It's all in the gene: myostatin and racehorses

"Horses ain't like people, man, they can't make themselves better than they're born. See, with a horse, it's all in the gene. It's the f#cking gene that does the running. The horse has got absolutely nothing to do with it." --- Paulie (Eric Roberts) in The Pope of Greenwich Village.

For more on myostatin mutations in people and dogs, see here.

The genetic origin and history of speed in the Thoroughbred racehorse

Nature Communications 2012 Jan 24;3:643. doi: 10.1038/ncomms1644

Abstract
Selective breeding for speed in the racehorse has resulted in an unusually high frequency of the C-variant (g.66493737C/T) at the myostatin gene (MSTN) in cohorts of the Thoroughbred horse population that are best suited to sprint racing. Here we show using a combination of molecular- and pedigree-based approaches in 593 horses from 22 Eurasian and North-American horse populations, museum specimens from 12 historically important Thoroughbred stallions (b.1764-1930), 330 elite-performing modern Thoroughbreds and 42 samples from three other equid species that the T-allele was ancestral and there was a single introduction of the C-allele at the foundation stages of the Thoroughbred from a British-native mare. Furthermore, we show that although the C-allele was rare among the celebrated racehorses of the 18th and 19th centuries, it has proliferated recently in the population via the stallion Nearctic (b.1954), the sire of the most influential stallion of modern time, Northern Dancer (b.1961).

From the paper:

Athletic phenotypes are influenced markedly by environment, management and training; however, it has long been accepted that there are underlying genetic factors that influence a horse’s athletic performance capabilities. Indeed, selection and breeding of racehorses is predicated on the belief that racing performance is inherited. Although the physiological adaptations to elite athleticism and exercise are well described for the Thoroughbred, few genes have been identified to explain these traits. In humans more than 200 genes have been reported to be associated with fitness-related health and exercise traits17, and it is likely that racing performance in the Thoroughbred is also polygenic and is influenced by genes that contribute to the wide range of anatomical, metabolic and physiological adaptations that enable elite-racing performance. The athletic potential of a racehorse will therefore depend on a favourable environment as well as inheriting the optimal combination of DNA variants at loci that significantly affect exercise.

Recently, variation at the MSTN locus has been found to be highly predictive of genetic potential for race distance aptitude in Thoroughbred racehorses18–21 and contributes to morphological type in other horse breeds22. The MSTN locus is associated with muscle hypertrophy phenotypes in a range of mammalian species23–27 and a single nucleotide polymorphism (SNP, g.66493737C/T) located in the first intron of the MSTN gene influences speed in the Thoroughbred19. Thoroughbred homozygous C/C horses are best suited to fast, shortdistance, sprint races (1,000–1,600m); heterozygous C/T horses compete favourably in middle-distance races (1,400–2,400m); and homozygous T/T horses have greater stamina (>2,000m). Evaluation of retrospective racecourse performance, physical growth and stallion progeny performance has demonstrated that C/C and C/T horses are more likely to be physically precocious and enjoy greater racecourse success as 2-year-old racehorses than T/T horses19,28.

These findings have been subsequently validated in three independent genome-wide association (GWA) studies18,20,21 in populations of Thoroughbreds originating in Ireland, Great Britain, New Zealand20, USA18 and Japan21. The singular, genomic influence on optimum race distance at the MSTN locus in the Thoroughbred is supported by a high heritability for race distance (h2=0.94)29. Further evidence for the role of chromosomes containing the C-allele in influencing speed comes from association tests with field-measured speed indices30 and from previous analysis of g.66493737C/T genotypes in the Quarter Horse, for which a high frequency of C/C homozygotes (0.83) has been reported19. The Quarter Horse is a North-American breed that excels at sprinting over distances of a quarter of a mile (400m) or less. Because of the specificity of its role in short-distance racing, this breed has undergone intense selection for speed since its foundation in the mid-1800s.

As flies to wanton boys are we to the gods

An earlier post, Discrete genetic modules can control complex behavior, described genetic control of burrowing behavior in deer mice. A reader commented that the results were entirely unsurprising. I wasn't aware of similar results in mammals, but of course this sort of thing has long been known in drosophila, thanks to Seymour Benzer and collaborators.

WSJ: ... When the great California Institute of Technology geneticist Seymour Benzer set out in the mid-1960s to find mutations in fruit flies that affected behavior, rather than mere anatomy, he was ridiculed for challenging the consensus that all behavior must be learned.

Benzer told the geneticist Max Delbrück about the plan to find behavioral mutants; Delbrück said it was impossible. To which Benzer replied: "But, Max, we found the gene, we've already done it!" (Benzer's mother was more succinct: "From this, you can make a living?") He was soon able to identify mutations related to hyperexcitability, learning, homosexuality and unusual circadian rhythms, like his own: Benzer was almost wholly nocturnal.

Since then, thanks to studies of human twins and a rash of genetic investigations in animals, it has become routinely accepted that most things, including personality, sexual orientation and intelligence, are to some degree affected by genes. The University of Virginia's Eric Turkheimer has declared what he calls the "first law of behavior genetics": that all human behavioral traits are heritable.

Benzer started in solid state physics, migrated to molecular biology, and then to neuroscience.

