We used a hybridization approach to enrich the DNA from 17,367 protein-coding genes in two Neandertal individuals from Spain and Croatia. By analyzing these two exomes together with the genome sequence of a Neandertal from Siberia we show that the genetic diversity of Neandertals was lower than that of present-day humans and that the pattern of coding variation suggests that Neandertal populations were small and isolated from one another.

We further analyzed these Neandertal individuals enriching DNA from their chromosome 21 to provide evidence of the decline of their populations for hundreds of thousands of years before their disappearance about 30,000 years ago. We also show that genes involved in skeletal morphology have changed more than expected on the Neandertal evolutionary lineage whereas genes involved in pigmentation and behavior have changed more on the modern human lineage.