr. Akey pointed out that skin performs other important jobs, like shielding us from pathogens. “We don’t understand enough about the biology of those particular genes yet,” he said. “It makes it hard to pinpoint a reason why they’re beneficial.”

Both teams of scientists also found long stretches of the living human genomes where Neanderthal DNA was glaringly absent. This pattern could be produced if modern humans with certain Neanderthal genes could not have as many children on average as people without them. For example, living humans have very few genes from Neanderthals involved in making sperm. That suggests that male human-Neanderthal hybrids might have had lower fertility or were even sterile.

Overall, said Dr. Reich, “most of the Neanderthal genetic material was more bad than good.”

Some of the Neanderthal genes that have endured until today may be influencing people’s health. Dr. Reich and his colleagues identified nine Neanderthal genes in living humans that are known to raise or reduce the risk of various diseases, including diabetes and lupus.

To better understand the legacy of Neanderthals, Dr. Reich and his colleagues are collaborating with the UK Biobank, which collects genetic information from hundreds of thousands of volunteers. The scientists will search for Neanderthal genetic markers, and investigate whether Neanderthal genes cause any noticeable differences in anything from weight to blood pressure to scores on memory tests.

“This experiment of nature has been done,” said Dr. Reich, “and we can study it.”

Correction: January 29, 2014
An earlier version of this article misstated the living groups in which Neanderthal genes involved in skin and hair are very common. They are very common in non-Africans, not non-Asians.

Genomes of Modern Dogs and Wolves Provide New Insights On Domestication (Science Daily)

Jan. 16, 2014 — Dogs and wolves evolved from a common ancestor between 9,000 and 34,000 years ago, before humans transitioned to agricultural societies, according to an analysis of modern dog and wolf genomes from areas of the world thought to be centers of dog domestication.

This chart depicts wolf and dog lineages as they diverge over time. (Credit: Freedma, et al / PLoS Genetics)

The study, published in PLoS Geneticson January 16, 2014, also shows that dogs are more closely related to each other than wolves, regardless of geographic origin. This suggests that part of the genetic overlap observed between some modern dogs and wolves is the result of interbreeding after dog domestication, not a direct line of descent from one group of wolves.

This reflects a more complicated history than the popular story that early farmers adopted a few docile, friendly wolves that later became our beloved, modern-day companions. Instead, the earliest dogs may have first lived among hunter-gatherer societies and adapted to agricultural life later.

“Dog domestication is more complex than we originally thought,” said John Novembre, associate professor in the Department of Human Genetics at the University of Chicago and a senior author on the study. “In this analysis we didn’t see clear evidence in favor of a multi-regional model, or a single origin from one of the living wolves that we sampled. It makes the field of dog domestication very intriguing going forward.”

The team generated the highest quality genome sequences to date from three gray wolves: one each from China, Croatia and Israel, representing three regions where dogs are believed to have originated. They also produced genomes for two dog breeds: a basenji, a breed which originates in central Africa, and a dingo from Australia, both areas that have been historically isolated from modern wolf populations. In addition to the wolves and dogs, they sequenced the genome of a golden jackal to serve as an “outgroup” representing earlier divergence.

Their analysis of the basenji and dingo genomes, plus a previously published boxer genome from Europe, showed that the dog breeds were most closely related to each other. Likewise, the three wolves from each geographic area were more closely related to each other than any of the dogs.

Novembre said this tells a different story than he and his colleagues anticipated. Instead of all three dogs being closely related to one of the wolf lineages, or each dog being related to its closest geographic counterpart (i.e. the basenji and Israeli wolf, or the dingo and Chinese wolf), they seem to have descended from an older, wolf-like ancestor common to both species.

“One possibility is there may have been other wolf lineages that these dogs diverged from that then went extinct,” he said. “So now when you ask which wolves are dogs most closely related to, it’s none of these three because these are wolves that diverged in the recent past. It’s something more ancient that isn’t well represented by today’s wolves.”

Accounting for gene flow between dogs and wolves after domestication was a crucial step in the analyses. According to Adam Freedman, a postdoctoral fellow at the University of California, Los Angeles (UCLA) and the lead author on the study, gene flow across canid species appears more pervasive than previously thought.

“If you don’t explicitly consider such exchanges, these admixture events get confounded with shared ancestry,” he said. “We also found evidence for genetic exchange between wolves and jackals. The picture emerging from our analyses is that these exchanges may play an important role in shaping the diversification of canid species.”

Domestication apparently occurred with significant bottlenecks in the historical population sizes of both early dogs and wolves. Freedman and his colleagues were able to infer historical sizes of dog and wolf populations by analyzing genome-wide patterns of variation, and show that dogs suffered a 16-fold reduction in population size as they diverged from wolves. Wolves also experienced a sharp drop in population size soon after their divergence from dogs, implying that diversity among both animals’ common ancestors was larger than represented by modern wolves.

The researchers also found differences across dog breeds and wolves in the number of amylase (AMY2B) genes that help digest starch. Recent studies have suggested that this gene was critical to domestication, allowing early dogs living near humans to adapt to an agricultural diet. But the research team surveyed genetic data from 12 additional dog breeds and saw that while most dog breeds had high numbers of amylase genes, those not associated with agrarian societies, like the Siberian husky and dingo, did not. They also saw evidence of this gene family in wolves, meaning that it didn’t develop exclusively in dogs after the two species diverged, and may have expanded more recently after domestication.

Novembre said that overall, the study paints a complex picture of early domestication.

“We’re trying to get every thread of evidence we can to reconstruct the past,” he said. “We use genetics to reconstruct the history of population sizes, relationships among populations and the gene flow that occurred. So now we have a much more detailed picture than existed before, and it’s a somewhat surprising picture.”

Journal Reference:

  1. Adam H. Freedman, Ilan Gronau, Rena M. Schweizer, Diego Ortega-Del Vecchyo, Eunjung Han, Pedro M. Silva, Marco Galaverni, Zhenxin Fan, Peter Marx, Belen Lorente-Galdos, Holly Beale, Oscar Ramirez, Farhad Hormozdiari, Can Alkan, Carles Vilà, Kevin Squire, Eli Geffen, Josip Kusak, Adam R. Boyko, Heidi G. Parker, Clarence Lee, Vasisht Tadigotla, Adam Siepel, Carlos D. Bustamante, Timothy T. Harkins, Stanley F. Nelson, Elaine A. Ostrander, Tomas Marques-Bonet, Robert K. Wayne, John Novembre. Genome Sequencing Highlights the Dynamic Early History of DogsPLoS Genetics, 2014; 10 (1): e1004016 DOI:10.1371/journal.pgen.1004016

Facebook Data Scientists Prove Memes Mutate And Adapt Like DNA (TechCrunch)

Posted Jan 8, 2014 by  (@joshconstine)

Richard Dawkins likened memes to genes, but a new study by Facebook shows just how accurate that analogy is. Memes adapt to their surroundings in order to survive, just like organisms. Post a liberal meme saying no one should die for lack of healthcare, and conservatives will mutate it to say no one should die because Obamacare rations their healthcare. And nerds will make it about Star Wars.

Facebook’s data scientists used anonymized data to determine that “Just as certain genetic mutations can be advantageous in specific environments, meme mutations can be propagated differentially if the variant matches the subpopulation’s beliefs or culture.”

Take this meme:

“No one should die because they cannot afford health care, and no one should go broke because they get sick. If you agree, post this as your status for the rest of the day”.

In September 2009, 470,000 Facebook users posted this exact phrase as a status update. But a total of 1.14 million status updates containing 121,605 variants of the meme were spawned, such as “No one should be frozen in carbonite because they can’t pay Jabba The Hut”. Why? Because humans help bend memes to better fit their audience.

In the chart below you can see how people of different political leanings adapted the meme to fit their own views, and likely the views of people they’re friends with. As Facebook’s data scientists explain, “the original variant in support of Affordable Care Act (aka Obamacare) was propagated primarily by liberals, while those mentioning government and taxes slanted conservative. Sci-fi variants were slightly liberal, alcohol-related ones slightly conservative”. That matches theories by Dawkins and Malcom Gladwell.


Average political bias (-2 being very liberal, +2 being very conservative) of users reposting different variants of the “no one should” meme.

As I wrote in my Stanford Cybersociology Master’s program research paper, memes are more shareable if they’re easy to remix. When a meme has a clear template with substitutable variables, people recognize how to put their own spin on it. They’re then more likely to share their own modified creations, which drives awareness of the original. When I recognized this back in 2009, I based my research on Lolcats and Soulja Boy, but more recently The Harlem Shake meme proved me right.

Facebook’s findings and my own have signficant implications for marketers or anyone looking to make a message go viral. Once you know memes are naturally inclined to mutate, and that these mutations increase sharing, you can try to purposefully structure your message in a remixable way. By creating and seeding a few variants of your own, you can crystallize how the template works and encourage your audience to make their own remixes.

As you can see in this graph from my research paper, usage of the word “haz” as in the Lolcat phrase “I can haz cheezburger” grew increasingly popular for several years. Meanwhile, less remixable memes often only create a spike in mentions for a few days. I posit that high remixability — or adaptability — keeps memes popular for a much longer period of time.

Screen Shot 2014-01-08 at 12.11.11 PM

Rise in mentions of the word “haz” in Facebook wall posts, indicating sustained popularity of the highly remixable Lolcats memes – as shown on the now defunct Facebook Lexicon tool

For social networks like Facebook, understanding how memes evolve could make sure we continue to see fresh content. Rather than showing us the exact copies of a meme over and over again in the News Feed, Facebook’s algorithms could purposefully search for and promote mutated variations.

That way instead of hearing about healthcare over and over, you might see that “No one should twerk just because they can’t avoid hearing Miley Cyrus on the radio. If you agree, sit perfectly still with your tongue safely inside your mouth for the rest of the day.”

Homem evolui mais devagar que macaco, diz estudo (Folha de S.Paulo)

24 de outubro de 2013

Reportagem da Folha de SP mostra que pesquisa descobriu que diferenças entre espécies está em genes ativos

A comparação da atividade genética de humanos com a de chimpanzés sugere que o Homo sapiens está evoluindo de forma mais lenta que os macacos. A descoberta foi feita por cientistas que investigam por que o homem e seu primo mais próximo são tão diferentes, apesar de terem 98% do DNA idêntico.

O segredo das diferenças físicas e comportamentais está em quais genes são de fato ativos em cada espécie. Analisando células embrionárias, a brasileira Carolina Marchetto, do Instituto Salk, de San Diego (EUA), descobriu mecanismos que freiam a taxa de transformação genética da espécie humana.

A descoberta favorece a hipótese de que o advento da cultura desacelerou a evolução biológica: uma vez que humanos se adaptam a distintos ambientes usando o conhecimento, nossa espécie não depende mais tanto de variação genética para evoluir e sobreviver a mudanças.

Já os macacos, mamíferos de cognição mais limitada, precisam que seu DNA evolua de forma rápida para sobreviver a mudanças: eles não têm como compensar a falta de características inatas necessárias usando apenas conhecimento e tecnologia.

Mas o DNA humano também não carece de evoluir? “Não sabemos o que estamos pagando por isso em termos de adaptação, mas por enquanto funciona de forma eficiente”, diz Marchetto.

O trabalho da cientista, descrito hoje na revista “Nature”, ajuda a explicar o mistério da maior diversidade do DNA símio. Um leigo pode achar que todos os chimpanzés são iguais, mas uma só colônia selvagem desses macacos na África tem mais variabilidade genética do que toda a humanidade.


Segundo o estudo de Marcheto, a maior variabilidade genética dos macacos tem a ver com os chamados transpósons, genes que saltam de um lugar para outro dos cromossomos. Nesse processo, os transpósons reorganizam o genoma, ativando alguns genes e desativando outros.

Esses “genes saltadores” são bastante ativos em chimpanzés e bonobos (macacos igualmente próximos da linhagem humana). Em humanos, o transpóson é suprimido por dois outros genes que são ativados em abundância e inibem o “pulo” genético.

Chimpanzés, de certa forma, precisam de transpósons. Com ferramentas rudimentares e sem linguagem para transmitir conhecimento, eles têm de oferecer maior variabilidade genética à seleção natural para que ela os torne mais bem adaptados, caso o ambiente se altere.

A pesquisa de Marchetto só foi possível porque seu o laboratório no Salk, liderado pelo biólogo Fred Gage, domina a técnica de reverter células ao estágio embrionário.

O material usado na pesquisa foi extraído da pele de macacos e pessoas, pois há uma série de limitações para o uso de embriões em experimentos científicos.

Revertido ao estágio de “células pluripotentes induzidas”, o tecido cutâneo se comporta como embrião, e é possível investigar a biologia molecular dos estágios iniciais do desenvolvimento, quando o surgimento de diversidade genética tem consequências futuras.

