A haplotype at STAT2 Introgressed from neanderthals and serves as a candidate of positive selection in Papua New Guinea

Abstract

Signals of archaic admixture have been identified through comparisons of the draft Neanderthal and Denisova genomes with those of living humans. Studies of individual loci contributing to these genome-wide average signals are required for characterization of the introgression process and investigation of whether archaic variants conferred an adaptive advantage to the ancestors of contemporary human populations. However, no definitive case of adaptive introgression has yet been described. Here we provide a DNA sequence analysis of the innate immune gene STAT2 and show that a haplotype carried by many Eurasians (but not sub-Saharan Africans) has a sequence that closely matches that of the Neanderthal STAT2. This haplotype, referred to as N, was discovered through a resequencing survey of the entire coding region of STAT2 in a global sample of 90 individuals. Analyses of publicly available complete genome sequence data show that haplotype N shares a recent common ancestor with the Neanderthal sequence (~80 thousand years ago) and is found throughout Eurasia at an average frequency of ~5%. Interestingly, N is found in Melanesian populations at ~10-fold higher frequency (~54%) than in Eurasian populations. A neutrality test that controls for demography rejects the hypothesis that a variant of N rose to high frequency in Melanesia by genetic drift alone. Although we are not able to pinpoint the precise target of positive selection, we identify nonsynonymous mutations in ERBB3, ESYT1, and STAT2-all of which are part of the same 250 kb introgressive haplotype-as good candidates.

Figure 1

Schematic Representation of Studied Region (A) Chromosome 12. A vertical bar indicates the position of STAT2. (B) The physical location of the genes surrounding STAT2. STAT2 is indicated with a black box, other genes are indicated with gray boxes, and the spans of two haplotypes (described in the main text as the short and long variants of N) are indicated with horizontal lines and labeled as “short block” and “long block.” (C) STAT2. The six sets of contiguous resequenced amplicons are indicated with boxes below the scheme of the gene. In the representation of the gene, boxes indicate exons (wide boxes correspond to coding sequence).

Figure 2

Cladogram for the Inferred Haplotypes in the Resequenced Region of STAT2 The nomenclature of the haplotypes follows Table 1. Nonsynonymous mutations are indicated with a cross hatch if they are predicted as benign and with a cross within a circle and the name of the gene if they are predicted as functional. The mutation at COQ10A is restricted to the short variant of N, and it is unknown whether the mutation at ERBB3 was present in the long variant of N before the origin of the short variant. The presence of the mutation at ESYT1 in the ancestry of D was inferred by the association of D with the Denisova sequence. The additional resolution obtained through analysis of an extended genomic sequence in two samples not included in the resequencing panel (NA19026 and KB1) is highlighted in boxes indicated with dashed lines. For example, a mutation at position 55,027,495 is shared by the M and S clades, a mutation at position 54,799,412 is shared by Neanderthal and Denisova, and a mutation at position 55,041,325 is shared by haplotypes in the Ma clade (Table S3). Two recombinant haplotypes (i.e., between haplotypes in clades M and N and clades M and S) are not shown.

Figure 3

Joint Log-Likelihood for the Divergence Times between the Sequences of NA18956 and the Human Reference and between the Sequence of NA18956 and the Published Neanderthal Sequence

Figure 4

Geographic Distribution of the N Lineage The N lineage is shown in the filled region of the pie chart.

Figure 5

Cumulative Distribution Function for Derived Allele Frequencies For (A) Papuans and (B) Nasioi, the distribution is conditional on the observed derived allele frequency of the SNP rs7962107 in East Asians. The gray bar indicates the observed frequency f of rs7962107 for the HGDP samples in the public SNP panel. Panels (A) and (B) are based on 6,213 SNPs, whereas panel (C), for East Asians, is based on 660,219 SNPs.