profiles

Nicholas Wade profiles Duke University geneticist David Goldstein in the current NY Times. This article covers several different topics that are worth comment.

He begins by describing the flawed premise of the HapMap:

The principal rationale for the $3 billion spent to decode the human genome was that it would enable the discovery of the variant genes that predispose people to common diseases like cancer and Alzheimer’s. A major expectation was that these variants had not been eliminated by natural selection because they harm people only later in life after their reproductive years are over, and hence that they would be common.

This idea, called the common disease/common variant hypothesis, drove major developments in biology over the last five years. Washington financed the HapMap, a catalog of common genetic variation in the human population. Companies like Affymetrix and Illumina developed powerful gene chips for scanning the human genome. Medical statisticians designed the genomewide association study, a robust methodology for discovering true disease genes and sidestepping the many false positives that have plagued the field.

Of course, it turned out great for me, and others who wanted to study recent evolution of human genes. But the entire thing was built on an idea that was obviously false. Sure, a variant that causes mortality late in life might be only weakly selected. But it still shouldn't be common! And any knowledgeable reader of the early HapMap publications could tell that the common variant model was built on illusions. To sell the idea, they depended on genetic disorders like sickle cell, cystic fibrosis, and lactose intolerance. Most were selective balances; the few that weren't (like lactase) would later turn out to be cases of very recent selection.

In other words, the common variant idea needed selection to be common, even ubiquitous -- even as its proponents were arguing that selection was rare or nonexistent.

Goldstein points this out:

“After doing comprehensive studies for common diseases, we can explain only a few percent of the genetic component of most of these traits,” he said. “For schizophrenia and bipolar disorder, we get almost nothing; for Type 2 diabetes, 20 variants, but they explain only 2 to 3 percent of familial clustering, and so on.”

The reason for this disappointing outcome, in his view, is that natural selection has been far more efficient than many researchers expected at screening out disease-causing variants. The common disease/common variant idea is largely wrong. What has happened is that a multitude of rare variants lie at the root of most common diseases, being rigorously pruned away as soon as any starts to become widespread.

I should add to those comments: Of the variants that have been found in these genome-wide association studies, for Alzheimer's, Type 2 diabetes, schizophrenia -- a significant number appear to have been recently selected. So even these few that have been found wouldn't have been predicted under the "common variant" model. But most variants that cause senescence must be rare. That's Medawar's theory. Or they may be balances. That's Williams' theory. This is a case where modern evolutionary theory gives very clear predictions, which have now been confirmed at enormous cost.

I suppose I shouldn't worry. After all, the physicists certainly spend a lot of money to confirm their theories...

The article goes into some detail about Goldstein's work on genetics and Jewish history, the subject of his recent book. I don't have much to add, but I'll be linking to another interesting article on that topic later on.

Toward the end, the article moves into my special area of expertise:

Another pursuit that interests him, one of high promise for reconstructing human evolutionary history, is that of discovering which genes bear the mark of recent natural selection. When a new version of a gene becomes more common, it leaves a pattern of changes that geneticists can detect with various statistical tests. Many of these selected genes reflect new diets or defenses against disease or adaptations to new climates. But they tend to differ from one race to another because each human population, after the dispersal from Africa some 50,000 years ago, has had to adapt to different circumstances.

This newish finding has raised fears that other, more significant differences might emerge among races, spurring a resurrection of racist doctrines. “There is a part of the scientific community which is trying to make this work off limits, and that I think is hugely counterproductive,” Dr. Goldstein said.

This has indeed become a great concern for the people who fund research into genetic variation. NIH is conducting a panel next month on the "ethical concerns" raised by the study of recent selection, complete with advice to journal editors about how to review such research. I think Goldstein's worry -- that some are "trying to make this work off limits" -- is largely justified.

Goldstein argues that finding recent selection will be ultimately unimportant:

He says he thinks that no significant genetic differences will be found between races because of his belief in the efficiency of natural selection. Just as selection turns out to have pruned away most disease-causing variants, it has also maximized human cognitive capacities because these are so critical to survival. “My best guess is that human intelligence was always a helpful thing in most places and times and we have all been under strong selection to be as bright as we can be,” he said.

