NEW YORK (GenomeWeb) – Sequence variants that many modern humans inherited from ancient mixing with Neanderthals may still influence expression levels of genes involved in human traits and disease susceptibility, new research suggests.
As they reported online today in Cell, a trio of University of Washington researchers tapped data from the Genotype-Tissue Expression (GTEx) project to track allele-specific expression patterns associated with thousands of SNPs in individuals heterozygous for one Neanderthal and one human allele.
Based on expression profiles from dozens of human tissues and hundreds of individuals, the team saw distinct expression for around one-quarter of the Neanderthal alleles considered, relative to human versions of the same variants — expression differences that appeared to be amplified in certain tissues, including the brain and testes.
"Those little bits and pieces, our Neanderthal relics, are influencing gene expression in pervasive and important ways," senior author Joshua Akey, a genome sciences researcher at the University of Washington, said in a statement.
Traces of Neanderthal ancestry have been detected in modern human populations outside of Africa, apparently reflecting interbreeding events between humans and the archaic hominins that occurred roughly 50,000 years ago.
Though some teams have detected evidence for selection against Neanderthal genes in the human genome, others have focused on the Neanderthal sequences that made the cut and stuck around in the human genome over thousands of years, including some that appear to influence present-day human traits.
For their new analysis, Akey and his colleagues came up with a statistical approach for quantifying allele-specific expression in 52 tissues from hundreds of deceased individuals that were tested by RNA sequencing for GTEx. In combination with genotyping information from GTEx, when available, the expression data helped the researchers to narrow in on instances of enhanced or diminished expression involving Neanderthal alleles.
Starting from more than 5,000 SNPs that tagged Neanderthal-introgressed haplotypes affecting 2,034 genes, the team's computational analyses highlighted 1,236 Neanderthal SNPs with significant allele-specific expression.
Tissue from the brain and testes tended to show muted levels of Neanderthal allele expression, in general. Neanderthal alleles at variants implicated in cystic fibrosis, systemic lupus erythematosus, and schizophrenia risk were also present at diminished expression levels. For example, the researchers found decreased expression of a Neanderthal version of a variant in ADAMTSL3, which alters splicing of the gene's transcripts in ways that diminish schizophrenia risk and influence height.
On the other hand, the expression of genes involved in innate immunity appeared to be enhanced when Neanderthal versions of related variants were present.
"Our study demonstrates that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have measurable impacts on gene expression that contribute to variation in modern human phenotypes," the authors wrote.