I have reason to believe that few people understand genetic load very well, probably for self-referential reasons, but better explanations are possible.
One key point is that the amount of neutral variation is determined by the long-term mutational rate and population history, while the amount of deleterious variation [genetic load] is set by the selective pressures and the prevailing mutation rate over a much shorter time scale. For example, if you consider the class of mutations that reduce fitness by 1%, what matters is the past few thousand years, not the past few tens or hundreds of of thousands of years.
There is a recent article in BMC genetics that illustrates this. They found that rhesus macaques are three times as diverse as humans, surely because of a larger effective population size. But when you look at nonsynonyous mutations, macaques have only 1.2 times as many as humans. Now probably some of those nonsynonymous mutations are actually harmless, but most must actually be deleterious – else why are they relatively scarcer than neutral variation? Furthermore, in macaques, a smaller fraction of those nonsynonymous mutations seem likely to be damaging than in humans, so the actual number of deleterious mutations in macaques may not be much different than the human average.
So, assuming that African populations have more neutral variation than non-African populations (which is well-established), what do we expect to see when we compare the levels of probably-damaging mutations in those two populations? If the Africans and non-Africans had experienced essentially similar mutation rates and selective pressures over the past few thousand years, we would expect to see the same levels of probably-damaging mutations. Bottlenecks that happened at the last glacial maximum or in the expansion out of Africa are irrelevant – too long ago to matter.
But we don’t. The amount of rare synonymous stuff is about 22% higher in Africans. The amount of rare nonsynonymous stuff (usually at least slightly deleterious) is 20.6% higher. The number of rare variants predicted to be more deleterious is ~21.6% higher. The amount of stuff predicted to be even more deleterious is ~27% higher. The number of harmful looking loss-of-function mutations (yet more deleterious) is 25% higher.
It looks as if the excess grows as the severity of the mutations increases. There is a scenario in which this is possible: the mutation rate in Africa has increased recently. Not yesterday, but, say, over the past few thousand years.
It takes a long time to change the frequency of deleterious mutations of small effect. A change in selective pressures, or in the mutation rate, can change the frequency of deleterious mutations of large effect much more rapidly. So it is perfectly possible for a population to simultaneously have a lower-than-average level of small-effect mutations and a higher-than-average level of moderate to severe mutations, or vice versa.
What is the most likely cause of such variations in the mutation rate? Right now, I’d say differences in average paternal age. We know that modest differences (~5 years) in average paternal age can easily generate ~20% differences in the mutation rate. Such between-population differences in mutation rates seem quite plausible, particularly since the Neolithic.
What about the various comments in the coverage of Decode’s work about how harmless a higher mutation rate must be, usually referring to the past couple of centuries or so? They’re wrong, although not as spectacularly as Stefánsson . He reminds me of that old Saturday Night Live skit about how ‘inflation is your friend!”. Wouldn’t you like to own a $4,000 suit, and smoke a $75 cigar, drive a $600,000 car? I know I would ! In the same way, mutation is your friend. Doesn’t everyone want to be one of the X-men? Sheesh, we should restart atmospheric nuclear testing immediately, the bigger the better.
West Hunter 
It seems the most parsimonious explanation is that African populations didn’t until recently experience the dramatic changes in habitat and selection which Eurasian populations have experienced. Successive waves of plagues brought about by existing in regions with high population density; dramatic changes in digestion brought about by the arrival of milk, alcohol, and mass grain production; and intensive selection for intelligence and neoteny.
This predicts a precipitous drop in genetic “background static” with a seemingly paradoxical increase in genetic diseases…diseases which are the products of intensive selection for immune resistance, cognition, and neoteny. …”Overclocking”, to use your own metaphor.
I would appreciate it if you could offer your thoughts on dramatic differences between human populations in terms of the disparity between male sex-linked and female sex-linked chromosome diversity. What do the numbers imply about human mating patterns, and what might those mating patterns imply about sexual selective pressure?
“The amount of stuff predicted to be even more deleterious is ~27% higher. The number of harmful looking loss-of-function mutations (yet more deleterious) is 25% higher.”
Did you switch these?
Nope.
Decreased IQs seem like the only real evidence for Africans having more functional developmental problems, but that trait is common outside of Africa as well.
Polygamy and older men having many wives (and I am reminded of Henry’s post on the loose conception of parenthood held in the polygamous societies he described) does not seem to map the IQ distribution – it may do, but it does not seem to. Also most of the specifically polygamy linked personality traits (craziness) seem to have selective explanations, and look like adaptations.