“Uma das coisas especiais do nosso estudo é que a reprogramação de células de chimpanzés e bonobos nos dá um modelo para começar a estudar questões evolutivas que antes não tínhamos como abordar”, diz Marchetto.


As diferenças de ativação de genes entre humanos e chimpanzés, explica, não se restringem a células embrionárias. A ideia de Marcheto e de seus colegas agora é transformar essas células em neurônios, por exemplo, para entender como a biologia molecular de ambos se altera durante a formação do cérebro.

(Rafael Garcia/ Folha de São Paulo)

EUA vetam patente sobre gene humano (Folha de S.Paulo)

JC e-mail 4747, de 14 de Junho de 2013.

Suprema Corte decide que empresa não pode ter propriedade sobre genes usados em teste de risco de câncer. Decisão pode levar à redução no preço do exame, o mesmo feito por Angelina Jolie antes de retirada das mamas

A Suprema Corte dos EUA decidiu ontem que genes humanos não podem ser patenteados, o que pode afetar empresas de biotecnologia e baratear testes que se baseiam na procura de certas mutações no país e até no Brasil.

A decisão dos magistrados reverte três décadas de concessões de patentes pelo governo americano. No Brasil, não é permitido patentear seres vivos ou parte deles, o que inclui os genes.

O caso em discussão na Suprema Corte diz respeito ao registro de propriedade intelectual da empresa MyriadGenetics sobre os genes BRCA 1 e 2, cujas mutações indicam um risco maior de câncer de mama e ovário.

O teste que procura essas mutações ganhou maior notoriedade recentemente, depois que a atriz Angelina Jolie, 37, revelou, em junho, ter se submetido a uma cirurgia de retirada das mamas após descobrir ter as mutações que aumentam o risco de desenvolver um tumor.

O exame é recomendado principalmente para as mulheres que têm câncer antes dos 45 anos. É possível também rastrear a mutação em outros membros da família para decidir sobre medidas preventivas, que incluem o uso de remédios, o acompanhamento com exames de imagem e até retirada preventiva de mamas e ovários.

O preço do exame é uma barreira ao seu acesso. Nos EUA, o custo fica em torno de US$ 3.000; no Brasil, ainda que não haja o impedimento da patente, o preço também é alto, chegando a R$ 8.000.

Com a decisão, espera-se uma queda nesses valores. “O reflexo vai ser imediato aqui. As empresas se guiam pelo preço cobrado no exterior”, afirma Maria Isabel Achatz, diretora de oncogenética do A.C. Camargo Cancer Center, em São Paulo.

Para David Schlesinger, geneticista e fundador do laboratório Mendelics, a identificação de genes únicos, como no teste BRCA 1 e 2, já está ficando obsoleta.

“Em vez de procurar genes específicos, agora se sabe que é mais vantajoso fazer um exoma [sequenciamento da parte do genoma que codifica proteínas] e ter um panorama geral do paciente.”


Segundo a decisão, uma parte do DNA que ocorre naturalmente é um produto da natureza e não pode ser patenteado só por ter sido isolada pela empresa.

No entanto, o tribunal deu à Myriad uma vitória parcial, dizendo que o DNA complementar sintetizado em laboratório pode ser patenteado.

O chamado cDNA não acontece naturalmente. Grosso modo, é uma espécie de DNA que exclui as informações que não codificam proteína usada como parte do processo de desenvolvimento de alguns testes genéticos.

Os grupos que pedem o fim das patentes argumentam que a sequência dos nucleotídeos do cDNA segue a ordem imposta pela natureza e, por isso, não devem ser alvo de registros.

Para Fernando Soares, do Departamento de Patologia do A.C. Camargo Cancer Center, manter a patente do cDNA só deve ter impacto em questões de pesquisa e em análise de larga escala.

Envolvido no projeto do genoma do câncer, em 2002, o médico comemorou a decisão. “O genoma é um patrimônio da humanidade.”

Veja também o assunto no Jornal O Globo: Genes humanos não podem ser patenteados, decide Suprema Corte dos EUA.

Schizophrenia Symptoms Eliminated in Animal Model (Science Daily)

May 22, 2013 — Overexpression of a gene associated with schizophrenia causes classic symptoms of the disorder that are reversed when gene expression returns to normal, scientists report. 

Overexpression of a gene associated with schizophrenia causes classic symptoms of the disorder that are reversed when gene expression returns to normal, scientists report. Pictured are (left to right) Drs. Lin Mei, Dongmin Yin and Yongjun Chen, Medical College of Georgia at Georgia Regents University. (Credit: Phil Jones, Georgia Regents University Photographer)

They genetically engineered mice so they could turn up levels of neuregulin-1 to mimic high levels found in some patients then return levels to normal, said Dr. Lin Mei, Director of the Institute of Molecular Medicine and Genetics at the Medical College of Georgia at Georgia Regents University.

They found that when elevated, mice were hyperactive, couldn’t remember what they had just learned and couldn’t ignore distracting background or white noise. When they returned neuregulin-1 levels to normal in adult mice, the schizophrenia-like symptoms went away, said Mei, corresponding author of the study in the journal Neuron.

While schizophrenia is generally considered a developmental disease that surfaces in early adulthood, Mei and his colleagues found that even when they kept neuregulin-1 levels normal until adulthood, mice still exhibited schizophrenia-like symptoms once higher levels were expressed. Without intervention, they developed symptoms at about the same age humans do.

“This shows that high levels of neuregulin-1 are a cause of schizophrenia, at least in mice, because when you turn them down, the behavior deficit disappears,” Mei said. “Our data certainly suggests that we can treat this cause by bringing down excessive levels of neuregulin-1 or blocking its pathologic effects.”

Schizophrenia is a spectrum disorder with multiple causes — most of which are unknown — that tends to run in families, and high neuregulin-1 levels have been found in only a minority of patients. To reduce neuregulin-1 levels in those individuals likely would require development of small molecules that could, for example, block the gene’s signaling pathways, Mei said. Current therapies treat symptoms and generally focus on reducing the activity of two neurotransmitters since the bottom line is excessive communication between neurons.

The good news is it’s relatively easy to measure neuregulin-1 since blood levels appear to correlate well with brain levels. To genetically alter the mice, they put a copy of the neuregulin-1 gene into mouse DNA then, to make sure they could control the levels, they put in front of the DNA a binding protein for doxycycline, a stable analogue for the antibiotic tetracycline, which is infamous for staining the teeth of fetuses and babies.

The mice are born expressing high levels of neuregulin-1 and giving the antibiotic restores normal levels. “If you don’t feed the mice tetracycline, the neuregulin-1 levels are always high,” said Mei, noting that endogenous levels of the gene are not affected. High-levels of neuregulin-1 appear to activate the kinase LIMK1, impairing release of the neurotransmitter glutamate and normal behavior. The LIMK1 connection identifies another target for intervention, Mei said.

Neuregulin-1 is essential for heart development as well as formation of myelin, the insulation around nerves. It’s among about 100 schizophrenia-associated genes identified through genome-wide association studies and has remained a consistent susceptibility gene using numerous other methods for examining the genetics of the disease. It’s also implicated in cancer.

Mei and his colleagues were the first to show neuregulin-1’s positive impact in the developed brain, reporting in Neuron in 2007 that it and its receptor ErbB4 help maintain a healthy balance of excitement and inhibition by releasing GABA, a major inhibitory neurotransmitter, at the sight of inhibitory synapses, the communication paths between neurons. Years before, they showed the genes were also at excitatory synapses, where they also could quash activation. In 2009, the MCG researchers provided additional evidence of the role of neuregulin-1 in schizophrenia by selectively deleting the gene for its receptor, ErbB4 and creating another symptomatic mouse.

Schizophrenia affects about 1 percent of the population, causing hallucinations, depression and impaired thinking and social behavior. Babies born to mothers who develop a severe infection, such as influenza or pneumonia, during pregnancy have a significantly increased risk of schizophrenia.

Journal Reference:

  1. Dong-Min Yin, Yong-Jun Chen, Yi-Sheng Lu, Jonathan C. Bean, Anupama Sathyamurthy, Chengyong Shen, Xihui Liu, Thiri W. Lin, Clifford A. Smith, Wen-Cheng Xiong, Lin Mei.Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1.Neuron, 2013; 78 (4): 644 DOI:10.1016/j.neuron.2013.03.028

Cientistas americanos conseguem clonar embriões humanos (O Globo)

Trabalho é o primeiro a obter êxito em humanos com a técnica que deu origem à ovelha Dolly

Autores dizem que não se trata de fazer clones humanos, mas sim avançar apenas até a fase de blastocisto para obter as células-tronco

Em 2004, sul-coreano anunciou o mesmo feito mas foi desmentido um ano depois


Publicado:15/05/13 – 16h03; atualizado:15/05/13 – 20h56

Clone de embrião obtido no estudoFoto: DivulgaçãoClone de embrião obtido no estudo Divulgação

OREGON. Dezesseis anos depois da clonagem do primeiro mamífero, a ovelha Dolly, cientistas conseguiram, pela primeira vez, clonar um embrião humano em seus primeiros estágios de desenvolvimento. Os protoembriões foram usados para produzir células-tronco embrionárias — capazes de se transformar em qualquer tecido do corpo —, num avanço bastante significativo e há muito tempo esperado para o tratamento de lesões e doenças graves como Parkinson, esclerose múltipla e problemas cardíacos. Especialistas envolvidos no processo garantem que o objetivo não é clonar seres humanos, mas, sim criar novas terapias personalizadas.

Tanto é assim que os embriões humanos clonados usados na pesquisa foram destruídos em estágios ainda muito iniciais de desenvolvimento, logo depois da extração das células-tronco, e não levados ao crescimento, como no caso da ovelha Dolly e de tantos outros animais clonados depois dela. A técnica usada, no entanto, foi bastante similar à que criou a ovelha. Células da pele de um indivíduo foram colocadas em um óvulo previamente esvaziado de seu material genético e estimuladas a se desenvolver. Quando atingiram a fase de blastocisto, as células-tronco embrionárias foram extraídas e os embriões destruídos. O estudo foi publicado na revista “Cell”.

Conseguir gerar grande quantidade de células-tronco do próprio paciente era uma espécie de Santo Graal da atual ciência médica, como comparou o jornalista Steve Connor, no “Independent”. Embora o procedimento tenha sido feito com animais, até agora nunca tinha sido obtido com material humano, a despeito de inúmeras tentativas. Aparentemente, a dificuldade viria da maior fragilidade do óvulo humano.

Em 2004, um grupo coordenado por Woo Suk Hwang, da Universidade Nacional de Seoul, anunciou ter produzido o primeiro embirão humano clonado e, em seguida, obtido células-tronco embionárias a partir dele. Menos de um ano depois, no entanto, o grupo, que já havia clonado um cachorro, foi acusado de fraude e desmentiu os resultados obtidos. Outros grupos tentaram, mas os embriões não passaram do estágio de 6 a 12 células.

A corrida pela obtenção das células-tronco embrionárias faz todo o sentido. Cultivadas em laboratório, essas células podem dar origem a qualquer tecido do corpo humano. Por isso, em tese ao menos, poderiam curar lesões na medula, recompor órgãos, tratar problemas graves de visão, oferecendo tratamentos inéditos para muitas doenças hoje incuráveis. Como os tecidos seriam feitos a partir do material genético do próprio paciente (que, no caso, cedeu as células de sua pele), não haveria risco algum de rejeição. A medicina personalizada alcançaria o seu ápice.

— Nossa descoberta oferece novas maneiras de gerar células-tronco embrionárias para pacientes com problemas em tecidos e órgãos — afirmou o coordenador do estudo, Shoukhrat Mitalipov, da Universidade de Ciência e Saúde do Oregon, nos EUA, em comunicado oficial sobre o estudo. — Essas células-tronco podem regenerar órgãos ou substituir tecidos danificados, levando à cura de doenças que hoje afetam milhões de pessoas.

O grupo também conseguiu observar a capacidade de diferenciação das células obtidas em tecidos específicos

— Um atento exame das células-tronco obtidas por meio desta técnica demonstrou sua capacidade de se converter, como qualquer célula-tronco embrionária normal, em diferentes tipos de células, entre elas, células nervosas, células do fígado e céluas cardíacas — disse Mitalipov, em entrevista ao “Independent”.

No entanto, o estudo já levanta sérias preocupações éticas, sobretudo em relação à criação de clones humanos. Há o temor de que a técnica seja incorporada às oferecidas por clínicas de fertilização in vitro, como alternativa para casais estéreis, por exemplo. Outros grupos argumentam que é simplesmente antiético manipular embriões humanos.

— A pesquisa tem como único objetivo gerar células-tronco embrionárias para tratar doenças graves; e não aumentar as chances de produzir bebês clonados — garantiu Mitalipov. — Este não é o nosso foco e não acreditamos que nossas descobertas sejam usadas por outros grupos como um avanço na clonagem humana reprodutiva.

