Arquivo da tag: Epigenética

Are Humans Still Evolving? Scientists Weigh In (Science Alert)

Eva Hamrud, Metafact – 20 Sept. 2020

As a species, humans have populated almost every corner of the earth. We have developed technologies and cultures which shape the world we live in.

The idea of ‘natural selection’ or ‘survival of the fittest’ seems to make sense in Stone Age times when we were fighting over scraps of meat, but does it still apply now?

We asked 12 experts whether humans are still evolving. The expert consensus is unanimously ‘yes’, however scientists say we might have the wrong idea of what evolution actually is.

Evolution is not the same as natural selection

Evolution is often used interchangeable with the phrases ‘survival of the fittest’ or ‘natural selection’. Actually, these are not quite the same thing.

‘Evolution’ simply means the gradual change of a population over time.

‘Natural selection’ is a mechanism by which evolution can occur. Our Stone Age ancestors who were faster runners avoided being trampled by mammoths and were more likely to have children. That is ‘natural selection’.

Overtime, the human population became faster at running. That’s evolution.

Evolution can happen without natural selection

That makes sense for Stone Age humans, but what about nowadays? We don’t need to outrun mammoths, we have medicines for when we’re sick and we can go to the shops to get food.

Natural selection needs a ‘selection pressure’ (e.g. dangerous trampling mammoths), so if we don’t have these anymore, does this mean we stop evolving?

Even with no selection pressures, experts say evolution still occurs by other mechanisms.

Professor Stanley Ambrose, an anthropologist from the University of Illinois, explains that “any change in the proportions of genes or gene variants over time is also considered evolution. The variants may be functionally equivalent, so evolution does not automatically equate with ‘improvement'”.

Whilst some genes can be affected by natural selection (e.g. genes that help us run faster), other changes in our DNA might have no obvious effect on us. ‘Neutral’ variations can also spread through a population by a different mechanism called ‘genetic drift’.

Genetic drift works by chance: some individuals might be unlucky and die for reasons which have nothing to do with their genes. Their unique gene variations will not be passed on to the next generation, and so the population will change.

Genetic drift doesn’t need any selection pressures, and it is still happening today.

Natural selection is still happening in humans

As much as we have made things easier for ourselves, there are still selection pressures around us, which mean that natural selection is still happening.

Like all mammals, humans lose the ability to digest milk when they stop breastfeeding. This is because we stop making an enzyme called lactase. In some countries, the population has acquired ‘lactase persistence’, meaning that people make lactase throughout their lives.

In European countries we can thank one specific gene variation for our lactase persistence, which is called ‘-13910*T’. By studying this specific gene variation in modern and ancient DNA samples, researchers suggest that it became common after humans started domesticated and milking animals.

This is an example of natural selection where we have actually made the selection pressure ourselves – we started drinking milk, so we evolved to digest it!

Another example of humans undergoing natural selection to adapt to a lifestyle is the Bajau people, who traditionally live in houseboats in the waters of South East Asia and spend much of their lives diving to hunt fish or collect shellfish.

Ultrasound imaging has found that Bajau people have larger spleens than their neighbours – an adaption which allows them to stay underwater for longer.

There are always selective pressures around us, even ones that we create ourselves.

As Dr Benjamin Hunt from the University of Birmingham puts it, “Our technological and cultural changes alter the strength and composition of the selection pressures within our environment, but selection pressures still exist.”

Evolution can’t be stopped

So, evolution can happen by different mechanisms like natural selection and genetic drift. As our environment is always changing, natural selection is always happening. And even if our environment was ‘just right’ for us, we would evolve anyway!

Dr Alywyn Scally, an expert in evolution and genetics from the University of Cambridge, explains: “As long as human reproduction involves randomness and genetic mutation (and the laws of the Universe pretty much guarantee that this will always be the case at some level), there will continue to be differences from one generation to the next, meaning that the process of evolution can never be truly halted.”

Takeaway: Evolution means change in a population. That includes both easy-to-spot changes to adapt to an environment as well as more subtle, genetic changes.

Humans are still evolving, and that is unlikely to change in the future.

Article based on 12 expert answers to this question: Are humans still evolving?

This expert response was published in partnership with independent fact-checking platform Subscribe to their weekly newsletter here.

Interdisciplinary approach yields new insights into human evolution (Vanderbilt University)


Vanderbilt biologist Nicole Creanza Nicole Creanza takes interdisciplinary approach to human evolution as guest editor of Royal Society journal

The evolution of human biology should be considered part and parcel with the evolution of humanity itself, proposes Nicole Creanza, assistant professor of biological sciences. She is the guest editor of a new themed issue of the Philosophical Transactions of the Royal Society B, the oldest scientific journal in the world, that focuses on an interdisciplinary approach to human evolution.

Stanford professor Marc Feldman and Stanford postdoc Oren Kolodny collaborated with Creanza on the special issue.

“Within the blink of an eye on a geological timescale, humans advanced from using basic stone tools to examining the rocks on Mars; however, our exact evolutionary path and the relative importance of genetic and cultural evolution remain a mystery,” said Creanza, who specializes in the application of computational and theoretical approaches to human and cultural evolution, particularly language development. “Our cultural capacities-to create new ideas, to communicate and learn from one another, and to form vast social networks-together make us uniquely human, but the origins, the mechanisms, and the evolutionary impact of these capacities remain unknown.”

The special issue brings together researchers in biology, anthropology, archaeology, economics, psychology, computer science and more to explore the cultural forces affecting human evolution from a wider perspective than is usually taken.

“Researchers have begun to recognize that understanding non-genetic inheritance, including culture, ecology, the microbiome, and regulation of gene expression, is fundamental to fully comprehending evolution,” said Creanza. “It is essential to understand the dynamics of cultural inheritance at different temporal and spatial scales, to uncover the underlying mechanisms that drive these dynamics, and to shed light on their implications for our current theory of evolution as well as for our interpretation and predictions regarding human behavior.”

In addition to an essay discussing the need for an interdisciplinary approach to human evolution, Creanza included an interdisciplinary study of her own, examining the origins of English’s contribution to Sranan, a creole that emerged in Suriname following an influx of indentured servants from England in the 17th century.

Creanza, along with linguists Andre Sherriah and Hubert Devonish of the University of the West Indes and psychologist Ewart Thomas from Stanford, sought to determine the geographic origins of the English speakers whose regional dialects formed the backbone of Sranan. Their work combined linguistic, historical and genetic approaches to determine that the English speakers who influenced Sranan the most originated largely from two counties on opposite sides of southern England: Bristol, in the west, and Essex, in the east.

“Thus, analyzing the features of modern-day languages might give us new information about events in human history that left few other traces,” Creanza said.

O peso através das gerações (Pesquisa Fapesp)

Entre ratos, efeitos do consumo excessivo ou da falta de comida podem ser transmitidos para filhos e netos 


Experimentos com ratos feitos por pesquisadores de universidades de São Paulo reforçam a ideia de que o excesso de peso pode ser um fenômeno que transcende gerações – e não apenas porque os filhos tendem a herdar dos pais genes que favorecem o acúmulo de energia e os tornam predispostos à obesidade ou porque vivem em um ambiente com disponibilidade excessiva de comida. Alterações na oferta de alimento para as fêmeas um pouco antes ou durante a gravidez parecem aumentar, por mecanismos ainda pouco compreendidos, a probabilidade de que tenham filhos e até netos com sobrepeso.

Em uma série de testes, a bióloga Maria Martha Bernardi e sua equipe na Universidade Paulista (Unip) alimentaram algumas ratas no início da vida reprodutiva e outras já grávidas com uma dieta bastante calórica e aguardaram para ver o que acontecia com a primeira geração de filhotes e também com os filhos desses filhotes. Tanto os roedores que nasceram de mães superalimentadas quanto os da geração seguinte apresentaram mais predisposição a desenvolver sobrepeso.

A tendência de ganho excessivo de peso ocorreu mesmo quando os filhos e os netos dessas ratas foram alimentados apenas com a dieta padrão de laboratório. Segundo Martha, esses resultados indicam que o período em que o feto está se desenvolvendo no útero é crucial para definir a regulação do metabolismo do animal e, ao menos, o da geração seguinte.

Se essas mudanças aparecessem apenas na primeira geração, o mais natural seria imaginar que alterações hormonais provocadas pela dieta materna teriam afetado os filhotes. Como o efeito avança até a segunda geração, os pesquisadores suspeitam que a propensão a ganhar peso seja mantida por mecanismos epigenéticos: alterações no padrão de ativação e desligamento dos genes provocadas por fatores ambientais, como a dieta, e transmitidas às gerações seguintes. Essas mudanças no perfil de acionamento dos genes não alteram diretamente a sequência de “letras químicas” do DNA, apesar de serem herdadas através das gerações. Embora o grupo de Martha não tenha analisado o padrão de atividade dos genes, dados obtidos por cientistas mundo afora indicam que mudanças no perfil de ativação gênica sem alteração na sequência de DNA podem acontecer tanto em animais quanto em seres humanos.

Dieta que engorda
Curiosamente, não foi só a superalimentação materna durante a gestação que parece ter mexido com o perfil de ativação de seus genes e deixado filhos e netos com tendência a engordar. Em um dos experimentos, realizado em parceria com pesquisadores das universidades de São Paulo (USP), Federal do ABC (UFABC) e Santo Amaro (Unisa), 12 fêmeas de ratos receberam 40% menos comida do que o considerado normal para as roedoras prenhes, enquanto oito ratas do grupo de controle foram alimentadas com a dieta habitual de laboratório.

As fêmeas que passaram fome durante a gestação ganharam menos da metade do peso das ratas que puderam comer à vontade. Os filhotes das mães submetidas à restrição alimentar nasceram menores e continuaram mais magros durante algum tempo, ainda que recebessem a mesma quantidade de comida que os filhos das ratas que não passaram fome. Só na idade adulta a diferença desapareceu e os dois grupos de roedores alcançaram peso semelhante, embora os filhos das ratas famintas apresentassem uma proporção maior de gordura corporal – em especial, de uma forma de gordura que se acumula entre os órgãos (gordura visceral), associada a maior risco de problemas cardiovasculares.