Caltech Oral History:  ... I had my nose on the transistor. It’s like Max Delbrück [professor of biology at Caltech; d. 1981] failed to discover fission, and he had it under his nose. [Laughter] I failed to discover the transistor, because I had three electrodes in there, and I was measuring things—using one to measure what the other one was doing—but I never had the idea of trying to use that arrangement as an amplifier. Instead, I had a different idea; I had the idea of making a crystal amplifier, but it was too sophisticated. It was based on putting a metal layer on top of a semiconductor and using a tunnel effect to control the current that’s passing through, but I never got it to work. Instead, the Bell Labs guy did the most simpleminded thing, which was to have just these two wires next to each other and have one influence the other. It escaped me, and it was under my nose. Some time later, there was a big demonstration of it at Bell Labs. These guys grabbed me and said, “You should have done this.” [Laughter] And they were right. But, you know, maybe to some extent, because I was already into biology at that time, I wasn’t really focused on that problem. Of course, being a graduate student and not being all that able or having big resources [played a role]. But by the time I got my Ph.D. in 1947, I was already interested in biology.

Aspaturian: What had happened?

Benzer: I was always interested in biology. But two things happened. One of the guys in the lab — his name was Lou [Louis L.] Boyarsky—told me about mapping genes on chromosomes, the work that had been done here at Caltech by [Alfred H.] Sturtevant and [Thomas Hunt] Morgan and their group. I thought that was very exciting. And then I read this book by [Erwin] Schrödinger, written around 1944, called What Is Life?, which inspired a number of other people as well—Francis Crick, for one. Max Delbrück was in the book—he had been at Caltech in the thirties, switching from physics to biology—and there’s a chapter in there on Delbrück’s model of mutation. ...

Aspaturian: What brought you to Caltech, the first time you came?

Benzer: During the sixties, I was getting more and more interested in behavior. One reason was my two children. I have two daughters with very different personalities. If you have one daughter, you don’t notice anything, but if you have a second one, you begin to wonder, “Are we doing things differently, or is it genetic?” So I got interested in this general problem of personality and behavior—how much is genetics and how much is environment? And how do you study such a problem? I had actually begun to be interested even before that time. There was a meeting about ’63, I think, at Cold Spring Harbor, where I remember having a conversation with Marshall Nirenberg. We had this feeling that all the molecular biology problems were on the verge of being solved. It was a little bit like the physicists at the end of the nineteenth century saying, “All we have left to do is one more decimal place.” Little did we anticipate all the recombinant DNA technology. So that was another part of it, the fact that molecular biology was going so well, becoming rather crowded. When things get to that stage, you wonder why you should be doing something somebody else is already doing. It’s just redundant. ...

Aspaturian: Would you say that Drosophila is about the most complex organism with which you can get really rigorous results in this kind of research?

Benzer: Well, I don’t know. It depends on what you want to study. You can get rigorous results with humans now. Modern technology makes it almost as easy to work with humans as with flies, and that’s why I have the courage to get into the human business now.

Aspaturian: But there are so many more behaviors to look at in humans.

Benzer: Humans are wonderful. There’s a book on viewing disorders of man, containing 4,000 hereditary disorders in humans, one or two thousand of which have been actually mapped on the chromosome. Many of these have behavioral components, and hundreds affect the eye. There’s a similar book on Drosophila. And we’re finding that more and more of the genes correspond to one another.

See also this video interview of Benzer. Among other things, he discusses specific mutations that control sexual behavior in drosophila (e.g., length of copulation, courtship), learning ability, memory, etc. Of course, these are just flies  ;-)

For more on Max Delbruck, see For the historians and the ladies; for more on physicists and early molecular biology, see The Eighth Day of Creation.


King Lear, Act 4, Scene 1:

GLOUCESTER: "As flies to wanton boys are we to the gods. They kill us for their sport."

Bolt: 19.19 200m!!!

Shocking! I never expected to see 19.19 in my lifetime, but then I expected Michael Johnson's 19.32 WR to last for decades, like Bob Beamon's long jump WR. (Bolt is such a mutant that I won't be surprised if no one else comes close to MJ's 19.32 for a long time.)

During the Beijing Olympics some readers objected to my stating flat out that Bolt is a more exceptional and impressive athlete than Michael Phelps. Does anyone (who knows something about both track and swimming) still disagree?

It's all in da gene: sleep

I could really use this mutation. It seems I naturally need 8+ hours of sleep -- very inconvenient!

Related posts: All in da gene , mutants

"Horses ain't like people, man, they can't make themselves better than they're born. See, with a horse, it's all in the gene. It's the fucking gene that does the running. The horse has got absolutely nothing to do with it." --- Paulie (Eric Roberts) in The Pope of Greenwich Village.

ScienceNOW:

Early Risers Are Mutants

Don't hate those people who are perky and efficient after only a few hours of sleep. They can't help it. New research suggests that a genetic mutation may explain why some people sleep less.

Researchers don't know exactly why some people do fine with as little as 4 hours of sleep a night, while others need 12. "We've believed for a long time that there's a genetic basis," says Paul Shaw, a neurobiologist at Washington University in St. Louis, Missouri. But scientists have only recently begun to ferret out which genes are responsible.

In 2001, geneticist Ying-Hui Fu and colleagues identified a mutation in a gene called Per2 that appeared to cause familial advanced sleep-phase syndrome (FASPS). People who have this condition sleep a normal 8 hours, but they go to bed earlier than most people, retiring at 6 or 7 in the evening and waking at 3 or 4 in the morning. "After that was published, a lot of these people [with unusual sleep schedules] came to us," says Fu, who is now at Stanford University in Palo Alto, California. "So we started to collect DNA samples." The team now has genetic information from more than 60 families.

