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Pair of Papers Characterizes Neandertal Genes in Non-African Modern Humans

NEW YORK (GenomeWeb Daily News) – Interbreeding between Neandertals and early modern humans led to the introgression of both beneficial and disadvantageous genetic material into modern humans, according to a pair of studies appearing today in Science and Nature.

Additionally, the two teams reported that not only are there stretches of Neandertal-derived DNA in non-African modern humans, but there are regions where Neandertal-derived DNA is noticeably absent.

A team of researchers reported in 2010 that modern humans of European and East Asian descent could trace nearly two percent of their DNA to Neandertals, due to admixture between the populations some 40,000 to 80,000 years ago. People of African descent have little or no Neandertal DNA as admixture occurred with humans that had moved out of Africa to Europe and Asia where Neandertals lived.

In the current studies, both groups of researchers examined the extent to which there is Neandertal DNA in modern humans of European and Asian descent and what affect that Neandertal DNA may have had on human biology.

"Now that we can estimate the probability that a particular genetic variant arose from Neandertals, we can begin to understand how that inherited DNA affects us," David Reich, a professor of genetics at Harvard Medical School and senior author of the Nature paper, said in a statement. "We may also learn more about what Neandertals themselves were like."

Both groups noted Neandertal DNA may have provided alleles affecting skin and hair that may have allowed people to better adapt to out-of-Africa environments, but Neandertal DNA, the Nature group noted, is also linked to diseases like type 2 diabetes and lupus, among others, and some of it may have been selected against.

As they reported in Science, the University of Washington's Benjamin Vernot and Joshua Akey turned to a two-stage computational strategy to uncover Neandertal DNA in modern humans. For the first part, the duo used the summary statistic S*, which is both sensitive to introgression and can be calculated without using the Neandertal reference genome.

Drawing on a number of coalescent simulations from a variety of demographic scenarios, the researchers reported that their implementation of S* could differentiate introgressed sequences from non-introgressed sequences. They further refined that set of candidate introgressed sequences by comparing them to the Neandertal genome and determining whether they matched significantly more than would be expected by chance.

By applying this framework to whole-genome sequences from 379 Europeans and 286 East Asians from the 1,000 Genomes Project dataset, Vernot and Akey uncovered some 15 gigabases of introgressed sequence across all individuals, averaging about 23 megabases of introgressed sequence per person, with East Asians having higher levels of introgressed sequence than Europeans.

Broadly, the duo noted that the distribution of Neandertal introgression exhibited high heterogeneity. For instance, certain chromosome arms lacked Neandertal sequences entirely, including the region on chromosome 7q that houses the FOXP2 locus, whose transcript is involved in human speech and language.

Based on their findings, the duo also tested whether the patterns of introgression they observed was due to one or more waves of admixture. Based on an ABC framework, they noted that the pattern they saw was consistent with two bouts of gene flow: one into the common ancestor of Europeans and East Asians and a second into the East Asian population after its split from Europeans.

Introgression from the Neandertal also led to the inclusion of adaptive alleles in non-African modern humans, Vernot and Akey reported. For example, they found two introgressed haplotypes that spanned genes involved in the integumentary system, including genes like BNC2 and POU2F3 that are involved in skin pigmentation.

This, Vernot and Akey said, indicates "that Neandertals provided modern humans with adaptive variation for skin phenotypes."

Similarly, Reich and his colleagues reported in Nature that they used a conditional random field approach — based on SNP patterns, sequence divergence, and haplotype length — to search for Neandertal haplotypes in 1,000 Genomes Project data from 1,004 modern-day people. They used the Altai Neandertal genome to determine alleles present in Neandertals as well as a six-primate consensus to determine the ancestral allele and 176 genomes from a Yoruban cohort as a reference, as Africans are assumed to have little or no Neandertal ancestry.

From this, they developed a tiling map of inferred Neandertal haplotypes. This introgression map also indicated that there are regions of the non-African modern human genome that are devoid of Neandertal ancestry.

Like what Vernot and Akey reported in Science, Reich and his colleagues noted that genes involved in keratin filament formation were among those predicted to have the highest levels of Neandertal ancestry.

"It's tempting to think that Neandertals were already adapted to the non-African environment and provided this genetic benefit to humans," Reich said.

However, a number of alleles of presumed Neandertal origin are also linked to human disease. For instance, they reported that Neandertal-linked genes have been associated with Crohn's disease, lupus, and type 2 diabetes, among others.

Additionally, a number of regions, including the X chromosome, appeared resistant to Neandertal introgression. Using a B statistic that gauges whether a region contains high levels of functionally important elements, the researchers investigated whether those deserts were due to selection. Indeed, they reported that regions with a B statistic indicating low functional importance had higher levels of Neandertal ancestry.

The X chromosome, they calculated, has a mean Neandertal ancestry that is about a fifth of what it is on the autosomes. They noted that genes linked to male sterility disproportionately map to the X chromosome and could explain why the X chromosome was resistant to Neandertal introgression. Further, by examining gene transcripts from 16 human tissues, they found that genes expressed in the testes were less likely to be of Neandertal origin.

"It suggests the introduction of some of these Neandertal mutations was harmful to the ancestors of non-Africans and that these mutations were later removed by the action of natural selection," first author Sriram Sankararaman from Harvard and the Broad Institute said in a statement.