End the Hype over Epigenetics & Lamarckian Evolution                   

Alex B. Berezow, 03/31/14

You might recall from high school biology a scientist by the name of Jean-Baptiste Lamarck. He proposed a mechanism of evolution in which organisms pass on traits acquired during their lifetimes to their offspring. The textbook example is a proposed mechanism of giraffe evolution: If a giraffe stretches its neck to reach higher leaves on a tree, the giraffe would pass on a slightly longer neck to its offspring.

Lamarck's proposed mechanism of evolution was tested by August Weismann. He cut off the tails of mice and bred them. If Lamarck was correct, then the next generation of mice should be born without tails. Alas, the offspring had tails. Lamarck's theory therefore died and remained largely forgotten for over 100 years.

However, some scientists believe that new data may at least partially resurrect Lamarckian thinking. This recent resurgence is due to a new field called epigenetics. Unlike regular genetics, which studies changes in the sequence of the DNA letters (A, T, C, and G) that make up our genes, epigenetics examines small chemical tags placed on those letters. Environmental factors play an enormous role in determining where and when the tags are placed. This is a big deal because these chemical tags help determine whether or not a gene is turned "on" or "off." In other words, the environment can influence the presence of epigenetic tags, which in turn can influence gene expression.

That finding is certainly intriguing, but it isn't revolutionary. We've long known that the environment affects gene expression.

But, what is potentially revolutionary is the discovery that these epigenetic tags, in some organisms, can be passed on to the next generation. That means that environmental factors may not only affect gene expression in parents, but in their yet-to-be-born children (and possibly grandchildren), as well.

Yikes. Does that mean Lamarck was right? That question was addressed by Edith Heard and Robert Martienssen in a detailed review in the journal Cell.

Of particular concern is the idea that mammalian health can be affected by epigenetic tags received from parents or grandparents. For example, one group reported that pre-diabetic mice have different epigenetic tag patterns in their sperm and that their offspring have a higher chance of contracting diabetes. (Virginia Hughes has written an excellent article summarizing this and other related epigenetic studies.) A flurry of other biomedical and epidemiological research has strongly hinted that a susceptibility to obesity, diabetes, and heart disease can be passed on through epigenetic tags.

However, Heard & Martienssen are not convinced. In their Cell review, they admit that epigenetic inheritance has been demonstrated in plants and worms. But, mammals are completely different beasts, so to speak. Mammals go through two rounds of epigenetic "reprogramming" -- once after fertilization and again during the formation of gametes (sex cells) -- in which most of the chemical tags are wiped clean.

They insist that characteristics many researchers assume to be the result of epigenetic inheritance are actually caused by something else. The authors list four possibilities: Undetected mutations in the letters of the DNA sequence, behavioral changes (which themselves can trigger epigenetic tags), alterations in the microbiome, or transmission of metabolites from one generation to the next. The authors claim that most epigenetic research, particularly when it involves human health, fails to eliminate these possibilities.

It is true that environmental factors can influence epigenetic tags in children and developing fetuses in utero. What is far less clear, however, is whether or not these modifications truly are passed on to multiple generations. Even if we assume that epigenetic tags can be transmitted to children or even grandchildren, it is very unlikely that they are passed on to great-grandchildren and subsequent generations. The mammalian epigenetic "reprogramming" mechanisms are simply too robust.

Therefore, be very skeptical of studies which claim to have detected health effects due to epigenetic inheritance. The hype may soon fade, and the concept of Lamarckian evolution may once again return to the grave.

Source: Edith Heard and Robert Martienssen. "Transgenerational Epigenetic Inheritance: Myths and Mechanisms." Cell 157 (1): 95–109. (2014). DOI: http://dx.doi.org/10.1016/j.cell.2014.02.045

http://www.realclearscience.com/blog/2014/03/end_the_hype_over_epigenetics__lamarckian_evolution.html

Evolution, You’re Drunk

DNA studies topple the ladder of complexity.

Amy Maxmen, 01/30/14

Amoebas are puny, stupid blobs, so scientists were surprised to learn that they contain 200 times more DNA than Einstein did. Because amoebas are made of just one cell, researchers assumed they would be simpler than humans genetically. Plus, amoebas date back farther in time than humans, and simplicity is considered an attribute of primitive beings. It just didn’t make sense.

The idea of directionality in nature, a gradient from simple to complex, began with the Greeks, who called nature physis, meaning growth. That idea subtly extended from changes over an organism’s lifetime, to changes over evolutionary time after Charles Darwin argued that all animals descend from a single common ancestor. When his contemporaries drew evolutionary trees of life, they assumed increasing complexity. Worms originated early in animal evolution. Creatures with more complex structures originated later. Biologists tweaked evolutionary trees over the following century, but generally, simple organisms continued to precede the complex.

Take the textbook scenario on early animal evolution. It essentially goes as follows:

Single-celled organisms gained the ability to adhere to and communicate with one another more than 600 million years ago, and from the resulting colonies, the first multicellular animals emerged. Today’s sponges, sedentary animals on the sea floor with no guts, brains, or tissue layers, descend directly from some of these creatures. Some early animals then organized their cells into distinct tissue layers, and some of the cells formed nerve cells, muscle cells, and other types. Later yet, some animals developed serially repeated segments that served as a platform for legs and claws in their descendants. Then an animal with a spinal column evolved, and then one with a column surrounded by bony vertebrae. A recent branch to split from the tree blossomed into humans.

Scientists’ belief in this scenario has remained relatively unchanged for a century. It reflects the growth we observe during an organism’s development, and it’s been tracked over evolutionary time, too. Paleontologists have found fossils to support this arrangement, and they’ve also quantified increasing complexity within animal lineages. For example, an analysis of the waves, or sutures, in shells of extinct mollusks called ammonoids -- snail-like sisters to nautiluses -- shows that their designs became eight times as complex over 108 million years.¹

Before the advent of rapid, accurate, and inexpensive DNA sequencing technology in the early 2000s, biologists guessed that genes would provide more evidence for increasing complexity in evolution. Simple, early organisms would have fewer genes than complex ones, they predicted, just as a blueprint of Dorothy’s cottage in Kansas would be less complicated than one for the Emerald City. Instead, their assumptions of increasing complexity began to fall apart. First to go was an easy definition of how complexity manifested itself. After all, amoebas had huge genomes. Now, DNA analyses are rearranging evolutionary trees, suggesting that the arrow scientists envisioned between simplicity and complexity actually spins like a weather vane caught in a tornado.

After genome sizes failed to fit notions of simplicity and complexity, researchers hypothesized that gene number -- genes being the sections of the genome that encode proteins -- might instead reflect them. For a few years, that seemed about right. Humans have about 22,000 genes while the mosquito Anopheles gambiae has about 14,000. Then, in 2007, an international team of researchers sequenced the genome of the plant-like sea anemones, marine creatures that lack muscles, heads, rear-ends, and brains. To their surprise, anemones had more genes than insects, including some genes that humans possess but flies do not. Even more perplexing: Sea anemones evolved before flies and humans, some 560 million years ago. That meant animals might have been genetically complex from the start. “When I was younger, and we knew less, we thought that organisms gained genes over millions of years and that the earliest animals were genetically very simple,” says Bill Pearson, a computational biologist at the University of Virginia who developed some of the first techniques to compare protein sequences among organisms. “We think that less now,” he adds.

Then molecular analyses did something else. They rearranged the order of branches on evolutionary trees. Biologists pushed aside trees based on how similar organisms looked to one another, and made new ones based on similarities in DNA and protein sequences. The results suggested that complex body parts evolved multiple times and had also been lost. One study found that winged stick insects evolved from wingless stick insects who had winged ancestors.² Another analysis suggested that extremely simple animals called acoel worms -- a quarter inch long and with just one hole for eating and excreting -- evolved from an ancestor with a separate mouth and anus.³ Biologists’ arrow of time swung forward and backward and forward again.

Late last year, the animal evolutionary tree quaked at its root. A team led by Joseph Ryan, an evolutionary biologist who splits his time between the National Genome Research Institute in Bethesda, Md. and the Sars International Center for Marine Molecular Biology in Bergen, Norway, analyzed the genome from a comb jelly, Mnemiopsis leidyi, a complex marine predator with muscles, nerves, a rudimentary brain, and bioluminescence, and found that the animals may have originated before simple sponges, which lack all of those features.⁴

If comb jellies evolved before sponges, the sponges might have lost the complexity that the ancestor uniting them and comb jellies possessed. Or, that ancestor -- the ancestor of all living animals -- had the genes to build brains and muscles, but did not form those parts, and neither did sponges. If this is true, then comb jellies deployed the genome they inherited to build a brain, nervous system, and muscles, independent of other animals. There’s some support for this possibility: A unique set of genes seems to underlie comb jellies’ muscles.

