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Geneticist: Can`t Find Nuthin`
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September 16, 2008, 05:43 PM
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Nicholas Wade of the NYT has an article on the genetics of mental diseases and intelligence that focuses on a geneticist named David B. Goldstein. (I don`t like using initials in names because I can`t really remember them, so I have to laboriously look them up, but the "B." in his name is necessary because there are so many mildly prominent David Goldsteins.)

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.

But David B. Goldstein of Duke University, a leading young population geneticist known partly for his research into the genetic roots of Jewish ancestry, says the effort to nail down the genetics of most common diseases is not working. �There is absolutely no question,� he said, �that for the whole hope of personalized medicine, the news has been just about as bleak as it could be.�

Of the HapMap and other techniques developed to make sense of the human genome, Dr. Goldstein said, �Technically, it was a tour de force.� But in his view, this prodigious labor has produced just a handful of genes that account for very little of the overall genetic risk.

�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.

It takes large, expensive trials with hundreds of patients in different countries to find even common variants behind a disease. Rare variants lie beyond present reach. �It’s an astounding thing,� Dr. Goldstein said, �that we have cracked open the human genome and can look at the entire complement of common genetic variants, and what do we find? Almost nothing. That is absolutely beyond belief.�

If rare variants account for most of the genetic burden of disease, then the idea of decoding everyone’s genome to see to what diseases they are vulnerable to will not work, at least not in the form envisaged. �I don’t believe we should do more and more genomewide association studies for common diseases,� Dr. Goldstein said. Instead, he suggested, the �missing heritability� might be tracked by thoroughly studying the genome of specific patients.

This is what Greg Cochran predicted back in the 1990s would be found. Contrary to the impression you`d get from reading the newspaper (at least when the estimable Mr. Wade is on book leave), your genes didn`t evolve to kill you. They evolved to help you survive and reproduce. (Here`s the February 1999 cover story in The Atlantic Monthly, "A New Germ Theory," on Cochran and his research partner Paul Ewald.) The Cochran-Ewald theory predicts that germs— bacteria and viruses—will be found to be the causes of many major diseases.

From an alternative perspective, you could also blame an infectious disease on your genes by saying that if you only had the necessary gene variant, your immune system would have been equipped to wipe out the germ before it caused the disease. On the other hand a lot of the diseases of old age are caused by by wear and tear, with a germ or the lack of a gene as merely the trigger for something that was going to fail sooner or later anyway.

Which perspective is most useful for medical progress is a difficult question. Perhaps they all should be borne in mind.

Goldstein also can`t find any genes for IQ, which would seem more like a capability than a disease:

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.

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.

The idea of standardization in evolution is attractive. After all, we standardized on one head, two eyes, and so forth a long, long time ago. Just about everybody who isn`t clearly defective can learn to speak a language and even learn some moderately complex grammar. (Although that doesn`t mean my grammar is as good as William F. Buckley`s was.)

Okay, but one problem with applying the idea of standardization to intelligence is that intelligence clearly isn`t standardized. David B. Goldstein, to pick an example, is smarter than the average person. Heck, he`s a lot smarter than the average David Goldstein.

But, as last month`s whoop-tee-doo in Beijing demonstrated once again, just because something "was developed early in human evolutionary history and was then standardized" doesn`t mean that everybody can do it equally well now. For example, running presumably developed tens of thousands of generations ago, and everybody pretty much runs today using the same basic, natural technique (as opposed to the various swimming strokes or ways that horses can move). Further, as Dr. Goldstein might say, my best guess is that human footspeed was always a helpful thing in most places and times and we have all been under strong selection to be as fast as we can be.

Yet, you and I still can`t run anywhere near as fast as Usain Bolt can.

So, my guess is that the answer to the problem is that quite a bit of IQ variance is in the genes, it`s just in a whole lot of genes.