A diferença mais importante surgiu na segunda geração. Os netos de ratas que haviam comido pouco enquanto estavam prenhes nasceram menores, mas, depois de adultos, eram um pouco (de 10% a 15%) mais pesados que os netos das ratas alimentadas normalmente. Eles tinham mais gordura visceral e também sinais de inflamação no cérebro. Esse ganho extra de peso ocorreu mesmo com as fêmeas da primeira geração, portanto, mães desses animais, tendo sido alimentadas normalmente. É como se a privação de alimento experimentada pelas ratas da geração inicial provocasse uma reprogramação metabólica duradoura em seus descendentes, afirmam os pesquisadores em artigo publicado em maio de 2016 na revista Reproduction, Fertility and Development.

O trabalho da equipe paulista, nesse ponto, confirma pesquisas anteriores que já haviam encontrado uma associação entre episódios de fome na gravidez e o nascimento de filhos com propensão ao aumento de peso e aos problemas de saúde a ele associados. Embora não tenham identificado o mecanismo específico por trás desse efeito, Martha Bernardi e sua equipe suspeitam que compostos produzidos pelo organismo das mães da geração inicial, parcialmente privadas de comida na gestação, ativem genes que favorecem o rápido ganho de peso no filhote. Assim, os sinais químicos emitidos pelo corpo materno funcionariam como um alerta de que o ambiente é de escassez e que é preciso usar com máxima eficiência os recursos alimentares disponíveis. Essa sinalização recebida pelo organismo do filhote poderia fazer toda a diferença, representando a chance de crescer e sobreviver em um ambiente com privação de alimento. “Mas também pode levar à obesidade, caso a oferta de alimentos volte a se normalizar depois que ele nasce”, explica Martha.

Estudos realizados nas décadas anteriores mostraram uma situação muito parecida com a descrita acima entre os descendentes das mulheres que ficaram grávidas durante o chamado Hongerwinter (inverno da fome, em holandês), quando os exércitos nazistas que recuavam na Holanda diante do avanço dos Aliados cortaram boa parte do transporte de suprimentos para o país entre o fim de 1944 e o começo de 1945, no final da Segunda Grande Guerra. Tanto os filhos quanto os netos das sobreviventes do Hongerwinter apresentavam taxas de obesidade e problemas metabólicos acima do esperado para a população geral.

Inflamação no cérebro
Em outro estudo, Martha e seus colegas forneceram alimentação hipercalórica – uma mistura de ração padrão mais um suplemento líquido rico em diferentes tipos de gordura – para 10 ratas logo após o desmame, enquanto outro grupo de fêmeas recebeu a alimentação normal e serviu de controle. Conforme o esperado, as ratas submetidas à dieta hipercalórica quando bebês ficaram acima do peso, ainda que não obesas, ao chegar à puberdade. Efeitos semelhantes foram observados em suas filhas: eram ratas que, quando adultas, apresentaram sobrepeso e alterações metabólicas, como o acúmulo de gordura visceral, embora tenham sido tratadas apenas com uma dieta balanceada durante toda a vida. Também publicado na Reproduction, Fertility and Development, esse trabalho e outros estudos do grupo indicam que o sobrepeso foi o desencadeador de processos inflamatórios que afetaram o cérebro da mãe e da prole, de forma aparentemente duradoura.

Se parece estranho imaginar que o excesso de peso pode levar a uma inflamação cerebral, é preciso lembrar que as células de gordura não são meros depósitos de calorias. Os adipócitos, como são chamados, produzem uma grande variedade de substâncias, entre as quais moléculas desencadeadoras de inflamações, que chegam à corrente sanguínea e, a partir dela, ao hipotálamo, região do cérebro associada, entre outras funções, ao controle da fome.

Trabalhos do grupo da Unip ainda não publicados indicam ainda que essa inflamação pode atingir outras áreas cerebrais dos roedores. A hipótese dos pesquisadores é de que o processo inflamatório no órgão esteja ligado à reprogramação do organismo transmitida da mãe para os filhotes, incluindo aí alterações no controle do apetite que podem se manter durante a vida adulta.

Para Alicia Kowaltowski, pesquisadora do Instituto de Química da USP que estuda a relação entre a dieta e os mecanismos de produção de energia das células, é bastante forte a possibilidade de que a tendência ao sobrepeso e à obesidade seja passada de uma geração para outra por meios que não envolvem a herança de genes favorecedores do ganho de peso. “A questão é saber quais são os mecanismos que estão por trás desses fenômenos”, conta a pesquisadora.

Entre tais mecanismos, um candidato que tem ganhado força são as transformações epigenéticas. O prefixo grego epi significa superior, e na palavra epigenética, cunhada nos anos 1940 pelo embriologista inglês Conrad Waddington, designa a área da biologia que estuda as modificações químicas motivadas pelo ambiente que levam à ativação ou inativação dos genes e alteram o funcionamento do organismo. Uma das modificações químicas mais comuns e simples sofrida pelos genes é a chamada metilação. Nela, um grupo metila, formado por um átomo de carbono e três de hidrogênio (CH3), acopla-se a um trecho de DNA, impedindo que ele seja lido pelo maquinário da célula. O resultado é o silenciamento daquela região. Estudos com dezenas de espécies de animais, plantas e fungos já mostraram que o perfil de metilação pode ser transmitido de uma geração para outra e afetar as características da prole.

Influência paterna
O papel das mães no sobrepeso dos filhos parece cada vez mais sólido. E quanto ao papel do pai? “Há alguns indícios de que a influência paterna também pode ocorrer, mas eles são menos claros”, diz Martha Bernardi. Por um lado, faz sentido que influências epigenéticas possam ser transmitidas pelo lado paterno – assim como outras células do organismo, os espermatozoides podem ser afetados por alterações no padrão de ativação dos genes produzidas por influência do ambiente. Se tais mudanças não forem totalmente eliminadas após o encontro entre as células sexuais masculinas e os óvulos, o novo indivíduo gerado pela fecundação poderia carregar parte da memória epigenética de seu pai.

Um estudo de 2015, feito por uma equipe da Universidade de Copenhague, na Dinamarca, e liderado por Romain Barrès, mostrou que esse cenário é plausível ao estudar os espermatozoides de 16 homens obesos e outros 10 com peso normal. No caso dos voluntários obesos, os padrões epigenéticos, como os de metilação, concentravam-se em genes ligados ao desenvolvimento do sistema nervoso, em especial os que são importantes para o controle do apetite (e, portanto, do peso), o que não ocorria com os homens magros.

Barrès e seus colegas fizeram outra comparação sugestiva entre as marcações epigenéticas dos espermatozoides dos obesos antes da cirurgia de redução de estômago e as desses mesmos participantes após a operação. Resultado: depois da cirurgia, o padrão epigenético das células lembrava o de homens com peso normal.

“O mais importante a respeito dessas descobertas é sugerir que tais modificações podem ocorrer em células germinativas, ou seja, os óvulos e espermatozoides, e ser transmitidas para gerações seguintes”, diz o médico Licio Augusto Velloso, professor da Faculdade de Ciências Médicas da Universidade Estadual de Campinas (FCM-Unicamp), que estuda os mecanismos celulares e moleculares ligados à origem da obesidade e do diabetes. “Os estudos epigenéticos avançaram muito na última década e se espera que, num futuro não muito distante, o mapeamento de fatores ambientais e de seu impacto em diferentes aspectos da epigenética nos ajude a prevenir doenças importantes”, afirma Velloso.

Enxergar o excesso de peso pelo prisma epigenético pode trazer mais uma peça relevante para o quebra-cabeça da epidemia global de obesidade e de doenças metabólicas ligadas a ela. Historicamente associado à saúde e à fartura, o excesso de peso se tornou um problema de grandes proporções primeiro nos países ricos, mas hoje é cada vez mais comum em países mais pobres – a começar pelo Brasil, onde quase 60% da população adulta está acima do peso considerado saudável, conforme dados do Instituto Brasileiro de Geografia e Estatística (IBGE). Muitos países em desenvolvimento passaram rapidamente de um contexto em que a desnutrição era um problema grave para outro em que a obesidade é muito mais preocupante.

Artigos científicos
JOAQUIM, A. O. et al. Maternal food restriction in rats of the F0 generation increases retroperitoneal fat, the number and size of adipocytes and induces periventricular astrogliosis in female F1 and male F2 generationsReproduction, Fertility and Development. 31 mai. 2016.
JOAQUIM, A. O. et alTransgenerational effects of a hypercaloric dietReproduction, Fertility and Development. 25 ago. 2015.

Cultural differences may leave their mark on DNA (Science Daily)

January 10, 2017
University of California – San Francisco
Signatures of ethnicity in the genome appear to reflect an ethnic group’s shared culture and environment, rather than their common genetic ancestry, report scientists. Epigenetic signatures distinguishing Mexican and Puerto Rican children in this study cannot be explained by genetic ancestry alone, the researchers say.

The researchers identified several hundred differences in methylation associated with either Mexican or Puerto Rican ethnicity, but discovered that only three-quarters of the epigenetic difference between the two ethnic subgroups could be accounted for by differences in the children’s genetic ancestry. Credit: © DigitalGenetics / Fotolia

A UC San Francisco-led study has identified signatures of ethnicity in the genome that appear to reflect an ethnic group’s shared culture and environment, rather than their common genetic ancestry.

The study examined DNA methylation — an “annotation” of DNA that alters gene expression without changing the genomic sequence itself — in a group of diverse Latino children. Methylation is one type of “epigenetic mark” that previous research has shown can be either inherited or altered by life experience. The researchers identified several hundred differences in methylation associated with either Mexican or Puerto Rican ethnicity, but discovered that only three-quarters of the epigenetic difference between the two ethnic subgroups could be accounted for by differences in the children’s genetic ancestry. The rest of the epigenetic differences, the authors suggest, may reflect a biological stamp made by the different experiences, practices, and environmental exposures distinct to the two ethnic subgroups.

The discovery could help scientists understand how social, cultural, and environmental factors interact with genetics to create differences in health outcomes between different ethnic populations, the authors say, and provides a counterpoint to long-standing efforts in the biomedical research community to replace imprecise racial and ethnic categorization with genetic tests to determine ancestry.

