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Evidence That the Adaptive Allele of the Brain Size Gene Microcephalin Introgressed Into Homo Sapiens from an Archaic Homo Lineage

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Evidence That the Adaptive Allele of the Brain Size Gene Microcephalin Introgressed Into Homo Sapiens from an Archaic Homo Lineage Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage Patrick D. Evans*†‡, Nitzan Mekel-Bobrov*†‡, Eric J. Vallender*†‡, Richard R. Hudson§, and Bruce T. Lahn*†¶ *Howard Hughes Medical Institute, Departments of †Human Genetics and §Ecology and Evolution, and ‡Committee on Genetics, University of Chicago, Chicago, IL 60637 Edited by Henry C. Harpending, University of Utah, Salt Lake City, UT, and approved October 5, 2006 (received for review August 10, 2006) At the center of the debate on the emergence of modern humans and admixture between humans and archaic Homo lineages has been their spread throughout the globe is the question of whether archaic invoked as a possible explanation. However, these studies cannot Homo lineages contributed to the modern human gene pool, and differentiate the admixture model from other possibilities, such as more importantly, whether such contributions impacted the evolu- long-standing balancing selection, that also could contribute to tionary adaptation of our species. A major obstacle to answering this deep genealogies (see Discussion). As such, proponents of the question is that low levels of admixture with archaic lineages are not admixture scenario have yet to identify a concrete example of a expected to leave extensive traces in the modern human gene pool genetic locus for which there is compelling evidence of admixture. because of genetic drift. Loci that have undergone strong positive Furthermore, most discussions of admixture tend to treat it as a selection, however, offer a unique opportunity to identify low-level selectively neutral event, one that happened simply as a byproduct admixture with archaic lineages, provided that the introgressed of the geographical overlap between modern humans and archaic archaic allele has risen to high frequency under positive selection. The populations. Such discussions often overlook the possibility that gene microcephalin (MCPH1) regulates brain size during development admixture with archaic lineages, if it indeed occurred, might have and has experienced positive selection in the lineage leading to Homo brought adaptive alleles (along with the traits they determine) into sapiens. Within modern humans, a group of closely related haplo- the modern human gene pool, thus profoundly impacting the types at this locus, known as haplogroup D, rose from a single copy biological evolution of our species. Ϸ37,000 years ago and swept to exceptionally high frequency (Ϸ70% A major difficulty in looking for traces of ancient admixture in the worldwide today) because of positive selection. Here, we examine modern human gene pool is that, under neutrality, very low levels the origin of haplogroup D. By using the interhaplogroup divergence of admixture are not expected to be readily detectable because of test, we show that haplogroup D likely originated from a lineage the effects of genetic drift. Indeed, simulations of ancient admixture separated from modern humans Ϸ1.1 million years ago and intro- showed that an archaic genetic contribution of Ͻ0.1% is unlikely to gressed into humans by Ϸ37,000 years ago. This finding supports the be detectable even in a very large set of polymorphism data (25). possibility of admixture between modern humans and archaic Homo Thus, the absence at present of conclusive genetic data in support populations (Neanderthals being one possibility). Furthermore, it of the introgression scenario should not be taken as evidence buttresses the important notion that, through such adminture, our against the possibility of any introgression. species has benefited evolutionarily by gaining new advantageous If introgression of archaic lineages into the modern human gene alleles. The interhaplogroup divergence test developed here may be pool indeed occurred, then genes that have been subject to recent broadly applicable to the detection of introgression at other loci in the positive selection in humans may be enriched for introgressed human genome or in genomes of other species. alleles. Although selectively neutral alleles introgressed from ar- chaic lineages at low levels are likely lost by drift or swamped by the human evolution ͉ introgression ͉ admixture large influx of modern human DNA, an introgressed allele that is selectively advantageous could escape the effect of genetic drift and ossil records indicate that anatomically modern humans first rise to high frequency. As such, these alleles might become detect- Femerged Ϸ200,000 years ago in Africa and since then spread able in the modern human gene pool. throughout the world (1). For most of the period since their The gene microcephalin is a critical regulator of brain size. In emergence, anatomically modern humans are known to have humans, loss-of-function mutations in this gene cause a condition coexisted with several now-extinct Homo lineages, such as Nean- known as