David Goldstein profile

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 Alzheimers. 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.