Leia mais sobre esse assunto em  © 1996 – 2013. Todos direitos reservados a Infoglobo Comunicação e Participações S.A. Este material não pode ser publicado, transmitido por broadcast, reescrito ou redistribuído sem autorização.

The Ethics of Resurrecting Extinct Species (Science Daily)

Apr. 8, 2013 — At some point, scientists may be able to bring back extinct animals, and perhaps early humans, raising questions of ethics and environmental disruption.

Within a few decades, scientists may be able to bring back the dodo bird from extinction, a possibility that raises a host of ethical questions, says Stanford law Professor Hank Greely. (Credit: Frederick William Frohawk/Public domain image)

Within a few decades, scientists may be able to bring back the dodo bird from extinction, a possibility that raises a host of ethical questions, says Stanford law Professor Hank Greely.

Twenty years after the release ofJurassic Park, the dream of bringing back the dinosaurs remains science fiction. But scientists predict that within 15 years they will be able to revive some more recently extinct species, such as the dodo or the passenger pigeon, raising the question of whether or not they should — just because they can.

In the April 5 issue of Science, Stanford law Professor Hank Greely identifies the ethical landmines of this new concept of de-extinction.

“I view this piece as the first framing of the issues,” said Greely, director of the Stanford Center for Law and the Biosciences. “I don’t think it’s the end of the story, rather I think it’s the start of a discussion about how we should deal with de-extinction.”

In “What If Extinction Is Not Forever?” Greely lays out potential benefits of de-extinction, from creating new scientific knowledge to restoring lost ecosystems. But the biggest benefit, Greely believes, is the “wonder” factor.

“It would certainly be cool to see a living saber-toothed cat,” Greely said. “‘Wonder’ may not seem like a substantive benefit, but a lot of science — such as the Mars rover — is done because of it.”

Greely became interested in the ethics of de-extinction in 1999 when one of his students wrote a paper on the implications of bringing back wooly mammoths.

“He didn’t have his science right — which wasn’t his fault because approaches on how to do this have changed in the last 13 years — but it made me realize this was a really interesting topic,” Greely said.

Scientists are currently working on three different approaches to restore lost plants and animals. In cloning, scientists use genetic material from the extinct species to create an exact modern copy. Selective breeding tries to give a closely-related modern species the characteristics of its extinct relative. With genetic engineering, the DNA of a modern species is edited until it closely matches the extinct species.

All of these techniques would bring back only the physical animal or plant.

“If we bring the passenger pigeon back, there’s no reason to believe it will act the same way as it did in 1850,” said co-author Jacob Sherkow, a fellow at the Stanford Center for Law and the Biosciences. “Many traits are culturally learned. Migration patterns change when not taught from generation to generation.”

Many newly revived species could cause unexpected problems if brought into the modern world. A reintroduced species could become a carrier for a deadly disease or an unintentional threat to a nearby ecosystem, Greely says.

“It’s a little odd to consider these things ‘alien’ species because they were here before we were,” he said. “But the ‘here’ they were in is very different than it is now. They could turn out to be pests in this new environment.”

When asked whether government policies are keeping up with the new threat, Greely answers “no.”

“But that’s neither surprising nor particularly concerning,” he said. “It will be a while before any revised species is going to be present and able to be released into the environment.”

Greely and Sherkow recommend that the government leave de-extinction research to private companies and focus on drafting new regulations. Sherkow says the biggest legal and ethical challenge of de-extinction concerns our own long-lost ancestors.

“Bringing back a hominid raises the question, ‘Is it a person?’ If we bring back a mammoth or pigeon, there’s a very good existing ethical and legal framework for how to treat research animals. We don’t have very good ethical considerations of creating and keeping a person in a lab,” said Sherkow. “That’s a far cry from the type of de-extinction programs going on now, but it highlights the slippery slope problem that ethicists are famous for considering.”

Journal Reference:

  1. J. S. Sherkow, H. T. Greely. What If Extinction Is Not Forever? Science, 2013; 340 (6128): 32 DOI:10.1126/science.1236965

Fetal Exposure to Excessive Stress Hormones in the Womb Linked to Adult Mood Disorders (Science Daily)

Apr. 6, 2013 — Exposure of the developing fetus to excessive levels of stress hormones in the womb can cause mood disorders in later life and now, for the first time, researchers have found a mechanism that may underpin this process, according to research presented April 7 at the British Neuroscience Association Festival of Neuroscience (BNA2013) in London.

(Credit: © Tatyana Gladskih / Fotolia)

The concept of fetal programming of adult disease, whereby the environment experienced in the womb can have profound long-lasting consequences on health and risk of disease in later life, is well known; however, the process that drives this is unclear. Professor Megan Holmes, a neuroendocrinologist from the University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science in Scotland (UK), will say: “During our research we have identified the enzyme 11ß-HSD2 which we believe plays a key role in the process of fetal programming.”

Adverse environments experienced while in the womb, such as in cases of stress, bereavement or abuse, will increase levels of glucocorticoids in the mother, which may harm the growing baby. Glucocorticoids are naturally produced hormones and they are also known as stress hormones because of their role in the stress response.

“The stress hormone cortisol may be a key factor in programming the fetus, baby or child to be at risk of disease in later life. Cortisol causes reduced growth and modifies the timing of tissue development as well as having long lasting effects on gene expression,” she will say.

Prof Holmes will describe how her research has identified an enzyme called 11ß-HSD2 (11beta-hydroxysteroid dehydrogenase type 2) that breaks down the stress hormone cortisol to an inactive form, before it can cause any harm to the developing fetus. The enzyme 11ß-HSD2 is present in the placenta and the developing fetal brain where it is thought to act as a shield to protect against the harmful actions of cortisol.

Prof Holmes and her colleagues developed genetically modified mice that lacked 11ß-HSD2 in order to determine the role of the enzyme in the placenta and fetal brain. “In mice lacking the enzyme 11ß-HSD2, fetuses were exposed to high levels of stress hormones and, as a consequence, these mice exhibited reduced fetal growth and went on to show programmed mood disorders in later life. We also found that the placentas from these mice were smaller and did not transport nutrients efficiently across to the developing fetus. This too could contribute to the harmful consequences of increased stress hormone exposure on the fetus and suggests that the placental 11ß-HSD2 shield is the most important barrier.

“However, preliminary new data show that with the loss of the 11ß-HSD2 protective barrier solely in the brain, programming of the developing fetus still occurs, and, therefore, this raises questions about how dominant a role is played by the placental 11ß-HSD2 barrier. This research is currently ongoing and we cannot draw any firm conclusions yet.

“Determining the exact molecular and cellular mechanisms that drive fetal programming will help us identify potential therapeutic targets that can be used to reverse the deleterious consequences on mood disorders. In the future, we hope to explore the potential of these targets in studies in humans,” she will say.

Prof Holmes hopes that her research will make healthcare workers more aware of the fact that children exposed to an adverse environment, be it abuse, malnutrition, or bereavement, are at an increased risk of mood disorders in later life and the children should be carefully monitored and supported to prevent this from happening.

In addition, the potential effects of excessive levels of stress hormones on the developing fetus are also of relevance to individuals involved in antenatal care. Within the past 20 years, the majority of women at risk of premature delivery have been given synthetic glucocorticoids to accelerate fetal lung development to allow the premature babies to survive early birth.

“While this glucocorticoid treatment is essential, the dose, number of treatments and the drug used, have to be carefully monitored to ensure that the minimum effective therapy is used, as it may set the stage for effects later in the child’s life,” Prof Holmes will say.

Puberty is another sensitive time of development and stress experienced at this time can also be involved in programming adult mood disorders. Prof Holmes and her colleagues have found evidence from imaging studies in rats that stress in early teenage years could affect mood and emotional behaviour via changes in the brain’s neural networks associated with emotional processing.

The researchers used fMRI (Functional Magnetic Resonance Imaging) to see which pathways in the brain were affected when stressed, peripubertal rats responded to a specific learned task. [1].

Prof Holmes will say: “We showed that in stressed ‘teenage’ rats, the part of the brain region involved in emotion and fear (known as amygdala) was activated in an exaggerated fashion when compared to controls. The results from this study clearly showed that altered emotional processing occurs in the amygdala in response to stress during this crucial period of development.”

Abstract title: “Perinatal programming of stress-related behaviour by glucocorticoids.” Symposium: “Early life stress and its long-term effects — experimental studies.”

Story Source:

The above story is reprinted from materials provided byBritish Neuroscience Association, via AlphaGalileo.

You Don’t ‘Own’ Your Own Genes: Researchers Raise Alarm About Loss of Individual ‘Genomic Liberty’ Due to Gene Patents (Science Daily)

Mar. 25, 2013 — Humans don’t “own” their own genes, the cellular chemicals that define who they are and what diseases they might be at risk for. Through more than 40,000 patents on DNA molecules, companies have essentially claimed the entire human genome for profit, report two researchers who analyzed the patents on human DNA.

In a new study, researchers report that through more than 40,000 patents on DNA molecules, companies have essentially claimed the entire human genome for profit. (Credit: © X n’ Y hate Z / Fotolia)

Their study, published March 25 in the journal Genome Medicine, raises an alarm about the loss of individual “genomic liberty.”

In their new analysis, the research team examined two types of patented DNA sequences: long and short fragments. They discovered that 41 percent of the human genome is covered by longer DNA patents that often cover whole genes. They also found that, because many genes share similar sequences within their genetic structure, if all of the “short sequence” patents were allowed in aggregate, they could account for 100 percent of the genome.

Furthermore, the study’s lead author, Dr. Christopher E. Mason of Weill Cornell Medical College, and the study’s co-author, Dr. Jeffrey Rosenfeld, an assistant professor of medicine at the University of Medicine & Dentistry of New Jersey and a member of the High Performance and Research Computing Group, found that short sequences from patents also cover virtually the entire genome — even outside of genes.

“If these patents are enforced, our genomic liberty is lost,” says Dr. Mason, an assistant professor of physiology and biophysics and computational genomics in computational biomedicine at the Institute for Computational Biomedicine at Weill Cornell. “Just as we enter the era of personalized medicine, we are ironically living in the most restrictive age of genomics. You have to ask, how is it possible that my doctor cannot look at my DNA without being concerned about patent infringement?”

The U.S. Supreme Court will review genomic patent rights in an upcoming hearing on April 15. At issue is the right of a molecular diagnostic company to claim patents not only on two key breast and ovarian cancer genes — BRCA1 and BRCA2 — but also on any small sequence of code within BRCA1, including a striking patent for only 15 nucleotides.

In its study, the research team matched small sequences within BRCA1 to other genes and found that just this one molecular diagnostic company’s patents also covered at least 689 other human genes — most of which have nothing to do with breast or ovarian cancer; rather, its patents cover 19 other cancers as well as genes involved in brain development and heart functioning.

“This means if the Supreme Court upholds the current scope of the patents, no physician or researcher can study the DNA of these genes from their patients, and no diagnostic test or drug can be developed based on any of these genes without infringing a patent,” says Dr. Mason.

One Patented Sequence Matched More Than 91 Percent of Human Genes

Dr. Mason undertook the study because he realized that his research into brain and cancer disorders inevitably involved studying genes that were protected by patents.

Under U.S. patent law, genes can be patented by those researchers, either at companies or institutions, who are first to find a gene that promises a useful application, such as for a diagnostic test. For example, the patents received by a company in the 1990s on BRCA1 and BRCA2 enables it to offer a diagnostic test to women who may have, or may be at risk for, breast or ovarian cancer due to mutations in one or both of these genes. Women and their doctors have no choice but to use the services of the patents’ owner, which costs $3,000 per test, “whereas any of the hundreds of clinical laboratories around the country could perform such a test for possibly much less,” says Dr. Mason.

The impact on these patents is equally onerous on research, Dr. Mason adds.

“Almost every day, I come across a gene that is patented — a situation that is common for every geneticist in every lab,” says Dr. Mason.

Dr. Mason and his research partner sought to determine how many other genes may be impacted by gene patents, as well as the overall landscape of intellectual property on the human genome.

To conduct the study, Dr. Mason and Dr. Rosenfeld examined the structure of the human genome in the context of two types of patented sequences: short and long fragments of DNA. They used matches to known genes that were confirmed to be present in patent claims, ranging from as few as 15 nucleotides (the building blocks of DNA) to the full length of all patented DNA fragments.

Before examining the patented sequences, the researchers first calculated how many genes had common segments of 15 nucleotide (15mer), and found that every gene in the human genome matched at least one other gene in this respect, ranging from as few as five matches 15mer to as many as 7,688 gene matches. They also discovered that 99.999 percent of 15mers in the human genome are repeated at least twice.

“This demonstrates that short patent sequences are extremely non-specific and that a 15mer claim from one gene will always cross-match and patent a portion of another gene as well,” says Dr. Mason. “This means it is actually impossible to have a 15mer patent for just one gene.”