“These data suggest that the interplay between race and ethnicity as social constructs and genetic ancestry as a biological construct is more complex than we had realized,” said Noah Zaitlen, PhD, a UCSF assistant professor of medicine and co-senior author on the new study. “In a medical context both elements may provide valuable information.”

The research — published January 3, 2017 in the online journal eLife — was led by Joshua Galanter, MD, MAS, formerly an assistant professor of medicine, of bioengineering and therapeutic sciences, and of epidemiology and biostatistics at UCSF, who is now a scientist at Genentech. The research was jointly supervised by Zaitlen and co-senior author Esteban Burchard, MD, MPH, a professor of bioengineering and therapeutic sciences and of medicine in UCSF’s schools of Pharmacy and Medicine and the Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences II at UCSF.

“This is a big advancement of our understanding of race and ethnicity,” Burchard said. “There’s this whole debate about whether race is fundamentally genetic or is just a social construct. To our knowledge this is the first time anyone has attempted to quantify the molecular signature of the non-genetic components of race and ethnicity. It demonstrates in a whole new way that race combines both genetics and environment.”

Teasing apart roles of genetics, environment in ethnic differences in disease

Researchers and clinicians have known for many years that different racial and ethnic populations get diseases at different rates, respond differently to medications, and show very different results on standard clinical tests: “For a whole range of medical tests, whether your physician is told that your lab result is normal or abnormal depends entirely on the race/ethnicity box that you tick on an intake form,” Zaitlen said.

It’s tempting to assume that such health disparities between races and ethnicities all stem from inherited genetic differences, but that’s not necessarily the case. Different racial and ethnic groups also eat different diets, live in neighborhoods with more or less pollution, experience different levels of poverty, and are more or less likely to smoke tobacco, all of which could also impact their health outcomes.

“A lot of our research involves trying to tease apart how much of health differences between populations are genetic and how much are environmental,” Zaitlen said.

The researchers turned to epigenetics to search for answers to these questions because these molecular annotations of the genetic code have a unique position between genetic ancestry and environmental influence. Unlike the rest of the genome, which is only inherited from an individual’s parents (with random mutations here and there), methylation and other epigenetic annotations can be modified based on experience. These modifications influence when and where particular genes are expressed and appear to have significant impacts on disease risk, suggesting explanations for how environmental factors such as maternal smoking during pregnancy can influence a child’s risk of later health problems.

Epigenetic signatures of ethnicity could be biomarkers for shared cultural experiences

In the new study, the team examined methylation signatures in 573 children of self-identified Mexican or Puerto-Rican identity drawn from the GALA II study, a cohort previously developed by Burchard to study environmental and genetic components of asthma risk in Latino children. They identified 916 methylation sites that varied with ethnic identity, but found that only 520 of these differences could be completely explained by genetic ancestry — 109 could be partially explained by ancestry, while 205 could not be explained by ancestry at all.

Overall, the researchers found that about 76 percent of the effect of ethnicity on DNA methylation could be accounted for by controlling for genetic ancestry, suggesting that nearly a quarter of the effect must be due to other, unknown factors. The researchers found that many of these additional methylation sites corresponded to sites that previous studies had shown to be sensitive to environmental and social factors such as maternal smoking, exposure to diesel exhaust, and psychosocial stress. This led the team to hypothesize that a large fraction of their newly disovered epigenetic markers of ethnicity likely reflect biological signatures of environmental, social, or cultural differences between ethnic subgroups.

“This suggests that using epigenetics as a biomarker could give you a lot of information about environmental exposures within particular populations that’s not captured by genetics,” Zaitlen said. “Our next step will be to understand how specific epigenetic signatures are linked to particular environmental exposures, and use those signals to understand patient risk.”

Scientists and clinicians have increasingly tried to move away from simplistic racial and ethnic categories in disease research, the authors say, and — with the rise of precision medicine — in clinical diagnosis and treatment as well. Studies by the Burchard group and others have found that using genetic ancestry rather than ethnic self-identification significantly improves diagnostic accuracy for certain diseases.

But the new data showing that a large fraction of epigenetic signatures of ethnicity reflect something other than ancestry suggests that abandoning the idea of race and ethnicity altogether could sacrifice a lot of valuable information about the drivers of differences in health and disease between different communities.

“Like a standard family history, ethnicity is association with disease for both genetic and environmental reasons,” Zaitlen said. “If your dad or mom had a heart attack, that tells doctors a lot about your risk for a heart attack. Part of that is genetic, but part of it is that your lifestyle is influenced heavily by your parents’ lifestyle. Your ethnic group is like a much bigger family — it’s partly a matter of genetics, but it also reflects the environment of your broader community.”

Journal Reference:

  1. Joshua M Galanter, Christopher R Gignoux, Sam S Oh, Dara Torgerson, Maria Pino-Yanes, Neeta Thakur, Celeste Eng, Donglei Hu, Scott Huntsman, Harold J Farber, Pedro C Avila, Emerita Brigino-Buenaventura, Michael A LeNoir, Kelly Meade, Denise Serebrisky, William Rodríguez-Cintrón, Rajesh Kumar, Jose R Rodríguez-Santana, Max A Seibold, Luisa N Borrell, Esteban G Burchard, Noah Zaitlen. Differential methylation between ethnic sub-groups reflects the effect of genetic ancestry and environmental exposureseLife, 2017; 6 DOI: 10.7554/eLife.20532

Scientists Seek to Update Evolution (Quanta Magazine)

Recent discoveries have led some researchers to argue that the modern evolutionary synthesis needs to be amended. 

By Carl Zimmer. November 22, 2016

Douglas Futuyma, a biologist at Stony Brook University, defends the “Modern Synthesis” of evolution at the Royal Society earlier this month.  Kevin Laland looked out across the meeting room at a couple hundred people gathered for a conference on the future of evolutionary biology. A colleague sidled up next to him and asked how he thought things were going.

“I think it’s going quite well,” Laland said. “It hasn’t gone to fisticuffs yet.”

Laland is an evolutionary biologist who works at the University of St. Andrews in Scotland. On a chilly gray November day, he came down to London to co-host a meeting at the Royal Society called “New Trends in Evolutionary Biology.” A motley crew of biologists, anthropologists, doctors, computer scientists, and self-appointed visionaries packed the room. The Royal Society is housed in a stately building overlooking St. James’s Park. Today the only thing for Laland to see out of the tall meeting-room windows was scaffolding and gauzy tarps set up for renovation work. Inside, Laland hoped, another kind of renovation would be taking place.

In the mid-1900s, biologists updated Darwin’s theory of evolution with new insights from genetics and other fields. The result is often called the Modern Synthesis, and it has guided evolutionary biology for over 50 years. But in that time, scientists have learned a tremendous amount about how life works. They can sequence entire genomes. They can watch genes turn on and off in developing embryos. They can observe how animals and plants respond to changes in the environment.

As a result, Laland and a like-minded group of biologists argue that the Modern Synthesis needs an overhaul. It has to be recast as a new vision of evolution, which they’ve dubbed the Extended Evolutionary Synthesis. Other biologists have pushed back hard, saying there is little evidence that such a paradigm shift is warranted.

This meeting at the Royal Society was the first public conference where Laland and his colleagues could present their vision. But Laland had no interest in merely preaching to the converted, and so he and his fellow organizers also invited prominent evolutionary biologists who are skeptical about the Extended Evolutionary Synthesis.

Both sides offered their arguments and critiques in a civil way, but sometimes you could sense the tension in the room — the punctuations of tsk-tsks, eye-rolling, and partisan bursts of applause.

But no fisticuffs. At least not yet.

Making Evolution as We Know It

Every science passes through times of revolution and of business as usual. After Galileo and Newton dragged physics out of its ancient errors in the 1600s, it rolled forward from one modest advance to the next until the early 1900s. Then Einstein and other scientists established quantum physics, relativity and other new ways of understanding the universe. None of them claimed that Newton was wrong. But it turns out there’s much more to the universe than matter in motion.

Evolutionary biology has had revolutions of its own. The first, of course, was launched by Charles Darwin in 1859 with his book On the Origin of Species. Darwin wove together evidence from paleontology, embryology and other sciences to show that living things were related to one another by common descent. He also introduced a mechanism to drive that long-term change: natural selection. Each generation of a species was full of variations. Some variations helped organisms survive and reproduce, and those were passed down, thanks to heredity, to the next generation.

Darwin inspired biologists all over the world to study animals and plants in a new way, interpreting their biology as adaptations produced over many generations. But he succeeded in this despite having no idea what a gene was. It wasn’t until the 1930s that geneticists and evolutionary biologists came together and recast evolutionary theory. Heredity became the transmission of genes from generation to generation. Variations were due to mutations, which could be shuffled into new combinations. New species arose when populations built up mutations that made interbreeding impossible.

In 1942, the British biologist Julian Huxley described this emerging framework in a book called Evolution: The Modern Synthesis. Today, scientists still call it by that name. (Sometimes they refer to it instead as neo-Darwinism, although that’s actually a confusing misnomer. The term “neo-Darwinism” was actually coined in the late 1800s, to refer to biologists who were advancing Darwin’s ideas in Darwin’s own lifetime.)

The Modern Synthesis proved to be a powerful tool for asking questions about nature. Scientists used it to make a vast range of discoveries about the history of life, such as why some people are prone to genetic disorders like sickle-cell anemia and why pesticides sooner or later fail to keep farm pests in check. But starting not long after the formation of the Modern Synthesis, various biologists would complain from time to time that it was too rigid. It wasn’t until the past few years, however, that Laland and other researchers got organized and made a concerted effort to formulate an extended synthesis that might take its place.

The researchers don’t argue that the Modern Synthesis is wrong — just that it doesn’t capture the full richness of evolution. Organisms inherit more than just genes, for example: They can inherit other cellular molecules, as well as behaviors they learn and the environments altered by their ancestors. Laland and his colleagues also challenge the pre-eminent place that natural selection gets in explanations for how life got to be the way it is. Other processes can influence the course of evolution, too, from the rules of development to the environments in which organisms have to live.

“It’s not simply bolting more mechanisms on what we already have,” said Laland. “It requires you to think of causation in a different way.”

