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.

Keywords: DNA repair; complex traits; evolution; microsatellites; selection; short tandem repeats.

FIGURE 1

Overview of STR mutations. (a) Patterns of STR mutations. The majority of STR mutations result in small stepwise variation in repeat copy number. These frequent mutations are likely to have little or no phenotypic effects. Larger expansion mutations are rare but may have severe phenotypic consequences in humans, such as in the case of Huntington's Disease, Fragile X Syndrome, or hereditary ataxias (Hannan, 2018). (b) Multiple mechanisms promote STR mutations. STR mutations frequently arise from misalignment of DNA strands. Strand misalignment may lead to expansions or contractions in repeat copy number depending on which strand the loop forms on. Misalignment may happen due to multiple processes including strand slippage (left), formation of secondary structures such as G4 quadruplexes or hairpins during replication (middle left) or as part of R‐loops during transcription (middle right), during homologous recombination, or during repair of double‐stranded breaks (DSB; right).

FIGURE 2

Example simulated allele length distributions for STRs with different mutation properties. Each panel shows allele frequencies at a single STR locus based on a single forward simulation (see Supplementary Methods). (a) Some STRs, such as very short repeats or those with long repeat units (>4bp), have low mutation rates and may not be polymorphic in a population. (b) Repeats with rapid mutation rates may show a wide range of repeat copy numbers. (c) Many STRs show length‐dependent mutation rates, which can result in bimodal allele length distributions.

FIGURE 3

Variability in STR abundance and repeat unit lengths across species. We used Tandem Repeats Finder (Benson, 1999) to detect STRs with repeat units 1‐6bp in genomes from 93 eukaryotic species available from the UCSC Genome Browser (Kent et al., 2002) and 4 prokaryotic species available from NCBI. This analysis is described in more detail in Supplementary Methods. (a) Number of STRs identified per species. (b) STR density (number of STRs divided by genome size). (c) Proportion of STRs by repeat unit length. Gray = mononucleotides; red = dinucleotides; gold = trinucleotides; blue = tetranucleotides; green = pentanucleotides; purple = hexanucleotides. Black boxes highlight specific findings reviewed in the text.

FIGURE 4

Schematic representation of an association between the length of an STR and a quantitative phenotype. Repeats positioned upstream of a gene's transcription start site are depicted. Left: Green boxes indicate STR units and black boxes indicate SNPs. The number of green boxes shows the STR copy number of different alleles. This variation serves as the y‐axis of the gene expression graph and the phenotype graph on the right side. Variation in STRs is often in low linkage disequilibrium (LD) with nearby SNPs (Jakubosky et al., ; Saini et al., 2018). The bar at the bottom right depicts enrichment of STRs in gene regulatory regions as documented in Sawaya et al. (2013) with increased abundance in upstream regions and immediately downstream of genes as well as in first introns (Bilgin Sonay et al., 2015).