This week's Science carries two research articles from Bruce Lahn's lab documenting recent (and potentially ongoing) genetic changes in human brains.
I say "human brains" rather than "the human brain" quite deliberately: with these alleles, some people have them, and other people don't. And more noteworthy, some populations have them, and others don't.
I've had copies of these papers for a while; the story has now gone live (Google News) so I'll share some of my comments.
The genes are two that we have seen before: ASPM and Microcephalin. Both genes were subjects of papers by Lahn's students Patrick Evans and Jeffrey Anderson last year in Human Molecular Genetics (Evans et al. 2004a; Evans et al. 2004b). Both genes underwent repeated adaptive subtitutions in the primate lineages leading to humans: these changes in Microcephalin were concentrated in the ancient hominoid ancestors of humans and chimpanzees; ASPM fixed a new adaptive substitution on average every 300,000 or so years since the human-chimpanzee common ancestor. Disease-causing alleles of both genes are associated with forms of microcephaly. The normal functions of neither have been characterized, although their effects in microcephaly would indicate that one important function is in early neural growth and differentiation. Thus, it is reasonable to think that they may have been involved in the evolution of brain size and structure in humans and other primates.
The lab's strategy has been a simple one: find brain-expressed genes and see if they have been under selection in humans and primates (see also this interview with Lahn). An elegant expression of the simplicity of the project was the paper by Dorus and colleagues from late last year (Dorus et al. 2004), which found a high rate of selection in brain-expressed genes in the human (and hominoid) lineage compared to macaques (discussed in this earlier post). The meat of the lab's work so far has been papers like the two cited above (and others such as Choi and Lahn 2003) finding out how genes have changed leading to humans and other primates.
The current papers take the next logical step: Take the genes that have changed a lot during human evolution, and see whether they vary among people today. A functional difference between alleles in different people might reflect a difference in the structure or function of their brains. Microcephalin is covered by Evans et al. (2005); ASPM by Mekel-Bobrov et al. (2005).
The team sequenced each gene in around 90 "ethnically diverse" people. For each, they found considerable variation scattered across the genes, but one haplotype that occupied a large proportion (21% and 33% respectively) of the sequence samples. In each case, the proportion was so disproportionately large compared to other variants, that the haplotype almost certainly corresponded with a recently selected allele -- one that has expanded in numbers so quickly that it has not had time to recombine very much with other alleles. Conveniently (or confusingly), both papers name the selected alleles "haplogroup D", for "derived". The haplogroup is comprised of the original selected haplotype plus the small number of variants by recombination or mutation that have happened to it since it came under selection.
Both genes have an allele that has been recently selected. For both genes, this allele is still segregating in human populations. This means that if the allele is positively selected (i.e. on its way to fixation), it hasn't had time to get there yet. On the other hand, if the allele is subject to some kind of balancing selection (e.g. heterozygotes have an advantage relative to homozygotes), then it may or may not be at equilibrium yet in some populations; we just don't know.
But in either case, we can estimate how long the alleles have been selected, because selection caused these alleles to greatly increase in numbers. All of the variability encompassed by variant haplotypes that share a selected site must have accumulated since that selection began. The two papers each do this calculation, with some surprising results.
Haplogroup D for Microcephalin apparently came under selection around 37,000 years ago (confidence limit from 14,000 to 60,000 years ago). This is very, very recent compared to the overall coalescence age of all the haplotypes at the locus (1.7 million years). Some populations have this allele at 100 percent, while many others are above 70 or 80 percent. Selection on the allele must therefore have been pretty strong to cause this rapid increase in frequency. If the effect of the allele is additive or dominant, this selective advantage would be on the order of 2 or 3 percent -- an advantage in reproduction.
The story for ASPM is similar, but even more extreme. Here, the selected allele came under selection only 5800 years ago (!) (confidence between 500 and 14,100 years). Its proliferation has almost entirely occurred within the bounds of recorded history. And to come to its present high proportion in some populations of near 50 percent in such a short time, its selective advantage must have been very strong indeed -- on the order of 5 to 8 percent. In other words, for every twenty children of people without the selected D haplogroup, people with a copy of the allele averaged twenty-one, or slightly more.
Nobody currently knows what these alleles may have done. It seems likely that people with the allele have some sort of cognitive advantage, which ultimately translates into a reproductive benefit. This advantage is probably not associated with greater brain sizes, because the average brain size appears not to have changed appreciably during the past 30,000 years -- if anything, in fact it has gotten smaller, although this reduction in size is probably associated with reductions in body size over the same time period (Ruff et al. 1997). Figuring this out is going to take more work assessing the phenotypic characters of people have the alleles -- how do they score on tests, for example, and is there any apparent structural difference between their brains and non-allele carriers?