How might we test this theory? Perhaps to look at the mutation rate in different Y-dna lineages over the past thousand years? I am reminded of the recent and contentious study which attempted to link y-dna haplogroups with cognitive ability – perhas this data could be useful.
On schizophrenia – http://en.wikipedia.org/wiki/File:Schizophrenia_world_map_-_DALY_-_WHO2004.svg – The global distrubtion of schizophrenia appears to peak in China and South East Asia (where Japan is a unique low schiz country). Since this pattern is very robust and schizophrenia should be very obvious, I would not think it due to measurement differences.
I suppose some groups with habitually older parental reproduction may have adapted by reducing the mutation rate (as I would guess the case would be for humans vis-a-vis animals with shorter generation time, because there is a greater pressure).
Also, would one prediction of this model be that the pygmies, with their reduced generation time, should show a reduced mutation rate and a lower rate of LOF mutations, relative to their African neighbours with longer generation time.
Paragraph by paragraph:
1. No. Higher rates of miscarriage, shorter lifespans. Adaptations? You must be crazy.
2. unclear
3. No.
4. I have zero confidence that the diagnostic criteria for schizophrenia are the same or almost the same in different countries.
5. I doubt it. The advantages of more accurate repair at the individual level are small.
6. A fair question.
Uroko Onoja became rich in later life and then he married 5 women. But It is only recently that kind of success became an important way for African to marry multiple wives. Historically, the way to wealth was land and the line of causation ran the other way. In hoe farming the women do the work, and the more women a man can get the more land he can farm. In traditional African agriculturist society mens’ main function was to compete with other men for wives.
The mutations caused by polygyny would be burnt out by consanguineous marriage. Most places where polygyny is practised also have consanguineous marriage (In Senegal, the most polgynous country, a girl’s maternal uncle is seen as the ideal match for her)
Testosterone reaches a very high peaks in African men, at about 24, it declines to below European levels by 50. The typical schizophrenia age of onset coincides with sex hormones peaking, and black men in western countries have high rates of schizophrenia
Hoe farming is/was a relatively recent advent in human evolutionary terms, i.e., within the last 10,000 years or so. So the degree of its impact on human genetics is surely questionable.
I am confused about the meaning of effective population size. Having consulted that fount of all wisdom, Wikipedia, it seems to mean a population size that would provide the same variance in allele frequencies as a Sewell Wright theoretical population, or something.
So, does this mean that humans have less random mating than Macaques?
It means that the harmonic integral of population size was smaller in humans than macaques over the past, say, couple of million years.
Now let me explain the harmonic integral of population size. Integrate the _inverse_ of population size over time, then invert that number. The harmonic integral is thus dominated by periods in which the population was particularly small.
“The amount of rare synonymous stuff is about 22% higher in Africans. The amount of rare nonsynonymous stuff (usually at least slightly deleterious) is 20.6% higher. The number of rare variants predicted to be more deleterious is ~21.6% higher. The amount of stuff predicted to be even more deleterious is ~27% higher. The number of harmful looking loss-of-function mutations (yet more deleterious) is 25% higher.”
Greg,
If a population stays put, it tends to accumulate “junk variability” over time. Some of these “junk” variants are truly neutral but most aren’t. The latter are weakly deleterious mutations that are very slowly eliminated by natural selection.
Here we come to the “nonsynonymous stuff.” These are variants that have some effect, but the effects vary in their consequences. Although some nonsynonymous variants have serious consequences, some don’t. The latter will thus accumulate over time. So there should be a greater number of nonsynonymous variants in Africans than in non-Africans. But one cannot extrapolate from this fact and assume that Africans are more likely than non-Africans to have mutations with serious consequences.
What about loss-of-function mutations? You say they are “yet more deleterious.” In fact, many of them are pretty innocuous. The various hair colors we see in Europeans are LOF mutations. These mutations probably have some selective value, but their value is determined more by sexual selection than by natural selection. In any case, a proportion of all LOF mutations doesn’t have serious consequences. Even if that proportion is only a third of all LOF mutations, it would be enough to account for the figures you provide above.
Such mutations will tend to accumulate because their removal rate via natural selection is too low. So, yes, Africans should have more of them because that population has not undergone the sort of bottlenecks and founder effects that non-Africans have undergone.
Peter, I have no idea why you can’t understand this.