Fu and her colleagues have spent the past several years mining this vast genetic storehouse for more mutations that might affect sleep patterns. In 2005, they uncovered another mutation associated with FASPS. And now they say they have found the first genetic mutation in humans that appears to affect sleep duration rather than sleep timing. The mutation lies in DEC2, a gene that codes for a protein that helps turn off expression of other genes, including some that control circadian rhythm, the internal clock that regulates a person's sleep-wake cycle. The mutation occurred in just two people, a mother and her daughter. The women sleep an average of only 6.25 hours, whereas the rest of the family members sleep a more typical 8 hours.

To confirm that this mutation shortens sleep, Fu and colleagues engineered mice to carry the mutant form of DEC2. The mutant mice slept about an hour less than normal mice, the team reports today in Science. The finding also held for fruit flies: Mutant flies slept about 2 hours less than normal flies.

DEC2 likely isn't the whole story when it comes to short sleep. "Genetic control of sleep is going to be complex and is going to include multiple types of genes," says Shaw, who was not affiliated with the study. But that doesn't diminish the importance of this paper, he notes. "It's really an amazing piece of work."

The findings, says Fu, could lead to better treatments for sleep disorders. If the mutated form of DEC2 were available in a pill, Fu says she'd take it, noting that she needs about 8 hours of shuteye a night to feel rested. "All my life I've wanted to be able to sleep less."

Science:

The Transcriptional Repressor DEC2 Regulates Sleep Length in Mammals

Ying He,1 Christopher R. Jones,2 Nobuhiro Fujiki,3 Ying Xu,1,* Bin Guo,4 Jimmy L. Holder, Jr.,1,{dagger} Moritz J. Rossner,5 Seiji Nishino,3 Ying-Hui Fu1,{ddagger}

Sleep deprivation can impair human health and performance. Habitual total sleep time and homeostatic sleep response to sleep deprivation are quantitative traits in humans. Genetic loci for these traits have been identified in model organisms, but none of these potential animal models have a corresponding human genotype and phenotype. We have identified a mutation in a transcriptional repressor (hDEC2-P385R) that is associated with a human short sleep phenotype. Activity profiles and sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice in a zeitgeber time– and sleep deprivation–dependent manner. These mice represent a model of human sleep homeostasis that provides an opportunity to probe the effect of sleep on human physical and mental health.

Recent evolution in humans

Did evolution stop once modern humans emerged in Africa? Or, to the contrary, did it speed up?

This question is addressed in the forthcoming book by Greg Cochran and Henry Harpending: The 10,000 Year Explosion. Harpending is an anthropogist and Cochran a physicist. Together they have produced a number of interesting research ideas in the area of human evolution (see below). I've read a pre-release draft of the book and recommend it highly. If you enjoyed Guns, Germs and Steel by Jared Diamond, then you owe it to yourself to read this book, which directly engages Diamond's thesis that geography (not DNA) is destiny.





I discussed research supporting accelerated recent human evolution by Cochran, Harpending and collaborators in an earlier post: We are all mutants now. The figure below is from a Times article by Nicholas Wade.

We are all mutants now: Some interesting new science suggests that human evolution has accelerated in the last tens of thousands of years. The study by Hawks, Wang, Cochran, Harpending and Moyzis (of UW Madison, Affymetrix, U Utah and UC Irvine) uses linkage disequilibrium tests on hapmap SNP data to determine that roughly 7% of all genes have undergone strong selection recently. The method looks for regions of DNA with similar SNP patterns. If an advantageous gene swept through a population in a relatively short time, replacing other variants, then the pattern of nucleotide polymorphisms in that area of the chromosome will be particularly uniform throughout the group. The results imply that we are all descended from mutants who, relatively recently, out-competed and replaced their contemporaries. The distribution of mutations is not uniform in different geographical populations (i.e., races). Recent evolution is causing genetic divergence, not convergence.

There is a good theoretical argument for why evolution may speed up due to population growth. Given a particular probability distribution for producing beneficial mutations, a large population implies a faster rate of incidence of such mutations. Because reproductive dynamics leads to exponential solutions (i.e., a slight increase in expected number of offspring compounds rapidly), the time required for an advantageous allele to sweep through a population only grows logarithmically with the population, while the rate of incidence grows linearly.

To elaborate on the last point, consider the set of mutations that are sufficiently advantageous that they would sweep through a population of N humans (i.e. reach fixation) in some specified period of time, such as 5000 years. If the probability of such a mutation is p, the rate of occurrence in the population is proportional to pN. Now imagine the population of the group increases to 100N. The rate of mutations is then much higher -- 100pN -- but the time necessary for fixation has only increased by the logarithm of 100 since selective advantage works exponentially: the population fraction with the mutant gene grows as exp( r t ), where r is the reproductive advantage and t is time. This rather obvious point -- that linear beats log -- suggests that the rate of evolution will speed up as population size increases. (A possible loophole is if the probability of mutations as a function of relative advantage is itself an exponential function, and falls off rapidly with increasing advantage.) If the Hawks et al. results are any guide, as many as 7% of all genes have been under intense selection in the last 10-50,000 years. (See here for another summary of the research with a nice illustration of how linkage disequilibrium arises due to favorable mutations.) Importantly, the variants that reached fixation over this period are different in different geographical regions.

Thus civilization, with its consequently larger populations supported by agriculture, enhanced rather than suppressed the rate of human evolution.