Adding to Darwin

Eva Jablonka, a biologist at Tel Aviv University, used her talk to explore the evidence for a form of heredity beyond genes.

Our cells use a number of special molecules to control which of their genes make proteins. In a process called methylation, for example, cells put caps on their DNA to keep certain genes shut down. When cells divide, they can reproduce the same caps and other controls on the new DNA. Certain signals from the environment can cause cells to change these so-called “epigenetic” controls, allowing organisms to adjust their behavior to new challenges.

Some studies indicate that — under certain circumstances — an epigenetic change in a parent may get passed down to its offspring. And those children may pass down this altered epigenetic profile to their children. This would be kind of heredity that’s beyond genes.

The evidence for this effect is strongest in plants. In one study, researchers were able to trace down altered methylation patterns for 31 generations in a plant called Arabidopsis. And this sort of inheritance can make a meaningful difference in how an organism works. In another study, researchers found that inherited methylation patterns could change the flowering time of Arabidopsis, as well as the size of its roots. The variation that these patterns created was even bigger than what ordinary mutations caused.

After presenting evidence like this, Jablonka argued that epigenetic differences could determine which organisms survived long enough to reproduce. “Natural selection could work on this system,” she said.

While natural selection is an important force in evolution, the speakers at the meeting presented evidence for how it could be constrained, or biased in a particular direction. Gerd Müller, a University of Vienna biologist, offered an example from his own research on lizards. A number of species of lizards have evolved feet that have lost some toes. Some have only four toes, while others have just one, and some have lost their feet altogether.

The Modern Synthesis, Müller argued, leads scientists to look at these arrangements as simply the product of natural selection, which favors one variant over others because it has a survival advantage. But that approach doesn’t work if you ask what the advantage was for a particular species to lose the first toe and last toe in its foot, instead of some other pair of toes.

“The answer is, there is no real selective advantage,” said Müller.

The key to understanding why lizards lose particular toes is found in the way that lizard embryos develop toes in the first place. A bud sprouts off the side of the body, and then five digits emerge. But the toes always appear in the same sequence. And when lizards lose their toes through evolution, they lose them in the reverse order. Müller suspects this constraint is because mutations can’t create every possible variation. Some combinations of toes are thus off-limits, and natural selection can never select them in the first place.

Development may constrain evolution. On the other hand, it also provides animals and plants with remarkable flexibility. Sonia Sultan, an evolutionary ecologist from Wesleyan University, offered a spectacular case in point during her talk, describing a plant she studies in the genus Polygonum that takes the common name “smartweed.”

The Modern Synthesis, Sultan said, would lead you to look at the adaptations in a smartweed plant as the fine-tuned product of natural selection. If plants grow in low sunlight, then natural selection will favor plants with genetic variants that let them thrive in that environment — for example, by growing broader leaves to catch more photons. Plants that grow in bright sunlight, on the other hand, will evolve adaptations that let them thrive in those different conditions.

“It’s a commitment to that view that we’re here to confront,” Sultan said.

If you raise genetically identical smartweed plants under different conditions, Sultan showed, you’ll end up with plants that may look like they belong to different species.

For one thing, smartweed plants adjust the size of their leaves to the amount of sunlight they get. In bright light, the plants grow narrow, thick leaves, but in low light, the leaves become broad and thin. In dry soil, the plants send roots down deep in search of water, while in flood soil, they grow shallow hairlike roots that that stay near the surface.

Scientists at the meeting argued that this flexibility — known as plasticity — can itself help drive evolution. It allows plants to spread into a range of habitats, for example, where natural selection can then adapt their genes. And in another talk, Susan Antón, a paleoanthropologist at New York University, said that plasticity may play a significant role in human evolution that’s gone underappreciated till now. That’s because the Modern Synthesis has strongly influenced the study of human evolution for the past half century.

Paleoanthropologists tended to treat differences in fossils as the result of genetic differences. That allowed them to draw an evolutionary tree of humans and their extinct relatives. This approach has a lot to show for it, Antón acknowledged. By the 1980s, scientists had figured out that our early ancient relatives were short and small-brained up to about two million years ago. Then one lineage got tall and evolved big brains. That transition marked the origin of our genus, Homo.

But sometimes paleoanthropologists would find variations that were harder to make sense of. Two fossils might look in some ways like they should be in the same species but look too different in other respects. Scientists would usually dismiss those variations as being caused by the environment. “We wanted to get rid of all that stuff and get down to their essence,” Antón said.

But that stuff is now too abundant to ignore. Scientists have found a dizzying variety of humanlike fossils dating back to 1.5 to 2.5 million years ago. Some are tall, and some are short. Some have big brains and some have small ones. They all have some features of Homo in their skeletonbut each has a confusing mix-and-match assortment.

Antón thinks that the Extended Evolutionary Synthesis can help scientists make sense of this profound mystery. In particular, she thinks that her colleagues should take plasticity seriously as an explanation for the weird diversity of early Homo fossils.

To support this idea, Antón pointed out that living humans have their own kinds of plasticity. The quality of food a woman gets while she’s pregnant can influence the size and health of her baby, and those influences can last until adulthood. What’s more, the size of a woman — influenced in part by her own mother’s diet — can influence her own children. Biologists have found that women with longer legs tend to have larger children, for example.

Antón proposed that the weird variations in the fossil record might be even more dramatic examples of plasticity. All these fossils date to when Africa’s climate fell into a period of wild climate swings. Droughts and abundant rains would have changed the food supply in different parts of the world, perhaps causing early Homo to develop differently.

The Extended Evolutionary Synthesis may also help make sense of another chapter in our history: the dawn of agriculture. In Asia, Africa and the Americas, people domesticated crops and livestock. Melinda Zeder, an archaeologist at the Smithsonian Institution, gave a talk at the meeting about the long struggle to understand how this transformation unfolded.

Before people farmed, they foraged for food and hunted wild game. Zeder explained how many scientists treat the behavior of the foragers in a very Modern Synthesis way: as finely tuned by natural selection to deliver the biggest payoff for their effort to find food.

The trouble is that it’s hard to see how such a forager would ever switch to farming. “You don’t get the immediate gratification of grabbing some food and putting it in your mouth,” Zeder told me.

Some researchers suggested that the switch to agriculture might have occurred during a climate shift, when it got harder to find wild plants. But Zeder and other researchers have actually found no evidence of such a crisis when agriculture arose.

Zeder argues that there’s a better way of thinking about this transition. Humans are not passive zombies trying to survive in a fixed environment. They are creative thinkers who can change the environment itself. And in the process, they can steer evolution in a new direction.

Scientists call this process niche construction, and many species do it. The classic case is a beaver. It cuts down trees and makes a dam, creating a pond. In this new environment, some species of plants and animals will do better than others. And they will adapt to their environment in new ways. That’s true not just for the plants and animals that live around a beaver pond, but for the beaver itself.

When Zeder first learned about niche construction, she says, it was a revelation. “Little explosions were going off in my head,” she told me. The archaeological evidence she and others had gathered made sense as a record of how humans changed their own environment.

Early foragers show signs of having moved wild plants away from their native habitats to have them close at hand, for example. As they watered the plants and protected them from herbivores, the plants adapted to their new environment. Weedy species also moved in and became crops of their own. Certain animals adapted to the environment as well, becoming dogs, cats and other domesticated species.

Gradually, the environment changed from sparse patches of wild plants to dense farm fields. That environment didn’t just drive the evolution of the plants. It also began to drive the cultural evolution of the farmers, too. Instead of wandering as nomads, they settled down in villages so that they could work the land around them. Society became more stable because children received an ecological inheritance from their parents. And so civilization began.

Niche construction is just one of many concepts from the Extended Evolutionary Synthesis that can help make sense of domestication, Zeder said. During her talk, she presented slide after slide of predictions it provides, about everything from the movements of early foragers to the pace of plant evolution.

“It felt like an infomercial for the Extended Evolutionary Synthesis,” Zeder told me later with a laugh. “But wait! You can get steak knives!”

The Return of Natural Selection

Among the members of the audience was a biologist named David Shuker. After listening quietly for a day and a half, the University of St Andrews researcher had had enough. At the end of a talk, he shot up his hand.

The talk had been given by Denis Noble, a physiologist with a mop of white hair and a blue blazer. Noble, who has spent most of his career at Oxford, said he started out as a traditional biologist, seeing genes as the ultimate cause of everything in the body. But in recent years he had switched his thinking. He spoke of the genome not as a blueprint for life but as a sensitive organ, detecting stress and rearranging itself to cope with challenges. “I’ve been on a long journey to this view,” Noble said.

To illustrate this new view, Noble discussed an assortment of recent experiments. One of them was published last year by a team at the University of Reading. They did an experiment on bacteria that swim by spinning their long tails.

First, the scientists cut a gene out of the bacteria’s DNA that’s essential for building tails. The researchers then dropped these tailless bacteria into a petri dish with a meager supply of food. Before long, the bacteria ate all the food in their immediate surroundings. If they couldn’t move, they died. In less than four days in these dire conditions, the bacteria were swimming again. On close inspection, the team found they were growing new tails.

“This strategy is to produce rapid evolutionary genome change in response to the unfavorable environment,” Noble declared to the audience. “It’s a self-maintaining system that enables a particular characteristic to occur independent of the DNA.”

That didn’t sound right to Shuker, and he was determined to challenge Noble after the applause died down.

“Could you comment at all on the mechanism underlying that discovery?” Shuker asked.

Noble stammered in reply. “The mechanism in general terms, I can, yes…” he said, and then started talking about networks and regulation and a desperate search for a solution to a crisis. “You’d have to go back to the original paper,” he then said.

While Noble was struggling to respond, Shuker went back to the paper on an iPad. And now he read the abstract in a booming voice.

“‘Our results demonstrate that natural selection can rapidly rewire regulatory networks,’” Shuker said. He put down the iPad. “So it’s a perfect, beautiful example of rapid neo-Darwinian evolution,” he declared.

Shuker distilled the feelings of a lot of skeptics I talked to at the conference. The high-flying rhetoric about a paradigm shift was, for the most part, unwarranted, they said. Nor were these skeptics limited to the peanut gallery. Several of them gave talks of their own.

