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Tuesday, October 23, 2012

Deleterious variants affecting traits that have been under selection are rare and of small effect

This NYTimes article discusses ideas similar to the ones in my BGA 2012 talk (slides): because of previous selection (e.g., over the last millions of years of hominid development), most rare alleles affecting intelligence will have slightly negative effect. That is, the alleles of large, positive effect (to be precise: on fitness) will be found in every "normal" person, whereas alleles of small negative effect will still linger at low frequency. Being smarter is a consequence of having fewer of these rare deleterious variants.

Note, deleterious variants are not all the result of recent mutations. Even after a long period of selection, (+) alleles are not necessarily fully fixed (Minor Allele Frequency = MAF > 0); instead one has a distribution of MAFs and (+) causal alleles for a selected trait will have a distribution peaked at 1 whereas (-) alleles will have a distribution peaked at 0. (See figures below.)
NYTimes: Few of us are as smart as we’d like to be. You’re sharper than Jim (maybe) but dull next to Jane. Human intelligence varies. And this matters, because smarter people generally earn more money, enjoy better health, raise smarter children, feel happier and, just to rub it in, live longer as well.

But where does intelligence come from? How is it built? Researchers have tried hard to find the answer in our genes.

... Kevin Mitchell, a developmental neurogeneticist at Trinity College Dublin, thinks the latter. In an essay he published in July on his blog, Wiring the Brain, Dr. Mitchell proposed that instead of thinking about the genetics of intelligence, we should be trying to parse “the genetics of stupidity,” as his title put it. We should look not for genetic dynamics that build intelligence but for those that erode it.

The premise for this argument is that once natural selection generated the set of genes that build our big, smart human brains, those genes became “fixed” in the human population; virtually everyone receives the same set, and precious few variants affect intelligence. This could account for the researchers’ failure to find many variants of measurable effect.

But in some other genetic realms we do differ widely, for example, mutational load — the number of mutations we carry. This tends to run in families, which means some of us generate and retain more mutations than others do. Among our 23,000 genes, you may carry 500 mutations while I carry 1,000.

Most mutations have no effect. But those that do are more likely to bring harm than good, Dr. Mitchell said in an interview, because “there are simply many more ways of screwing something up than of improving it.”

Open the hood of a smooth-running car and randomly turn a few screws, and you’ll almost certainly make the engine run worse than before. Likewise, mutations that change the brain’s normal development or operation will probably slow it down. Smart Jane may be less a custom-built, high-performance model than a standard version pulling a smaller mutational load. ...

Here are some relevant figures from my slides showing the effect of selection on MAF distributions. Imagine millions of years of selection causing the distribution of alleles to change as shown in figures A and B. According to my estimates (based on actual data) most humans have (order of magnitude) 1000 rare (-) alleles for intelligence and height, and someone who is one standard deviation above average has (very roughly) 30 fewer (-) variants. (See slides for more details.) A human with none of the negative alleles might be 30 SD above average! Such a person has yet to exist in human history...

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