Both hypotheses run counter to scenarios in which organisms evolve to be increasingly complex. In one, a complex nervous system and muscles were lost in the sponges. In the other, the sponges had the genetic capability for complex features but stayed simple, while a more primitive group, the comb jellies, acquired brains and muscles that help them chase down prey. Furthermore, the idea that complex parts like a brain and nervous system -- including nerve cells, synapses, and neurotransmitter molecules -- could evolve separately multiple times perplexes evolutionary biologists because parts are gained one at a time. The chance of the same progression happening twice in separate lineages seems unlikely -- or so biologists thought. “Traditional views are based on our dependence on our nervous system,” says Ryan. “We think the nervous system is the greatest thing in the world so how could anything lose it,” he says. “Or, it’s the greatest thing in the world, so how could it happen twice.”

http://nautil.us/issue/9/time/evolution-youre-drunk

Die, selfish gene, die  

That much was clear by 1935. Naturally, some kinks remained, but more math-friendly biologists soon straightened those out. This took most of the middle part of the 20th century. Biologists now call this decades-long project the modern evolutionary synthesis. And it was all about maths.

The most vital calculations were run in the 1930s, when Ronald Fisher, J B S Haldane and Sewall Wright, two brilliant Brits and an American working more or less separately, worked out two key problems.

The first was how Mendel’s rather binary genetic model could create not just binary differences such as smooth versus wrinkled peas but the gradual evolutionary change of the sort that Darwin described. Fisher, Haldane and Wright, working the complicated maths of how multiple genes interacted through time in a large population, showed that significant evolutionary change revealed itself as many small changes yielded a large effect, just as a series of small nested equations within a long algebra equation could.

The second kink was tougher. If organisms prospered by out-competing others, why did humans and some other animals help one another? This might seem a non-mathy problem. Yet Fisher, Haldane and Wright solved it too with maths, devising formulas quantifying precisely how altruism could be selected for. Some animals act generously, they explained, because doing so can aid others, such as their children, parents, siblings, cousins, grandchildren, or tribal mates, who share or might share some of their genes. The closer the kin, the kinder the behaviour. Thus, as Haldane once said, ‘I would lay down my life for two brothers or eight cousins.’

Thus maths reconciled Mendel and Darwin and made modern genetics and evolutionary theory a coherent whole. Watson and Crick’s 1953 discovery of the structure of DNA simply iced the cake: now we knew the structure that performed the maths.

Finally, in the early 1960s, yet another Brit named William Hamilton (a funny statistician with a shaggy haircut) and an American named George Williams (kind and whipsmart, with an abominable haircut and beard) upped the ante on the gene’s primacy: with fancy maths, they argued that we should view any organism, including any human, as merely a sort of courier for genes and their traits. This flipped the usual thinking. It made the gene vital and the organism expendable. Our genes did not exist for us. We existed for them. We served only to carry these chemical codes forward through time, like those messengers in old sword-and-sandal war movies who run non-stop for days to deliver data and then drop dead. A radical idea. Yet it merely extended the logic of kin selection, in which any gene-courier -- say, a mom watching her children’s canoe overturn -- would risk her life to let her kin carry forth her DNA.

This notion of the gene as the unit selected, and the organism as a kludged-up cart for carrying it through time, placed the gene smack at the centre of things. It granted the gene something like agency.

At first, not even many academics paid this any heed. This might be partly because people resist seeing themselves as donkey carts. Another reason was that neither Hamilton nor Williams were masterly communicators.

But 15 years after Hamilton and Williams kited this idea, it was embraced and polished into gleaming form by one of the best communicators science has ever produced: the biologist Richard Dawkins. In his magnificent book The Selfish Gene (1976), Dawkins gathered all the threads of the modern synthesis -- Mendel, Fisher, Haldane, Wright, Watson, Crick, Hamilton, and Williams -- into a single shimmering magic carpet.

These days, Dawkins makes the news so often for buffoonery that some might wonder how he ever became so celebrated. The Selfish Gene is how. To read this book is to be amazed, entertained, transported. For instance, when Dawkins describes how life might have begun -- how a randomly generated strand of chemicals pulled from the ether could happen to become a ‘replicator’, a little machine that starts to build other strands like itself, and then generates organisms to carry it -- he creates one of the most thrilling stretches of explanatory writing ever penned. It’s breathtaking.

Dawkins assembles genetics’ dry materials and abstract maths into a rich but orderly landscape through which he guides you with grace, charm, urbanity, and humour. He replicates in prose the process he describes. He gives agency to chemical chains, logic to confounding behaviour. He takes an impossibly complex idea and makes it almost impossible to misunderstand. He reveals the gene as not just the centre of the cell but the centre of all life, agency, and behaviour. By the time you’ve finished his book, or well before that, Dawkins has made of the tiny gene -- this replicator, this strip of chemicals little more than an abstraction -- a huge, relentlessly turning gearwheel of steel, its teeth driving smaller cogs to make all of life happen. It’s a gorgeous argument. Along with its beauty and other advantageous traits, it is amenable to maths and, at its core, wonderfully simple.

Unfortunately, say Wray, West-Eberhard and others, it’s wrong.

Wray and West-Eberhard don’t say that Dawkins is dead wrong. They and other evolutionary theorists -- such as Massimo Pigliucci, professor of philosophy at the City University of New York; Eva Jablonka, professor of mathematics education at King’s College, London; Stuart Kauffman, professor of biochemistry and mathematics at the University of Vermont; Stuart A Newman, professor of cell biology and anatomy at the New York Medical College; and the late Stephen Jay Gould, to name a few -- have been calling for an ‘extended modern synthesis’ for more than two decades. They do so even though they agree with most of what Dawkins says a gene does. They agree, in essence, that the gene is a big cog, but would argue that the biggest cog doesn’t necessarily always drive the other cogs. In many cases, they drive it. The gene, in short, just happens to be the biggest, most obvious part of the trait-making inheritance and evolutionary machine. But not the driver.

Another way to put it: Mendel stumbled over the wrong chunk of gold.

Mendel ran experiments that happened to reveal strong single-gene dynamics whose effects -- flower colour, skin texture -- can seem far more significant than they really are. Many plant experiments since then, for instance, have shown that environmental factors such as temperature changes can spur gene-expression changes that alter a plant far more than Mendel’s gene variants do. As with grasshoppers, a new environment can quickly turn a plant into something almost unrecognisable from its original form. If Mendel had owned a DNA microarray machine and was in the habit of tracking gene expression changes, he might have spotted these. But microarray machines didn’t exist, so he crossed plants instead, and saw just one particularly obvious way that an organism can change.

The gene-centric view is thus ‘an artefact of history’, says Michael Eisen, an evolutionary biologist who researches fruit flies at the University of California, Berkeley. ‘It rose simply because it was easier to identify individual genes as something that shaped evolution. But that’s about opportunity and convenience rather than accuracy. People confuse the fact that we can more easily study it with the idea that it’s more important.’

The gene’s power to create traits, says Eisen, is just one of many evolutionary mechanisms. ‘Evolution is not even that simple. Anyone who’s worked on systems sees that natural selection takes advantage of the most bizarre aspects of biology. When something has so many parts, evolution will act on all of them.

‘It’s not that genes don’t sometimes drive evolutionary change. It’s that this mutational model -- a gene changes, therefore the organism changes -- is just one way to get the job done. Other ways may actually do more.’

Like what other ways?

There are several, but one called genetic accommodation is, according to West-Eberhard, particularly powerful and overlooked.

In the social wasps that West-Eberhard has been studying in Costa Rica since 1979, many of the most important distinctions among a colony’s individuals rise not from differences in their genomes, which vary little, but from the plasticity born of gene expression. This starts with the queen, who is genetically identical to her thousands of sisters yet whose gene expression makes her not only larger, but singles her out as the colony’s reproductive unit. Likewise with most honeybees. In social honeybees, the differences between workers, guards, and scouts all arise from gene expression, not gene sequence. Individual bees morph from one form to another -- worker to guard to scout -- by gene expression alone, depending on the needs of the hive.

Like Wray, Pigliucci and others, West-Eberhard has long tried to rescue the centrality of gene expression from the ‘cyclic amnesia’ that she says has ignored 150 years of evidence that gene selection’s role in evolution is overplayed. West-Eberhard is a particularly articulate advocate. Yet she’s frustrated at how little she’s been able to change things.