“I think I’m expected to represent the Jurassic view of evolution,” said Douglas Futuyma when he got up to the podium. Futuyma is a soft-spoken biologist at Stony Brook University in New York and the author of a leading textbook on evolution. In other words, he was the target of many complaints during the meeting that textbooks paid little heed to things like epigenetics and plasticity. In effect, Futuyma had been invited to tell his colleagues why those concepts were ignored.

“We must recognize that the core principles of the Modern Synthesis are strong and well-supported,” Futuyma declared. Not only that, he added, but the kinds of biology being discussed at the Royal Society weren’t actually all that new. The architects of the Modern Synthesis were already talking about them over 50 years ago. And there’s been a lot of research guided by the Modern Synthesis to make sense of them.

Take plasticity. The genetic variations in an animal or a plant govern the range of forms into which organism can develop. Mutations can alter that range. And mathematical models of natural selection show how it can favor some kinds of plasticity over others.

If the Extended Evolutionary Synthesis was so superfluous, then why was it gaining enough attention to warrant a meeting at the Royal Society? Futuyma suggested that its appeal was emotional rather than scientific. It made life an active force rather than the passive vehicle of mutations.

“I think what we find emotionally or aesthetically more appealing is not the basis for science,” Futuyma said.

Still, he went out of his way to say that the kind of research described at the meeting could lead to some interesting insights about evolution. But those insights would only arise with some hard work that leads to hard data. “There have been enough essays and position papers,” he said.

Some members in the audience harangued Futuyma a bit. Other skeptical speakers sometimes got exasperated by arguments they felt didn’t make sense. But the meeting managed to reach its end on the third afternoon without fisticuffs.

“This is likely the first of many, many meetings,” Laland told me. In September, a consortium of scientists in Europe and the United States received $11 million in funding (including $8 million from the John Templeton Foundation) to run 22 studies on the Extended Evolutionary Synthesis.

Many of these studies will test predictions that have emerged from the synthesis in recent years. They will see, for example, if species that build their own environments — spider webs, wasp nests and so on — evolve into more species than ones that don’t. They will look at whether more plasticity allows species to adapt faster to new environments.

“It’s doing the research, which is what our critics are telling us to do,” said Laland. “Go find the evidence.”

Correction: An earlier version of this article misidentified the photograph of Andy Whiten as Gerd Müller.

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Huge epigenomic map examines life’s impact on our genes (New Scientist)

18 February 2015 by Catherine Brahic

Magazine issue 3009.

THE nature versus nurture debate is getting a facelift this week, with the publication of a genetic map that promises to tell us which bits of us are set in stone by our DNA, and which bits we can affect by how we live our lives.

The new “epigenomic” map doesn’t just look at genes, but also the instructions that govern them. Compiled by a consortium of biologists and computer scientists, this information will allow doctors to pinpoint precisely which cells in the body are responsible for various diseases. It might also reveal how to adjust your lifestyle to counter a genetic predisposition to a particular disease.

“The epigenome is the additional information our cells have on top of genetic information,” says lead researcher Manolis Kellis of the Massachusetts Institute of Technology. It is made of chemical tags that are attached to DNA and its packaging. These tags act like genetic controllers, influencing whether a gene is switched on or off, and play an instrumental role in shaping our bodies and disease.

Researchers are still figuring out exactly how and when epigenetic tags are added to our DNA, but the process appears to depend on environmental cues. We inherit some tags from our parents, but what a mother eats during pregnancy, for instance, might also change her baby’s epigenome. Others tags relate to the environment we are exposed to as children and adults. “The epigenome sits in a very special place between nature and nurture,” says Kellis.

Each cell type in our body has a different epigenome – in fact, the DNA tags are the reason why our cells come in such different shapes and sizes despite having exactly the same DNA. So for its map, the Roadmap Epigenomics Consortium collected thousands of cells from different adult and embryonic tissues, and meticulously analysed all the tags.

So far, they have produced 127 epigenomes, each corresponding to a different cell type, from brain cells to skin cells. That’s a big advance on the 16 published in 2012 by the ENCODE project, which are included in the new map.

The consortium also cross-referenced these healthy epigenomes with previous data on the genetic components of dozens of diseases, including type 1 diabetes, Crohn’s disease, high blood pressure, inflammatory bowel disease and Alzheimer’s disease (see “Alzheimer’s epigenetics“).

The results, says Kellis, allow doctors to see what cell types are likely to be disrupted in people with these conditions. For instance, they suggest disruptions in the epigenome of the brain’s cingulate gyrus cells may play a role in attention deficit hyperactivity disorder (Nature, DOI: 10.1038/nature14248).

Richard Meehan of the University of Edinburgh, UK, says the work offers “incredibly valuable information which will be absorbed and debated for years to come”. He suggests that one day doctors will look at your epigenomes during routine health checks to suss out how the nature versus nurture battle is playing out inside your cells. These scans would reveal your genetic predisposition to certain conditions, and how your lifestyle is affecting those risks.

By adjusting your choices accordingly, you will be able to delay disease, or minimise its effects for as long as possible. “It’s not going to move any further forward the point at which your life ends, but make the years up to that point – years that are spent in physical decline – a whole lot better,” says Meehan.

“You see this on Star Trek,” he adds. “Nobody lives any longer but they just seem to be healthier up to the point where life, unfortunately, passes away.”

Alzheimer’s epigenetics

While you can’t change the genes you were born with, you might be able to alter your epigenome – and its influence on your health – through tinkering with your lifestyle.

Studying cells from people with Alzheimer’s and a mouse version of the disease highlights both immune cells and brain cells as key players. This finding supports other studies suggesting that an immune disorder is at least partially responsible for Alzheimer’s.

Manolis Kellis and his team at MIT (see main story) were able to identify both genetic and non-genetic effects. While the immune disruptions were coded in the cells’ genetics, the changes in the brain cells appeared to be influenced by environmental inputs like diet, education, physical activity and age, and are probably associated with epigenetic changes (Nature, DOI: 10.1038/nature14252).

“We have an interplay between genetics and epigenetics,” says Kellis. “You might not be able to do anything about the genetic but you might be able to do something about the epigenomic by – I don’t know – maybe reading more books.”

*   *   *

Cientistas publicam o primeiro atlas do epigenoma humano (O Globo)

Dados sobre processos que afetam células, responsáveis por sua diferenciação em 111 dos tecidos do corpo, podem ajudar na melhor compreensão de diversas doenças e no desenvolvimento de novos tratamentos para elas


No alvo: epigenoma abre caminho para novas abordagens no tratamento e cura de várias doenças
Foto: Alamy/Latinstock

No alvo: epigenoma abre caminho para novas abordagens no tratamento e cura de várias doenças – Alamy/Latinstock

RIO – Sequenciado completamente pela primeira vez há pouco mais de uma década, o genoma humano, com suas cerca de 3 bilhões de “letras”, guarda todas as informações necessárias para “construir” uma pessoa. Mas, apesar de quase todas nossas células terem o mesmo DNA, elas podem, e devem, ser muito diferentes umas das outras para que o corpo funcione bem. Afinal, os neurônios do cérebro cumprem trabalhos bem distintos do das células do músculo cardíaco, que por sua vez não poderiam fazer o que fazem as do fígado.

É a conhecida diferenciação celular, e para que isso aconteça é preciso controlar quais genes serão ativados e quais permanecerão dormentes nas células. E é aí que entra em cena o chamado epigenoma, nome dado ao conjunto de processos e reações químicas que regulam esta expressão genética. Ele teve seu primeiro atlas de ação em 111 tecidos que compõem o feto e o organismo humano publicado ontem na edição desta semana da revista “Nature”, junto com mais de 20 artigos neste e outros periódicos científicos abordando seus mecanismos e possíveis relações com doenças e condições como asma, câncer, problemas cardíacos e Alzheimer.


Isso porque, mesmo não alterando diretamente o DNA, o epigenoma tem grande importância na maneira como nossas células funcionam e pode ser influenciado por fatores ambientais e hábitos individuais, como a poluição e o tabagismo. Em alguns casos, inclusive, sua atuação pode até mesmo ser hereditária, ajudando a responder o mistério do que é fruto da natureza e o que é resultado da criação — cuja resposta, muitas vezes, deverá ser “ambos”. Segundo os pesquisadores, é como se o genoma fosse um mapa-múndi em branco ao qual o estudo do epigenoma agora acrescenta os nomes dos países, estados e cidades, suas rodovias e ferrovias e a localização de portos e aeroportos, tornando-o muito mais útil.

— Hoje, podemos sequenciar o genoma humano de forma rápida e barata, mas interpretar este genoma ainda é um desafio — lembra Bing Ren, professor da Universidade da Califórnia em San Diego e coautor de diversos dos artigos relacionados ao projeto de mapeamento do epigenoma. — Estes 111 mapas de referência do epigenoma são essencialmente um livro de vocabulário que nos ajuda a decifrar cada segmento do DNA em células distintas e tipos de tecido. Estes mapas são como retratos do genoma humano em ação.

Diante disso, ainda durante o projeto — no qual o Instituto Nacional de Saúde dos EUA (NIH) investiu US$ 300 milhões desde 2006 numa colaboração de centenas de cientistas de dezenas de instituições espalhadas pelo mundo —, diversos pesquisadores começaram a buscar na interação entre genoma e epigenoma possíveis fatores que levam ao desenvolvimento de doenças, abrindo caminho para novas abordagens na busca de tratamentos ou cura.

— As células do fígado e do cérebro usam diferentes pedaços do DNA para produzir um repertório distinto de proteínas dependendo de como os marcadores epigenéticos foram introduzidos em cada célula durante o desenvolvimento embrionário — destaca Steven Jones, professor da Universidade Simon Fraser, no Canadá e outro dos participantes no projeto. — E estes marcadores podem mudar ao longo da vida em resposta a fatores ambientais. De fato, mudanças nos padrões epigenéticos originais de uma célula já foram associadas a diversas doenças humanas, incluindo câncer e Alzheimer.

