A draft sequence of the Neandertal genome

Abstract

Neandertals, the closest evolutionary relatives of present-day humans, lived in large parts of Europe and western Asia before disappearing 30,000 years ago. We present a draft sequence of the Neandertal genome composed of more than 4 billion nucleotides from three individuals. Comparisons of the Neandertal genome to the genomes of five present-day humans from different parts of the world identify a number of genomic regions that may have been affected by positive selection in ancestral modern humans, including genes involved in metabolism and in cognitive and skeletal development. We show that Neandertals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa, suggesting that gene flow from Neandertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other.

Fig. 1

Samples and sites from which DNA was retrieved. (A) The three bones from Vindija from which Neandertal DNA was sequenced. (B) Map showing the four archaeological sites from which bones were used and their approximate dates (years B.P.).

Fig. 2

Nucleotide substitutions inferred to have occurred on the evolutionary lineages leading to the Neandertals, the human, and the chimpanzee genomes. In red are substitutions on the Neandertal lineage, in yellow the human lineage, and in pink the combined lineage from the common ancestor of these to the chimpanzee. For each lineage and each bone from Vindija, the distributions and numbers of substitutions are shown. The excess of C to T and G to A substitutions are due to deamination of cytosine residues in the Neandertal DNA.

Fig. 3

Divergence of Neandertal and human genomes. Distributions of divergence from the human genome reference sequence among segments of 100 kb are shown for three Neandertals and the five present-day humans.

Fig. 4

Selective sweep screen. (A) Schematic illustration of the rationale for the selective sweep screen. For many regions of the genome, the variation within current humans is old enough to include Neandertals (left). Thus, for SNPs in present-day humans, Neandertals often carry the derived allele (blue). However, in genomic regions where an advantageous mutation arises (right, red star) and sweeps to high frequency or fixation in present-day humans, Neandertals will be devoid of derived alleles. (B) Candidate regions of selective sweeps. All 4235 regions of at least 25 kb where S (see SOM Text 13) falls below two standard deviations of the mean are plotted by their S and genetic width. Regions on the autosomes are shown in orange and those on the X chromosome in blue. The top 5% by S are shadowed in light blue. (C) The top candidate region from the selective sweep screen contains two genes, ZFP36L2 and THADA. The red line shows the log-ratio of the number of observed Neandertal-derived alleles versus the number of expected Neandertal-derived alleles, within a 100 kilobase window. The blue dots above the panel indicate all SNP positions, and the green dots indicate SNPs where the Neandertal carries the derived allele.

Fig. 5

Segments of Neandertal ancestry in the human reference genome. We examined 2825 segments in the human reference genome that are of African ancestry and 2797 that are of European ancestry. (A) European segments, with few differences from the Neandertals, tend to have many differences from other present-day humans, whereas African segments do not, as expected if the former are derived from Neandertals. (B) Scatter plot of the segments in (A) with respect to their divergence to the Neandertals and to Venter. In the top left quandrant, 94% of segments are of European ancestry, suggesting that many of them are due to gene flow from Neandertals.

Fig. 6

Four possible scenarios of genetic mixture involving Neandertals. Scenario 1 represents gene flow into Neandertal from other archaic hominins, here collectively referred to as Homo erectus. This would manifest itself as segments of the Neandertal genome with unexpectedly high divergence from present-day humans. Scenario 2 represents gene flow between late Neandertals and early modern humans in Europe and/or western Asia. We see no evidence of this because Neandertals are equally distantly related to all non-Africans. However, such gene flow may have taken place without leaving traces in the present-day gene pool. Scenario 3 represents gene flow between Neandertals and the ancestors of all non-Africans. This is the most parsimonious explanation of our observation. Although we detect gene flow only from Neandertals into modern humans, gene flow in the reverse direction may also have occurred. Scenario 4 represents old substructure in Africa that persisted from the origin of Neandertals until the ancestors of non-Africans left Africa. This scenario is also compatible with the current data.