Microsatellite Tandem Repeats Are Abundant in Human Promoters and Are Associated with Regulatory Elements

Abstract

Tandem repeats are genomic elements that are prone to changes in repeat number and are thus often polymorphic. These sequences are found at a high density at the start of human genes, in the gene’s promoter. Increasing empirical evidence suggests that length variation in these tandem repeats can affect gene regulation. One class of tandem repeats, known as microsatellites, rapidly alter in repeat number. Some of the genetic variation induced by microsatellites is known to result in phenotypic variation. Recently, our group developed a novel method for measuring the evolutionary conservation of microsatellites, and with it we discovered that human microsatellites near transcription start sites are often highly conserved. In this study, we examined the properties of microsatellites found in promoters. We found a high density of microsatellites at the start of genes. We showed that microsatellites are statistically associated with promoters using a wavelet analysis, which allowed us to test for associations on multiple scales and to control for other promoter related elements. Because promoter microsatellites tend to be G/C rich, we hypothesized that G/C rich regulatory elements may drive the association between microsatellites and promoters. Our results indicate that CpG islands, G-quadruplexes (G4) and untranslated regulatory regions have highly significant associations with microsatellites, but controlling for these elements in the analysis does not remove the association between microsatellites and promoters. Due to their intrinsic lability and their overlap with predicted functional elements, these results suggest that many promoter microsatellites have the potential to affect human phenotypes by generating mutations in regulatory elements, which may ultimately result in disease. We discuss the potential functions of human promoter microsatellites in this context.

Balancing selection maintains polymorphisms at neurogenetic loci in field experiments

“…This finding is consistent with evidence that microsatellites often are associated with generegulatory elements (52). Changes in microsatellite allele length may alter the position of regulatory DNA motifs, such as transcription factor-binding sites.…”

DNA topology and transcription

“…64 Accordingly, in silico analyses showed a high enrichment of these sequences at regulatory regions of the genome and, notably, at the promoters of a wide range of oncogenes. [85][86][87][88] In addition, several conformation-sensitive proteins with regulatory function bind and stabilize non-B DNAs, suggesting an important role of these structures in transcriptional output. 64 Another way to make genetic processes more tolerant to the constrained DNA topology is weakening the DNA through introducing double strand breaks or nicks.…”

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

“…Thus, the high incidence of TRs in regulatory regions in some species (Gemayel et al 2010;Payseur et al 2011) and their high mutability (Weber and Wong 1993;Brinkmann et al 1998;Li et al 2002;Legendre et al 2007), suggests that it may be important to study TR variation to understand fundamental differences in gene expression across species and populations. In particular, since TRs constitute 3% of the human genome (Lander et al 2001) and are dramatically enriched in promoter regions (Vinces et al 2009;Sawaya et al 2013), clarifying their functional role may provide important insights for the human biology field.…”