A related question is whether selection pressure remained strong after the development of civilization. Perhaps reproductive success became largely decoupled from genetic influences once humans became civilized? Not only is this implausible, but it seems to be directly contradicted by evidence. The graph below, based on English inheritance records, shows that the rich gradually out-reproduced the poor: the wealthy had more than twice as many surviving children as the poor. (Note the range of inheritances in the graph covers the middle class to moderately wealthy; the poor and very rich are not shown.) Thus, in this period of history wealth was a good proxy for reproductive success. Genes which were beneficial for the accrual of wealth (e.g., for intelligence, self-discipline, delayal of gratification, etc.) would have become more prevalent over time. In a simple population model, any lineage that remained consistently poor over a few hundred year period would contribute almost zero to today's population of Britons.



The graph is taken from this paper:

Survival of the Richest: The Malthusian Mechanism in Pre-Industrial England

GREGORY CLARK AND GILLIAN HAMILTON

Fundamental to the Malthusian model of pre-industrial society is the assumption that higher income increased reproductive success. Despite the seemingly inescapable logic of this model, its empirical support is weak. We examine the link between income and net fertility using data from wills on reproductive success, social status and income for England 1585–1638. We find that for this society, close to a Malthusian equilibrium, wealth robustly predicted reproductive success. The richest testators left twice as many children as the poorest. Consequently, in this static economy, social mobility was predominantly downwards. The result extends back to at least 1250 in England.

See also my review of Clark's A Farewell to Alms, and this video of a talk by Clark. When Clark wrote the book he wasn't sure whether it was genetic change or cultural change that led to the industrial revolution in England. In the video lecture he comments that he has since become convinced it was largely genetic. That doesn't jibe with the back of the envelope calculation I give below -- even in the optimistic case (largest effect) it would seem to take a thousand years to have a big shift in overall population characteristics.

Here's a very crude back of the envelope calculation: if, in a brutal Malthusian setting, the top 10% in wealth were to out-reproduce the average by 20% per generation, then after only 10 generations or so (say 2-300 years), essentially everyone in the population would trace their heritage in some way to this group. In our population the average IQ of the high income group is about +.5 SD relative to the average. If the heritability of IQ is .5, then in an ideal case we could see a selection-driven increase of +.25 SD every 2-300 years, or +1 SD per millenium. This is highly speculative, of course, and oversimplified, but it shows that there is (plausibly) no shortage of selection pressure to drive noticeable, even dramatic, change. If the estimate is too high by an order of magnitude (the rich group doesn't directly replace the others; there is inevitably a lot of intermarriage between descendants of the rich and non-rich), a change of +1 SD per 10,000 years would still be possible. There's clearly no shortage in genetic variation affecting intelligence: we see 1 SD variations not just within populations but commonly in individual families!


So where does this leave us?

1) The rate of positive mutations went up due to population growth. More importantly, the rate of mutations that were likely to sweep the entire population in a fixed period of time probably went up.

2) Natural selection did not abate: there is evidence for differential reproductive rates that are impacted by genes.

3) Humans living today are possibly quite different from our ancestors of 50,000 years ago. I would guess we are smarter and better suited to living in a complex society that requires cooperation and planning. We are also probably more likely to be lactose tolerant, nearsighted and bad at hunting ;-)

Cochran and Harpending's new book deserves wide attention and serious discussion.

More mutants

From the Economist, a nice summary of the Hawks et al. paper on a possible recent speedup in human evolution.

Economist: ...Dr Moyzis's paper suggests is a wider phenomenon—that Homo sapiens is continuing to undergo local evolution. He and his colleagues reckon they can both estimate the rate of evolution and identify many of the evolving genes, by using a trick with the clumsy name of linkage disequilibrium.

Genes are linked together in cell nuclei on structures called chromosomes. These come in pairs, one from each parent. However, when sperm and egg cells are formed, the maternal and paternal chromosomes swap bits of DNA to create a new mixture. The pieces of DNA swapped are complementary—that is, they contain the same types of gene. But they may contain different versions of the genes in question, and these different versions can have different biological effects.

Over the generations this process of swapping mixes the genes up thoroughly, and an equilibrium emerges. If a new mutation appears, however, it will take quite a while for that thorough mixing to happen. This means recent mutations can be spotted because they are still linked to the same neighbouring bits of DNA as they were when they first appeared. Moreover, the size of these neighbouring blocks gives an indication of how long ago the mutation in question emerged; long blocks suggest a recent mutation because the mixing process has not had time to break them up.

All this has been known for decades, but it is only recently that enough human DNA sequences have become available for the technique to be used to compare people from different parts of the world. And this is what Dr Moyzis and his colleagues have now done.


What they have found is that about 1,800 protein-coding genes, some 7% of the total known, show signs of having been subject to recent natural selection. By recent, they mean within the past 80,000 years. Moreover, as the chart shows, the rate of change has speeded up over the course of that period. (The sudden fall-off at the end is caused because the linkage-disequilibrium method cannot easily detect very recent mutations, rather than by a sudden reduction in the rate of evolution.) The researchers put this acceleration down to two things. First, the human population has expanded rapidly during that period, which increases the size of the gene pool in which mutations can occur. Second, the environment in which people find themselves has also changed rapidly, creating new contexts in which those mutations might have beneficial effects.