As a David to Dawkins’s Goliath, West-Eberhard faces distinct challenges. For starters, she’s a she while Dawkins is a he, which should not matter but does. And while Dawkins holds forth from Oxford, one of the most prestigious universities on earth, and deploys from London an entire foundation in his name, West-Eberhard studies and writes from a remote outpost in Central America. Dawkins commands locust-sized audiences any time he speaks and probably turns down enough speaking engagements to fill five calendars; West-Eberhard speaks mainly to insect-crazed colleagues at small conferences. Dawkins wrote a delicious 300-page book that has sold tens of millions of copies; West-Eberhard has written a bunch of fine obscure papers and an 800-page tome, Developmental Plasticity and Evolution (2003), which, though not without its sweet parts, is generally consumed as a meal of obligation.

She does have her pithy moments. ‘The gene does not lead,’ she says. ‘It follows.’

There lies the quick beating heart of her argument: the gene follows. And one of the ways the gene follows is through this process called genetic accommodation. Genetic accommodation is a clunky term for a graceful process. It takes a moment to explain. But bear with me a moment, and you’ll understand how you, dear reader, could evolve into a fast and deadly predator.

Genetic accommodation involves a three-step process.

First, an organism (or a bunch of organisms, a population) changes its functional form -- its phenotype -- by making broad changes in gene expression.

Second, a gene emerges that happens to help lock in that change in phenotype.

Third, the gene spreads through the population.

For example, suppose you’re a predator. You live with others of your ilk in dense forest. Your kind hunts by stealth: you hide among trees, then jump out and snag your meat. You needn’t be fast, just quick and sneaky.

Then a big event -- maybe a forest fire, or a plague that kills all your normal prey -- forces you into a new environment. This new place is more open, which nixes your jump-and-grab tactic, but it contains plump, juicy animals, the slowest of which you can outrun if you sprint hard. You start running down these critters. As you do, certain genes ramp up expression to build more muscle and fire the muscles more quickly. You get faster. You’re becoming a different animal. You mate with another fast hunter, and your kids, hunting with you from early on, soon run faster than you ever did. Via gene expression, they develop leaner torsos and more muscular, powerful legs. By the time your grandchildren show up, they seem almost like different animals: stronger legs, leaner torsos, and they run way faster than you ever did. And all this has happened without taking on any new genes.

Then a mutation occurs in one grandkid. This mutation happens to create stronger, faster muscle fibres. This grandchild of yours can naturally and easily run faster than her fastest siblings and cousins. She flies. Her children inherit the gene, and because their speed wows their mating prospects, they mate early and often, and bear lots of kids. Through the generations, this sprinter’s gene thus spreads through the population.

Now the thing is complete. Your descendants have a new gene that helps secure the adaptive trait you originally developed through gene expression alone. But the new gene didn’t create the new trait. It just made it easier to keep a trait that a change in the environment made valuable. The gene didn’t drive the train; it merely hopped aboard. Had the gene showed up earlier (either through mutation or mating with an outsider), back when you lived in the forest and speed didn’t mean anything, it would have given no advantage. Instead of being selected for and spreading, the gene would have disappeared or remained in just a few animals. But because the gene was now of value, the population took it in, accommodated it, and spread it wide.

This isn’t the gene-centric world in which genotype creates phenotype. It’s a phenotype accommodating a new genotype by making it relevant.

Gene Robinson, an entomologist who studies honeybees at the University of Illinois, says genetic accommodation probably helped to create African honeybees, the ‘killer bee’ subspecies that is genetically distinct from the sweeter European honeybees that most beekeepers keep. Honeybee hives in certain parts of Africa, he says, were and are raided by predators more often than hives elsewhere, so their inhabitants had to react more sharply to attacks. This encouraged gene-expression changes that made the African bees respond more aggressively to threat. When new genes showed up that reinforced this aggression, those genes would have been selected for and spread through the population. This, Robinson says, is quite likely how African bees became genetically distinct from their European honeybee cousins. And they’d have been led there not by a gene, but by gene expression.

After several weeks of reading and talking to this phenotypic plasticity crowd, I phoned Richard Dawkins to see what he thought of all this. Did genes follow rather than lead? I asked him specifically about whether processes such as gene accommodation might lead instead. Then he did something so slick and wonderful I didn’t quite realise what he’d done till after we hung up: he dismissed genetic accommodation… by accommodating it. Specifically, he said that genetic accommodation doesn’t really change anything, because since the gene ends up locking in the change and carrying it forward, it all comes back to the gene anyway.

‘This doesn’t modify the gene-centric model at all,’ he said. ‘The gene-centric model is all about the gene being the unit in the hierarchy of life that is selected. That remains the gene.’

‘He’s backfilling,’ said West-Eberhard. ‘He and others have long been arguing for the primacy of an individual gene that creates a trait that either survives or doesn’t.’

Yet West-Eberhard understands why many biologists stick to the gene-centric model. ‘It makes it easier to explain evolution,’ she says. ‘I’ve seen people who work in gene expression who understand all of this. But when they get asked about evolution, they go straight to Mendel. Because people understand it more easily.’ It’s easy to see why: even though life is a zillion bits of biology repeatedly rearranging themselves in a webwork of constantly modulated feedback loops, the selfish-gene model offers a step-by-step account as neat as a three-step flow chart. Gene, trait, phenotype, done.

In other words, the gene-centric model survives because simplicity is a hugely advantageous trait for an idea to possess. People will select a simple idea over a complex idea almost every time. This holds especially in a hostile environment, like, say, a sceptical crowd. For example, Sean B Carroll, professor of molecular biology and genetics at the University of Wisconsin, spends much of his time studying gene expression, but usually uses gene-centric explanations, because when talking to the public, he finds a simple story is a damned good thing to have.

Which drives West-Eberhard nuts.

‘Dawkins understands very well that gene expression is powerful,’ she says. ‘He sees things are more complex than a selfish gene. He could turn on its head the whole language.’

Yet Dawkins, and with him much of pop science, sticks to the selfish gene. The gene explains all. So far it has worked. The extended synthesis crowd has published scores of papers, quite a few books, and held meetings galore. They have changed the way many biologists think about evolution, at least when those biologists are thinking. But they have scarcely touched the public’s understanding. And they have not found a way to displace a meme so powerful as the selfish gene.

This meme, methinks, forms the true bone of contention and the true obstacle to progress. It’s one of the gruesome beauties of this whole mess that Dawkins himself coined the term meme, and did so in The Selfish Gene. He defined it as a big idea that competes for dominance in a tough environment -- an idea that, like a catchy tune or a good joke, ‘propagates itself by leaping from brain to brain’. The selfish-gene meme has done just that. It has made of evolutionary theory a vehicle for its replication. The selfish gene has become a selfish meme.

If you’re West-Eberhard or of like mind, what are you to replace it with? The slave-ish gene? Not likely to leap from brain to brain. The accommodating gene? Mmmmmaybe -- but I’m betting that phrase lacks the needed bling. And as West-Eberhard notes, either phrase still encourages a focus on single genes. And ‘evolution is not about single genes,’ she says. ‘It’s about genes working together.’

Better then to speak not of genes but the genome -- all your genes together. And not the genome as a unitary actor, but the genome in conversation with itself, with other genomes, and with the outside environment. If you’re into gene expression -- if grasshoppers and honeybees and genetic accommodation are to be believed -- it’s those conversations that define the organism and drive the evolution of new traits and species. It’s not a selfish gene or a solitary genome. It’s a social genome.

What would Mendel think of that? Let’s play this out.

Mendel actually studied bees as a boy, and he studied them again for a couple years after he finished his pea-plant studies. In crossbreeding two species at the monastery, he accidentally created a strain of bees so vicious that he couldn’t work with them. If he’d had a microarray machine, he, like Gene Robinson, could have studied how much of the bees’ aggression rose from changes in the genetic code or how much rose from changes in gene expression. If he had, the father of genetics might have seen right then that traits change and species evolve not just when genes change, but when gene expression does. He might have discovered not just genes, but genetic accommodation. Not the selfish gene, but the social genome.

Alas, no such equipment existed, and Mendel worked in a monastery in the middle of town. His vicious bees promised not a research opportunity but trouble. So he killed them. He would found genetics not through a complex story of morphing bees, but through a simple tale of one pea wrinkled, one pea smooth.

Correction, 3 December 2013: the original version of this article stated that Sewall Wright was a Brit. He was in fact an American.

