STaRRRT: a table of short tandem repeats in regulatory regions of the human genome

Abstract

BackgroundTandem repeats (TRs) are unstable regions commonly found within genomes that have consequences for evolution and disease. In humans, polymorphic TRs are known to cause neurodegenerative and neuromuscular disorders as well as being associated with complex diseases such as diabetes and cancer. If present in upstream regulatory regions, TRs can modify chromatin structure and affect transcription; resulting in altered gene expression and protein abundance. The most common TRs are short tandem repeats (STRs), or microsatellites. Promoter located STRs are considerably more polymorphic than coding region STRs. As such, they may be a common driver of phenotypic variation. To study STRs located in regulatory regions, we have performed genome-wide analysis to identify all STRs present in a region that is 2 kilobases upstream and 1 kilobase downstream of the transcription start sites of genes.ResultsThe Short Tandem Repeats in Regulatory Regions Table, STaRRRT, contains the results of the genome-wide analysis, outlining the characteristics of 5,264 STRs present in the upstream regulatory region of 4,441 human genes. Gene set enrichment analysis has revealed significant enrichment for STRs in cellular, transcriptional and neurological system gene promoters and genes important in ion and calcium homeostasis. The set of enriched terms has broad similarity to that seen in coding regions, suggesting that regulatory region STRs are subject to similar evolutionary pressures as STRs in coding regions and may, like coding region STRs, have an important role in controlling gene expression.ConclusionsSTaRRRT is a readily-searchable resource for investigating potentially polymorphic STRs that could influence the expression of any gene of interest. The processes and genes enriched for regulatory region STRs provide potential novel targets for diagnosing and treating disease, and support a role for these STRs in the evolution of the human genome.

Exceptionally long 5′ UTR short tandem repeats specifically linked to primates

“…Indeed, selection could shape STRs into "tuning knobs" that facilitate evolutionary adaptation (King et al, 2006). This possibility is consistent with evolutionary conservation of STRs, in genes with neurological and neurodevelopmental functions (Darvish et al, 2013;Bolton et al 2013;King, 2012;Heidari et al, 2011;Zarif Yeganeh et al, 2010). Indeed, genes driven by repeat-containing promoters show significantly higher rates of transcriptional divergence, and variations in repeat length result in changes in expression and local nucleosome positioning, where substitution of the repeats with identical length of non-repetitive DNA does not restore gene expression activity (Vinces et al, 2009).…”

Beyond SNPs and CNV: Pharmacogenomics of Polymorphic Tandem Repeats

“…First, microsatellite tandem repeats are overrepresented in the vicinity of transcription start points within the promoter regions of many genes in the human genome [6,7]. Next, polymorphic promoters STR are associated with increased variance in local gene expression and DNA methylation, suggesting functional role for STR [18].…”

“…Phenotypic manifestation of variability in the length of STR remains poorly understood despite the fact that their association with neuromuscular and neurodegenerative diseases, several complex disorders, and several types of cancer has been convincingly demonstrated [6]. While genome-wide association studies of complex phenotypes are complicated, pharmacogenomic analysis of drug therapy provides a simpler model for deducing macro scale characteristics of a human organism based on his/her genome.…”

“…Within genes, microsatellite repeats are non-randomly distributed across protein-coding sequences, untranslated regions (UTRs), and introns. In the coding regions of the genes, repeats predominantly have either trimeric or hexameric repeat unit, likely as a result of selection against frameshift mutations [4,6]. STR containing dinucleotide repeat units are much more abundant in the regulatory or UTR regions than in other genomic regions [2].…”

“…Microsatellite repeats are concentrated at the start of human genes, where they are highly conserved near transcription start sites [6,7]. About 19% of human genes contain at least one STR in their upstream regulatory region [6,8].…”