Next, researchers examined the total sequence space in human genes covered by 15mers in current patent claims. They found 58 patents whose claims covered at least 10 percent of all bases of all human genes. The broadest patent claimed sequences that matched 91.5 percent of human genes. Then, when they took existing gene patents and matched patented 15mers to known genes, they discovered that 100 percent of known genes are patented.

“There is a real controversy regarding gene ownership due to the overlap of many competing patent claims. It is unclear who really owns the rights to any gene,” says Dr. Rosenfeld. “While the Supreme Court is hearing one case concerning just the BRCA1 patent, there are also many other patents whose claims would cover those same genes. Do we need to go through every gene to look at who made the first claim to that gene, even if only one small part? If we resort to this rule, then the first patents to be granted for any DNA will have a vast claim over portions of the human genome.”

A further issue of concern is that patents on DNA can readily cross species boundaries. A company can have a patent that they received for cow breeding and have that patent cover a large percentage of human genes. Indeed, the researchers found that one company owns the rights to 84 percent of all human genes for a patent they received for cow breeding. “It seems silly that a patent designed to study cow genetics also claims the majority of human genes,” says Dr. Rosenfeld.

Finally, they also examined the impact of longer claimed DNA sequences from existing gene patents, which ranged from a few dozen bases up to thousands of bases of DNA, and found that these long, claimed sequences matched 41 percent (9,361) of human genes. Their analysis concluded that almost all clinically relevant genes have already been patented, especially for short sequence patents, showing all human genes are patented many times over.

“This is, so to speak, patently ridiculous,” adds Dr. Mason. “If patent claims that use these small DNA sequences are upheld, it could potentially create a situation where a piece of every gene in the human genome is patented by a phalanx of competing patents.”

In their discussion, the researchers argue that the U.S. Supreme Court now has a chance to shape the balance between the medical good versus inventor protection, adding that, in their opinion, the court should limit the patenting of existing nucleotide sequences, due to their broad scope and non-specificity in the human genome.

“I am extremely pro-patent, but I simply believe that people should not be able to patent a product of nature,” Dr. Mason says. “Moreover, I believe that individuals have an innate right to their own genome, or to allow their doctor to look at that genome, just like the lungs or kidneys. Failure to resolve these ambiguities perpetuates a direct threat to genomic liberty, or the right to one’s own DNA.”

Journal Reference:

  1. Jeffrey Rosenfeld, and Christopher E Mason. Pervasive sequence patents cover the entire human genome.Genome Medicine, 2013 (in press) DOI: 10.1186/gm431

DNA Damage Occurs as Part of Normal Brain Activity, Scientists Discover (Science Daily)

Mar. 24, 2013 — Scientists at the Gladstone Institutes have discovered that a certain type of DNA damage long thought to be particularly detrimental to brain cells can actually be part of a regular, non-harmful process. The team further found that disruptions to this process occur in mouse models of Alzheimer’s disease — and identified two therapeutic strategies that reduce these disruptions.

Neurons. Scientists have discovered that a certain type of DNA damage long thought to be particularly detrimental to brain cells can actually be part of a regular, non-harmful process. (Credit: © Roberto Robuffo / Fotolia)

Scientists have long known that DNA damage occurs in every cell, accumulating as we age. But a particular type of DNA damage, known as a double-strand break, or DSB, has long been considered a major force behind age-related illnesses such as Alzheimer’s. Today, researchers in the laboratory of Gladstone Senior Investigator Lennart Mucke, MD, report in Nature Neuroscience that DSBs in neuronal cells in the brain can also be part of normal brain functions such as learning — as long as the DSBs are tightly controlled and repaired in good time. Further, the accumulation of the amyloid-beta protein in the brain — widely thought to be a major cause of Alzheimer’s disease — increases the number of neurons with DSBs and delays their repair.

“It is both novel and intriguing team’s finding that the accumulation and repair of DSBs may be part of normal learning,” said Fred H. Gage, PhD, of the Salk Institute who was not involved in this study. “Their discovery that the Alzheimer’s-like mice exhibited higher baseline DSBs, which weren’t repaired, increases these findings’ relevance and provides new understanding of this deadly disease’s underlying mechanisms.”

In laboratory experiments, two groups of mice explored a new environment filled with unfamiliar sights, smells and textures. One group was genetically modified to simulate key aspects of Alzheimer’s, and the other was a healthy, control group. As the mice explored, their neurons became stimulated as they processed new information. After two hours, the mice were returned to their familiar, home environment.

The investigators then examined the neurons of the mice for markers of DSBs. The control group showed an increase in DSBs right after they explored the new environment — but after being returned to their home environment, DSB levels dropped.

“We were initially surprised to find neuronal DSBs in the brains of healthy mice,” said Elsa Suberbielle, DVM, PhD, Gladstone postdoctoral fellow and the paper’s lead author. “But the close link between neuronal stimulation and DSBs, and the finding that these DSBs were repaired after the mice returned to their home environment, suggest that DSBs are an integral part of normal brain activity. We think that this damage-and-repair pattern might help the animals learn by facilitating rapid changes in the conversion of neuronal DNA into proteins that are involved in forming memories.”

The group of mice modified to simulate Alzheimer’s had higher DSB levels at the start — levels that rose even higher during neuronal stimulation. In addition, the team noticed a substantial delay in the DNA-repair process.

To counteract the accumulation of DSBs, the team first used a therapeutic approach built on two recent studies — one of which was led by Dr. Mucke and his team — that showed the widely used anti-epileptic drug levetiracetam could improve neuronal communication and memory in both mouse models of Alzheimer’s and in humans in the disease’s earliest stages. The mice they treated with the FDA-approved drug had fewer DSBs. In their second strategy, they genetically modified mice to lack the brain protein called tau — another protein implicated in Alzheimer’s. This manipulation, which they had previously found to prevent abnormal brain activity, also prevented the excessive accumulation of DSBs.

The team’s findings suggest that restoring proper neuronal communication is important for staving off the effects of Alzheimer’s — perhaps by maintaining the delicate balance between DNA damage and repair.

“Currently, we have no effective treatments to slow, prevent or halt Alzheimer’s, from which more than 5 million people suffer in the United States alone,” said Dr. Mucke, who directs neurological research at Gladstone and is a professor of neuroscience and neurology at the University of California, San Francisco, with which Gladstone is affiliated. “The need to decipher the causes of Alzheimer’s and to find better therapeutic solutions has never been more important — or urgent. Our results suggest that readily available drugs could help protect neurons against some of the damages inflicted by this illness. In the future, we will further explore these therapeutic strategies. We also hope to gain a deeper understanding of the role that DSBs play in learning and memory — and in the disruption of these important brain functions by Alzheimer’s disease.”

Other scientists who participated in this research at Gladstone include Pascal Sanchez, PhD, Alexxai Kravitz, PhD, Xin Wang, Kaitlyn Ho, Kirsten Eilertson, PhD, Nino Devidze, PhD, and Anatol Kreitzer, PhD. This research was supported by grants from the National Institutes of Health and the S.D. Bechtel, Jr. Foundation.

Journal Reference:

  1. Elsa Suberbielle, Pascal E Sanchez, Alexxai V Kravitz, Xin Wang, Kaitlyn Ho, Kirsten Eilertson, Nino Devidze, Anatol C Kreitzer, Lennart Mucke. Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-βNature Neuroscience, 2013; DOI: 10.1038/nn.3356

Pioneiro da epigenética fala sobre relação entre ambiente e genoma (Fapesp)

Moshe Szyf, da Universidade McGill, participa de simpósio internacional organizado pela FAPESP e pela Natura. Discussões do evento embasarão edital para a criação de centros de pesquisa (foto: Edu César)


Por Karina Toledo

Agência FAPESP – Um dos primeiros cientistas a sugerir que os hábitos de vida e o ambiente social em que uma pessoa está inserida poderiam modular o funcionamento de seus genes foi Moshe Szyf, professor de Farmacologia e Terapêutica da Universidade McGill, no Canadá.

Szyf também foi pioneiro ao afirmar que essa programação do genoma – que ocorre por meio de processos bioquímicos batizados de mecanismos epigenéticos – seria um processo fisiológico, uma espécie de resposta adaptativa ao ambiente que começa ainda na vida uterina.

Entre os mecanismos epigenéticos conhecidos, o mais comum e o mais estudado por Szyf é a metilação do DNA, que ocorre quando um conjunto de partículas de hidrogênio e carbono se agrupa na base de alguns genes e impede que eles se expressem.

Embora o processo seja fisiológico, pode se tornar patológico quando acontece no contexto errado. Por exemplo, quando os genes que deveriam nos proteger contra o câncer são desligados.

Pesquisas realizadas pelo grupo de Szyf e colaboradores nos últimos anos mostraram que o padrão de metilação do DNA pode ser alterado por fatores como a qualidade do cuidado materno nos primeiros anos de vida ou a exposição a maus-tratos na infância, criando marcas epigenéticas que perduram ao longo da vida.

Os resultados de alguns desses estudos foram apresentados por Szyf durante o Simpósio Internacional Integração Corpo-Mente-Meio, realizado na sede da FAPESP no dia 12 de março, em parceria com a Natura.

Em um trabalho de 2004, feito com o neurocientista Michael Meaney, também da Universidade McGill, foram comparados dois grupos de ratas: aquelas que tinham recebido lambidas frequentes de suas mães quando ainda eram bebês e aquelas que não haviam recebido cuidados maternos.

Os resultados mostraram que os animais lambidos pelas mães se tornaram adultos mais tranquilos. Isso porque o amor materno alterou os níveis de metilação nas regiões do hipocampo que regulam o gene do receptor de glicocorticoides, ou seja, alteraram a regulação dos níveis de hormônios do estresse durante toda a vida adulta.

Para mostrar que essa lógica se aplicava também a humanos, os pesquisadores da McGill se associaram ao Instituto Universitário de Saúde Mental Douglas, também do Canadá, e ao Instituto de Ciências Clínicas de Cingapura, para analisar cérebros de vítimas de suicídio.

Por meio de seus históricos médicos e de entrevistas com familiares, foi possível identificar entre os suicidas aqueles que tinham sofrido abuso severo durante a infância – seja verbal, sexual ou físico.

Os pesquisadores viram que nesse grupo que teve uma infância difícil os genes que regulam os receptores de glicocorticoides estavam 40% menos ativos quando comparados aos dos suicidas que não sofreram abuso e também quando comparados aos do grupo controle (pessoas que morreram por outras causas, como acidentes de carro).

Os resultados sugerem, portanto, que o abuso infantil deixou essas pessoas mais sensíveis aos danos causados pelo estresse no cérebro; eles foram publicados em 2009 na revista Nature Neuroscience.

Em outros estudos apresentados durante o evento, o cientista mostrou que o padrão de expressão dos genes também pode ser influenciado pela condição socioeconômica na infância e pelo estresse vivenciado pela mãe durante a gestação.

“O avanço no conhecimento sobre a relação entre o ambiente e o genoma ajuda a combater o determinismo genético, ou seja, aquela ideia de que, se você nasce com genes da inteligência, você será inteligente, e se você nasce com genes saudáveis, você será saudável, não importa o que você faça a respeito. Isso coloca mais peso em nossas escolhas. Mostra que temos controle enquanto pais, enquanto formuladores de políticas públicas e enquanto sociedade. Isso pode definir novos modelos para políticas públicas”, disse Szyf à Agência FAPESP.

Para o pesquisador, muitas coisas na prática médica e no cotidiano têm sido feitas sem levar em conta as consequências disso no futuro, mas o avanço no conhecimento sobre a epigenética deve mudar a atitude das pessoas.

“Quando eu era um jovem pai, a ideia predominante era deixar a criança chorar para ela aprender a se virar sozinha. Hoje não fazemos isso porque temos medo do estresse que isso vai causar e de suas consequências. Da mesma forma, temos feito fertilização in vitro, barriga de aluguel, cesarianas desnecessárias sem pensar muito sobre as consequências disso para a criança. Precisamos começar a avaliar o custo-benefício e tomar decisões conscientes, com base em informações”, defendeu.

No campo da medicina, a epigenética traz outras implicações importantes. Uma delas é a possibilidade de identificar biomarcadores que permitam identificar a população mais vulnerável a desenvolver doenças como câncer, infarto, pressão alta ou transtornos mentais.

“O maior desafio é encontrar formas de intervir antes que os sinais clínicos apareçam e a situação se deteriore. Por isso, é tão importante entender o que torna as pessoas vulneráveis. Esse conhecimento também vai nos guiar quanto ao tipo de intervenção mais adequada”, disse.

No rol das intervenções epigenéticas possíveis, afirmou Szyf, estão as drogas capazes de reverter as alterações no padrão de expressão dos genes – algo que já é feito na área de oncologia e começa a ser testado na área psiquiátrica.

