Mutation and selection processes regulating short tandem repeats give rise to genetic and phenotypic diversity across species

Abstract

Short tandem repeats (STRs) are units of 1-6 bp that repeat in a tandem fashion in DNA. Along with single nucleotide polymorphisms and large structural variations, they are among the major genomic variants underlying genetic, and likely phenotypic, divergence. STRs experience mutation rates that are orders of magnitude higher than other well-studied genotypic variants. Frequent copy number changes result in a wide range of alleles, and provide unique opportunities for modulating complex phenotypes through variation in repeat length. While classical studies have identified key roles of individual STR loci, the advent of improved sequencing technology, high-quality genome assemblies for diverse species, and bioinformatics methods for genome-wide STR analysis now enable more systematic study of STR variation across wide evolutionary ranges. In this review, we explore mutation and selection processes that affect STR copy number evolution, and how these processes give rise to varying STR patterns both within and across species. Finally, we review recent examples of functional and adaptive changes linked to STRs.

Short tandem repeat mutations regulate gene expression in colorectal cancer

“…Using the quartile of eSTR mutations with the highest expected impact, we reached over 75% accuracy in predicting the direction of gene expression change. This fits with the idea that eSTRs can function as ’tuning knobs’ in gene regulation (Verbiest et al ., 2023), with larger changes in allele lengths leading to bigger, more readily detectable shifts in gene expression.…”

“…These smaller repeat length changes can have functional implications as well, especially when aggregated across the genome (Mitra et al . (2021); Verbiest et al . (2023)).…”

“…However, stepwise STR mutations are much more common. These smaller repeat length changes can have functional implications as well, especially when aggregated across the genome (Mitra et al (2021); Verbiest et al (2023)). Apart from inducing frameshift mutations in coding regions, STR length variations have been found to affect DNA methylation (Martin-Trujillo et al, 2023) and gene expression (Gymrek et al (2016); Fotsing et al (2019); Shi et al (2023)) under physiological conditions.…”

Seq2Sat and SatAnalyzer toolkit: Towards comprehensive microsatellite genotyping from sequencing data

“…Microsatellites are short motif (1 to 6) nucleotide arrays (Ellegren, 2004; Jarne & Lagoda, 1996; Verbiest et al., 2023; Vieira et al., 2016). They are highly polymorphic and abundant within eukaryotic genomes due to a combination of processes during DNA replication, such as replication errors, DNA polymerase slippage and limited selection pressures (Ellegren, 2004; Jarne & Lagoda, 1996; Verbiest et al., 2023; Vieira et al., 2016).…”

“…Microsatellites are short motif (1 to 6) nucleotide arrays (Ellegren, 2004; Jarne & Lagoda, 1996; Verbiest et al., 2023; Vieira et al., 2016). They are highly polymorphic and abundant within eukaryotic genomes due to a combination of processes during DNA replication, such as replication errors, DNA polymerase slippage and limited selection pressures (Ellegren, 2004; Jarne & Lagoda, 1996; Verbiest et al., 2023; Vieira et al., 2016). Combining multiple variable microsatellite loci generates individual‐specific genetic profiles that are widely applied in medicine (Schaid, 2004; Sidransky, 2002), forensics (Butler, 2006) and molecular ecology (Selkoe & Toonen, 2006).…”