primary microcephaly, which is characterized by a severe derthals (Homo neanderthalis). This long period of coexistence, reduction in brain volume (by 3- to 4-fold) but, remarkably, a including cohabitation in the Middle East and Europe, raises the retention of overall neuroarchitecture and a lack a overt defects intriguing possibility of genetic admixture between anatomically outside of the brain (26). The exact biochemical function of modern humans and archaic Homo populations, which could have microcephalin has yet to be elucidated, but this gene likely plays an resulted in contributions by these extinct lineages to the modern essential role in promoting the proliferation of neural progenitor human gene pool. cells during neurogenesis (26). microcephalin has been shown to be The extent to which anatomically modern humans admixed with the target of strong positive selection in the evolutionary lineage archaic Homo has been the subject of repeated speculation, par- ticularly in regards to Neanderthals (2–22). Thus far, the main- stream view from fossil and genetic studies leans toward a model Author contributions: B.T.L. designed research; P.D.E., N.M.-B., and B.T.L. performed where anatomically modern humans fully replaced archaic Homo research; E.J.V. and R.R.H. contributed new reagents/analytic tools; P.D.E., N.M.-B., E.J.V., R.R.H., and B.T.L. analyzed data; and N.M.-B. and B.T.L. wrote the paper. lineages rather than admixed with them (2–8). However, a number of investigators have voiced opposition to this total replacement The authors declare no conflict of interest. model on a number of grounds, and the debate has yet to be This article is a PNAS direct submission. resolved (9–22). Particularly needed to settle this debate is the Freely available online through the PNAS open access option. identification of genetic loci that show telltale signs of admixture. Abbreviation: MRCA, most recent common ancestor. There have been several reports of loci in the human genome that ¶To whom correspondence should be addressed. E-mail: [email protected]. display unusually deep genealogy (15, 16, 23, 24), and in some cases, © 2006 by The National Academy of Sciences of the USA 18178–18183 ͉ PNAS ͉ November 28, 2006 ͉ vol. 103 ͉ no. 48 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0606966103 Downloaded by guest on October 1, 2021 25% A Divergence among D chromosomes Divergence among non-D chromosomes 20% Divergence between D and non-D chromosomes ~1,700,000 years 15% Frequency 10% ~990,000 years 5% ~37,000 years 0% 02040 60 80 100 Non-D chromosomes D chromosomes (~30% worldwide frequency) (~70% worldwide frequency) Pairwise sequence divergence (bp) Fig. 1. Distribution of pairwise sequence divergence between and within D B and non-D chromosomes at the microcephalin locus. leading from ancestral primates to humans (27, 28). This observa- tion, coupled with the fact that this gene is a critical regulator of brain size, suggests the possibility that the molecular evolution of microcephalin may have contributed to the phenotypic evolution of the human brain (27, 28). In a recent study, we found that the haplotype structure at the Chromosomes not Chromosomes under human microcephalin locus is consistent with the action of recent under positive selection positive selection positive selection (29). Specifically, we found that a class of hap- Fig. 2. Comparison of the microcephalin genealogy with an idealized lotypes at the locus, dubbed haplogroup D, has a remarkably young genealogy. Each filled triangle represents a genealogical clade, with the width coalescence age (Ϸ37,000 years) despite an exceptionally high of the triangle representing frequency in the population. (A) The genealogy worldwide frequency (Ϸ70%). This observation implies a rapid rise consistent with the haplotype data at the microcephalin locus. The coales- cence age of D chromosomes (Ϸ37,000 years), non-D chromosomes (Ϸ990,000 in the frequency of haplogroup D in humans, which is incompatible Ϸ with genetic drift and instead supports the notion that positive years), and between D and non-D chromosomes ( 1,700,000 years) are indi- cated. (B) The idealized genealogy of a partial positive selective sweep, EVOLUTION selection has operated on haplogroup D to drive up its frequency. wherein the adaptive allele first emerged by a mutational event on a random In the present work, we examine the origin of haplogroup D. We chromosome in the population. provide evidence that haplogroup D may have originated from a lineage separated from modern humans for Ϸ1.1 million years and introgressed into the human gene pool by Ϸ37,000 years ago. We D chromosomes coalesce to its most recent common ancestor discuss the implications of our findings for the understanding of (MRCA) at Ϸ37,000 years before present, whereas the non-D modern human origins and the biological adaptation of our species chromosomes coalesce at a far older Ϸ990,000 years before present. as it spreads around the globe. The much younger coalescence age of the D chromosomes, despite their much higher frequency, is consistent with the action of positive Results selection on the D allele as reported previously (29).
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