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Epigenética na agricultura é tema de livro (Facesp)

11 de fevereiro de 2015

Por Diego Freire

Agência FAPESP – Pesquisadores da Universidade de São Paulo (USP) estão entre os autores e editores do livro Epigenetics in Plants of Agronomic Importance: Fundamentals and Applications, publicado pela editora Springer, que trata do controle da expressão gênica de plantas de interesse agronômico, como o tomate.

Um dos editores é Juan Armando Casas-Mollano, que conduz no Instituto de Química (IQ) a pesquisa “Caracterização funcional de uma recentemente identificada família de MUT9 kinases in Arabidopsis thaliana e cana-de-açúcar”, com apoio da FAPESP na modalidade Jovem Pesquisador, no âmbito do Programa FAPESP de Pesquisa em Bioenergia (BIOEN).

“O livro reúne informações sobre plantas além das chamadas plantas modelo, como a Arabidopsis, amplamente utilizada em todas as áreas da ciência por ter um genoma pequeno e um ciclo de vida rápido e por ser de fácil manipulação”, disse Casas-Mollano.

A epigenética é o estudo de qualquer transformação na expressão de genes que ocorre sem haver mudança na sequência do DNA. Essas alterações, de ordem química, podem ocorrer na molécula de DNA e em proteínas chamadas histonas, podendo ser herdadas na divisão celular. O fenômeno tem alto impacto na biologia do organismo e na definição de diferentes fenótipos, isto é, da sua morfologia, do seu desenvolvimento e de aspectos do comportamento.

“O livro tem informações detalhadas sobre os mecanismos epigenéticos em plantas de importância agronômica. Essas informações podem trazer contribuições para o desenvolvimento de técnicas de manipulação, inibição ou ativação e seleção de proteínas e vias metabólicas, permitindo criar plantas resistentes a patógenos e a estresse ambiental, além de aumentar a produtividade”, afirmou Casas-Mollano.

O pesquisador é coautor do capítulo Histone H3 Phosphorylation in Plants and Other Organisms, com Izabel Moraes, também do IQ. O capítulo revisa e discute avanços mais recentes no estudo de fosforilação de proteínas histonas em plantas.

A fosforilação é a adição de um grupo fosfato a uma proteína ou a outra molécula, sendo um dos principais elementos nos mecanismos de regulação das proteínas, associada ao silenciamento gênico.

“Trata-se de ‘desligar’ a expressão de um gene por meio de mecanismos que não estejam relacionados à modificação de sua sequência gênica. Dessa forma, um gene que está sendo expresso, ou ‘ligado’, naturalmente é ‘desligado’, conforme a necessidade, por meio da fosforilação”, explicou Moraes.

A pesquisadora investiga no IQ o papel de determinados genes no controle do tempo de floração das plantas, fundamental para o sucesso da sua propagação, no projeto de pós-doutorado Compreendendo o papel das kinases MUT9 na regulação do tempo de floração em Arabidopsis thaliana, realizado com apoio da FAPESP e orientação de Casas-Mollano.

O livro conta ainda com um capítulo de autoria do também pesquisador da USP Fabio Tebaldi Silveira Nogueira, da Escola Superior de Agricultura Luiz de Queiroz (Esalq), que trata da epigenética do tomate. Nogueira conduz em Piracicaba a pesquisa Análise funcional do papel de microRNAs no controle da arquitetura vegetativa e desenvolvimento de frutos, com apoio da FAPESP.

Epigenetics in Plants of Agronomic Importance: Fundamentals and Applications – Transcriptional Regulation and Chromatin Remodelling in Plants
Editores: Raul Alvarez-Venegas, Clelia de la Peña, Juan Armando Casas-Mollano
Lançamento: 2014
Preço: US$ 149
Páginas: 152

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Do viruses make us smarter? (Science Daily)

Date: January 12, 2015

Source: Lund University

Summary: Inherited viruses that are millions of years old play an important role in building up the complex networks that characterize the human brain, researchers say. They have found that retroviruses seem to play a central role in the basic functions of the brain, more specifically in the regulation of which genes are to be expressed, and when.

Retroviruses seem to play a central role in the basic functions of the brain, more specifically in the regulation of which genes are to be expressed, and when, researchers say. Credit: © Sergey Bogdanov / Fotolia

A new study from Lund University in Sweden indicates that inherited viruses that are millions of years old play an important role in building up the complex networks that characterise the human brain.

Researchers have long been aware that endogenous retroviruses constitute around five per cent of our DNA. For many years, they were considered junk DNA of no real use, a side-effect of our evolutionary journey.

In the current study, Johan Jakobsson and his colleagues show that retroviruses seem to play a central role in the basic functions of the brain, more specifically in the regulation of which genes are to be expressed, and when. The findings indicate that, over the course of evolution, the viruses took an increasingly firm hold on the steering wheel in our cellular machinery. The reason the viruses are activated specifically in the brain is probably due to the fact that tumours cannot form in nerve cells, unlike in other tissues.

“We have been able to observe that these viruses are activated specifically in the brain cells and have an important regulatory role. We believe that the role of retroviruses can contribute to explaining why brain cells in particular are so dynamic and multifaceted in their function. It may also be the case that the viruses’ more or less complex functions in various species can help us to understand why we are so different,” says Johan Jakobsson, head of the research team for molecular neurogenetics at Lund University.

The article, based on studies of neural stem cells, shows that these cells use a particular molecular mechanism to control the activation processes of the retroviruses. The findings provide us with a complex insight into the innermost workings of the most basal functions of the nerve cells. At the same time, the results open up potential for new research paths concerning brain diseases linked to genetic factors.

“I believe that this can lead to new, exciting studies on the diseases of the brain. Currently, when we look for genetic factors linked to various diseases, we usually look for the genes we are familiar with, which make up a mere two per cent of the genome. Now we are opening up the possibility of looking at a much larger part of the genetic material which was previously considered unimportant. The image of the brain becomes more complex, but the area in which to search for errors linked to diseases with a genetic component, such as neurodegenerative diseases, psychiatric illness and brain tumours, also increases.”

Journal Reference:

  1. Liana Fasching, Adamandia Kapopoulou, Rohit Sachdeva, Rebecca Petri, Marie E. Jönsson, Christian Männe, Priscilla Turelli, Patric Jern, Florence Cammas, Didier Trono, Johan Jakobsson. TRIM28 Represses Transcription of Endogenous Retroviruses in Neural Progenitor CellsCell Reports, 2015; 10 (1): 20 DOI: 10.1016/j.celrep.2014.12.004


Transgenerational effects of prenatal exposure to the 1944–45 Dutch famine – BJOG: An International Journal of Obstetrics & Gynaecology

Volume 120, Issue 5, pages 548–554, April 2013

MVE Veenendaal et al.

DOI: 10.1111/1471-0528.12136

*   *  *

Mothers’ stress during 1998 ice storm shows up in children’s DNA, study says (Fox News)

Mothers' stress during 1998 ice storm shows up in children's DNA: study

File photo of the aftermath of an ice storm. (AP Photo/Matt Rourke)

Just how bad was an epic 1998 ice storm in Canada? You can read all about it in the DNA of kids who were born around that time.

An intriguing study in PLoS One finds that women who were especially stressed during the storm gave birth to kids whose immune cells have telltale signs of their mothers’ trouble, reports Raw Story.

The storm was brutal, leaving people without power for more than a month. Researchers at the time surveyed expectant moms to gauge their “objective” distress, measuring things such as how many days they went without electricity.

Then they tracked down their kids more than a decade later and found that moms who were in the most distress bore children whose DNA had specific markers as a result.

The genes affected are related to immune function and sugar metabolism. Toronto’s Globe and Mail has a nice explanation of what’s going on, with help from Suzanne King of McGill University.

It involves “epigenetics,” as opposed to genetics:

  • “An individual’s genetics are like a musical score, and what’s written comes from the mother and father. … Although nothing can change what’s written on the page, environmental factors act as an orchestral conductor might, amplifying some aspects and tempering others, leaving markings, or methylation of the DNA.”

This isn’t necessarily a bad thing.

A pregnant woman in a famine, for instance, might “amplify” traits that would give her child a better chance of surviving—traits that could then backfire in terms of health if the famine goes away.

It’s not clear what, if any, health effects the Canadian kids will see as a result, explains a post at McGill University. But given the genes affected, they might have a greater risk of developing asthma, diabetes, or obesity.

(You can blame your coffee craving on DNA, too.)

This article originally appeared on Newser: Moms’ Stress in Ice Storm Shows Up in Kids’ DNA

What gave us the advantage over extinct types of humans? (The Hebrew University of Jerusalem)


Jerry Barach

The answer lies in changes in the way our genes work

Jerusalem, April 22, 2014 — In parallel with modern man (Homo sapiens), there were other, extinct types of humans with whom we lived side by side, such as Neanderthals and the recently discovered Denisovans of Siberia. Yet only Homo sapiens survived. What was it in our genetic makeup that gave us the advantage?

The truth is that little is known about our unique genetic makeup as distinguished from our archaic cousins, and how it contributed to the fact that we are the only species among them to survive. Even less is known about our unique epigenetic makeup, but it is exactly such epigenetic changes that may have shaped our own species.

While genetics deals with the DNA sequence itself and the heritable changes in the DNA (mutations), epigenetics deals with heritable traits that are not caused by mutations. Rather, chemical modifications to the DNA can efficiently turn genes on and off without changing the sequence. This epigenetic regulatory layer controls where, when and how genes are activated, and is believed to be behind many of the differences between human groups.

Indeed, many epigenetic changes distinguish us from the Neanderthal and the Denisovan, researchers at the Hebrew University of Jerusalem and Europe have now shown.

In an article just published in Science, Dr. Liran Carmel, Prof. Eran Meshorer and David Gokhman of the Alexander Silberman Institute of Life sciences at the Hebrew University, along with scientists from Germany and Spain, have reconstructed, for the first time, the epigenome of the Neanderthal and the Denisovan. Then, by comparing this ancient epigenome with that of modern humans, they identified genes whose activity had changed only in our own species during our most recent evolution.

Among those genetic pattern changes, many are expressed in brain development. Numerous changes were also observed in the immune and cardiovascular systems, whereas the digestive system remained relatively unchanged.