Intervenções epigenéticas podem ser feitas também por meio de psicoterapia ou de políticas públicas que promovam a mudança do comportamento. “A grande revolução virá quando aprendermos como nos comportar para atingir o mesmo efeito que as drogas são capazes de promover. Descobrir como intervir no sistema de forma que se possa reverter adaptações epigenéticas adversas unicamente pelo comportamento”, afirmou.

Parceria entre FAPESP e Natura

O Simpósio Internacional Integração Corpo-Mente-Meio também contou com a participação do professor Paul Rozin, da Universidade da Pennsylvania (Estados Unidos), que falou sobre as perspectivas na área de Psicologia Positiva – definida como o estudo das forças e virtudes que permitem aos indivíduos e às comunidades prosperar.

Também participaram os brasileiros Silvia Koller, da Universidade Federal do Rio Grande do Sul (UFRGS), Mirian Galvonas Jasiulionis, da Universidade Federal de São Paulo (Unifesp), e Edson Amaro Júnior, da Faculdade de Medicina da Universidade de São Paulo (FMUSP). Respectivamente, eles apresentaram o cenário nacional das pesquisas em Psicologia Positiva, Epigenética e Neurociências.

Segundo o diretor científico da FAPESP, Carlos Henrique de Brito Cruz, as discussões do evento vão embasar a elaboração de um edital que será lançado pela Fundação e pela Natura para a criação de um ou mais centros de pesquisa nos moldes do CEPID (Centros de Pesquisa, Inovação e Difusão), caso em que o financiamento pode durar até dez anos.

“Queremos aprender mais sobre os desafios relacionados a esses temas para que possamos definir como será o financiamento, qual é a melhor forma de montar a armadilha para o conhecimento e obter bons resultados. Nem sempre é simples acertar o relacionamento entre as pessoas das universidades e as pessoas das empresas. Sempre há objetivos não convergentes. Nossa tarefa é achar as convergências possíveis”, afirmou Brito Cruz.

Além do diretor científico da FAPESP, também participou da abertura do evento o diretor de Ciência e Tecnologia da Natura, Victor Fernandes. “Estamos aqui tentando entender qual é a interface científica entre três ciências muito relevantes: Neurosciência Comportamental, Psicologia Positiva e Epigenética. O objetivo é entender como o comportamento e o cotidiano influenciam o comportamento biológico e, em cima disso, buscar oportunidades de fomento à ciência e à inovação”, destacou.

Some Plants Are Altruistic, Too, New Study Suggests (Science Daily)

Feb. 1, 2013 — We’ve all heard examples of animal altruism: Dogs caring for orphaned kittens, chimps sharing food or dolphins nudging injured mates to the surface. Now, a study led by the University of Colorado Boulder suggests some plants are altruistic too.

A new study led by CU-Boulder involving graduate student Chi-Chih Wu, shown here, indicates corn plants may have an altruistic side. (Credit: Photo courtesy CU-Boulder)

The researchers looked at corn, in which each fertilized seed contained two “siblings” — an embryo and a corresponding bit of tissue known as endosperm that feeds the embryo as the seed grows, said CU-Boulder Professor Pamela Diggle. They compared the growth and behavior of the embryos and endosperm in seeds sharing the same mother and father with the growth and behavior of embryos and endosperm that had genetically different parents.

“The results indicated embryos with the same mother and father as the endosperm in their seed weighed significantly more than embryos with the same mother but a different father,” said Diggle, a faculty member in CU-Boulder’s ecology and evolutionary biology department. “We found that endosperm that does not share the same father as the embryo does not hand over as much food — it appears to be acting less cooperatively.”

A paper on the subject was published during the week of Jan. 21 in the Proceedings of the National Academy of Sciences. Co-authors on the study included Chi-Chih Wu, a CU-Boulder doctoral student in the ecology and evolutionary biology department and Professor William “Ned” Friedman, a professor at Harvard University who helped conduct research on the project while a faculty member at CU-Boulder.

Diggle said it is fairly clear from previous research that plants can preferentially withhold nutrients from inferior offspring when resources are limited. “Our study is the first to specifically test the idea of cooperation among siblings in plants.”

“One of the most fundamental laws of nature is that if you are going to be an altruist, give it up to your closest relatives,” said Friedman. “Altruism only evolves if the benefactor is a close relative of the beneficiary. When the endosperm gives all of its food to the embryo and then dies, it doesn’t get more altruistic than that.”

In corn reproduction, male flowers at the top of the plants distribute pollen grains two at a time through individual tubes to tiny cobs on the stalks covered by strands known as silks in a process known as double fertilization. When the two pollen grains come in contact with an individual silk, they produce a seed containing an embryo and endosperm. Each embryo results in just a single kernel of corn, said Diggle.

The team took advantage of an extremely rare phenomenon in plants called “hetero-fertilization,” in which two different fathers sire individual corn kernels, said Diggle, currently a visiting professor at Harvard. The manipulation of corn plant genes that has been going on for millennia — resulting in the production of multicolored “Indian corn” cobs of various colors like red, purple, blue and yellow — helped the researchers in assessing the parentage of the kernels, she said.

Wu, who cultivated the corn and harvested more than 100 ears over a three-year period, removed, mapped and weighed every individual kernel out of each cob from the harvests. While the majority of kernels had an endosperm and embryo of the same color — an indication they shared the same mother and father — some had different colors for each, such as a purple outer kernel with yellow embryo.

Wu was searching for such rare kernels — far less than one in 100 — that had two different fathers as a way to assess cooperation between the embryo and endosperm. “It was very challenging and time-consuming research,” said Friedman. “It was like looking for a needle in a haystack, or in this case, a kernel in a silo.”

Endosperm — in the form of corn, rice, wheat and other crops — is critical to humans, providing about 70 percent of calories we consume annually worldwide. “The tissue in the seeds of flowering plants is what feeds the world,” said Friedman, who also directs the Arnold Arboretum at Harvard. “If flowering plants weren’t here, humans wouldn’t be here.”

Journal Reference:

  1. K. Baruch, N. Ron-Harel, H. Gal, A. Deczkowska, E. Shifrut, W. Ndifon, N. Mirlas-Neisberg, M. Cardon, I. Vaknin, L. Cahalon, T. Berkutzki, M. P. Mattson, F. Gomez-Pinilla, N. Friedman, M. Schwartz. CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging.Proceedings of the National Academy of Sciences, 2013; DOI: 10.1073/pnas.1211270110

Scientists discover how epigenetic information could be inherited (University of Cambridge)

Public release date: 24-Jan-2013
By Genevieve Maul

Research reveals the mechanism of epigenetic reprogramming

New research reveals a potential way for how parents’ experiences could be passed to their offspring’s genes. The research was published today, 25 January, in the journal Science.

Epigenetics is a system that turns our genes on and off. The process works by chemical tags, known as epigenetic marks, attaching to DNA and telling a cell to either use or ignore a particular gene.

The most common epigenetic mark is a methyl group. When these groups fasten to DNA through a process called methylation they block the attachment of proteins which normally turn the genes on. As a result, the gene is turned off.

Scientists have witnessed epigenetic inheritance, the observation that offspring may inherit altered traits due to their parents’ past experiences. For example, historical incidences of famine have resulted in health effects on the children and grandchildren of individuals who had restricted diets, possibly because of inheritance of altered epigenetic marks caused by a restricted diet.

However, it is thought that between each generation the epigenetic marks are erased in cells called primordial gene cells (PGC), the precursors to sperm and eggs. This ‘reprogramming’ allows all genes to be read afresh for each new person – leaving scientists to question how epigenetic inheritance could occur.

The new Cambridge study initially discovered how the DNA methylation marks are erased in PGCs, a question that has been under intense investigation over the past 10 years. The methylation marks are converted to hydroxymethylation which is then progressively diluted out as the cells divide. This process turns out to be remarkably efficient and seems to reset the genes for each new generation. Understanding the mechanism of epigenetic resetting could be exploited to deal with adult diseases linked with an accumulation of aberrant epigenetic marks, such as cancers, or in ‘rejuvenating’ aged cells.

However, the researchers, who were funded by the Wellcome Trust, also found that some rare methylation can ‘escape’ the reprogramming process and can thus be passed on to offspring – revealing how epigenetic inheritance could occur. This is important because aberrant methylation could accumulate at genes during a lifetime in response to environmental factors, such as chemical exposure or nutrition, and can cause abnormal use of genes, leading to disease. If these marks are then inherited by offspring, their genes could also be affected.

Dr Jamie Hackett from the University of Cambridge, who led the research, said: “Our research demonstrates how genes could retain some memory of their past experiences, revealing that one of the big barriers to the theory of epigenetic inheritance – that epigenetic information is erased between generations – should be reassessed.”

“It seems that while the precursors to sperm and eggs are very effective in erasing most methylation marks, they are fallible and at a low frequency may allow some epigenetic information to be transmitted to subsequent generations. The inheritance of differential epigenetic information could potentially contribute to altered traits or disease susceptibility in offspring and future descendants.”

“However, it is not yet clear what consequences, if any, epigenetic inheritance might have in humans. Further studies should give us a clearer understanding of the extent to which heritable traits can be derived from epigenetic inheritance, and not just from genes. That could have profound consequences for future generations.”

Professor Azim Surani from the University of Cambridge, principal investigator of the research, said: “The new study has the potential to be exploited in two distinct ways. First, the work could provide information on how to erase aberrant epigenetic marks that may underlie some diseases in adults. Second, the study provides opportunities to address whether germ cells can acquire new epigenetic marks through environmental or dietary influences on parents that may evade erasure and be transmitted to subsequent generations, with potentially undesirable consequences.”

We Are All Mosaics (National Geographic)

by Virginia Hughes, 21 December 2012

Here’s something you probably learned once in a biology class, more or less. There’s this molecule called DNA. It contains a long code that created you and is unique to you. And faithful copies of the code live inside the nucleus of every one of the trillions of cells in your body.

In a later class you may have learned a few exceptions to that “faithful copies” bit. Sometimes, especially during development, when cells are dividing into more cells, a mutation pops up in the DNA of a daughter cell. This makes the daughter cell and all of its progeny genetically distinct. The phenomenon is called ‘somatic mosaicism’, and it tends to happen in sperm cells, egg cells, immune cells, and cancer cells. But it’s pretty infrequent and, for most healthy people, inconsequential.

That’s what the textbooks say, anyway, and it’s also a common assumption in medical research. For instance, genetic studies of living people almost always collect DNA from blood draws or cheek swabs, even if investigating the tangled roots of, say, heart disease or diabetes or autism. The assumption is that whatever genetic blips show up in blood or saliva will recapitulate what’s in the (far less accessible) cells of the heart, pancreas, or brain.

Two recent reports suggest that somatic mosaicism is far more common than anybody ever realized — and that might be a good thing.


Colored bars show the locations of genetic glitches in tissues from each of the six subjects (inner vertical numbers). The numbers on the outer edge of the circle correspond to each of our 23 chromosomes, and each color represents a different organ. Image courtesy of PNAS

In the first study Michael Snyder and colleagues looked at cells in 11 different organs and tissues obtained from routine autopsies of six unrelated people who had not died of cancer or any hereditary disease.

Then the scientists screened each tissue for small deletions or duplications of DNA, called copy number variations, or CNVs. These are fairly common in all of us.

In order to do genetic screens, researchers have to mash up a bunch of cells and pull DNA out of the aggregate. That makes research on somatic mutations tricky, because you can’t tell how some cells in the tissue might be different from others. The researchers got around that problem by doing side-by-side comparisons of the tissues from each person. If one tissue has a CNV and the other one doesn’t, they reasoned, then it must be a somatic glitch.

As they reported in October in the Proceedings of the National Academy of Sciences, Snyder’s team found a total of 73 somatic CNVs in the six people, cropping up in tissues all over the body, including the brain, liver, pancreas and small intestine. “Your genome is not static — it does change through development,” says Snyder, chair of the genetics department at Stanford. “People knew that, but it had never been systematically studied.”

OK, but do somatic mutations do anything? It’s hard to tell, particularly because postmortem studies offer no living person to observe. Still, the scientists showed that 79 percent of the somatic mutations fell inside of genes, and most of those genes play a role in the cell’s everyday regulatory processes, like metabolism, phosphorylation, and turning genes on. So the somatic mutations could very well have had an impact.

In the last paragraph of their paper the researchers mention that the findings could also have big implications for studies of induced pluripotent stem (iPS) cells. This line of research is getting increasingly popular, for good reason. With iPS technology, researchers start with a small piece of skin (or…) from a living person. They then expose those skin cells to a certain chemical concoction that reprograms them back into a primordial state. Once the stem cells are created, researchers can put them in yet another chemical soup that coaxes them to differentiate into whatever type of cell the scientists want to study. You can see why it’s cool: The technique allows scientists to create cells — each holding an individual’s unique DNA code, remember — in a Petri dish. Researchers can study neurons of children with autism, for example, without ever touching their brains.