That environmental change itself has two causes. The past 80,000 years is the period in which humanity has spread out of Africa to the rest of the world, and each new place brings its own challenges. It has also been a period of enormous cultural change, and that, too, creates evolutionary pressures. In acknowledgment of these diverse circumstances, the researchers looked in detail at the DNA of four groups of people from around the planet: Yoruba from Africa, Han Chinese and Japanese from Asia, and Europeans.

Various themes emerged. An important one was protection from disease, suspected to be a consequence of the increased risk of infection that living in settlements brings. In this context, for example, various mutations of a gene called G6PD that are thought to offer protection from malaria sprang up independently in different places.

A second theme is response to changes in diet caused by the domestication of plants and animals. One example of this is variation in LCT, a gene involved in the metabolism of lactose, a sugar found in milk. All human babies can metabolise lactose, but only some adults can manage the trick. That fact, and the gene involved, have been known for some time. But Dr Moyzis's team have worked out the details of the evolution of LCT. They suspect that it was responsible for the sudden spread of the Indo-European group of humanity about 4,000 years ago, and also for the more recent spread of the Tutsis in Africa, whose ancestors independently evolved a tolerant version of the gene.

The pressures behind other changes are less obvious. In the past 2,000-3,000 years, for example, Europeans have undergone changes in the gene for a protein that moves potassium ions in and out of nerve cells and taste buds. There have also been European changes in genes linked to cancer and Alzheimer's disease. Chinese, Japanese and Europeans, meanwhile, have all seen changes in a serotonin transporter. Serotonin is one of the brain's messenger molecules, and is particularly involved in establishing mood.

The finding that may cause most controversy, however, is that in the Asian groups there has been strong selection for one variant of a gene that, in a different form, is responsible for Gaucher's disease. A few years ago two of the paper's other authors, Gregory Cochran and Henry Harpending, suggested that the Gaucher's form of the gene might be connected with the higher than average intelligence notable among Ashkenazi Jews. The unstated inference is that something similar might be true in Asians, too.

The Ashkenazim paper caused quite a stir at the time. It was merely a hypothesis, but it did suggest a programme of research that could be conducted to test the hypothesis. So far, no one—daring or foolish—has tried. Eventually, however, such questions will have to be faced. The paper Dr Moyzis and his colleagues have just published is a ranging shot, but the amount of recent human evolution it has exposed is surprising. Others will no doubt follow, and the genetic meaning of the term “race”, if it has one, will be exposed for all to see.

We are all mutants now

Some interesting new science suggests that human evolution has accelerated in the last tens of thousands of years. The study by Hawks, Wang, Cochran, Harpending and Moyzis (of UW Madison, Affymetrix, U Utah and UC Irvine) uses linkage disequilibrium tests on hapmap SNP data to determine that roughly 7% of all genes have undergone strong selection recently. The method looks for regions of DNA with similar SNP patterns. If an advantageous gene swept through a population in a relatively short time, replacing other variants, then the pattern of nucleotide polymorphisms in that area of the chromosome will be particularly uniform throughout the group. The results imply that we are all descended from mutants who, relatively recently, out-competed and replaced their contemporaries. The distribution of mutations is not uniform in different geographical populations (i.e., races). Recent evolution is causing genetic divergence, not convergence.

There is a good theoretical argument for why evolution may speed up due to population growth. Given a particular probability distribution for producing beneficial mutations, a large population implies a faster rate of incidence of such mutations. Because reproductive dynamics leads to exponential solutions (i.e., a slight increase in expected number of offspring compounds rapidly), the time required for an advantageous allele to sweep through a population only grows logarithmically with the population, while the rate of incidence grows linearly.

Note Cochran is a physicist who does evolutionary biology as a hobby :-) For some reason, this seldom happens in the opposite direction...





(original graphic from the Times; PNAS paper; University of Utah press release.)

NYTimes: Researchers analyzing variation in the human genome have concluded that human evolution accelerated enormously in the last 40,000 years under the force of natural selection.

The finding contradicts a widely held assumption that human evolution came to a halt 10,000 years ago or even 50,000 years ago. Some evolutionary psychologists, for example, assume that the mind has not evolved since the Ice Age ended 10,000 years ago.

But other experts expressed reservations about the new report, saying it is interesting but more work needs to be done.

The new survey — led by Robert K. Moyzis of the University of California, Irvine, and Henry C. Harpending of the University of Utah — developed a method of spotting human genes that have become more common through being favored by natural selection. They say that some 7 percent of human genes bear the signature of natural selection.

By dating the time that each of the genes came under selection, they have found that the rate of human evolution was fairly steady until about 50,000 years ago and then accelerated up until 10,000 years ago, they report in the current issue of The Proceedings of the National Academy of Sciences. The high rate of selection has probably continued to the present day, Dr. Moyzis said, but current data are not adequate to pick up recent selection.

The brisk rate of human selection occurred for two reasons, Dr. Moyzis’ team says. One was that the population started to grow, first in Africa and then in the rest of the world after the first modern humans left Africa. The larger size of the population meant that there were more mutations for natural selection to work on. The second reason for the accelerated evolution was that the expanding human populations in Africa and Eurasia were encountering climates and diseases to which they had to adapt genetically. The extra mutations in their growing populations allowed them to do so.

Dr. Moyzis said it was widely assumed that once people developed culture, they protected themselves from the environment and from the forces of natural selection. But people also had to adapt to the environments that their culture created, and the new analysis shows that evolution continued even faster than before.

