Tandem repeat variation in human and great ape populations and its impact on gene expression divergence

Abstract

Tandem repeats (TRs) are stretches of DNA that are highly variable in length and mutate rapidly. They are thus an important source of genetic variation. This variation is highly informative for population and conservation genetics. It has also been associated with several pathological conditions and with gene expression regulation. However, genome-wide surveys of TR variation in humans and closely related species have been scarce due to technical difficulties derived from short-read technology. Here we explored the genome-wide diversity of TRs in a panel of 83 human and nonhuman great ape genomes, in a total of six different species, and studied their impact on gene expression evolution. We found that population diversity patterns can be efficiently captured with short TRs (repeat unit length, 1–5 bp). We examined the potential evolutionary role of TRs in gene expression differences between humans and primates by using 30,275 larger TRs (repeat unit length, 2–50 bp). Genes that contained TRs in the promoters, in their 3′ untranslated region, in introns, and in exons had higher expression divergence than genes without repeats in the regions. Polymorphic small repeats (1–5 bp) had also higher expression divergence compared with genes with fixed or no TRs in the gene promoters. Our findings highlight the potential contribution of TRs to human evolution through gene regulation.

Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31

“…Indeed, the UGUGU pentamers are highly enriched in introns, lncRNAs and intergenic RNAs, which contain many putative TDP-43-binding sequences (Polymenidou et al, 2011; Tollervey et al, 2011). Given that microsatellites within the promoters and other cis -regulatory regions can greatly increase the divergence of gene expression profiles across the great apes (Bilgin Sonay et al, 2015; Gymrek et al, 2016), microsatellites located in untranslated regions or introns may also have a physiological role for proteotoxicity as disease modifiers.…”

Evolution of the Human Nervous System Function, Structure, and Development

“…For example, a recent analysis of tandem repeats between humans and NHPs found that genes containing repeats show higher expression divergence between species, including in brain samples (Bilgin Sonay et al, 2015). Repeats that are conserved in NHPs but different in human (either fixed across humans or polymorphic) show enrichment for neural-development-related categories.…”

The mechanism of transactivation regulation due to polymorphic short tandem repeats (STRs) using IGF1 promoter as a model

“…Sonay et al . studied STRs in both human and nonhuman great ape genomes and showed that STRs contribute significantly to the diversity and divergence of gene expression among species13181920. These findings indicate that STRs are essential elements in molecular evolution and underscore their functional potential.…”

“…First, STRs are abundantly located in promoters across eukaryotic organisms (ranging from yeast to rodents and humans)121314 and variations in the length of a few STRs in model organisms have been associated with changes in phenotype or gene transactivation141516. Second, an increasing body of evidence suggests that STRs play important roles in molecular evolution17.…”