This is more than just a guess, however. As part of a project on schizophrenia, Dr. Goldstein has done a genomewide association study on 2,000 volunteers of all races who were put through cognitive tests. “We have looked at the effect of common variation on cognition, and there is nothing,” Dr. Goldstein said, meaning that he can find no common genetic variants that affect intelligence. His view is that intelligence was developed early in human evolutionary history and was then standardized.

I have no opinion about whether Goldstein's argument about genetic causation of IQ is correct. It's clearly heritable within populations, but there has been very little success identifying genes that may explain the genetic variance. So his argument about common variants could well be right.

Still, it seems to me that he wants to have his cake and eat it too. Some thoughts:

1. The passage seems contradictory. If we're not going to find anything interesting, why is it such an interesting topic?

2. Of course, intelligence isn't the only thing that's interesting. My research on language and hearing, diet change, food preferences, disease resistance, aging and longevity -- all those things are pretty interesting too, and vary historically among populations. I can understand why people think intelligence is ominous and threatening, but is it really more so than, say, disease susceptibility?

3. If Goldstein is right, and IQ is like other traits for which the common variant model is false, that still doesn't lead to his conclusion. After all, Type 2 diabetes varies in risk both among individuals and between populations for genetic reasons, even though we've found few common alleles of significant effect. The logical conclusion of Goldstein's argument is that the brain is complicated, thousands of rare genetic variants may have relatively large effects on IQ in different families, and any differences that exist must have many causes.

4. If the "intelligence" function of the brain is really affected by thousands of different rare mutations, in hundreds or maybe thousands of different genes, doesn't that mean that IQ should be strongly influenced by pleiotropy? After all, at least some of those hundreds of genes must be doing other things, and if they're anything like the rest of the genome, around one in seven of them has been strongly selected in the last 10,000 years.

The assumption here that I find the most troubling is that intelligence is somehow the purpose of recent human evolution -- so much so that populations could not be anything but identical. But nothing could refute that assumption more eloquently than the scans for recent selection. Yes, the brain is represented on those lists, but so are the testes. And the blood. And the gut. We know from functional genomics and gene expression that brain, gut, bone, and blood are often influenced by the same genes. Recent human evolution is not progress toward a pinnacle. The human population is a snowdrift where ten thousand trade-offs have blown together, mostly by the luck of mutations.

I prefer to fall back on Dobzhansky. We should not confuse equality with identity.

Reporter Bruce Lieberman profiles geneticist Ajit Varki in this week's Nature. It's a good summary of Varki's work in sialic acid evolution, focusing on one particular change in the N-glycolyl neuraminic acid (Neu5Gc), work that I touched on here around 3 years ago.

On a molecular level, the difference between Neu5Gc and Neu5Ac is tiny -- a single added oxygen atom perched on one arm distinguishes one from the other (see graphic). But on a biological level, the difference could be enormous. "We thought if monkeys and all of our closest relatives have Neu5Gc and humans don't, then there must be a molecular basis for that," Varki says. He subsequently found it in an enzyme that converts Neu5Ac to Neu5Gc, but which is disabled by mutation in humans.

The article also covers the founding of the Center for Academic Research and Training in Anthropogeny, a research effort of the University of California, San Diego and the Salk Institute. Led by Varki, Margaret Schoeninger, and Pascal Gagneux, the center aims to become an important focus of interdisciplinary work in human origins. I was lucky enough to be invited to one of their research seminars two years ago, and I can say it's a wonderful environment for collaboration, if the project can continue and build on these small meetings:

Between 1998 and 2007, the Project for Explaining the Origin of Humans drew in anthropologists, primate biologists, geneticists, immunologists, neuroscientists, linguists and many others. They discussed topics ranging from the evolution of language to the differences between humans, Neanderthals and Homo erectus, the first hominid to leave Africa. Goodman says the interdisciplinary nature of the series made it extremely important to the field. "You really had the chance to explore an issue as it relates to the evolutionary origins of our species," he says.

...

Varki estimates that he has listened to more than 300 talks on various aspects of this discipline. "The idea is the linguist needs to talk to the molecular biologist who needs to talk to the neuroscientist who needs to talk to the psychologist and philosopher about these issues," he says. "Most areas of human knowledge are somewhere relevant."