Trouble is, several groups have reported that iPS cells carry mutations that the original skin cells don’t have. This suggests that something screwy is happening during the reprogramming process, defeating the whole purpose of making the cells. (Fellow Phenomena contributor Ed Yong wrote a fantastic post about the hoopla last year.)

But that last paragraph of Snyder’s study offers a bit of hope. What if the mutations that crop up in iPS cells actually were in the skin cells they came from, but just didn’t get picked up because those skin cells were mixed with other skin cells that didn’t have the mutations? In other words, what if skin cells, like all those other tissues they looked at in the paper, are mosaics?

The second new study, published last month in Naturefinds exactly that.

Flora Vaccarino‘s team at Yale sequenced the entire genome of 21 iPS cell lines, three each from seven people, as well as the skin cells that the iPS cells originated from. It turns out that each iPS line has an average of two CNVs and that at least half of these come from somatic mutations in the skin cells. (The researchers used special techniques for amplifying the DNA of the skin cells, so that they could detect CNVs that are present only in a fraction of the cells.)

That means two things. First, researchers using iPS cells can exhale. Their freaky reprogramming process doesn’t seem to create too much genetic havoc in the iPS cells. And second, somatic mosaicism happens a lot. Vaccarino’s study estimates that a full 30 percent of the skin cells carry somatic mutations.

Our widespread mosaicism may have implications for certain diseases. Somatic mutations have been strongly linked to tumors, for example, so it could be that people who have a lot of mosaicism are at a higher risk of cancer. But there’s also a positive way to spin it. Somatic mutations give our genomes an extra layer of flexibility, in a sense, that can come in handy. Snyder gives a good example in his study. If you have a group of cells that are constantly exposed to viruses, say, then it might be beneficial to have a somatic mutation pop up that damages receptors on the cell that viruses can latch on to.

But there’s likely a more parsimonious explanation for all of those genetic copying mistakes. “When you’re replicating DNA, there’s a certain expense to keep everything perfect,” Snyder says, meaning that it would cost the cell a lot of energy to ensure that every new cell was identical to the last. And in the end, he adds, that extra expense may not be worth it. “Having imperfections could just be an economically beneficial way for organisms to do things.”

Photos from Shannon O’Hara and James Diin, courtesy of National Geographic’s My Shot

Bullying by Childhood Peers Leaves a Trace That Can Change the Expression of a Gene Linked to Mood (Science Daily)

Dec. 18, 2012 — A recent study by a researcher at the Centre for Studies on Human Stress (CSHS) at the Hôpital Louis-H. Lafontaine and professor at the Université de Montréal suggests that bullying by peers changes the structure surrounding a gene involved in regulating mood, making victims more vulnerable to mental health problems as they age.

The study published in the journal Psychological Medicine seeks to better understand the mechanisms that explain how difficult experiences disrupt our response to stressful situations. “Many people think that our genes are immutable; however this study suggests that environment, even the social environment, can affect their functioning. This is particularly the case for victimization experiences in childhood, which change not only our stress response but also the functioning of genes involved in mood regulation,” says Isabelle Ouellet-Morin, lead author of the study.

A previous study by Ouellet-Morin, conducted at the Institute of Psychiatry in London (UK), showed that bullied children secrete less cortisol — the stress hormone — but had more problems with social interaction and aggressive behaviour. The present study indicates that the reduction of cortisol, which occurs around the age of 12, is preceded two years earlier by a change in the structure surrounding a gene (SERT) that regulates serotonin, a neurotransmitter involved in mood regulation and depression.

To achieve these results, 28 pairs of identical twins with a mean age of 10 years were analyzed separately according to their experiences of bullying by peers: one twin had been bullied at school while the other had not. “Since they were identical twins living in the same conditions, changes in the chemical structure surrounding the gene cannot be explained by genetics or family environment. Our results suggest that victimization experiences are the source of these changes,” says Ouellet-Morin. According to the author, it would now be worthwhile to evaluate the possibility of reversing these psychological effects, in particular, through interventions at school and support for victims.

Journal Reference:

  1. I. Ouellet-Morin, C. C. Y. Wong, A. Danese, C. M. Pariante, A. S. Papadopoulos, J. Mill, L. Arseneault. Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twinsPsychological Medicine, 2012; DOI: 10.1017/S0033291712002784

Reading history through genetics (Columbia University)

5-Dec-2012, by Holly Evarts

New method analyzes recent history of Ashkenazi and Masai populations, paving the way to personalized medicine

New York, NY—December 5, 2012—Computer scientists at Columbia’s School of Engineering and Applied Science have published a study in the November 2012 issue of The American Journal of Human Genetics (AJHG) that demonstrates a new approach used to analyze genetic data to learn more about the history of populations. The authors are the first to develop a method that can describe in detail events in recent history, over the past 2,000 years. They demonstrate this method in two populations, the Ashkenazi Jews and the Masai people of Kenya, who represent two kinds of histories and relationships with neighboring populations: one that remained isolated from surrounding groups, and one that grew from frequent cross-migration across nearby villages.

“Through this work, we’ve been able to recover very recent and refined demographic history, within the last few centuries, in contrast to previous methods that could only paint broad brushstrokes of the much deeper past, many thousands of years ago,” says Computer Science Associate Professor Itsik Pe’er, who led the research. “This means that we can now use genetics as an objective source of information regarding history, as opposed to subjective written texts.”

Pe’er’s group uses computational genetics to develop methods to analyze DNA sequence variants. Understanding the history of a population, knowing which populations had a shared origin and when, which groups have been isolated for a long time, or resulted from admixture of multiple original groups, and being able to fully characterize their genetics is, he explains, “essential in paving the way for personalized medicine.”

For this study, the team developed the mathematical framework and software tools to describe and analyze the histories of the two populations and discovered that, for instance, Ashkenazi Jews are descendants of a small number—in the hundreds—of individuals from the late medieval times, and since then have remained genetically isolated while their population has expanded rapidly to several millions today.

“Knowing that the Ashkenazi population has expanded so recently from a very small number has practical implications,” notes Pe’er. “If we can obtain data on only a few hundreds of individuals from this population, a perfectly feasible task in today’s technology, we will have effectively collected the genomes of millions of current Ashkenazim.” He and his team are now doing just that, and have already begun to analyze a first group of about 150 Ashkenazi genomes.

The genetic data of the Masai, a semi-nomadic people, indicates the village-by-village structure of their population. Unlike the isolated Ashkenazi group, the Masai live in small villages but regularly interact and intermarry across village boundaries. The ancestors of each village therefore typically come from many different places, and a single village hosts an effective gene pool that is much larger than the village itself.

Previous work in population genetics was focused on mutations that occurred very long ago, say the researchers, and therefore able to only describe population changes that occurred at that timescale, typically before the agricultural revolution. Pe’er’s research has changed that, enabling scientists to learn more about recent changes in populations and start to figure out, for instance, how to pinpoint severe mutations in personal genomes of specific individuals—mutations that are more likely to be associated with disease.

“This is a thrilling time to be working in computational genetics,” adds Pe’er, citing the speed in which data acquisition has been accelerating; much faster than the ability of computing hardware to process such data. “While the deluge of big data has forced us to develop better algorithms to analyze them, it has also rewarded us with unprecedented levels of understanding.”


Pe’er’s team worked closely on this research with study co-authors, Ariel Darvasi, PhD of the Hebrew University of Jerusalem, who was responsible for collecting most of the study samples, and Todd Lencz, PhD of Feinstein institute for Medical Research, who handled genotyping of the DNA samples. The team’s computing and analysis took place in the Columbia Initiative in Systems Biology (CISB).

This research is supported by the National Science Foundation (NSF). The computing facility of CISB is supported by the National Institutes of Health (NIH).

Life span of humans took a huge jump in past century (MSNBC)

Researchers credit environmental improvements, not genetics, for the increaseBy Trevor Stokes

updated 10/15/2012 7:11:26 PM ET

Humans are living longer than ever, a life-span extension that occurred more rapidly than expected and almost solely from environmental improvements as opposed to genetics, researchers said Monday.

Four generations ago, the average Swede had the same probability of dying as a hunter-gatherer, but improvements in our living conditions through medicine, better sanitation and clean drinking water (considered “environmental” changes) decreased mortality rates to modern levels in just 100 years, researchers found.

In Japan, 72 has become the new 30, as the likelihood of a 72-year-old modern-day person dying is the same as a 30-year-old hunter-gatherer ancestor who lived 1.3 million years ago. Though the researchers didn’t specifically look at the United States, they say the trends are not country-specific and not based in genetics.

Quick jump in life span
The same progress of decreasing average probability of dying at a certain age in hunters-gatherers that took 1.3 million years to achieve was made in 30 years during the 21st century.

“I pictured a more gradual transition from a hunter-gatherer mortality profile to something like we have today, rather than this big jump, most of which occurred in the last four generations, to me that was surprise,” lead author Oskar Burger, postdoctoral fellow at the Max Planck Institute for Demographic Research in Germany, told LiveScience.

Biologists have lengthened life spans of worms, fruit flies and mice in labs by selectively breeding for old-age survivorship or tweaking their endocrine system, a network of glands that affects every cell in the body. However, the longevity gained in humans over the past four generations is even greater than can be created in labs, researchers concluded. [Extending Life: 7 Ways to Live Past 100]

Genetics vs. environment
In the new work, Burger and colleagues analyzed previously published mortality data from Sweden, France and Japan, from present-day hunter-gatherers and from wild chimpanzees, the closet living relative to humans.

Humans have lived for an estimated 8,000 generations, but only in the past four have mortalities decreased to modern-day levels. Hunter-gatherers today have average life spans on par with wild chimpanzees.

The research suggests that while genetics plays a small role in shaping human mortality, the key in driving up our collective age lies with the advent of medical technologies, improved nutrition, higher education, better housing and several other improvements to the overall standards of living.

“This recent progress has been just astronomically fast compared to what we made since the split from chimpanzees,” Burger said.

Most of the brunt of decreased mortality comes in youth: By age 15, hunters and gatherers have more than 100 times the chance of dying as modern-day people.

What’s next?
“In terms of what’s going on in the next four generations, I want to be very clear that I don’t make any forecasts,” Burger said. “We’re in a period of transition and we don’t know what the new stable point will be.”

However, some researchers say that humans may have maxed out their old age.

“These mortality curves (that show the probability of dying by a certain age), they are now currently at their lowest possible value, which makes a very strong prediction that life span cannot increase much more,” Caleb Finch, a neurogerontology professor at the University of Southern California who studies the biological mechanisms of aging, told LiveScience in an email.

Further, Finch, who was not involved in the current study, argues that environmental degradation, including climate change and ozone pollution, combined with increased obesity “are working to throw us back to an earlier phase of our improvements, they’re regressive.”

“It’s impossible to make any reasonable predictions, but you can look, for example, in local environments in Los Angeles where the density of particles in the air predict the rate of heart disease and cancer,” Finch said, illustrating the link between the environment and health.

The study was detailed Monday in the journal Proceedings of the National Academy of Sciences.

As rotas das suçuaranas (Fapesp)

Felinos conseguem se movimentar em zonas de ocupação humana, mas encontram obstáculos nas estradas

MARIA GUIMARÃES | Edição 199 – Setembro de 2012

A onça-parda (Puma concolor), um dos maiores predadores das Américas, ainda é pouco conhecida pela ciência brasileira. © EDUARDO CESAR (FOTO FEITA NA FUNDAÇÃO ZOOLÓGICO DE SÃO PAULO)

Análises genéticas estão revelando um pouco da história e da ecologia da suçuarana, ou onça-parda (Puma concolor), um dos maiores felinos do Brasil, atrás apenas da onça-pintada. Esses discretos animais são altamente adaptáveis e vivem mesmo em zonas com pouca floresta. Mas enfrentam problemas com a caça e nas estradas, conforme vem mostrando o trabalho paralelo de duas pesquisadoras que nunca se encontraram pessoalmente: Camila Castilho, atualmente na Universidade de São Paulo (USP), e Renata Miotto, agora na Escola Superior de Agricultura Luiz de Queiroz (Esalq), também da USP, em Piracicaba.

As duas estudaram aspectos genéticos de populações locais de suçuaranas, chegando em grande parte a resultados semelhantes, conforme mostram o artigo de Renata naConservation Genetics em 2011, e de Camila publicado este ano na Genetics and Molecular Biology. O primeiro aspecto importante é que há pouca diferenciação genética nas áreas estudadas, sinal de uma população não fragmentada. Isso indica que esses animais conseguem percorrer grandes distâncias e manter o fluxo de material genético, apesar de não haver continuidade de floresta. É bem diferente do que acontece com a onça-pintada, que se aventura pouco fora das áreas de mata e acaba ficando isolada em fragmentos e gerando populações diferenciadas, conforme já mostraram outros estudos.