The researchers took their data from the HapMap project, a survey designed by the National Institutes of Health to look at sites of common variation in the human genome and to help identify the genes responsible for common diseases. The HapMap data, generated by analyzing the genomes of people from Africa, East Asia and Europe, has also been a trove for people studying human evolutionary history.

David Reich, a population geneticist at the Harvard Medical School, said the new report was “a very interesting and exciting hypothesis” but that the authors had not ruled out other explanations of the data. The power of their test for selected genes falls off in looking both at more ancient and more recent events, he said, so the overall picture might not be correct.

Similar reservations were expressed by Jonathan Pritchard, a population geneticist at the University of Chicago.

“My feeling is that they haven’t been cautious enough,” he said. “This paper will probably stimulate others to study this question.”

University of Utah press release:

ARE HUMANS EVOLVING FASTER?

FINDINGS SUGGEST WE ARE BECOMING MORE DIFFERENT, NOT ALIKE

Media Contacts

Dec. 10, 2007 - Researchers discovered genetic evidence that human evolution is speeding up - and has not halted or proceeded at a constant rate, as had been thought - indicating that humans on different continents are becoming increasingly different.

"We used a new genomic technology to show that humans are evolving rapidly, and that the pace of change has accelerated a lot in the last 40,000 years, especially since the end of the Ice Age roughly 10,000 years ago," says research team leader Henry Harpending, a distinguished professor of anthropology at the University of Utah.

Harpending says there are provocative implications from the study, published online Monday, Dec. 10 in the journal Proceedings of the National Academy of Sciences:

"We aren't the same as people even 1,000 or 2,000 years ago," he says, which may explain, for example, part of the difference between Viking invaders and their peaceful Swedish descendants. "The dogma has been these are cultural fluctuations, but almost any Temperament trait you look at is under strong genetic influence."

"Human races are evolving away from each other," Harpending says. "Genes are evolving fast in Europe, Asia and Africa, but almost all of these are unique to their continent of origin. We are getting less alike, not merging into a single, mixed humanity." He says that is happening because humans dispersed from Africa to other regions 40,000 years ago, "and there has not been much flow of genes between the regions since then."
"Our study denies the widely held assumption or belief that modern humans [those who widely adopted advanced tools and art] appeared 40,000 years ago, have not changed since and that we are all pretty much the same. We show that humans are changing relatively rapidly on a scale of centuries to millennia, and that these changes are different in different continental groups."

The increase in human population from millions to billions in the last 10,000 years accelerated the rate of evolution because "we were in new environments to which we needed to adapt," Harpending adds. "And with a larger population, more mutations occurred."

Study co-author Gregory M. Cochran says: "History looks more and more like a science fiction novel in which mutants repeatedly arose and displaced normal humans - sometimes quietly, by surviving starvation and disease better, sometimes as a conquering horde. And we are those mutants."

Harpending conducted the study with Cochran, a New Mexico physicist, self-taught evolutionary biologist and adjunct professor of anthropology at the University of Utah; anthropologist John Hawks, a former Utah postdoctoral researcher now at the University of Wisconsin, Madison; geneticist Eric Wang of Affymetrix, Inc. in Santa Clara, Calif.; and biochemist Robert Moyzis of the University of California, Irvine.

No Justification for Discrimination

The new study comes from two of the same University of Utah scientists - Harpending and Cochran - who created a stir in 2005 when they published a study arguing that above-average intelligence in Ashkenazi Jews - those of northern European heritage - resulted from natural selection in medieval Europe, where they were pressured into jobs as financiers, traders, managers and tax collectors. Those who were smarter succeeded, grew wealthy and had bigger families to pass on their genes. Yet that intelligence also is linked to genetic diseases such as Tay-Sachs and Gaucher in Jews.

That study and others dealing with genetic differences among humans - whose DNA is more than 99 percent identical - generated fears such research will undermine the principle of human equality and justify racism and discrimination. Other critics question the quality of the science and argue culture plays a bigger role than genetics.

Harpending says genetic differences among different human populations "cannot be used to justify discrimination. Rights in the Constitution aren't predicated on utter equality. People have rights and should have opportunities whatever their group."

Analyzing SNPs of Evolutionary Acceleration

The study looked for genetic evidence of natural selection - the evolution of favorable gene mutations - during the past 80,000 years by analyzing DNA from 270 individuals in the International HapMap Project, an effort to identify variations in human genes that cause disease and can serve as targets for new medicines.

The new study looked specifically at genetic variations called "single nucleotide polymorphisms," or SNPs (pronounced "snips") which are single-point mutations in chromosomes that are spreading through a significant proportion of the population.

Imagine walking along two chromosomes - the same chromosome from two different people. Chromosomes are made of DNA, a twisting, ladder-like structure in which each rung is made of a "base pair" of amino acids, either G-C or A-T. Harpending says that about every 1,000 base pairs, there will be a difference between the two chromosomes. That is known as a SNP.

Data examined in the study included 3.9 million SNPs from the 270 people in four populations: Han Chinese, Japanese, Africa's Yoruba tribe and northern Europeans, represented largely by data from Utah Mormons, says Harpending.

Over time, chromosomes randomly break and recombine to create new versions or variants of the chromosome. "If a favorable mutation appears, then the number of copies of that chromosome will increase rapidly" in the population because people with the mutation are more likely to survive and reproduce, Harpending says.

"And if it increases rapidly, it becomes common in the population in a short time," he adds.