David Dobbs has written for The New York Times, National Geographic, NewYorker.com and Slate.

http://aeon.co/magazine/nature-and-cosmos/why-its-time-to-lay-the-selfish-gene-to-rest/

 Die, selfish gene, die  

The selfish gene is one of the most successful science metaphors ever invented. Unfortunately, it’s wrong

David Dobbs, The Aeon, 12/13

A couple of years ago, at a massive conference of neuroscientists -- 35,000 attendees, scores of sessions going at any given time -- I wandered into a talk that I thought would be about consciousness but proved (wrong room) to be about grasshoppers and locusts. At the front of the room, a bug-obsessed neuroscientist named Steve Rogers was describing these two creatures -- one elegant, modest, and well-mannered, the other a soccer hooligan.

The grasshopper, he noted, sports long legs and wings, walks low and slow, and dines discreetly in solitude. The locust scurries hurriedly and hoggishly on short, crooked legs and joins hungrily with others to form swarms that darken the sky and descend to chew the farmer’s fields bare.

Related, yes, just as grasshoppers and crickets are. But even someone as insect-ignorant as I could see that the hopper and the locust were wildly different animals -- different species, doubtless, possibly different genera. So I was quite amazed when Rogers told us that grasshopper and locust are in fact the same species, even the same animal, and that, as Jekyll is Hyde, one can morph into the other at alarmingly short notice.

Not all grasshopper species, he explained (there are some 11,000), possess this morphing power; some always remain grasshoppers. But every locust was, and technically still is, a grasshopper -- not a different species or subspecies, but a sort of hopper gone mad. If faced with clues that food might be scarce, such as hunger or crowding, certain grasshopper species can transform within days or even hours from their solitudinous hopper states to become part of a maniacally social locust scourge. They can also return quickly to their original form.

In the most infamous species, Schistocerca gregaria, the desert locust of Africa, the Middle East and Asia, these phase changes (as this morphing process is called) occur when crowding spurs a temporary spike in serotonin levels, which causes changes in gene expression so widespread and powerful they alter not just the hopper’s behaviour but its appearance and form. Legs and wings shrink. Subtle camo colouring turns conspicuously garish. The brain grows to manage the animal’s newly complicated social world, which includes the fact that, if a locust moves too slowly amid its million cousins, the cousins directly behind might eat it.

How does this happen? Does something happen to their genes? Yes, but -- and here was the point of Rogers’s talk -- their genes don’t actually change. That is, they don’t mutate or in any way alter the genetic sequence or DNA. Nothing gets rewritten. Instead, this bug’s DNA -- the genetic book with millions of letters that form the instructions for building and operating a grasshopper -- gets reread so that the very same book becomes the instructions for operating a locust. Even as one animal becomes the other, as Jekyll becomes Hyde, its genome stays unchanged. Same genome, same individual, but, I think we can all agree, quite a different beast.

Why?

Transforming the hopper is gene expression -- a change in how the hopper’s genes are ‘expressed’, or read out. Gene expression is what makes a gene meaningful, and it’s vital for distinguishing one species from another. We humans, for instance, share more than half our genomes with flatworms; about 60 per cent with fruit flies and chickens; 80 per cent with cows; and 99 per cent with chimps. Those genetic distinctions aren’t enough to create all our differences from those animals -- what biologists call our particular phenotype, which is essentially the recognisable thing a genotype builds. This means that we are human, rather than wormlike, flylike, chickenlike, feline, bovine, or excessively simian, less because we carry different genes from those other species than because our cells read differently our remarkably similar genomes as we develop from zygote to adult. The writing varies -- but hardly as much as the reading.

This raises a question:

if merely reading a genome differently can change organisms so wildly, why bother rewriting the genome to evolve?

How vital, really, are actual changes in the genetic code? Do we even need DNA changes to adapt to new environments? Is the importance of the gene as the driver of evolution being overplayed?

You’ve probably noticed that these questions are not gracing the cover of Time or haunting Oprah, Letterman, or even TED talks. Yet for more than two decades they have been stirring a heated argument among geneticists and evolutionary theorists. As evidence of the power of rapid gene expression mounts, these questions might (or might not, for pesky reasons we’ll get to) begin to change not only mainstream evolutionary theory but our more everyday understanding of evolution.

Twenty years ago, phase changes such as those that turn grasshopper to locust were relatively unknown, and, outside of botany anyway, rarely viewed as changes in gene expression. Now, notes Mary Jane West-Eberhard, a wasp researcher at the Smithsonian Tropical Research Institute in Costa Rica, sharp phenotype changes due to gene expression are ‘everywhere’. They show up in gene-expression studies of plants, microbes, fish, wasps, bees, birds, and even people. The genome is continually surprising biologists with how fast and fluidly it can change gene expression -- and thus phenotype.

These discoveries closely follow the recognition, during the 1980s, that gene-expression changes during very early development -- such as in embryos or sprouting plant seeds -- help to create differences between species. At around the same time, genome sequencing began to reveal the startling overlaps mentioned above between the genomes of wildly different creatures. (To repeat: you are 80 per cent cow.)

Gregory Wray, a biologist at Duke University in North Carolina who studies fruit flies, sees this flexibility of genomic interpretation as a short path to adaptive flexibility. When one game plan written in the book can’t provide enough flexibility, fast changes in gene expression -- a change in the book’s reading -- can provide another plan that better matches the prevailing environment.

‘Different groups of animals succeed for different reasons,’ says Wray. ‘Primates, including humans, have succeeded because they’re especially flexible. You could even say flexibility is the essence of being a primate.’

According to Wray, West-Eberhard and many others, this recognition of gene expression’s power requires that we rethink how we view genes and evolution. For a century, the primary account of evolution has emphasised the gene’s role as architect: a gene creates a trait that either proves advantageous or not, and is thus selected for, changing a species for the better, or not. Thus, a genetic blueprint creates traits and drives evolution.

This gene-centric view, as it is known, is the one you learnt in high school. It’s the one you hear or read of in almost every popular account of how genes create traits and drive evolution. It comes from Gregor Mendel and the work he did with peas in the 1860s. Since then, and especially over the past 50 years, this notion has assumed the weight, solidity, and rootedness of an immovable object.

But a number of biologists argue that we need to replace this gene-centric view with one that more heavily emphasises the role of gene expression -- that we need to see the gene less as an architect and more as a member of a collaborative remodelling and maintenance crew.

‘We have a more complicated understanding of football than we do genetics and evolution. Nobody thinks just the quarterback wins the game’

They ask for something like the rejection a century ago of the Victorian-era ‘Great Man’ model of history. This revolt among historians recast leaders not as masters of history, as Tolstoy put it, but as servants. Thus the Russian Revolution exploded not because Marx and Lenin were so clever, but because fed-up peasants created an impatience and an agenda that Marx articulated and Lenin ultimately hijacked. Likewise, D-Day succeeded not because Eisenhower was brilliant but because US and British soldiers repeatedly improvised their way out of disastrously fluid situations. Wray, West-Eberhard and company want to depose genes likewise. They want to cast genes not as the instigators of change, but as agents that institutionalise change rising from more dispersed and fluid forces.

This matters like hell to people like West-Eberhard and Wray. Need it concern the rest of us?

It should. We are rapidly entering a genomic age. A couple of years ago, for instance, I became one of what is now almost a half-million 23andMe customers, paying the genetic-profiling company to identify hundreds of genetic variants that I carry. I now know ‘genes of interest’ that reveal my ancestry and help determine my health. Do I know how to make sense of them? Do they even make sense? Sometimes; sometimes not. They tell me, for instance, that I’m slightly more likely than most to develop Alzheimer’s disease, which allows me to manage my health accordingly. But those genes also tell me I should expect to be short and bald, when in fact I’m 6’3” with a good head of hair.

Soon, it will be practical to buy my entire genome. Will it tell me more? Will it make sense? Millions of people will face this puzzle. Along with our doctors, we’ll draw on this information to decide everything from what drugs to take to whether to have kids, including kids a few days past conception -- a true make-or-break decision.

Yet we enter this genomic age with a view of genetics that, were we to apply it, say, to basketball, would reduce that complicated team sport to a game of one-on-one. A view like that can be worse than no view. It tempts you to think you understand the game when you don’t. We need something more complex.

‘And it’s not as if people can’t handle things more complex,’ says Wray. ‘Educated people handle ideas more complex than this all the time. We have a more complicated understanding of football than we do genetics and evolution. Nobody thinks just the quarterback wins the game.

‘We’re stuck in an outmoded way of thinking that should have fallen long ago.’