The teams took one further step: they assayed over 1000 people in populations around the world to see where the selected alleles were more or less common.
Some populations have these alleles at high frequencies; other populations have them at lower frequencies or not at all. The genes are slightly different in their pattern: for example, the Microcephalin haplogroup D is virtually universal in New World populations; the recently-selected ASPM haplogroup D is almost completely absent there. The selected ASPM variant is most common in Europe and West Asia and less so in East Asia; Microcephalin haplogroup D is common across Eurasia from west to east. These differences may reflect time -- with the ASPM variant much more recently selected. Or they may reflect different selective gradients: perhaps the alleles are adaptive in some ecological contexts or genetic backgrounds but not others.
Both selected alleles are relatively rare in subsaharan Africa. Again, one of two explanations is possible: either they are advantageous but haven't had time to increase in frequency there yet, or their adaptive value is less in Africa than in other places where they are found.
Geneticists are increasingly finding genetic variants that affect behavior. Several of these variants are now known to vary in frequency in different human populations. These alleles are two; the 7r allele of the dopamine receptor D4 (DRD4) gene is another that influences ADD/ADHD susceptibility (Harpending and Cochran 2002). The selective structure underlying DRD4 variation may be frequency-dependent, with different alleles correlating with alternative behavioral strategies that pose greater or lesser advantages in some populations. It is not clear whether such a mechanism is true of ASPM and Microcephalin; the selected alleles have risen to such high frequencies in some populations that it seems they are not mere alternatives; they are unilaterally advantageous -- at least where they have become common already.
The question is whether there is anything keeping them from spreading through Africa. Is it possible that the ecology of Africa has led to a different level of selection on these alleles? Or have they just not had time since their origin to reach very far into Africa? At any rate, it is premature to say what their effects may be within different populations, particularly until something is known about the phenotypes of people who carry the alleles.
I'm keeping a list of quotes related to the research, as more stories appear I'll continue to add. Here's the list so far:
Francis Collins in the San Jose Mercury News (an AP article):
That the genetic changes have anything to do with brain size or intelligence "is totally unproven and potentially dangerous territory to get into with such sketchy data," stressed Dr. Francis Collins, director of the National Human Genome Research Institute.
Mark Stoneking in Science:
"The case for selection acting on [the genes] is reasonably strong," says anthropologist Mark Stoneking of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. "However, there is absolutely nothing in either paper to relate the signature of selection to any brain-related phenotype."
David Goldstein in the New York Times -- my candidate for the "not even wrong" award:
Another geneticist, David Goldstein of Duke University, said the new results were interesting but that "it is a real stretch to argue for example that microcephalin is under selection and that that selection must be related to brain size or cognitive function."
The gene could have risen to prominence through a random process known as genetic drift, Dr. Goldstein said.
I have to say, someone who seriously thinks that these alleles are drift must not believe in natural selection under any circumstances. But possibly Goldstein was misquoted, or may not have seen the papers before making this comment.
John Hawks in New Scientist:
"Whatever advantage these genes give, some groups have it and some don't. This has to be the worst nightmare for people who believe strongly there are no differences in brain function between groups," says anthropologist John Hawks of the University of Wisconsin in Madison, US.
My favorite thus far, Bruce Lahn in New Scientist:
"It could be advantageous to be dumber," Lahn says. "I highly doubt it, but it's possible."
Dorus S, Vallender EJ, Evans PD, Anderson JR, Gilbert SL, Mahowald M, Wyckoff GJ, Malcom CM, Lahn BT. 2004. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119:1027-1040.
Evans PD, Anderson JR, Vallender EJ, Gilbert SL, Malcom CM, Dorus S, Lahn BT. 2004a. Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Hum Mol Genet 13:489-494.
Evans PJ, Anderson JR, Vallender EJ, Choi SS, Lahn BT. 2004b. Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size. Hum Mol Genet 13:1139-1145.
Evans PJ, Gilbert SJ, Mekel-Bobrov N, Vallender EJ, Anderson JR, Vaez-Azizi LM, Tishkoff SA, Hudson RR, Lahn BT. 2005. Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans. Science 309:1717-1720. Full text (subscription required)
Harpending HC, Cochran G. 2002. In our genes. Proc Nat Acad Sci USA 99:10-12.
Mekel-Bobrov N, Gilbert SL, Evans PD, Vallender EJ, Anderson JR, Hudson RR, Tishkoff SA, Lahn BT. 2005. Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens. Science 309:1720-1722. Full text (subscription required)