The researchers took advantage of that to determine if genes on chromosomes had evolved recently. Humans have 23 pairs of chromosomes, with each parent providing one copy of each of the 23. If the same chromosome from numerous people has a segment with an identical pattern of SNPs, that indicates that segment of the chromosome has not broken up and recombined recently.

That means a gene on that segment of chromosome must have evolved recently and fast; if it had evolved long ago, the chromosome would have broken and recombined.

Harpending and colleagues used a computer to scan the data for chromosome segments that had identical SNP patterns and thus had not broken and recombined, meaning they evolved recently. They also calculated how recently the genes evolved.

A key finding: 7 percent of human genes are undergoing rapid, recent evolution.

The researchers built a case that human evolution has accelerated by comparing genetic data with what the data should look like if human evolution had been constant:

The study found much more genetic diversity in the SNPs than would be expected if human evolution had remained constant.

If the rate at which new genes evolve in Africans was extrapolated back to 6 million years ago when humans and chimpanzees diverged, the genetic difference between modern chimps and humans would be 160 times greater than it really is. So the evolution rate of Africans represents a recent speedup in evolution.

If evolution had been fast and constant for a long time, there should be many recently evolved genes that have spread to everyone. Yet, the study revealed many genes still becoming more frequent in the population, indicating a recent evolutionary speedup.
Next, the researchers examined the history of human population size on each continent. They found that mutation patterns seen in the genome data were consistent with the hypothesis that evolution is faster in larger populations.

Evolutionary Change and Human History: Got Milk?

"Rapid population growth has been coupled with vast changes in cultures and ecology, creating new opportunities for adaptation," the study says. "The past 10,000 years have seen rapid skeletal and dental evolution in human populations, as well as the appearance of many new genetic responses to diet and disease."

The researchers note that human migrations into new Eurasian environments created selective pressures favoring less skin pigmentation (so more sunlight could be absorbed by skin to make vitamin D), adaptation to cold weather and dietary changes.

Because human population grew from several million at the end of the Ice Age to 6 billion now, more favored new genes have emerged and evolution has speeded up, both globally and among continental groups of people, Harpending says.

"We have to understand genetic change in order to understand history," he adds.

For example, in China and most of Africa, few people can digest fresh milk into adulthood. Yet in Sweden and Denmark, the gene that makes the milk-digesting enzyme lactase remains active, so "almost everyone can drink fresh milk," explaining why dairying is more common in Europe than in the Mediterranean and Africa, Harpending says.

He now is studying if the mutation that allowed lactose tolerance spurred some of history's great population expansions, including when speakers of Indo-European languages settled all the way from northwest India and central Asia through Persia and across Europe 4,000 to 5,000 years ago. He suspects milk drinking gave lactose-tolerant Indo-European speakers more energy, allowing them to conquer a large area.

But Harpending believes the speedup in human evolution "is a temporary state of affairs because of our new environments since the dispersal of modern humans 40,000 years ago and especially since the invention of agriculture 12,000 years ago. That changed our diet and changed our social systems. If you suddenly take hunter-gatherers and give them a diet of corn, they frequently get diabetes. We're still adapting to that. Several new genes we see spreading through the population are involved with helping us prosper with high-carbohydrate diet."

Mutant memory: allele for emotional memory formation

A mutation in the gene for the α2b-adrenoceptor improves the formation of memories of strong emotional events. Students in Zurich with the mutation performed twice as well on a controlled test. Rwandan refugees with the mutation tended to suffer significantly more often from flashbacks of traumatic events. So, the mutation affects cognitive function in a clear way. It's also distributed unevenly among different populations -- 30% of Swiss and 12% of Rwandans have the mutant allele.

For related discussion see here and here.

Economist: ...Rare events that might have an impact on an individual's survival or reproduction should have a special fast lane into the memory bank—and they do. It is called the α2b-adrenoceptor, and it is found in the amygdala, a part of the brain involved in processing strong emotions such as fear. The role of the α2b-adrenoceptor is to promote memory formation—but only if it is stimulated by adrenaline. Since emotionally charged events are often accompanied by adrenaline secretion, the α2b-adrenoceptor acts as a gatekeeper that decides what will be remembered and what discarded.

However, the gene that encodes this receptor comes in two varieties. That led Dominique de Quervain, of the University of Zurich, to wonder if people with one variant would have better emotional memories than those with the other. The short answer, just published in Nature Neuroscience, is that they do. Moreover, since the frequencies of the two variants are different in different groups of people, whole populations may have different mixtures of emotional memory.

...in his first experiment. This involved showing students photographs of positive scenes such as families playing together, negative scenes such as car accidents, and neutral ones, such as people on the phone. Those students with at least one gene for the rarer version of the protein (everyone has two such genes, one from his father and one from his mother) were twice as good at remembering details of emotionally charged scenes than were those with only the common version. When phone-callers were the subject, there was no difference in the quality of recall.

That is an interesting result, but some of Dr de Quervain's colleagues at the University of Konstanz, in Germany, were able to take it further in a second experiment. In fact, they took it all the way along a dusty road in Uganda, to the Nakivale refugee camp. This camp is home to hundreds of refugees of the Rwandan civil war of 1994.

In this second experiment the researchers were not asking about photographs. With the help of specially trained interviewers, they recorded how often people in the camp suffered flashbacks and nightmares about their wartime experiences. They then compared those results with the α2b-adrenoceptor genes in their volunteers. As predicted, those with the rare version had significantly more flashbacks than those with only the common one.

