Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage

Abstract

At the center of the debate on the emergence of modern humans and their spread throughout the globe is the question of whether archaic Homo lineages contributed to the modern human gene pool, and more importantly, whether such contributions impacted the evolutionary adaptation of our species. A major obstacle to answering this question is that low levels of admixture with archaic lineages are not expected to leave extensive traces in the modern human gene pool because of genetic drift. Loci that have undergone strong positive selection, however, offer a unique opportunity to identify low-level admixture with archaic lineages, provided that the introgressed archaic allele has risen to high frequency under positive selection. The gene microcephalin (MCPH1) regulates brain size during development and has experienced positive selection in the lineage leading to Homo sapiens. Within modern humans, a group of closely related haplotypes at this locus, known as haplogroup D, rose from a single copy approximately 37,000 years ago and swept to exceptionally high frequency (approximately 70% worldwide today) because of positive selection. Here, we examine the origin of haplogroup D. By using the interhaplogroup divergence test, we show that haplogroup D likely originated from a lineage separated from modern humans approximately 1.1 million years ago and introgressed into humans by approximately 37,000 years ago. This finding supports the possibility of admixture between modern humans and archaic Homo populations (Neanderthals being one possibility). Furthermore, it buttresses the important notion that, through such adminture, our species has benefited evolutionarily by gaining new advantageous alleles. The interhaplogroup divergence test developed here may be broadly applicable to the detection of introgression at other loci in the human genome or in genomes of other species.

Fig. 1.

Distribution of pairwise sequence divergence between and within D and non-D chromosomes at the microcephalin locus.

Fig. 2.

Comparison of the microcephalin genealogy with an idealized genealogy. Each filled triangle represents a genealogical clade, with the width of the triangle representing frequency in the population. (A) The genealogy consistent with the haplotype data at the microcephalin locus. The coalescence age of D chromosomes (≈37,000 years), non-D chromosomes (≈990,000 years), and between D and non-D chromosomes (≈1,700,000 years) are indicated. (B) The idealized genealogy of a partial positive selective sweep, wherein the adaptive allele first emerged by a mutational event on a random chromosome in the population.

Fig. 3.

Distribution of congruent or near-congruent segregating sites in the 29-kb resequenced region of microcephalin. Congruent sites are defined as showing consistently different alleles between D and non-D haplotypes; near-congruent sites are defined as having no more than four differences from congruent sites. Sites for which the D chromosomes are characterized by the derived allele are indicated by long blue lines, whereas sites for which the D chromosomes are characterized by the ancestral allele are indicated by short red lines (for exact positions of these sites, see Table 1). Also indicated is the G37995C nonsynonymous site used to define the D chromosomes (bearing the derived C allele) and the non-D chromosomes (bearing the ancestral G allele).

Fig. 4.

Schematic depiction of two demographic scenarios compatible with the observed genealogy of the microcephalin locus. In both scenarios, an ancestral population, depicted in green, was subdivided into two reproductively isolated populations. One population, depicted in red, fixes the non-D allele, whereas the other population, depicted in blue, fixes the D allele. (A) In the first scenario, the blue population went through a severe bottleneck that dramatically reduced genetic diversity. It then expanded and merged with the other population. (B) In the second scenario, a rare interbreeding event occurred between the two populations, bringing a copy of the D allele from the blue into the red population. This copy subsequently amplified to high frequency under positive selective pressure. The first scenario depends on demography only and does not require selection. This scenario should therefore affect all sites in the genome. The second scenario requires the action of positive selection on the introgressed allele and is therefore not expected to have a genome-wide effect. The observation that the genealogy of microcephalin is not representative of the genome is consistent with the second scenario.

Fig. 5.

Relationship between the time separating two populations and the π₀/π₁ ratio. Each circle represents the average π₀/π₁ ratio of 1,000 simulations at a given separation time (see Materials and Methods). Dashed lines show that a separation time of ≈1,100,000 years produces the observed π₀/π₁ ratio. The average generation time is assumed to be 25 years.