On the negative side, the researchers found that many of the genes whose activity is unique to modern humans are linked to diseases like Alzheimer’s disease, autism and schizophrenia, suggesting that these recent changes in our brain may underlie some of the psychiatric disorders that are so common in humans today.

By reconstructing how genes were regulated in the Neanderthal and the Denisovan, the researchers provide the first insight into the evolution of gene regulation along the human lineage and open a window to a new field that allows the studying of gene regulation in species that went extinct hundreds of thousands of years ago.


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.

Mapping the Embryonic Epigenome: How Genes Are Turned On and Off During Early Human Development (Science Daily)

May 9, 2013 — A large, multi-institutional research team involved in the NIH Epigenome Roadmap Project has published a sweeping analysis in the current issue of the journal Cell of how genes are turned on and off to direct early human development. Led by Bing Ren of the Ludwig Institute for Cancer Research, Joseph Ecker of The Salk Institute for Biological Studies and James Thomson of the Morgridge Institute for Research, the scientists also describe novel genetic phenomena likely to play a pivotal role not only in the genesis of the embryo, but that of cancer as well. Their publicly available data, the result of more than four years of experimentation and analysis, will contribute significantly to virtually every subfield of the biomedical sciences.

After an egg has been fertilized, it divides repeatedly to give rise to every cell in the human body — from the patrolling immune cell to the pulsing neuron. Each functionally distinct generation of cells subsequently differentiates itself from its predecessors in the developing embryo by expressing only a selection of its full complement of genes, while actively suppressing others. “By applying large-scale genomics technologies,” explains Bing Ren, PhD, Ludwig Institute member and a professor in the Department of Cellular and Molecular Medicine at the UC San Diego School of Medicine, “we could explore how genes across the genome are turned on and off as embryonic cells and their descendant lineages choose their fates, determining which parts of the body they would generate.”

One way cells regulate their genes is by DNA methylation, in which a molecule known as a methyl group is tacked onto cytosine — one of the four DNA bases that write the genetic code. Another is through scores of unique chemical modifications to proteins known as histones, which form the scaffolding around which DNA winds in the nucleus of the cell. One such silencing modification, called H3K27me3, involves the highly specific addition of three methyl groups to a type of histone named H3. “People have generally not thought of these two ‘epigenetic’ modifications as being very different in terms of their function,” says Ren.

The current study puts an end to that notion. The researchers found in their analysis of those modifications across the genome — referred to, collectively, as the epigenome — that master genes that govern the regulation of early embryonic development tend largely to be switched off by H3K27me3 histone methylation. Meanwhile, those that orchestrate the later stages of cellular differentiation, when cells become increasingly committed to specific functions, are primarily silenced by DNA methylation.

“You can sort of glean the logic of animal development in this difference,” says Ren. “Histone methylation is relatively easy to reverse. But reversing DNA methylation is a complex process, one that requires more resources and is much more likely to result in potentially deleterious mutations. So it makes sense that histone methylation is largely used to silence master genes that may be needed at multiple points during development, while DNA methylation is mostly used to switch off genes at later stages, when cells have already been tailored to specific functions, and those genes are less likely to be needed again.”

The researchers also found that the human genome is peppered with more than 1,200 large regions that are consistently devoid of DNA methylation throughout development. It turns out that many of the genes considered master regulators of development are located in these regions, which the researchers call DNA methylation valleys (DMVs). Further, the team found that the DMVs are abnormally methylated in colon cancer cells. While it has long been known that aberrant DNA methylation plays an important role in various cancers, these results suggest that changes to the cell’s DNA methylation machinery itself may be a major step in the evolution of tumors.

Further, the researchers catalogued the regulation of DNA sequences known as enhancers, which, when activated, boost the expression of genes. They identified more than 103,000 possible enhancers and charted their activation and silencing in six cell types. Researchers will in all likelihood continue to sift through the data generated by this study for years to come, putting the epigenetic phenomena into biological context to investigate a variety of cellular functions and diseases.

“These data are going to be very useful to the scientific community in understanding the logic of early human development,” says Ren. “But I think our main contribution is the creation of a major information resource for biomedical research. Many complex diseases have their roots in early human development.”

Laboratories led by Michael Zhang, at the University of Texas, Dallas, and Wei Wang, at the University of California, La Jolla, contributed extensively to the computational analysis of data generated by the epigenetic mapping.

Journal Reference:

  1. Wei Xie, Matthew D. Schultz, Ryan Lister, Zhonggang Hou, Nisha Rajagopal, Pradipta Ray, John W. Whitaker, Shulan Tian, R. David Hawkins, Danny Leung, Hongbo Yang, Tao Wang, Ah Young Lee, Scott A. Swanson, Jiuchun Zhang, Yun Zhu, Audrey Kim, Joseph R. Nery, Mark A. Urich, Samantha Kuan, Chia-an Yen, Sarit Klugman, Pengzhi Yu, Kran Suknuntha, Nicholas E. Propson, Huaming Chen, Lee E. Edsall, Ulrich Wagner, Yan Li, Zhen Ye, Ashwinikumar Kulkarni, Zhenyu Xuan, Wen-Yu Chung, Neil C. Chi, Jessica E. Antosiewicz-Bourget, Igor Slukvin, Ron Stewart, Michael Q. Zhang, Wei Wang, James A. Thomson, Joseph R. Ecker, Bing Ren. Epigenomic Analysis of Multilineage Differentiation of Human Embryonic Stem CellsCell, 2013; DOI:10.1016/j.cell.2013.04.022

A ontogênese e o aprender (O Estado de São Paulo)

[A despeiro das boas intenções do autor, esse artigo é um retrocesso. Se acumulam evidências e contribuições da antropologia – ver Clifford Geertz, Tim Ingold, Bruno Latour, pra citar apenas alguns – em sentido oposto: desenvolvimento biológico e cultural estão relacionados diretamente; na genética, todo o campo da epigenética se desenvolve também na direção oposta. O discurso do artigo se funda mais em argumentos burocráticos, de organização do conhecimento e da atividade estatal de educação, do que numa discussão verdadeiramente ontológica. RT] 

JC e-mail 4703, de 11 de Abril de 2013.

Artigo de Fernando Reinach publicado no jornal O Estado de São Paulo

O uso da palavra aprender não acompanhou o progresso científico. O resultado é que ainda usamos a mesma palavra para descrever dois fenômenos distintos. Considere a seguinte frase: “Meu filho aprendeu a andar com 1 ano e aprendeu a escrever com 6”. Esses dois processos, descritos como “aprender”, são fenômenos muito diferentes. Não reconhecer essa diferença atrapalha nossa concepção de educação.

Todas as pessoas, de qualquer origem, nascidas em qualquer sociedade nos últimos milhares de séculos, começaram a andar na infância. Por outro lado, somente uma pequena fração das pessoas sabe escrever – e essa capacidade apareceu entre os humanos faz alguns milhares de anos. A razão é simples e conhecida dos biólogos há muito tempo. Andar faz parte de nossa ontogênese; escrever faz parte de nossa herança cultural.

Ontogênese é o nome dado ao processo de formação de um ser vivo. Descreve a transformação de uma semente em árvore ou o surgimento de uma pessoa a partir de um óvulo fecundado. Inicialmente, o conceito de ontogênese era usado para descrever as mudanças de forma durante o desenvolvimento de um ser vivo. Descrevia a formação da espinha vertebral, do coração, o aparecimento dos dedos, o crescimento do cabelo, e todas as mudanças que ocorrem antes do nascimento. Mas o processo de ontogênese continua após o nascimento. O corpo cresce, atingimos a maturidade sexual, paramos de crescer e finalmente começamos a envelhecer. São as etapas inevitáveis de nossa ontogênese.

A ontogênese se caracteriza por uma sequência de eventos que ocorrem de maneira precisa e semelhante em todos os seres vivos de uma espécie. Ela é determinada por nossos genes e modulada pelo meio ambiente. Todas as crianças crescem, mas, se bem alimentadas, crescem mais rápido.

Não é usual utilizarmos a palavra aprender para descrever processos que fazem parte da ontogênese. É por isso que afirmar que “minha filha aprendeu a menstruar aos 13 anos” soa estranho. Ao longo de todo o século XX houve uma melhor compreensão dos processos que fazem parte de nossa ontogênese e se descobriu que um número crescente de etapas pelas quais passamos durante a vida é parte de nossa ontogênese.

É o caso do andar e do falar, cujos aparecimentos estão codificados em nossos genes da mesma maneira que a capacidade de crescer pelos pubianos. É muito difícil, e é necessário um ambiente muito hostil, para evitar que uma criança desenvolva o andar e a capacidade de falar. No caso da fala, sabemos que a língua que a pessoa vai utilizar depende unicamente do ambiente ao qual ela está exposta, mas o surgimento, nos primeiros anos, da capacidade de falar alguma língua faz parte de nossa ontogênese.

Aos poucos, os cientistas descobriram que um número crescente de características que desenvolvemos em alguma fase de nossa vida faz parte de nossa ontogenia. Hoje sabemos que nascemos com a capacidade de fazer adições e subtrações de pequenos números (até três ou quatro). Sabemos que parte de nossa capacidade de julgamento moral, de convivência social, de comunicação por meio de expressões faciais e inúmeras outras características comportamentais também fazem parte de nosso processo ontogenético.

Nossa ontogênese surgiu à medida que nossa espécie e a de nossos ancestrais foi moldada pelo processo de seleção natural. Cada etapa e cada característica de nossa ontogênese foram incorporadas ao longo de milhões de anos e agora fazem parte das características de nossa espécie. O surgimento de um dedo durante nossa vida no útero e de nossa capacidade de somar números pequenos ao nascer é o resultado de um único e longo processo de seleção natural. É por isso que essas capacidades surgem aparentemente de forma espontânea durante as diferentes fases de nossa vida. Como são programadas para ocorrer, seu aparecimento é difícil de ser evitado e, caso seu aparecimento seja inibidos violentamente, as consequências podem ser nefastas para o indivíduo.