Besides bolstering Dr de Quervain's original hypothesis, this result is interesting because only 12% of the refugees had the rarer gene. In Switzerland, by contrast, 30% of the population has the rare variety—and the Swiss are not normally regarded as an emotional people.

It's all in da gene: muscles II

"Horses ain't like people, man, they can't make themselves better than they're born. See, with a horse, it's all in the gene. It's the fucking gene that does the running. The horse has got absolutely nothing to do with it." --- Paulie (Eric Roberts) in The Pope of Greenwich Village.

The Times has a nice article on the myostatin mutation in dogs, which leads to increased speed (one copy of mutant gene) and muscle mass ("bully whippet", with two copies). In the picture below, the bully whippet is on the right.



We discussed this in an earlier post, including data on the frequency of the human myostatin mutation in different population groups. Two copies of a myostatin mutation in humans can lead to super babies. (40% more muscle mass than an ordinary kid -- one baby could do the iron cross at 5 months old!)

...Free of most of the ethical concerns — and practical difficulties — associated with the practice of eugenics in humans, dog breeders are seizing on new genetic research to exert dominion over the canine gene pool. Companies with names like Vetgen and Healthgene have begun offering dozens of DNA tests to tailor the way dogs look, improve their health and, perhaps soon, enhance their athletic performance.

...“We’re on the verge of a real radical shift in the way we apply genetics in our society,” said Mark Neff, associate director of the veterinary genetics laboratory at the University of California, Davis. “It’s better to be first confronted with some of these issues when they concern our pets than when they concern us.”

...A mutation similar to the one that makes some whippets faster also exists in humans: a sliver of genetic code that regulates muscle development, is missing.

“It would be extremely interesting to do tests on the track finalists at the Olympics,” said Elaine Ostrander, the scientist at the National Institutes of Health who discovered that the fastest whippets had a single defective copy of the myostatin gene, while “bullies” had two.

“But we wouldn’t know what to do with the information,” Ms. Ostrander said. “Are we going to segregate the athletes who have the mutation to run separately?” For the moment, it is whippet owners who find themselves on the edge of that particular bioethical frontier.

It was not exactly news to breeders that speed is an inherited trait: whippets were developed in the late 1800s specifically for racing. But knowing that one of her dogs was sired by a carrier of the gene, said Jen Jensen, a whippet owner in Fair Oaks, Calif., makes its championships seem “less earned.” Ms. Jensen’s suggestion that a DNA test be required for all dogs and that the fastest ones without the mutation be judged and raced separately, however, has not gone over well.

At a recent race here in southern New Jersey, some whippet owners wanted the mutation eliminated altogether, even if that meant fewer fast dogs. But as the dogs pounded after a lure at 35 miles per hour, several owners allowed that they would prefer a whippet with the gene for speed.

“It’s more fun having fast dogs than slow dogs,” said Libby Kirchner, of Glassboro, N.J.

Mutants among us

Prosopagnosia, or face blindness, affects a surprisingly large fraction (few percent) of the population. Those who suffer from it have difficulty in distinguishing human faces, except by conscious effort (recalling particular features, or contextual clues). Preliminary evidence is that (a) we have a specialized module in our brains for face recognition and (b) there are one or more alleles (gene variants) which disable this function to various degrees.

How could these alleles survive selection? One would guess that face blindness is an evolutionary handicap, at least to some degree (although perhaps less so in small hunter gatherer groups, or in theoretical physics ;-). Is there a compensating advantage provided by the mutation?

It's fascinating to consider how many other strange cognitive mutations are present in our population at the percent (or fraction of percent level). Memory? Musical ability? Specialized mathematical ability (e.g., visualizing geometrical shapes, or a "feel" for magnitudes of quantities, or lightning calculation)?

I suspect we'll find more and more of these, and their associated alleles, as time goes by. See GNXP.com for more discussion and references.

It just occurred to me that there are likely dozens of readers of this blog who have prosopagnosia. Would anyone care to share their (anonymous) comments on how they adjust to the condition, and when they noticed having it?

NYTimes: Dr. Sellers, a professor of English at Hope College in Holland, Mich., has a disorder called prosopagnosia, or face blindness, and she has had it since birth. “I see faces that are human,” she said, “but they all look more or less the same. It’s like looking at a bunch of golden retrievers: some may seem a little older or smaller or bigger, but essentially they all look alike.”

Face blindness can be a rare result of a stroke or a brain injury, but a study published in the July issue of The American Journal of Medical Genetics Part A is the first report of the prevalence of a congenital or developmental form of the disorder.

The researchers say the phenomenon is much more common than previously believed: they found that 2.47 percent of 689 randomly selected students in Münster, Germany, had the disorder.

Dr. Thomas Grüter, a co-author of the paper, said there were reasons to believe that the condition was equally common in other populations. “First,” he said, “our population was not selected in terms of cognition deficits. And second, a study done by Harvard University with a different diagnostic approach yielded very similar figures.”

Dr. Grüter is himself prosopagnosic. His wife and co-author, Dr. Martina Grüter of the Institute for Human Genetics at the University of Münster, did not realize he was face blind until she had known him more than 20 years. The reason, she says, is he was so good at compensating for his deficits.

“How do you recognize a face?” she asked. “For most people, this is a silly question. You just do. But people who have prosopagnosia can tell you exactly why they recognize a person. Thomas consciously looks for the details that others notice unconsciously.”