I think that's exactly the right attitude -- we need more interdisciplinary efforts. I run up against the blind spots of various specialties all the time, and I'm just one person. On the other hand, it is very challenging to get people to invest the time to learn facts outside their narrow field. If this institute helps those efforts, it will be all to the good.

References:

Lieberman B. 2008. Human evolution: details of being human. Nature 454:21-23. doi:10.1038/454021a

This is a great profile of Alan Mann, on the occasion of the new human evolution exhibit at the University of Pennsylvania Museum of Archaeology and Anthropology:

Describing himself as an evolutionary biologist and a physical anthropologist, Mann remembers that when he began teaching at Penn in 1969, he thought "human evolution was one of the most im portant subjects going." But his students didn't always share his enthusiasm. "So I began thinking about how to make this information not only interesting but also personally important, so they could learn something about themselves that would be useful."

Calling on what he knew about how teeth have changed over time, he asked his students about their own experiences with wisdom teeth and crowded teeth. "Our ancestors had much bigger faces and jaws, with plenty of room for third molars," he says. "But as our faces have evolved, they've become much smaller. They've literally moved under our braincases and the dental arch has shortened. There's no longer room for the third molars" a situation Mann describes as a consequence, or "scar" of evolution.

The article goes though a number of other examples, all fitting the theme of the exhibit. But I especially liked this passage about creationism and evolution:

"Look," he says. "I have been studying human evolution for 40 years. I have traveled around the world. I have handled just about every human fossil, every relic of our evolution. I know them to be genuine. I know that they represent the development of our own kind from creatures who had many resemblances to apes but were not apes, and over time, I see a system of change that can be marked in the record of geology and in dating processes that show that over time, our kind evolved into who we are.

"When I say this to a creationist who has never handled a fossil, who doesn't really have my experience, and they suggest that this is wrong, that I don't know what I'm talking about, I am distressed. It's not to me a proper way of debate."

I pulled the quote for the headline of the post, because it has such a resonance for those of us who study the human fossil record.

It seems to be biomedical profile week in the NY Times, so in addition to the profile of Francisco Ayala, Claudia Dreifus presents a profile of Arno Motulsky. Known for his early work on enzyme interactions, he is now credited for essential ideas leading to pharmacogenomics.

Q. YOUR OBSERVATION IN 1957 ABOUT THE INTERACTIONS BETWEEN THE ENZYMES PRODUCED BY GENES AND SOME DRUGS -- DOES IT PLEASE YOU TO SEE HOW IMPORTANT IT HAS BECOME?

A. Yes, because at first the idea was not well accepted. I remember going to an important pharmaceutical executive and I said, "I found a new way to find out about drug reactions." And he kissed me off: "Drug reactions?"

Things also moved slowly for a long time because it was hard to test for this. But now, with the new DNA testing, you can do many things faster and better. And with the modern computerized genomics, you can even test for reactions to many different enzymes, all at the same time.

On the other hand, I think the promise of pharmacogenetics is sometimes overhyped. There are people who think we'll be able to solve almost everything with an individualized prescription. We need more research, which will be expensive.

It's a short interview, but includes some interesting biographical details.

Cornelia Dean writes a long profile of Francisco Ayala in today's Science Times. The occasion is the publication of his new book, Darwin's Gift to Science and Religion.

Dr. Ayala gives about 50 talks a year, he said in a recent interview in New York, a day after he delivered the inaugural Louis Levine-Gabriella de Beer lecture in genetics at City College. (He had spoken the day before, at North Carolina State University, on the evolution of morality, and spoke two days later at McGill University in Toronto, where his subject was Darwinism and religion.)

Because of his eminence -- he is a member of the National Academy of Sciences, a former president of the American Association for the Advancement of Science and a winner of the National Medal of Science -- Dr. Ayala "has a bully pulpit," said Eugenie Scott, who heads the National Center for Science Education, a group that advocates for the teaching of evolution and against creationism in public schools. "When Francisco speaks, people listen."

Ayala is a fascinating person to talk to, and his vines make some of the best wine I've ever had. The article is a nice portrait of his current work.

Michael Balter wrote a nice "Scientist at Work" profile of paleoneurologist Ralph Holloway.

Ralph is one of my real idols in the field, so it's a pleasure to read this. Of course it begins with the hobbit, but Balter devotes much of the piece to explaining the lunate sulcus controversy of the 1980's and 1990's.