This outmoded thinking grew from seeds planted 150 years ago by Gregor Mendel, the monk who studied peas. Mendel spent seven years breeding peas in a five-acre monastery garden in the town of Brno, now part of the Czech Republic. He crossed plants bearing wrinkled peas with those bearing smooth peas, producing 29,000 plants altogether. When he was done and he had run the numbers, he had exposed the gene.

Mendel didn’t expose the physical gene, of course (that would come a century later), but the conceptual gene. And this conceptual gene, revealed in the tables and calculations of this math-friendly monk, seemed an agent of mathematical neatness. Mendel’s thousands of crossings showed that the traits he studied -- smooth skin versus wrinkled, for instance, or purple flower versus white -- appeared or disappeared in consistent ratios dictated by clear mathematical formulas. Inheritance appeared to work like algebra. Anything so math-friendly had to be driven by discrete integers.

It was beautiful work. Yet when Mendel first published his findings in 1866, just seven years after Charles Darwin’s On the Origin of Species, no one noticed. Starting in 1900, however, biologists rediscovering his work began to see that these units of heredity he’d discovered -- dubbed genes in 1909 -- filled a crucial gap in Darwin’s theory of evolution. This recognition was the Holy Shit! moment that launched genetics’ Holy Shit! century. It seemed to explain everything. And it saved Darwin.

Darwin had legitimised evolution by proposing for it a viable mechanism -- natural selection, in which organisms with the most favourable traits survive and multiply at higher rates than do others. But he could not explain what created or altered traits.

Mendel could. Genes created traits, and both would spread through a population if a gene created a trait that survived selection.

Edited RNA Plus Invasive DNA Add Individuality

ScienceDaily

Nov. 8, 2013 -- A study in Nature Communications finds that an enzyme that edits RNA may loosen the genome's control over invasive snippets of DNA that affect how genes are expressed. In fruit flies, that newly understood mechanism appears to contribute to differences among individuals such as eye color and life span.

The story of why we are all so different goes well beyond the endless mixing and matching of DNA through breeding. A new study in the journal Nature Communications, for instance, reports a new molecular mechanism of individual variation found in fruit flies that uses components operating in a wide variety of species, including humans.

The new mechanism is based in a surprising genetic oddity. Nearly all genomes -- those of humans, fruit flies, and even corn and rice -- are constantly grappling with parasitic snippets of genetic material called "transposons." These snippets copy themselves, move around, and embed themselves within DNA. If left unchecked, transposons can alter how genetic instructions are carried out in the body, usually for the worse, sometimes for the better. But genomes don't leave transposons unchecked. They "look" for tell-tale double-stranded RNA associated with the transposons, chop the strands up and use the pieces to "silence" the invaders.

In the new paper, scientists show that an enzyme called ADAR, which edits RNA in humans, flies, and many other creatures, edits double-stranded RNAs. This loosens the system that keeps "Hoppel" transposons silenced in fruit flies. When transposons are silenced, it's done by keeping them locked tight around tiny balls of material called chromatin.

Since the amount of ADAR varies from one individual to the next, the amount of jailbreaking from those chromatin prison varies too, and that should lead to altered gene expression. After showing that an abundance of ADAR reduces silencing of a common transposon in the flies -- and that a lack of ADAR meant widespread silencing -- the researchers measured two consequences of different levels of ADAR activity: a 20-percent difference in life span and difference in eye color (red rather than white).

The study was focused on fruit flies, ADAR, and the double-stranded RNA of the Hoppel transposon, but the ability of RNA editors to loosen the silencing of at least some transposons may be a source of individual variation in humans and other species too, said Brown University biologist Robert Reenan, senior author of the new study published online. Editing of double-stranded RNA -- or a lack of editing -- has already been linked to diseases in people, including amyloid lateral sclerosis and, specifically in the case of ADAR, Aicardi-Goutières syndrome.

"ADAR in humans functions the same way it does in flies, and double-stranded RNAs are made in humans the same way," said Reenan, professor of biology in the Department of Molecular Biology, Cell Biology and Biochemistry. "They are all generic, off the shelf staples of the biological toolkit. This is not anything that is particular to flies."

Picking the double strand

Many of Reenan's studies focus on ADAR's editing activity in the development of the nervous system, but this investigation began years ago when lead author and then graduate student Yiannis Savva happened to overexpress ADAR in fruit fly salivary gland cells. He found some bound in an unexpected place: one specific site on chromosome four.

Reenan recalled: "I told him that's either an artifact or it will be the centerpiece of your thesis."

Various tests revealed that the chromosome four site was a home for several Hoppel transposons making a double-stranded RNA.

Savva and Reenan were curious about what business ADAR had with the transposon. A series of experiments in ensuing years did just that. They relocated the transposons to places where they weren't and found that ADAR followed. They deleted the double-stranded RNA from chromosome four and found that ADAR was no longer there. They identified specific editing sites and signs of editing on the double stranded RNA.

Savva and his collaborators then measured silencing of tranposons with varying levels of ADAR and found that the more ADAR there was, the less silencing there was.

Then, working with Stephen Helfand, an expert on the biology of aging, they noticed that a reduction of editing increases life span.

"As a loss of silencing has been associated with aging in Drosophila and other organisms, we performed lifespan analyses on [low-ADAR] adults and wild-type controls and found a ~20-percent increase in the median life span of [low-ADAR] males and females," the authors wrote in Nature Communications.

Look in their eyes

Later they looked at eye color, using natural (wild-type) flies and those where ADAR activity was either artificially hamstrung or excessively active. The natural flies have eyes that run a full continuum from red to white with various "variegating" blends in between that reflect the silencing state of their eye color gene. In the excessively ADAR-active flies there was little silencing and eyes turned out red much more often than normal. In the ADAR-hamstrug flies, virtually all of the eyes were white (reflecting a lot of silencing of the red color gene).

Ultimately, Savva said, ADAR appears to be allowing transposons like Hoppel to exercise their capacity to regulate gene expression, even though they are really just uninvited guests in the genome.

"What ADAR does is fine tune this regulatory network," Savva said. "In cells where you have ADAR, the network is activated. In cells where you don't it's silenced. It provides dynamicity."

In other words, some of the differences among us may be apparent in the eyes of flies.

In addition to Savva, Reenan, and Helfand, authors on the paper are James Jepson, Yoah-Jen Chang, Rachel Whitaker, Brian Jones, Nian Jiang, and Guyu Du of Brown; Georges St. Laurent of Brown and the St. Laurent Institute; and Michael Tackett and Phillipp Kapranov of the St. Laurent Institute.

The National Institute on Aging (grants: AG16667, AG24353, AG25277) and the Ellison Medial Foundation funded the research.

Story Source:

The above story is based on materials provided by Brown University.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

1.     Yiannis A. Savva, James E. C. Jepson, Yao-Jen Chang, Rachel Whitaker, Brian C. Jones, Georges St Laurent, Michael R. Tackett, Philipp Kapranov, Nan Jiang, Guyu Du, Stephen L. Helfand, Robert A. Reenan. RNA editing regulates transposon-mediated heterochromatic gene silencing. Nature Communications, 2013; 4 DOI: 10.1038/ncomms3745

http://www.sciencedaily.com/releases/2013/11/131108091312.htm

Novel Genetic Patterns May Make Us Rethink Biology and Individuality

ScienceDaily

Nov. 7, 2013 -- Professor of Genetics Scott Williams, PhD, of the Institute for Quantitative Biomedical Sciences (iQBS) at Dartmouth's Geisel School of Medicine, has made two novel discoveries:

first, a person can have several DNA mutations in parts of their body, with their original DNA in the rest -- resulting in several different genotypes in one individual -- and

second, some of the same genetic mutations occur in unrelated people. We think of each person's DNA as unique, so if an individual can have more than one genotype, this may alter our very concept of what it means to be a human, and impact how we think about using forensic or criminal DNA analysis, paternity testing, prenatal testing, or genetic screening for breast cancer risk, for example. Williams' surprising results indicate that genetic mutations do not always happen purely at random, as scientists have previously thought.

His work, done in collaboration with Professor of Genetics Jason Moore, PhD, and colleagues at Vanderbilt University, was published in PLOS Genetics journal on November 7, 2013.

Genetic mutations can occur in the cells that are passed on from parent to child and may cause birth defects. Other genetic mutations occur after an egg is fertilized, throughout childhood or adult life, after people are exposed to sunlight, radiation, carcinogenic chemicals, viruses, or other items that can damage DNA. These later or "somatic" mutations do not affect sperm or egg cells, so they are not inherited from parents or passed down to children. Somatic mutations can cause cancer or other diseases, but do not always do so. However, if the mutated cell continues to divide, the person can develop tissue, or a part thereof, with a different DNA sequence from the rest of his or her body.

