Patterns of coding variation in the complete exomes of three Neandertals

Abstract

We present the DNA sequence of 17,367 protein-coding genes in two Neandertals from Spain and Croatia and analyze them together with the genome sequence recently determined from a Neandertal from southern Siberia. Comparisons with present-day humans from Africa, Europe, and Asia reveal that genetic diversity among Neandertals was remarkably low, and that they carried a higher proportion of amino acid-changing (nonsynonymous) alleles inferred to alter protein structure or function than present-day humans. Thus, Neandertals across Eurasia had a smaller long-term effective population than present-day humans. We also identify amino acid substitutions in Neandertals and present-day humans that may underlie phenotypic differences between the two groups. We find that genes involved in skeletal morphology have changed more in the lineage leading to Neandertals than in the ancestral lineage common to archaic and modern humans, whereas genes involved in behavior and pigmentation have changed more on the modern human lineage.

Keywords: ancient DNA; exome capture; paleogenetics; site frequency spectra.

Fig. 1.

(A) Neighbor-joining tree based on the number of pairwise differences between individuals. Phenotypic categories enriched in amino acid-changing substitutions on the lines to Neandertals and to modern humans, respectively, are indicated. The bar indicates 50 inferred substitutions per megabase. (B) Neighbor-joining tree of pairwise F_ST values for the same individuals. The bar indicates an F_ST of 0.05.

Fig. 2.

Frequency spectra of nonsynonymous derived alleles classified by PolyPhen-2 as either benign or deleterious in Neandertals and present-day humans. The ratio of deleterious to benign derived alleles is higher in Neandertals than in the present-day humans. See Table S19 for the actual allele counts and Fig. S10 for the frequency spectra of nonsynonymous derived alleles assessed by PhastCons and GS.