I think that Balter really captures the most important aspect of Holloway's scientific work with this:

Most notably, during his 43 years at Columbia, Dr. Holloway has argued that hominid brains began to evolve important anatomical alterations several million years ago, when they were ape-size and had yet to undergo the striking expansion often seen as humanity's hallmark.

We humans are rightly proud of our big brains. But most anthropologists now agree with Dr. Holloway that increases in size alone cannot explain advanced human cognition. There have also been structural changes that distinguish the brain of Homo sapiens from those of our hominid ancestors, as well as those of close cousins like the chimpanzee.

The lunate sulcus story illustrates this point quite well, but far more important (and less controversial) has been Holloway's identification of an enlarged Broca's area in the KNM-ER 1470 endocast. Only recently has imaging analysis been able to flesh out some of the internal ways that brain reorganization has characterized primate and human evolution. But the external manifestations on endocasts were a leading indicator -- and remain the only direct source of evidence about brain function from fossils.

There's much more to say than this, but start with the profile!

Michael Balter has a nice profile of archaeologist Randall White in the NY Times:

Despite Dr. White's early success, he found it difficult to begin a dig of his own in the Périgord. Dr. White says that the French prehistorian responsible for issuing permits to excavate in the area preferred that he work as part of his team rather than independently.

"I was shut out of working in France the way I wanted to do it," Dr. White said. Rather than agree to work as part of the team, he began to look at collections of artifacts stored in museums in Canada and the United States, where he found thousands of objects from digs by Peyrony and other archaeologists, including artifacts from the Abri Castanet, sometimes stored in terrible conditions.

"I saw Upper Paleolithic engravings with drawers on top of them," Dr. White said, adding that these experiences fueled his early anger about the antiquities trade.

The profile starts with a quick summary of the argument in White's new book, about Otto Hauser and Denis Peyrony's early 20th century excavations. Sounds interesting -- I hope I get a review copy!

Claudia Dreifus profiles biological anthropologist Nina Jablonski in today's NY Times. She has a new book out, Skin, A Natural History.

Modern humans, we love to alter our skin. You'll find very few people walking around today with unadorned skin. They might make permanent changes -- piercing, scarring, tattooing -- to memorialize events and announce their identity. Or they might use cosmetics for temporary alterations to announce their attractiveness, mood or sexual availability. The bottom line: humans are the self-decorating ape.

The interview includes questions about skin color, cosmetics, and the first fossil chimpanzee.

Science this week has a long profile of Bruce Lahn, written by Michael Balter. What I find most remarkable is how some high-profile geneticists are willing to stand up against the idea that humans could be subject to natural selection.

A sidebar accompanying the profile reviews the lack of evidence for a connection between ASPM variants and IQ in two large studies. It also mentions the possible sperm-brain connection:

But genome researcher Chris Ponting of the University of Oxford, U.K., notes that microcephalin and ASPM are also expressed outside the brain. In last May's issue of Bioinformatics, he reported that part of ASPM's DNA sequence resembles that of genes involved in the function of flagella, which propel sperm. Earlier work had shown that ASPM is expressed during sperm production. Ponting suggests that natural selection might have acted on flagellar function rather than brain growth. "These genes could well have many functions in many parts of the body," Ponting says, "and any one of these could have driven their adaptive sequence changes."

This is an interesting suggestion considering the high rate of evolution of ASPM during primate evolution -- it tracks like a sperm production gene in that regard. But it doesn't explain microcephalin or the other brain-expressed genes enriched for positive selection on the human lineage. So if ASPM itself isn't under selection for brain function, plenty of other genes have been.

One thing is for sure -- with the strength of selection on ASPM, it has to be strongly correlated with something that influences fitness.

The Times Online has a short profile of Chris Stringer, with relation to the ancient Britain project. I just love the way it starts:

Shortly after marrying an archaeologist, Agatha Christie remarked: "An archaeologist is the best husband any woman can have. The older she gets, the more interested he is in her."

Professor Chris Stringer considers this as he makes his way through a maze of steel cupboards at the back of the Natural History Museum. His partner, Angela, is approaching her fiftieth birthday, but to interest him professionally she would need to be a good deal older: "Any younger than 10,000 years and I lose interest."

That is soooo cute!

(via Palanthsci)