"We are in reality diverse beings in that a single person is genetically not a single entity -- to be philosophical in ways I do not yet understand -- what does it mean to be a person if we are variable within?" says Williams, the study's senior author, and founding Director of the Center for Integrative Biomedical Sciences in iQBS. "What makes you a person? Is it your memory? Your genes?" He continues, "We have always thought, 'your genome is your genome.' The data suggest that it is not completely true."

In the past, it was always thought that each person contains only one DNA sequence (genetic constitution). Only recently, with the computational power of advanced genetic analysis tools that examine all the genes in one individual, have scientists been able to systematically look for this somatic variation. "This study is an example of the type of biomedical research project that is made possible by bringing together interdisciplinary teams of scientists with expertise in the biological, computational and statistical sciences." says Jason Moore, Director of the iQBS, who is also Associate Director for Bioinformatics at the Cancer Center, Third Century Professor, and Professor of Community and Family Medicine at Geisel.

Having multiple genotypes from mutations within one's own body is somewhat analogous to chimerism, a condition in which one person has cells inside his or her body that originated from another person (i.e., following an organ or blood donation; or sometimes a mother and child -- or twins -- exchange DNA during pregnancy. Also, occasionally a person finds out that, prior to birth, he or she had a twin who did not survive, whose genetic material is still contained within their own body). Chimerism has resulted in some famous DNA cases: one in which a mother had genetic testing that "proved" that she was unrelated to two of her three biological sons.

Williams says that, although this was a small study, "there is a lot more going on than we thought, and the results are, in some ways, astoundingly weird."

Because somatic changes are thought to happen at random, scientists do not expect unrelated people to exhibit the same mutations. Williams and colleagues analyzed the same 10 tissue samples in two unrelated people. They found several identical mutations, and detected these repeated mutations only in kidney, liver and skeletal body tissues. Their research examined "mitochondrial DNA" (mtDNA) -- a part of DNA that is only inherited from the mother. Technically all women would share mtDNA from one common female ancestor, but mutations have resulted in differences. The importance of Williams' finding is that these tissue-specific, recurrent, common mutations in mtDNA among unrelated study subjects -- only detected in three body tissues -- are "not likely being developed and maintained through purely random processes," according to Williams. They indicate "a completely different model …. a decidedly non-random process that results in particular mutations, but only in specific tissues."

If our human DNA changes, or mutates, in patterns, rather than randomly; if such mutations "match" among unrelated people; or if genetic changes happen only in part of the body of one individual, what does this mean for our understanding of what it means to be human? How may it impact our medical care, cancer screening, or treatment of disease? We don't yet know, but ongoing research may help reveal the answers.

Christopher Amos, PhD, Director of the Center for Genomic Medicine and Associate Director for Population Sciences at the Cancer Center, says, "This paper identifies mutations that develop in multiple tissues, and provides novel insights that are relevant to aging. Mutations are noticed in several tissues in common across individuals, and the aging process is the most likely contributor. The theory would be that selected mutations confer a selective advantage to mitochondria, and these accumulate as we age." Amos, who is also a Professor of Community and Family Medicine at Geisel, says, "To confirm whether aging is to blame, we would need to study tissues from multiple individuals at different ages." Williams concurs, saying, "Clearly these do accumulate with age, but how and why is unknown -- and needs to be determined."

As more and better data become available from high-throughput genetic analyses and high-powered computers, researchers are identifying an increasing number of medical conditions that result from somatic mutations, including neurological, hematological, and immune-related disorders. Williams and colleagues are conducting further research to examine how diseases, other than cancer or even benign conditions, may result from somatic changes. Williams, Moore and Amos will employ iQBS's Discovery supercomputer for next-generation sequencing to process subjects' DNA data. Future analyses will include large, whole-genome sequencing of the data for the two individuals studied in the current report.

Williams explains, "We know that cancer is caused by mutations that cause a tumor. But in this work, we chose to study mutations in people without any cancer. Knowing how we accumulate mutations may make it easier to separate genetic signals that may cause cancer from those that accumulate normally without affecting disease. It may also allow us to see that many changes that we thought caused cancer do not in many situations, if we find the same mutations in normal tissues."

Just as our bodies' immune systems have evolved to fight disease, interestingly, they can also stave off the effects of some genetic mutations. Williams states that, "Most genetic changes don't cause disease, and if they did, we'd be in big trouble. Fortunately, it appears our systems filter a lot of that out."

Mark Israel, MD, Director of Norris Cotton Cancer Center and Professor of Pediatrics and Genetics at Geisel, says, "The fact that somatic mutation occurs in mitochondrial DNA apparently non-randomly provides a new working hypothesis for the rest of the genome. If this non-randomness is general, it may affect cancer risks in ways we could not have previously predicted. This can have real impact in understanding and changing disease susceptibility."

Story Source:

The above story is based on materials provided by The Geisel School of Medicine at Dartmouth, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

1.     David C. Samuels, Chun Li, Bingshan Li, Zhuo Song, Eric Torstenson, Hayley Boyd Clay, Antonis Rokas, Tricia A. Thornton-Wells, Jason H. Moore, Tia M. Hughes, Robert D. Hoffman, Jonathan L. Haines, Deborah G. Murdock, Douglas P. Mortlock, Scott M. Williams. Recurrent Tissue-Specific mtDNA Mutations Are Common in Humans. PLoS Genetics, 2013; 9 (11): e1003929 DOI: 10.1371/journal.pgen.1003929

http://www.sciencedaily.com/releases/2013/11/131107204241.htm

New Study Shows Effects Genetics Have on Nature Vs. Nurture

Cecily Kellogg, Babble.com, Healthy Living, 06/24/13

My grandparents were interesting people. My maternal grandmother Elizabeth was the kind of woman that refused to "Heil Hitler!" the Nazi soldiers while in Germany while my grandfather King got his PhD in musicology at the University of Munich. My paternal grandfather Howard was raised in a small hotel in Belen, New Mexico (which my father suspected also operated as a brothel) by a friend of the family, while my grandmother Corrine was the grandchild of the youngest Senator to be elected (at the time) from Arkansas. 

I loved all my grandparents fiercely, even though I didn't see them too often as we were all scattered around the country. Some of the genetic legacy they gave me is obvious; my eyes look exactly like my paternal grandmother's, and I inherited alcoholism partly from my maternal grandfather. But I've generally assumed that while my physical characteristics are genetic, most of my behavior was based primarily on the way I raised, because I've believed that"nurture" is stronger in the debate of nature vs. nurture. 

But a group of scientists may have actually discovered that events in a person's life leave a GENETIC fingerprint that is passed down to children and grandchildren. Yes, MIND BLOWN.

If you aren't familiar with the nature vs. nurture argument, you can read all about it here. There are many schools of thought on this issue which are broken down in this great graphic (請至 http://www.simplypsychology.org/naturevsnurture.html 查看此表 -- 卜凱).

Generally, though, most psychologists believe that events in an individual's childhood have the biggest impact on behavior and emotional development. But a pair of scientists began to wonder if this is true; what they discovered is fascinating. It was well known that something called epigenetics could be changed in your lifetime due to changes in diet or exposure to chemicals. Here's an explanation of epigenetics. 

Related: 10 ways to be a happier person for life

One such extra element is the methyl group, a common structural component of organic molecules. The methyl group works like a placeholder in a cookbook, attaching to the DNA within each cell to select only those recipes - er, genes - necessary for that particular cell's proteins. Because methyl groups are attached to the genes, residing beside but separate from the double-helix DNA code, the field was dubbed epigenetics, from the prefix epi (Greek for over, outer, above).

But the scientists took this theory one step further and asked if diet and chemical exposure could bring changes to DNA and epigenetics, could severe stresses such as child abuse or neglect make the same changes? The answer is yes, launching a new field called behavioral epigenetics:

According to the new insights of behavioral epigenetics, traumatic experiences in our past, or in our recent ancestors' past, leave molecular scars adhering to our DNA. Jews whose great-grandparents were chased from their Russian shtetls; Chinese whose grandparents lived through the ravages of the Cultural Revolution; young immigrants from Africa whose parents survived massacres; adults of every ethnicity who grew up with alcoholic or abusive parents - all carry with them more than just memories.

I am alternately amazed and dismayed by this information. As a recovering alcoholic and drug addict married to a recovering alcoholic, I worry deeply about passing on the disease of alcoholism and addiction to my daughter. It's well known that alcoholism is a family illness, impacting even those family members that don't drink or use drugs. My husband and I watch our daughter for behaviors we've realized were in place for us long before we took our first drinks - particularly abnormal anxiety and fear that we both "treated" with alcohol.