Na prática, a onça-parda forma populações contínuas ao longo de áreas extensas. No caso de Camila, que desenvolveu o trabalho durante o doutorado pela Universidade Federal do Rio Grande do Sul (UFRGS), a área englobava boa parte de Santa Catarina, uma parte do sul do Paraná e algumas amostras no extremo norte do Rio Grande do Sul, um total de mais de 140 mil quilômetros quadrados (km2). O estudo de Renata, à época doutoranda na Universidade Federal de São Carlos (UFSCar), era mais circunscrito, mas nada diminuto: cerca de 1.700 km2 do interior paulista que incluem 15 municípios, entre eles Ribeirão Preto, Rio Claro e São Carlos.

O outro achado semelhante entre os dois estudos mostra que recentemente, em algum ponto do último século, houve uma drástica redução nos números das suçuaranas, que os geneticistas de populações chamam de gargalo populacional. Ao passar por um desses gargalos, a população perde parte da sua diversidade genética, o que em certos casos pode gerar problemas. “A perda de genes é aleatória e é possível que nada importante se vá”, explica Camila, “mas é maior a probabilidade de acontecer um azar”. Um azar seria o animal não poder contar com algum gene essencial para enfrentar a alterações no ambiente. Uma coisa é certa quando se detecta um gargalo: aconteceu algum desequilíbrio na população, seja uma redução importante em tamanho ou, mais raramente, uma alteração drástica na proporção entre machos e fêmeas.


É aí que começam as diferenças entre os dois estudos. O interior de São Paulo, onde Renata trabalha, está recoberto de cana-de-açúcar. “A maior parte foi plantada nos anos 1960 e 1970, em razão do Proálcool [Programa Nacional do Álcool]”, diz a pesquisadora. “Os dados genéticos indicam que o gargalo pode ter acontecido nessa época.” Nesse caso, muitas suçuaranas teriam morrido nesse período de intenso desmatamento, e depois aos poucos a população teria voltado a aumentar, à medida que suas presas se adaptaram a viver nos canaviais. “A dieta das onças na região consiste principalmente em tatus, cervos, capivaras e outros roedores”, conta. São animais que aparentemente vêm se adaptando bem à agricultura, alguns deles consumidores de cana-de-açúcar. Com alimento abundante, as suçuaranas podem facilmente viver na região, sem representar problemas para os donos das plantações.

O grande problema que esses animais enfrentam hoje são as estradas movimentadas, praticamente intransponíveis para pedestres – sejam eles humanos ou felinos –, que cortam o estado. Isso pode bloquear as rotas das suçuaranas e, com o tempo, reduzir a variabilidade genética.

Além de limitar o trânsito das suçuaranas, atropelamentos são uma causa importante de mortalidade. “Os machos jovens, que se dispersam para longe da área onde nasceram, são as principais vítimas”, diz Renata. Entre os 23 animais atropelados de sua amostragem, 16 são machos. A suçuarana Anhanguera, apelidada em 2009 com o nome da estrada em que foi atropelada, no interior paulista, era justamente um macho jovem. “Essa mortalidade diferencial pode alterar a razão sexual, o que pode ser detectado como um gargalo.” Isso acontece porque são eles os emissários do material genético, já que se mudam para uma zona distante onde afinal se estabelecem e acasalam.

As fêmeas permanecem mais próximas ao local onde nasceram, conforme Renata mostrou em cinco anos de monitoramento na Estação Ecológica de Jataí, no município de Luis Antônio, perto de Ribeirão Preto. Ao longo desse período ela percorreu trilhas e coletou fezes frescas, de onde extraiu material genético. Os dados, publicados este ano na Biotropica, mostram que todas as onças residentes são fêmeas.



Na Região Sul, Camila deparou com uma relação mais conflituosa entre os seres humanos e o leão-baio, como o felino é conhecido em terras catarinenses. Ali se criam vários tipos de gado – vacas, cabras, ovelhas – de forma extensiva, com os animais sempre soltos no pasto. Além das pacas, cutias e veados, os animais domésticos acabam virando boas refeições para as suçuaranas, que em seguida precisam enfrentar o fazendeiro armado. “Embora a caça seja ilegal, sabemos que acontece muito nessa região”, conta Camila, que aos poucos venceu as resistências e conseguiu que os donos das fazendas lhe cedessem amostras dos leões-baios caçados, para extração de material genético. A zona de estudo da pesquisadora se concentrou no sul de Santa Catarina, onde as fazendas se estendem por campos de altitude com resquícios de floresta – os capões – em meio ao pasto. É nesses capões, e nas matas ao longo de rios, que as suçuaranas se refugiam e onde por vezes encontram uma cabra ou bezerro também em busca de abrigo.

Assim como em São Paulo, os dados de Camila mostram que o gargalo populacional aconteceu no último século, coincidindo com a ampla derrubada da floresta de araucárias que caracterizava a região. Atualmente, a caça parece ser responsável pela maior parte da mortalidade por ali, e não a falta de hábitat. “Conectividade não parece ser um problema”, comenta Camila. Por meio de modelos ecológicos que analisam a paisagem ela sugere, em artigo de 2011 na Mammalian Biology, que não há impedimento para que esses animais se locomovam por toda a sua área de estudo, que abrange boa parte da Região Sul. Um dado genético que corrobora essa ideia é o baixo parentesco entre os indivíduos que conseguiu analisar. “Apenas 6,6% dos indivíduos que analisamos eram aparentados”, conta. Para ela, é preciso conscientizar os fazendeiros da importância ecológica dos grandes predadores e buscar soluções, como a construção de currais onde o gado possa passar a noite.

Mesmo nunca tendo conversado, as duas pesquisadoras continuam a seguir caminhos paralelos. Ambas, atualmente no pós-doutorado, deixaram a genética de lado para se concentrar na análise da paisagem. “São abordagens complementares”, explica Camila. Diante das informações fornecidas pela distribuição da variação genética, surgiram novas perguntas que as levaram a buscar entender o ambiente por onde as onças-pardas circulam em busca de detectar os problemas que elas enfrentam e propor soluções para manter populações viáveis desse grande felino encontrado em quase toda a América, exceto em boa parte da Argentina e na metade leste da América do Norte.

Agora ambas trabalham em São Paulo: Renata está construindo um banco de dados sobre a cobertura vegetal e a ocupação da mesma região que examinou até o momento, incluindo um mapeamento detalhado da malha viária e do fluxo de veículos, que em conjunto com os dados genéticos formarão um modelo de dispersão. Ao mesmo tempo compila dados de atropelamentos e, com ajuda da Polícia Florestal, aumenta sua coleção de amostras genéticas. “A partir desses modelos, quero avaliar as rotas preferenciais no deslocamento das onças para definir o que se pode fazer em termos de manejo da paisagem”, explica. Camila concentra seu projeto no mosaico das serras da Bocaina e da Mantiqueira, no nordeste paulista, que inclui a região de São José dos Campos. Nessa região, avaliará o hábitat disponível e as possibilidades de locomoção das suçuaranas. “Vou criar valores de permeabilidade para detectar as áreas prioritárias em termos de conservação.”

Em conjunto, os dois projetos podem contribuir para reduzir o desequilíbrio que existe entre a América do Norte e a do Sul no que diz respeito ao conhecimento a respeito desse imponente predador. Talvez também cheguem a propostas de práticas pecuárias que melhorem a convivência entre fazendeiros e predadores, e a passarelas ou túneis para travessia de suçuaranas.

Artigos científicos
CASTILHO, C. S. et alGenetic structure and conservation of Mountain Lions in the South-Brazilian Atlantic Rain ForestGenetics and Molecular Biology. v. 35 (1), p. 65-73. 2012.
CASTILHO, C. S. et alLandscape genetics of mountain lions (Puma concolor) in southern BrazilMammalian Biology. v. 76 (4), p. 476-83. 2011.
MIOTTO, R. A. et alMonitoring a puma (Puma concolor) population in a fragmented landscape in Southeast BrazilBiotropica. v. 44 (1), p. 98-104. 2012.
MIOTTO, R. A. et alGenetic diversity and population structure of pumas (Puma concolor) in southeastern Brazil: implications for conservation in a human-dominated landscapeConservation Genecits. v. 12 (6), p. 1.447-55. 2011.

Bits of Mystery DNA, Far From ‘Junk,’ Play Crucial Role (N.Y.Times)


Published: September 5, 2012

Among the many mysteries of human biology is why complex diseases like diabeteshigh blood pressure and psychiatric disorders are so difficult to predict and, often, to treat. An equally perplexing puzzle is why one individual gets a disease like cancer or depression, while an identical twin remains perfectly healthy.

Béatrice de Géa for The New York Times. “It is like opening a wiring closet and seeing a hairball of wires,” Mark Gerstein of Yale University said of the DNA intricacies.

Now scientists have discovered a vital clue to unraveling these riddles. The human genome is packed with at least four million gene switches that reside in bits of DNA that once were dismissed as “junk” but that turn out to play critical roles in controlling how cells, organs and other tissues behave. The discovery, considered a major medical and scientific breakthrough, has enormous implications for human health because many complex diseases appear to be caused by tiny changes in hundreds of gene switches.

The findings, which are the fruit of an immense federal project involving 440 scientists from 32 laboratories around the world, will have immediate applications for understanding how alterations in the non-gene parts of DNA contribute to human diseases, which may in turn lead to new drugs. They can also help explain how the environment can affect disease risk. In the case of identical twins, small changes in environmental exposure can slightly alter gene switches, with the result that one twin gets a disease and the other does not.

As scientists delved into the “junk” — parts of the DNA that are not actual genes containing instructions for proteins — they discovered a complex system that controls genes. At least 80 percent of this DNA is active and needed. The result of the work is an annotated road map of much of this DNA, noting what it is doing and how. It includes the system of switches that, acting like dimmer switches for lights, control which genes are used in a cell and when they are used, and determine, for instance, whether a cell becomes a liver cell or a neuron.

“It’s Google Maps,” said Eric Lander, president of the Broad Institute, a joint research endeavor of Harvard and the Massachusetts Institute of Technology. In contrast, the project’s predecessor, the Human Genome Project, which determined the entire sequence of human DNA, “was like getting a picture of Earth from space,” he said. “It doesn’t tell you where the roads are, it doesn’t tell you what traffic is like at what time of the day, it doesn’t tell you where the good restaurants are, or the hospitals or the cities or the rivers.”

The new result “is a stunning resource,” said Dr. Lander, who was not involved in the research that produced it but was a leader in the Human Genome Project. “My head explodes at the amount of data.”

The discoveries were published on Wednesday in six papers in the journal Nature and in 24 papers in Genome Research and Genome Biology. In addition, The Journal of Biological Chemistry is publishing six review articles, and Science is publishing yet another article.

Human DNA is “a lot more active than we expected, and there are a lot more things happening than we expected,” said Ewan Birney of the European Molecular Biology Laboratory-European Bioinformatics Institute, a lead researcher on the project.

In one of the Nature papers, researchers link the gene switches to a range of human diseases — multiple sclerosislupusrheumatoid arthritisCrohn’s diseaseceliac disease — and even to traits like height. In large studies over the past decade, scientists found that minor changes in human DNA sequences increase the risk that a person will get those diseases. But those changes were in the junk, now often referred to as the dark matter — they were not changes in genes — and their significance was not clear. The new analysis reveals that a great many of those changes alter gene switches and are highly significant.

“Most of the changes that affect disease don’t lie in the genes themselves; they lie in the switches,” said Michael Snyder, a Stanford University researcher for the project, called Encode, for Encyclopedia of DNA Elements.

And that, said Dr. Bradley Bernstein, an Encode researcher at Massachusetts General Hospital, “is a really big deal.” He added, “I don’t think anyone predicted that would be the case.”

The discoveries also can reveal which genetic changes are important in cancer, and why. As they began determining the DNA sequences of cancer cells, researchers realized that most of the thousands of DNA changes in cancer cells were not in genes; they were in the dark matter. The challenge is to figure out which of those changes are driving the cancer’s growth.

“These papers are very significant,” said Dr. Mark A. Rubin, a prostate cancer genomics researcher at Weill Cornell Medical College. Dr. Rubin, who was not part of the Encode project, added, “They will definitely have an impact on our medical research on cancer.”

In prostate cancer, for example, his group found mutations in important genes that are not readily attacked by drugs. But Encode, by showing which regions of the dark matter control those genes, gives another way to attack them: target those controlling switches.

Dr. Rubin, who also used the Google Maps analogy, explained: “Now you can follow the roads and see the traffic circulation. That’s exactly the same way we will use these data in cancer research.” Encode provides a road map with traffic patterns for alternate ways to go after cancer genes, he said.

Dr. Bernstein said, “This is a resource, like the human genome, that will drive science forward.”

The system, though, is stunningly complex, with many redundancies. Just the idea of so many switches was almost incomprehensible, Dr. Bernstein said.