Greg,
You’re committing a logical fallacy, much like the following:
1. The weather is cloudier in Ireland than in Alberta.
2. Nonetheless, even on non-overcast days, there is a higher level of ambient light in Alberta than in Ireland.
3. Therefore, a non-solar light source is contributing to this higher level of ambient light.
This conclusion ignores the fact that a non-overcast day is still cloudier, on average, in Ireland than in Alberta.
If we return to our original argument, LOF variants tend to have less adaptive significance in Africans than in non-Africans. This is not because of a higher mutation rate for less adaptive variants than for more adaptive ones. It’s because less adaptive variants are more likely to accumulate and not be weeded out by natural selection. And such accumulation is more likely in a population that stays put (like Africans) than in one that has resulted from a relatively recent founder effect (like non-Africans).
You’re wrong. Let me try again !
We start out knowing that there is more neutral variation in people of sub-Saharan African descent than in Europeans. Presumably because of larger effective population size in prehistory. Or, maybe they’ve always had a higher mutation rate – but I doubt that.
The exome paper looked for single-nucleotide variants (SNVs) in 15,585 human protein-coding genes, in a European (n = 1351)and an African-American sample (n = 1088).
They found many such variants. Most were rare (86% had a frequency < 0.5%) and previously unknown (82%).
On average, each person carried 13,595 such SNVs – 15,073 in the African-American ample, 12,406 in the European sample
About half of the SNVS were synonymous : 8508 in the AA population, 6963 in the EU population. 1.22 times more in the AA population than in the Eu population.
These synonymous variants are almost all neutral. If there was a different class of variants that was also neutral, we would expect that the ratio of the numbers of variants
in that would also be 1.22 – neutral is neutral. If we look at the class of deleterious variants, we would expect the numbers to be determined by the
mutation rate and the selective pressures. If the mutation rate and selective pressures had been the same for both populations, we would expect the number of deleterious mutations to be the
same, so the ratio would be 1. Examples help clarify this. Macaques have three times as much neutral variation as humans, but only 1.2 times as much nonsynonymous variation. Clearly the factors that determine the amount of neutral variation are not the same as those that determine the amount of nonsynonymous variation. Note also the results for the East Asian sample in the LOF paper: although East Asians have less neutral variation than Europeans, they have almost exactly the same number of deleterious-looking LOF variants as Europeans. In other words, the mutation-selection balance is almost the same in East Asians as it is in Europeans, but the factors that influence neutral variation
(mutation rate and population history) are not. I'd bet that population history accounts that difference in neutral variation.
If we looked a category that contained some neutral mutations, and some deleterious mutations, we would expect the ratio to be somewhere between 1.22 and 1.0
Now consider nonsynonymous mutations. We know that many of these are deleterious, particularly if rare. About 70% are deleterious (about 20% seriously, about 53% mildly) [Most Rare
Missense Alleles Are Deleterious in Humans: Implications for Complex Disease and Association Studies. Kryujov et al, 2007 AJHG Volume 80, Issue 4, April 2007, Pages 727–739]
The ratio is 1.206 – hasn't dropped much.
Lets look at a more-deleterious category, nonsynonymous SNVs that are predicted to be at least moderately deleterious. In this category, the deleterious fraction should be higher, and the
ratio should be closer to 1. But it's 1.216
Lets look at a yet-more-deleterious category, nonsynonymous changes that torque the protein more: that should be even closer to 1. But it's 1.27
Let's look at an even-more-deleterious category, loss-of-function mutations (from the LOF paper) . The ratio should be much closer to 1.0: but it's not. it's 1.25
Peter, you have said that that you expect lots more harmless LOF mutations in Africans. You're wrong. One expects some more: just as much more as the excess in general neutral genes.
You can’t get more neutral than neutral. So sure, some nonsynonymous mutations are neutral, or close enough to neutral (well under half): but you only expect to see about 1.22 times as many of them in Africans. As we look at categories that are, on average , more and more deleterious, the ratio should get closer and closer to 1.0, if we assume that the mutation-selection is the same in Africans as it is in Europeans and East Asians. But that’s not the case. So somethign is different in Africa: either the mutation rate, or selective pressures, or both.
As for comments about selected LOF mutations like skin color genes – that’s irrelevant. The stuff we are talking about is rare, not selected: either neutral or deleterious.
Greg,
Does this mean you’re rethinking your germ theory of common diseases like schizophrenia? Or is it that these mutations make an individual more vulnerable to complications from infections?
Any chance that that natural nuclear reactor in the ground in West Africa has any impact on the mutation rate?
Since it burned out about 2 billion years ago, no.
Is the argument then that different latitudes lead to different agricultural regimes which lead to differences in average paternal age?