 We've always comforted ourselves with the knowledge that our daughter has never seen us drunk (we'd been sober over a decade when she was born), and we've worked hard to not pass on the negative messages we got from our families about food and body image and intelligence. But my husband was badly abused by his mother, receiving little comforting or love from her; in fact, because of reading the article about behavioral epigenetics I asked him if his mother ever held him or comforted him and he said, "Once." Maybe this explains my daughter's need to constantly lean into me when we're together, even though she's been loved and held and cuddled her whole life. 

The good news is, even if these epigenetic changes are inherited, the damage can be helped or even undone:

The mechanisms of behavioral epigenetics underlie not only deficits and weaknesses but strengths and resiliencies, too. And for those unlucky enough to descend from miserable or withholding grandparents, emerging drug treatments could reset not just mood, but the epigenetic changes themselves. Like grandmother's vintage dress, you could wear it or have it altered. The genome has long been known as the blueprint of life, but the epigenome is life's Etch A Sketch: Shake it hard enough, and you can wipe clean the family curse.

What do you think? Read this whole article about the science (the article that inspired this post) and share your thoughts in the comments. But I think it might be time for the phrase "get over it!" to be excised from our language; if the damage is genetic as well as psychological, that might not be possible.

http://shine.yahoo.com/healthy-living/study-shows-effects-genetics-nature-vs-nurture-143500477.html

ENCODE and “Junk DNA,” Part 1: All Good Concepts are Fuzzy

"The BioLogos Forum" frequently features essays from The BioLogos Foundation's leaders and Senior Fellows. Please note the views expressed here are those of the author, not necessarily of The BioLogos Foundation. You can read more about what we believe here.

Today's entry was written by Dennis Venema. Dennis Venema is an associate professor and department chair for the biology department of Trinity Western University in Langley, British Columbia. His research is focused on the genetics of pattern formation and signaling.

The ENCODE project has recently taken the scientific world by storm by declaring that 80% of the human genome is functional. This has led the media and various science/faith groups to declare that in light of ENCODE’s results, the concept of “junk DNA” is dead. In this series, we explore the science and rhetoric surrounding ENCODE in search of a more meaningful understanding of biological function.

Dennis Venema, 09/24/12

Fuzzy, but useful

One of the challenges for my students learning biology is summed up in one of my favorite sayings (that I’m sure some students are tired of hearing from me): “All the good concepts are fuzzy.” Take a basic concept like “living” versus “non-living,” for example. Obviously this is a fundamental concept for a biologist, since “biology” means the study of living things. Even here, though, we find that a precise definition of what is “alive” is a hard thing to nail down. While things like humans, dogs and cats obviously qualify (though some days with early lectures I might have my doubts for humans), there are other entities out there that blur the boundary between life and non-life. Viruses, for example, have many of the features of living things, but lack some others. Transposons are less life-like even than viruses, and there are even transposon-like entities that parasitize viruses. Life and non-life are useful concepts, but the precise boundary between them is fuzzy.

More technology = greater fuzz

Often, an increase in technological ability exacerbates the “fuzziness” issue. One example in genetics (that we will later see to be highly relevant to understanding the results of ENCODE) is the concept of “dominant” versus “recessive” for different versions of a given gene. If you recall anything at all about genetics from high school, you might remember learning about Gregor Mendel crossing pea plants that differed in certain characteristics (purple versus white flowers, for example). Mendel deduced that the “particles” that controlled a certain trait (what we would later call “genes”) came in pairs, and that the presence of one type of particle (e.g. the one for purple flowers) could mask the presence of another (in this case the one for white flowers). He deduced that one gene version (what we now call an allele) was dominant over the other one, which in turn was recessive. For Mendel, one determined a dominant / recessive relationship by examining the appearance of a plant with both alleles: whichever allele determined the appearance was the dominant one.

Advances in technology would later do two things to Mendel’s model.

First, they would provide deeper insights to what was actually going on at the biochemical level.

Secondly, those deeper insights would cause the concept of “dominant” or “recessive” to become more fuzzy.

I’ll illustrate what I mean with a (hypothetical, but representative) example.

When Mendel did his work he was limited to what he could observe with the naked eye. Now we have the ability to examine the effects of alleles at much deeper levels than Mendel could. Let’s say, for the sake of the discussion, that the gene Mendel was working with made an enzyme that produced purple pigment. The “purple” allele of the gene (let’s represent it with the symbol “P”) made a fully functioning enzyme: its DNA is copied into mRNA, and that mRNA is used to code for the protein enzyme that does the work of making pigment. The “white” allele (let’s call it “p”), on the other hand, turns out to have a mutation in the protein coding portion of the gene. This single mutation has two effects: it stops translation early, resulting in a protein that is too short and cannot work as an enzyme. The mutation also has an effect on the stability of the mRNA: the mRNA produced by the white allele degrades more readily, resulting in a lower steady-state amount of the mRNA in the cell.

With this background in mind, suppose a scientist performs a series of different tests on a plant that has one purple allele and one white allele (i.e. is “Pp”):

If the scientist looks at the flower color of the Pp plant, she would conclude (as did Mendel) that the p allele is recessive to the P allele, since the Pp plant is as purple as a plant with two purple alleles (PP). This arises because one P allele can produce enough enzyme for complete flower pigmentation.

If the scientist compares the amount of mRNA for this gene between PP, Pp and pp plants, she would notice three different outcomes. PP would have the most, Pp would have less, and pp would have the least. For this test the Pp plant is intermediate between the PP and pp plants. The scientist would conclude that neither the P nor p allele is completely dominant over / recessive to the other (an effect known as “incomplete dominance”).

If the scientist did a test to compare the physical size of the protein enzyme in PP, Pp and pp plants, she would again notice three outcomes. PP plants would have only full-sized enzymes, pp plants would have only small enzyme fragments, and Pp plants would have both distinct sizes, full-sized and small. In this case, the Pp plant shows both character traits (full-sized and small) at the same time. The scientist would conclude that the P and p alleles are both dominant, since both alleles display their version of the trait with neither masking the other in any way (an effect known as “co-dominance”.)

So, is the P allele dominant, incompletely dominant, or co-dominant with respect to the p allele? The answer is “yes” – all three apply, but it depends specifically on the details that the new technology is revealing. Which answer is the most meaningful one? Well, it depends on the specific question the researcher is asking. Now that we have the ability to sequence DNA, we can directly observe the nature of all alleles in any given organism, and the presence of other alleles does not interfere with this observation. In effect, modern molecular biology has made all alleles “co-dominant” since all alleles display their “version of the trait” (i.e. their sequence) when they are sequenced. If one was so inclined, one could argue that “recessiveness” is an outdated concept, and that eventually we will determine through sequencing technology that all alleles are co-dominant. While this would be technically true, it would be very misleading. The p allele remains “recessive” in biologically meaningful ways: it is a loss of an enzyme function, and its complete loss has an effect on the appearance of the organism. Plants that have one of each allele (Pp) have the same enzyme content as PP plants. Anyone who would argue that “recessiveness” was no longer a feature of alleles in light of the new sequencing technology would have to address these issues in a meaningful way, since the evidence for “recessiveness” did not simply evaporate when we learned how to sequence genomes. By any measure, Mendel’s ideas of dominance and recessiveness are still useful concepts.

The relevance to ENCODE

So, how does this all relate to the ENCODE project? It hinges on another very useful, and therefore fuzzy term: “function.” Like “life” and “dominant”, “function” is a useful idea in biology, but much hinges on precisely how it is defined, and the technology used to assess its presence or absence.

The ENCODE definition of “function” is a useful one for the purposes of the large undertaking that this project represents. Specifically, ENCODE was seeking for biochemical activity in the genome: the interaction of chromatin proteins with DNA, regions of DNA that are made into RNA, and so on. This is all well and good, for we now have new tools available that allow us to test for these effects – we have new technology that can shed new insights on what is going on in the genome.

What these results don’t do, however, is cause the prior lines of evidence relating to non-functional DNA to suddenly disappear. As we saw with the dominance issue, the results from new techniques will need to be integrated into a more complete understanding of the data. We must also have a wider understanding of the strengths and weaknesses of various techniques to answer certain specific kinds of questions.