A distinção entre esses dois fenômenos seria mais fácil se a palavra aprender fosse restrita à aquisição de novas características e habilidades que não fazem parte de nosso processo ontogenético. Fazer operações matemáticas com números grandes, escrever, andar de bicicleta, calcular a órbita de um satélite e programar um computador são capacidades que podemos adquirir porque nosso corpo e cérebro têm a flexibilidade para incorporar novos comportamentos e conhecimentos, mas não foram moldadas pela seleção natural nem incorporadas à nossa ontogênese.

Essas habilidades foram descobertas muito recentemente pelo homem e derivam da evolução cultural. Esses aprendizados podem ser incluídos no repertório de cada um de nós de maneira opcional, num processo que chamamos de educação. E, como todos sabemos, sua incorporação depende de um grande esforço e dedicação de quem ensina e de quem aprende, leva um longo tempo e consome muita energia dos indivíduos e da sociedade.

Reconhecer as mudanças que fazem parte de nossa ontogênese e separar e cultivar de maneira distinta as mudanças ontogenéticas das induzidas pelo processo educacional podem gerar seres humanos mais felizes. Mas para isso não podemos confundir os dois fenômenos que hoje chamamos de “aprender”.

Fernando Reinach é biólogo.

Gene Today, Gone Tomorrow: Genes for Autism and Schizophrenia Only Active in Developing Brains (Science Daily)

Feb. 11, 2013 — Genes linked to autism and schizophrenia are only switched on during the early stages of brain development, according to a study in mice led by researchers at the University of Oxford.

This new study adds to the evidence that autism and schizophrenia are neurodevelopmental disorders, a term describing conditions that originate during early brain development.

The researchers studied gene expression in the brains of mice throughout their development, from 15-day old embryos to adults, and their results are published recently inProceedings of the National Academy of Sciences.

The study is a collaboration between researchers from the University of Oxford, King’s College London and Imperial College London, and was funded by the Medical Research Council and the Wellcome Trust.

The research focused on cells in the ‘subplate’, a region of the brain where the first neurons (nerve cells) develop. Subplate neurons are essential to brain development, and provide the earliest connections within the brain.

‘The subplate provides the scaffolding required for a brain to grow, so is important to consider when studying brain development,’ says Professor Zoltán Molnár, senior author of the paper from the University of Oxford, ‘Looking at the pyramids in Egypt today doesn’t tell us how they were actually built. Studying adult brains is like looking at the pyramids today, but by studying the developing brains we are able to see the transient scaffolding that has been used to construct it.’

The study shows that certain genes linked to autism and schizophrenia are only active in the subplate during specific stages of development. ‘The majority of the autism susceptibility genes are only expressed in the subplate of the developing mouse brain,’ explains Dr Anna Hoerder-Suabedissen, who led the study at the University of Oxford, ‘Many can only be found at certain stages of development, making them difficult to identify at later stages using previous techniques.’

The group were able to map gene activity in full detail thanks to powerful new methods which allowed them to dissect and profile gene expression from small numbers of cells. This also enabled them to identify the different populations of subplate neurons more accurately.

Subplate neurons were first discovered in the 1970s by Professors Ivica Kostović and Pasko Rakic of Yale University.

‘I am excited to see tangible genetic links supporting, even indirectly, the idea of a possible role of the transient embryonic subplate zone in the origin of disorders such as autism and schizophrenia,’ says Professor Rakic, ‘If this is possible to show in mice, where the subplate is relatively small, it is likely to be even more pronounced in humans, where it is much more evolved.

‘The study from Professor Molnár’s group at Oxford may be the first step toward finding more such links in the future and opens the possibility of directly examining the roles of genetic variation and exposure to various environmental factors in animal models.’

Professor David Edwards, Director of the Centre for the Developing Brain at King’s College London, and co-author of the paper, said: ‘Using advanced techniques we have been able to define the biochemical pathways that are important during a particular phase of brain developme

nt. It has been suspected for a long time that if the development of the cortex is disrupted by genetic abnormalities or environmental stress (such as prematurity) this would have long-lasting adverse effects on brain development and could lead to problems like ADHD or autism. This study defines genes that are important in mice at this critical period and this does indeed seem to include genes known to predispose to autism and schizophrenia. It focuses attention even more firmly on early brain development as a cause of these distressing neuropsychological problems.’

Professor Hugh Perry, chair of the Medical Research Council’s Neuroscience and Mental Health Board, said: ‘By being able to pinpoint common genetic factors for neurological conditions such as autism and schizophrenia, scientists are able to understand an important part of the story as to why things go awry as our brains develop. The Medical Research Council’s commitment to a broad portfolio of neuroscience and mental health research places us in a unique position to respond to the challenge of mental ill health and its relationship with physical health and wellbeing.’

Epigenetics Shapes Fate of Brain Vs. Brawn Castes in Carpenter Ants (Science Daily)

Feb. 13, 2013 — The recently published genome sequences of seven well-studied ant species are opening up new vistas for biology and medicine. A detailed look at molecular mechanisms that underlie the complex behavioral differences in two worker castes in the Florida carpenter ant, Camponotus floridanus, has revealed a link to epigenetics. This is the study of how the expression or suppression of particular genes by chemical modifications affects an organism’s physical characteristics, development, and behavior. Epigenetic processes not only play a significant role in many diseases, but are also involved in longevity and aging.

Florida carpenter ants – minor (left) and major (right). (Credit: Courtesy Brittany Enzmann, Arizona State University)

Interdisciplinary research led by Shelley Berger, PhD, from the Perelman School of Medicine at the University of Pennsylvania, in collaboration with teams led by Danny Reinberg from New York University and Juergen Liebig from Arizona State University, describe their work in Genome Research. The group found that epigenetic regulation is key to distinguishing one caste, the “majors,” as brawny Amazons of the carpenter ant colony, compared to the “minors,” their smaller, brainier sisters. These two castes have the same genes, but strikingly distinct behaviors and shape.

Ants, as well as termites and some bees and wasps, are eusocial species that organize themselves into rigid caste-based societies, or colonies, in which only one queen and a small contingent of male ants are usually fertile and reproduce. The rest of a colony is composed of functionally sterile females that are divided into worker castes that perform specialized roles such as foragers, soldiers, and caretakers. InCamponotus floridanus, there are two worker castes that are physically and behaviorally different, yet genetically very similar.

Lead author Daniel F. Simola, PhD, a postdoctoral researcher in the Penn Department of Cell and Developmental Biology, explains that “the major is also called a soldier, and it has a much larger head, so the force of its mandibles can break larger prey. It does more nest and colony defense.”

The minor caste, on the other hand, is smaller and more numerous. “They do most of the nursing within a colony, take care of the young, and they will also go out and collect most of the food,” says Simola. “On average, 75 to 80 percent of the foraging activity is done by the minors.” The minor also has a considerably shorter lifespan than the major caste, making the ant castes a good model for longevity studies as well as behavioral studies.

But how do such marked differences arise when both the major and the minor castes share the same genome? “For all intents and purposes, those two castes are identical when it comes to their gene sequences,” notes senior author Berger, professor of Cell and Developmental Biology. “The two castes are a perfect situation to understand how epigenetics, how regulation ‘above’ genes, plays a role in establishing these dramatic differences in a whole organism.”

To understand how caste differences arise, the team examined the role of modifications of histones (protein complexes around which DNA strands are wrapped in a cell’s nucleus) throughout the Camponotus floridanus genome, producing the first genome-wide epigenetic maps of genome structure in a social insect. Histones can be altered by the addition of small chemical groups, which affect the expression of genes. Therefore, specific histone modifications can create dramatic differences between genetically similar individuals, such as the physical and behavioral differences between ant castes.

“These chemical modifications of histones alter how compact the genome is in a certain region,” Simola explains. “Certain modifications allow DNA to open up more, and some of them to close DNA more. This, in turn, affects how genes get expressed, or turned on, to make proteins. These modifications establish specific features of different tissues within an individual, so we asked whether there are also overall differences in histone modifications between the brawny majors and the brainy minors that might alter specific features of the whole organism, such as behavior.”

In examining several different histone modifications, the team found a number of distinct differences between the major and minor castes. Simola states that the most notable modification, “both discriminates the two castes from each other and correlates well with the expression levels of different genes between the castes. And if you look at which genes are being expressed between these two castes, these genes correspond very nicely to the brainy versus brawny idea. In the majors we find that genes that are involved in muscle development are expressed at a higher level, whereas in the minors, many genes involved in brain development and neurotransmission are expressed at a higher level.”

These changes in histone modifications between ant castes are likely caused by a regulator gene, called CBP, that has “already been implicated in aspects of learning and behavior by genetic studies in mice and in certain human diseases,” Berger says. “The idea is that the same CBP regulator and histone modification are involved in a learned behavior in ants — foraging — mainly in the brainy minor caste, to establish a pattern of gene regulation that leads to neuronal patterning for figuring out where food is and being able to bring the food back to the nest.”

Simola notes that “we know from mouse studies that if you inactivate or delete the CBP regulator, it actually leads to significant learning deficits in addition to craniofacial muscular malformations. So from mammalian studies, it’s clear this is an important protein involved in learning and memory.”

These findings have established the crucial role of genome structure in general, and histone modifications in particular, in determining the acquisition of organism-level characteristics in ant castes. The research team is looking ahead to expand the work by manipulating the expression of the CBP regulator in ants to observe effects on caste development and behavior. They also hope to refine the technique of mapping histone modifications so that specific tissues, such as a brain from a single ant, can be analyzed, rather than using pooled samples, as in the current study.

Berger observes that all of the genes known to be major epigenetic regulators in mammals are conserved in ants, which makes them “a fantastic model for studying behavior and longevity. Ants provide an extraordinary opportunity to explore and understand the epigenetic processes that underlie many human diseases and the aging process.”

Berger is also the director of the Penn Epigenetics Program. The research was supported by a Howard Hughes Medical Institute Collaborative Innovation Award, a postdoctoral training grant from the Penn Department of Cell and Developmental Biology, and a postdoctoral fellowship from the Helen Hay Whitney Foundation.

Journal Reference:

  1. D. F. Simola, C. Ye, N. S. Mutti, K. Dolezal, R. Bonasio, J. Liebig, D. Reinberg, S. L. Berger. A chromatin link to caste identity in the carpenter ant Camponotus floridanusGenome Research, 2012; DOI:10.1101/gr.148361.112

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.

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.”