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. 2006 Nov 17;314(5802):1113-8.
doi: 10.1126/science.1131412.

Sequencing and analysis of Neanderthal genomic DNA

James P Noonan  1 , Graham Coop, Sridhar Kudaravalli, Doug Smith, Johannes Krause, Joe Alessi, Feng Chen, Darren Platt, Svante Pääbo, Jonathan K Pritchard, Edward M Rubin
Affiliations

Sequencing and analysis of Neanderthal genomic DNA

James P Noonan et al. Science. .

Abstract

Our knowledge of Neanderthals is based on a limited number of remains and artifacts from which we must make inferences about their biology, behavior, and relationship to ourselves. Here, we describe the characterization of these extinct hominids from a new perspective, based on the development of a Neanderthal metagenomic library and its high-throughput sequencing and analysis. Several lines of evidence indicate that the 65,250 base pairs of hominid sequence so far identified in the library are of Neanderthal origin, the strongest being the ascertainment of sequence identities between Neanderthal and chimpanzee at sites where the human genomic sequence is different. These results enabled us to calculate the human-Neanderthal divergence time based on multiple randomly distributed autosomal loci. Our analyses suggest that on average the Neanderthal genomic sequence we obtained and the reference human genome sequence share a most recent common ancestor approximately 706,000 years ago, and that the human and Neanderthal ancestral populations split approximately 370,000 years ago, before the emergence of anatomically modern humans. Our finding that the Neanderthal and human genomes are at least 99.5% identical led us to develop and successfully implement a targeted method for recovering specific ancient DNA sequences from metagenomic libraries. This initial analysis of the Neanderthal genome advances our understanding of the evolutionary relationship of Homo sapiens and Homo neanderthalensis and signifies the dawn of Neanderthal genomics.

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Figures

Fig. 1
Fig. 1
Generation of ancient metagenomic library DNAs for direct selection and pyrosequencing.
Fig. 2
Fig. 2
Size distribution, plotted in 10-bp bins, of Neanderthal and cave bear sequences obtained from metagenomic libraries by Sanger sequencing of individual clones. The average hit size in each case is indicated by a dotted line.
Fig. 3
Fig. 3
(A) Representation of each Neanderthal chromosome in 43.9 kb of NE1 hominid sequences displaying a statistically unambiguous best BLAST hit to the human genome, relative to the total sequenced length of each human chromosome minus gaps. Chromosomes are ranked by the amount of Neanderthal sequence aligned to each. Chromosomes X and Y are shown at half their total length to correct for their haploid state in males relative to the autosomes. (B) Representation of sequence features in the NE1 hominid sequence shown in (A).
Fig. 4
Fig. 4
Frequency distribution of 171 Neanderthal-specific substitutions observed in 37,636 bp of aligned human, Neanderthal, and chimpanzee genomic sequence. Complementary substitutions (such as C to T and G to A) are considered equivalent events.
Fig. 5
Fig. 5
(A) Log-likelihood curve of the time to the MRCA of the Neanderthal and human reference sequences. (B) Smoothed relative log-likelihood estimates of the split times between different human populations and the Neanderthal population. (C) Impact of changes in the ancient population size on split time estimates for five models that are consistent with modern polymorphism data. Ky, thousand years. Each curve is the smoothed log likelihood relative to the maximum over all five models. For each model, the text on the plot indicates the degree of expansion or contraction and the time before the present at which the size change occurred. The expansion models are less likely as compared to either constant population size or the contraction models. (D) The log-likelihood estimates of the contribution of the Neanderthal population to the ancestry of Europeans. The light blue line is a smoothed version of the estimates. The horizontal dashed maroon line in (A), (B), and (D) represents a 2 log-likelihood drop, and the region bounded by this line represents the 95% CI around the maximum likelihood estimates.
Fig. 6
Fig. 6
Divergence estimates for human and Neanderthal genomic sequences and ancestral human and Neanderthal populations, shown relative to dates of critical events in modern human and Neanderthal evolution (2, 22, 25). The branch lengths are schematic and not to scale. y.a., years ago.
Fig. 7
Fig. 7
Recovery of Neanderthal genomic sequences from library NE1 by direct genomic selection.
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References

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