As a way to illustrate these issues for the ENCODE project, let’s consider the hypothetical example we used to explore the dominance issue. The ENCODE definition of “function” includes any detectable biological activity such as the presence of an mRNA transcript. In our example, both the “P” allele (that produces a working protein enzyme) and the “p” allele (which does not) both produce an mRNA transcript. As such, the ENCODE project would indentify both alleles as equally functional. In fact, the ENCODE definition of “detectable biological activity” as “function” would not be able to distinguish between these two alleles in any meaningful way, despite the fact that they have real, biological, and obviously functional differences. This is not to criticize the working definition of function adopted by ENCODE, but merely to demonstrate that this definition, while useful in some contexts, has limitations.

These limitations should stand as a caution to any group that wishes to adopt the ENCODE definition as the only viable definition of biological function. To consider our example again, I suspect that many of those opposed to evolution would bristle at the suggestion that the p allele was equally functional to the P allele, given than it represents a clear loss of function in keeping with common Young Earth Creationist, Old Earth Creationist, and Intelligent Design definitions of loss-of-function alleles, and the propensity of these groups to insist that such mutations destroy functional information. Yet what we have seen from these groups, by and large, is a robust embrace of ENCODE and its view of function. I suspect that these groups, in their excitement over the media frenzy declaring the idea of “junk DNA” to be dead, have not yet had time to carefully think through the implications of that embrace.

In Part 2 of this series on Wednesday, we’ll explore other working definitions of “function,” look at other lines of evidence that are better suited to distinguishing between biologically functional and non-functional sequences, and revisit some examples from my previous series on “junk DNA” in light of ENCODE.

http://biologos.org/blog/encode-and-junk-dna-part-1

What Is ENCODE, and Why Does It Matter?

Life's Little Mysteries Staff, 09/06/12

A giant leap has just been taken in humanity's understanding of itself. That leap is called ENCODE. Here's what you need to know.

Eleven years ago, scientists sequenced the human genome. That is, they unraveled the spirals of DNA packed inside the nucleus of each of our cells and figured out the ordering of its 3.3 billion chemical "base pairs," or the molecular letters, of sorts, that spell out instructions for the cells to follow.

But although the Human Genome Project (as the endeavor was called) established the order of the base pairs, most of the code that these letters spelled out remained encrypted.

Scientists could see that roughly 23,000 sections of the genome, made up of about 1,000 base pairs each, coded for proteins. In other words, these sections, called genes, were structured in such a way that cells could read them off to build protein molecules, which then performed cellular functions. But the genes made up less than 2 percent of the total human genome. What did the rest of the endless spirals of DNA base pairs mean? Many scientists thought most of it was useless gobbledygook left over from our evolutionary past. They called it "junk DNA." [How to Speak Genetics: A Glossary]

Now, an international collaboration of 442 scientists has unveiled the Encyclopedia of DNA Elements, nicknamed ENCODE. In more than two dozen articles published in Nature, Science and other journals, the scientists present nine years of research showing that genes are just one element of a long "parts list" that makes up the human genome. Rather than being mostly junk, 80 percent of DNA has a function, and ENCODE is the encyclopedia that describes what all of it does.

Half or more of human DNA acts as "gene switches." These portions of code control when genes turn on and off, affecting how many proteins get built both throughout the day and over the course of a lifetime. There's a gene switch that tells an undifferentiated cell in an embryo to develop into a liver cell, for example; there's another switch that directs a cell in the pancreas to rev up its insulin production after a meal; and there's another that tells a skin cell it's time to bud off, notes Time Magazine.

"What we learned from ENCODE is how complicated the human genome is, and the incredible choreography that is going on with the immense number of switches that are choreographing how genes are used," Eric Green, director of the National Human Genome Research Institute (which ran the nine-year-long ENCODE project), told reporters during a teleconference.

So, why does it matter that we now have an encyclopedia of human DNA?

For one, knowing what so much more of the genetic code actually does will help pinpoint what makes us human; evolutionary biologists can study how the gene switches, as well as the genes, of Homo sapiens diverged from those of other animals.

More importantly, scientists say the new encyclopedia of DNA will tremendously accelerate our understanding of why diseases occur and how to prevent them. That's because, more often than not, diseases stem from changes that occur in regions of the genetic code formerly labeled "junk."

"Most of the changes that affect disease don't lie in the genes themselves; they lie in the switches," Michael Snyder, an ENCODE researcher based at Stanford University, told The New York Times.

Take cancer. It turns out that most of the changes to DNA that make cells turn cancerous do not occur in genes, but in the portions of DNA that exert control over genes: the switches. Knowing what these switches do, researchers say they can begin to develop drugs that target the control circuitry, rather than targeting the genes themselves, which, in many cases, are impervious to direct attack.

The ENCODE project "will definitely have an impact on our medical research on cancer," Dr. Mark Rubin, a prostate cancer genomics researcher at Weill Cornell Medical College, told the Times. [What If We Eradicated All Disease?]

Scientists have already found changes to gene switches that appear to usher in the development of multiple sclerosis, arthritis, Crohn's disease, lupus and celiac disease. Other common diseases such as diabetes, heart disease, hypertension and depression also fit the profile of conditions that likely result from changes to the way genes get turned on or off, rather than changes to genes themselves.

"By and large, we believe rare diseases may be caused by mutations in the protein [or gene-]coding region" of DNA, Green told reporters, while the "more common, complicated diseases may be traced to genetic changes in the switches."

Common diseases: we're coming for you.

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• The 7 Biggest Mysteries of the Human Body
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http://news.yahoo.com/encode-why-does-matter-203700119.html

Epigenetic 'Memory' Key to Nature Versus Nurture

ScienceDaily (July 25, 2011) — Researchers at the John Innes Centre have made a discovery, reported this evening (24 July) in Nature, that explains how an organism can create a biological memory of some variable condition, such as quality of nutrition or temperature. The discovery explains the mechanism of this memory -- a sort of biological switch -- and how it can also be inherited by offspring.

The work was led by Professor Martin Howard and Professor Caroline Dean at the John Innes Centre.

Professor Dean said "There are quite a few examples that we now know of where the activity of genes can be affected in the long term by environmental factors. And in some cases the environment of an individual can actually affect the biology or physiology of their offspring but there is no change to the genome sequence."

For example, some studies have shown that in families where there was a severe food shortage in the grandparents' generation, the children and grandchildren have a greater risk of cardiovascular disease and diabetes, which could be explained by epigenetic memory. But until now there hasn't been a clear mechanism to explain how individuals could develop a "memory" of a variable factor, such as nutrition.

The team used the example of how plants "remember" the length of the cold winter period in order to exquisitely time flowering so that pollination, development, seed dispersal and germination can all happen at the appropriate time.

Professor Howard said "We already knew quite a lot about the genes involved in flowering and it was clear that something goes on in winter that affects the timing of flowering, according to the length of the cold period."

Using a combination of mathematical modelling and experimental analysis the team has uncovered the system by which a key gene called FLC is either completely off or completely on in any one cell and also later in its progeny. They found that the longer the cold period, the higher the proportion of cells that have FLC stably flipped to the off position. This delays flowering and is down to a phenomenon known as epigenetic memory.

Epigenetic memory comes in various guises, but one important form involves histones -- the proteins around which DNA is wrapped. Particular chemical modifications can be attached to histones and these modifications can then affect the expression of nearby genes, turning them on or off. These modifications can be inherited by daughter cells, when the cells divide, and if they occur in the cells that form gametes (e.g. sperm in mammals or pollen in plants) then they can also pass on to offspring.

Together with Dr Andrew Angel (also at the John Innes Centre), Professor Howard produced a mathematical model of the FLC system. The model predicted that inside each individual cell, the FLC gene should be either completely activated or completely silenced, with the fraction of cells switching to the silenced state increasing with longer periods of cold.

To provide experimental evidence to back up the model, Dr Jie Song in Prof. Dean's group used a technique where any cell that had the FLC gene switched on, showed up blue under a microscope. From her observations, it was clear that cells were either completely switched or not switched at all, in agreement with the theory.

Dr Song also showed that the histone proteins near the FLC gene were modified during the cold period, in such a way that would account for the switching off of the gene.

Funding for the project came from BBSRC, the European Research Council, and The Royal Society.

Professor Douglas Kell, Chief Executive, BBSRC said "This work not only gives us insight into a phenomenon that is crucial for future food security -- the timing of flowering according to climate variation -- but it uncovers an important mechanism that is at play right across biology. This is a great example of where the research that BBSRC funds can provide not only a focus on real life problems, but also a grounding in the fundamental tenets of biology that will underpin the future of the field. It also demonstrates the value of multidisciplinary working at the interface between biology, physics and mathematics."

 http://www.sciencedaily.com/releases/2011/07/110724135553.htm