There also is a sort of DNA wiring system that is almost inconceivably intricate.

“It is like opening a wiring closet and seeing a hairball of wires,” said Mark Gerstein, an Encode researcher from Yale. “We tried to unravel this hairball and make it interpretable.”

There is another sort of hairball as well: the complex three-dimensional structure of DNA. Human DNA is such a long strand — about 10 feet of DNA stuffed into a microscopic nucleus of a cell — that it fits only because it is tightly wound and coiled around itself. When they looked at the three-dimensional structure — the hairball — Encode researchers discovered that small segments of dark-matter DNA are often quite close to genes they control. In the past, when they analyzed only the uncoiled length of DNA, those controlling regions appeared to be far from the genes they affect.

The project began in 2003, as researchers began to appreciate how little they knew about human DNA. In recent years, some began to find switches in the 99 percent of human DNA that is not genes, but they could not fully characterize or explain what a vast majority of it was doing.

The thought before the start of the project, said Thomas Gingeras, an Encode researcher from Cold Spring Harbor Laboratory, was that only 5 to 10 percent of the DNA in a human being was actually being used.

The big surprise was not only that almost all of the DNA is used but also that a large proportion of it is gene switches. Before Encode, said Dr. John Stamatoyannopoulos, a University of Washington scientist who was part of the project, “if you had said half of the genome and probably more has instructions for turning genes on and off, I don’t think people would have believed you.”

By the time the National Human Genome Research Institute, part of the National Institutes of Health, embarked on Encode, major advances in DNA sequencing and computational biology had made it conceivable to try to understand the dark matter of human DNA. Even so, the analysis was daunting — the researchers generated 15 trillion bytes of raw data. Analyzing the data required the equivalent of more than 300 years of computer time.

Just organizing the researchers and coordinating the work was a huge undertaking. Dr. Gerstein, one of the project’s leaders, has produced a diagram of the authors with their connections to one another. It looks nearly as complicated as the wiring diagram for the human DNA switches. Now that part of the work is done, and the hundreds of authors have written their papers.

“There is literally a flotilla of papers,” Dr. Gerstein said. But, he added, more work has yet to be done — there are still parts of the genome that have not been figured out.

That, though, is for the next stage of Encode.

*   *   *

Published: September 5, 2012

Rethinking ‘Junk’ DNA

A large group of scientists has found that so-called junk DNA, which makes up most of the human genome, does much more than previously thought.

GENES: Each human cell contains about 10 feet of DNA, coiled into a dense tangle. But only a very small percentage of DNA encodes genes, which control inherited traits like eye color, blood type and so on.

JUNK DNA: Stretches of DNA around and between genes seemed to do nothing, and were called junk DNA. But now researchers think that the junk DNA contains a large number of tiny genetic switches, controlling how genes function within the cell.

REGULATION: The many genetic regulators seem to be arranged in a complex and redundant hierarchy. Scientists are only beginning to map and understand this network, which regulates how cells, organs and tissues behave.

DISEASE: Errors or mutations in genetic switches can disrupt the network and lead to a range of diseases. The new findings will spur further research and may lead to new drugs and treatments.


First Holistic View of How Human Genome Actually Works: ENCODE Study Produces Massive Data Set (Science Daily)

ScienceDaily (Sep. 5, 2012) — The Human Genome Project produced an almost complete order of the 3 billion pairs of chemical letters in the DNA that embodies the human genetic code — but little about the way this blueprint works. Now, after a multi-year concerted effort by more than 440 researchers in 32 labs around the world, a more dynamic picture gives the first holistic view of how the human genome actually does its job.

William Noble, professor of genome sciences and computer science, in the data center at the William H. Foege Building. Noble, an expert on machine learning, and his team designed artificial intellience programs to analyze ENCODE data. These computer programs can learn from experience, recognize patterns, and organize information into categories understandable to scientists. The center houses systems for a wide variety of genetic research. The computer center has the capacity to store and analyze a tremendous amount of data, the equivalent of a 670-page autobiography of each person on earth, uncompressed.The computing resources analyze over 4 pentabytes of genomic data a year. (Credit: Clare McLean, Courtesy of University of Washington)

During the new study, researchers linked more than 80 percent of the human genome sequence to a specific biological function and mapped more than 4 million regulatory regions where proteins specifically interact with the DNA. These findings represent a significant advance in understanding the precise and complex controls over the expression of genetic information within a cell. The findings bring into much sharper focus the continually active genome in which proteins routinely turn genes on and off using sites that are sometimes at great distances from the genes themselves. They also identify where chemical modifications of DNA influence gene expression and where various functional forms of RNA, a form of nucleic acid related to DNA, help regulate the whole system.

“During the early debates about the Human Genome Project, researchers had predicted that only a few percent of the human genome sequence encoded proteins, the workhorses of the cell, and that the rest was junk. We now know that this conclusion was wrong,” said Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI), a part of the National Institutes of Health. “ENCODE has revealed that most of the human genome is involved in the complex molecular choreography required for converting genetic information into living cells and organisms.”

NHGRI organized the research project producing these results; it is called the Encyclopedia oDNA Elements or ENCODE. Launched in 2003, ENCODE’s goal of identifying all of the genome’s functional elements seemed just as daunting as sequencing that first human genome. ENCODE was launched as a pilot project to develop the methods and strategies needed to produce results and did so by focusing on only 1 percent of the human genome. By 2007, NHGRI concluded that the technology had sufficiently evolved for a full-scale project, in which the institute invested approximately $123 million over five years. In addition, NHGRI devoted about $40 million to the ENCODE pilot project, plus approximately $125 million to ENCODE-related technology development and model organism research since 2003.

The scale of the effort has been remarkable. Hundreds of researchers across the United States, United Kingdom, Spain, Singapore and Japan performed more than 1,600 sets of experiments on 147 types of tissue with technologies standardized across the consortium. The experiments relied on innovative uses of next-generation DNA sequencing technologies, which had only become available around five years ago, due in large part to advances enabled by NHGRI’s DNA sequencing technology development program. In total, ENCODE generated more than 15 trillion bytes of raw data and consumed the equivalent of more than 300 years of computer time to analyze.

“We’ve come a long way,” said Ewan Birney, Ph.D., of the European Bioinformatics Institute, in the United Kingdom, and lead analysis coordinator for the ENCODE project. “By carefully piecing together a simply staggering variety of data, we’ve shown that the human genome is simply alive with switches, turning our genes on and off and controlling when and where proteins are produced. ENCODE has taken our knowledge of the genome to the next level, and all of that knowledge is being shared openly.”

The ENCODE Consortium placed the resulting data sets as soon as they were verified for accuracy, prior to publication, in several databases that can be freely accessed by anyone on the Internet. These data sets can be accessed through the ENCODE project portal ( as well as at the University of California, Santa Cruz genome browser,, the National Center for Biotechnology Information, and the European Bioinformatics Institute,;

“The ENCODE catalog is like Google Maps for the human genome,” said Elise Feingold, Ph.D., an NHGRI program director who helped start the ENCODE Project. “Simply by selecting the magnification in Google Maps, you can see countries, states, cities, streets, even individual intersections, and by selecting different features, you can get directions, see street names and photos, and get information about traffic and even weather. The ENCODE maps allow researchers to inspect the chromosomes, genes, functional elements and individual nucleotides in the human genome in much the same way.”

The coordinated publication set includes one main integrative paper and five related papers in the journal Nature; 18 papers inGenome Research; and six papers in Genome Biology. The ENCODE data are so complex that the three journals have developed a pioneering way to present the information in an integrated form that they call threads.

“Because ENCODE has generated so much data, we, together with the ENCODE Consortium, have introduced a new way to enable researchers to navigate through the data,” said Magdalena Skipper, Ph.D., senior editor at Nature, which produced the freely available publishing platform on the Internet.

Since the same topics were addressed in different ways in different papers, the new website,, will allow anyone to follow a topic through all of the papers in the ENCODE publication set by clicking on the relevant thread at the Nature ENCODE explorer page. For example, thread number one compiles figures, tables, and text relevant to genetic variation and disease from several papers and displays them all on one page. ENCODE scientists believe this will illuminate many biological themes emerging from the analyses.

In addition to the threaded papers, six review articles are being published in the Journal of Biological Chemistry and two related papers in Science and one in Cell.

The ENCODE data are rapidly becoming a fundamental resource for researchers to help understand human biology and disease. More than 100 papers using ENCODE data have been published by investigators who were not part of the ENCODE Project, but who have used the data in disease research. For example, many regions of the human genome that do not contain protein-coding genes have been associated with disease. Instead, the disease-linked genetic changes appear to occur in vast tracts of sequence between genes where ENCODE has identified many regulatory sites. Further study will be needed to understand how specific variants in these genomic areas contribute to disease.

“We were surprised that disease-linked genetic variants are not in protein-coding regions,” said Mike Pazin, Ph.D., an NHGRI program director working on ENCODE. “We expect to find that many genetic changes causing a disorder are within regulatory regions, or switches, that affect how much protein is produced or when the protein is produced, rather than affecting the structure of the protein itself. The medical condition will occur because the gene is aberrantly turned on or turned off or abnormal amounts of the protein are made. Far from being junk DNA, this regulatory DNA clearly makes important contributions to human health and disease.”

Identifying regulatory regions will also help researchers explain why different types of cells have different properties. For example why do muscle cells generate force while liver cells break down food? Scientists know that muscle cells turn on some genes that only work in muscle, but it has not been previously possible to examine the regulatory elements that control that process. ENCODE has laid a foundation for these kinds of studies by examining more than 140 of the hundreds of cell types found in the human body and identifying many of the cell type-specific control elements.

Despite the enormity of the dataset described in this historic collection of publications, it does not comprehensively describe all of the functional genomic elements in all of the different types of cells in the human body. NHGRI plans to invest in additional ENCODE-related research for at least another four years. During the next phase, ENCODE will increase the depth of the catalog with respect to the types of functional elements and cell types studied. It will also develop new tools for more sophisticated analyses of the data.

Journal References:

  1. Magdalena Skipper, Ritu Dhand, Philip Campbell.Presenting ENCODENature, 2012; 489 (7414): 45 DOI:10.1038/489045a
  2. Joseph R. Ecker, Wendy A. Bickmore, Inês Barroso, Jonathan K. Pritchard, Yoav Gilad, Eran Segal. Genomics: ENCODE explainedNature, 2012; 489 (7414): 52 DOI:10.1038/489052a
  3. The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome.Nature, 2012; 489 (7414): 57 DOI: 10.1038/nature11247

The eyes have it: Men do see things differently to women (BioMed Central)

By Hilary Glover

BioMed Central

The way that the visual centers of men and women’s brains works is different, finds new research published in BioMed Central’s open access journal Biology of Sex Differences. Men have greater sensitivity to fine detail and rapidly moving stimuli, but women are better at discriminating between colors.

In the brain there are high concentrations of male sex hormone (androgen) receptors throughout cerebral cortex, especially in the visual cortex which is responsible for processing images. Androgens are also responsible for controlling the development of neurons in the visual cortex during embryogenesis, meaning that males have 25% more of these neurons than females.

Researchers from Brooklyn and Hunter Colleges of the City University of New York compared the vision of men and women aged over 16 from both college and high school, including students and staff. All volunteers were required to have normal color vision and 20/20 sight (or 20/20 when corrected by glasses or contact lenses).

When the volunteers were required to describe colors shown to them across the visual spectrum it became obvious that the color vision of men was shifted, and that they required a slightly longer wavelength to experience the same hue as the women. The males also had a broader range in the center of the spectrum where they were less able to discriminate between colors.

An image of light and dark bars was used to measure contrast-sensitivity functions (CSF) of vision; the bars were either horizontal or vertical and volunteers had to choose which one they saw. In each image, when the light and dark bars were alternated the image appeared to flicker.

By varying how rapidly the bars alternated or how close together they were, the team found that at moderate rates of image change, observers lost sensitivity for close together bars, and gained sensitivity when the bars were farther apart. However when the image change was faster both sexes were less able to resolve the images over all bar widths. Overall the men were better able to resolve more rapidly changing images that were closer together than the women.

Prof Israel Abramov, who led this study commented, “As with other senses, such as hearing and the olfactory system, there are marked sex differences in vision between men and women. The elements of vision we measured are determined by inputs from specific sets of thalamic neurons into the primary visual cortex. We suggest that, since these neurons are guided by the cortex during embryogenesis, that testosterone plays a major role, somehow leading to different connectivity between males and females. The evolutionary driving force between these differences is less clear.”


Sex & vision I: Spatio-temporal resolution Israel Abramov, James Gordon, Olga Feldman and Alla Chavarga Biology of Sex Differences (in press)

Sex and vision II: Color appearance of monochromatic lights Israel Abramov, James Gordon, Olga Feldman and Alla Chavarga Biology of Sex Differences (in press)