There’s a new paper out in Nature, by Wenqing Fu and many other people, about the recent origin of most variants in protein-coding genes. They conclude that most are less than 5-10,000 year old – younger in Europeans than in Africans. This is a natural consequence of the shape of human demographic history – there was a huge population increase with the advent of agriculture, and more people meant more mutations. That agricultural expansion happened somewhat earlier in the Middle East and Europe than in Africa.
More people means more mutations – that was clear to some of us five years ago. We were primarily interested in the rate at which adaptive mutations were generated – that increase, coupled with the selective pressures associated with a very different agricultural way of life, had to materially speed up adaptive evolution in humans. More so in some places than others, of course.
A very few mutations are beneficial, some are neutral and many are deleterious, although the degree of harm inflicted varies widely. So the population expansion also increased the number of bad mutations – but unless selection also relaxed, it would not have changed the per-capita number of deleterious mutations, or the distribution of their effects (what fraction had large, medium, or small effects on fitness). It increased the diversity of deleterious mutations – they are more motley, not more common. The article never talks about that per-capita number, or, if it did , I was unable to winkle it out. It talks about ages and numbers of mutations - but not the mean number, in either of the two populations studied (European Americans and African Americans) . I think it would been a lot clearer, confused fewer reporters, if it had made that distinction. On the other hand, depending on the facts on the ground, talking about mutational load might be a grant-killer. There was a paper earlier this year (with many of the same authors) that used about half of the same data and did mention per-capita numbers. I’ve discussed it.
Some of these deleterious mutations have negative effects large enough to be considered disease genes. You can imagine two extremes. In one, everyone with schizophrenia has the same nasty mutation. In the other, virtually every family with members suffering from schizophrenia has a different causal mutation. That second pattern is bad news for medicine: it reduces the chance of finding a drug that helps a big fraction of sufferers. People talk about individualized therapy, but of course that’s impractical. Hard to test (do we create an army of clones for phase II?), impossible to share the development costs among many customers.
Unfortunately, that second pattern is pretty close to reality. Most of it has little to do with anything that happened a few thousand years ago – any particular mutation with a strong enough effect to be much of a schizophrenia risk gene doesn’t last that long. So a recent (Bronze-Age) increase in the diversity of deleterious mutations doesn’t make much difference. We were already far from common-disease-common variant. On the other hand, a population with more genetic load, more deleterious mutations (and not ones with incredibly small effects), might well be more susceptible to schiz. But that doesn’t point to a drug either: it merely says that it is better to have fewer holes in your genome. That doesn’t suggest a therapy, at least not to me.
The paper says that there may be an excess of weakly deleterious mutations in Europeans due to bottlenecks back in the Ice Age. The idea works like this: selection is less efficient in small populations. Deleterious mutations with an effect s < 1/Ne drift freely and are not efficiently removed by selection. This effect takes on the order of Ne generations – so a population reduced to an effective size of of 10,000 for 10,000 generations ( ~250,000 years) would accumulate a large-than-usual number of deleterious mutations of effect size ~10-4. Lohmueller et al wrote about this back in 2008: the scenario they used had a European ancestral bottleneck 200,000 years long, which is A. what you need to make this scenario work and B. impossible, since it’s way before anatomically modern humans left Africa. Back to the drawing board.