The genome-wide determinants of human and chimpanzee microsatellite evolution

Abstract

Mutation rates of microsatellites vary greatly among loci. The causes of this heterogeneity remain largely enigmatic yet are crucial for understanding numerous human neurological diseases and genetic instability in cancer. In this first genome-wide study, the relative contributions of intrinsic features and regional genomic factors to the variation in mutability among orthologous human-chimpanzee microsatellites are investigated with resampling and regression techniques. As a result, we uncover the intricacies of microsatellite mutagenesis as follows. First, intrinsic features (repeat number, length, and motif size), which all influence the probability and rate of slippage, are the strongest predictors of mutability. Second, mutability increases nonuniformly with length, suggesting that processes additional to slippage, such as faulty repair, contribute to mutations. Third, mutability varies among microsatellites with different motif composition likely due to dissimilarities in secondary DNA structure formed by their slippage intermediates. Fourth, mutability of mononucleotide microsatellites is impacted by their location on sex chromosomes vs. autosomes and inside vs. outside of Alu repeats, the former confirming the importance of replication and the latter suggesting a role for gene conversion. Fifth, transcription status and location in a particular isochore do not influence microsatellite mutability. Sixth, compared with intrinsic features, regional genomic factors have only minor effects. Finally, our regression models explain ∼90% of variation in microsatellite mutability and can generate useful predictions for the studies of human diseases, forensics, and conservation genetics.[Supplemental material is available online at www.genome.org.]Microsatellites, i.e., tandemly recurring nucleotide sequences of short (1-6 bp) motifs, are ubiquitous in eukaryotic genomes and undergo rapid length changes due to insertion or deletion of one or multiple repeat units (Ellegren 2004;Pearson et al. 2005). Microsatellite mutation rates are high (10 ‫4מ‬-10 ‫2מ‬ mutations per locus per generation in humans) and vary greatly among loci (Ellegren 2004). The causes of this variation are not completely understood but are of great interest because microsatellite instability is implicated in cancer (Oda et al. 2005), expansions of microsatellites are responsible for over 40 neurological disorders (Pearson et al. 2005), and microsatellites are widely used markers in forensics and conservation genetics (Ellegren 2004). The most commonly proposed mutation mechanism for microsatellites is strand slippage, occurring predominantly during replication (Ellegren 2004); because of homology among microsatellite repeats, the two DNA strands might realign incorrectly after dissociation, introducing a loop at one strand and leading to microsatellite expansion/contraction (Ellegren 2004). However, experimental evidence indicates formation of unorthodox secondary DNA structures at microsatellites not only during replication but also during reco...

Empirical Evaluation Reveals Best Fit of a Logistic Mutation Model for Human Y-Chromosomal Microsatellites

“…It is well known that the pattern of microsatellite mutation varies across loci (Kelkar et al 2008). To our knowledge, however, the present study is the first to systematically compare novel as well as previously described microsatellite mutation models for Y-STRs in a locus-specific fashion.…”

“…In any case, it is well established that the mutation rate of microsatellites (i) depends upon the respective repeat number (Xu et al 2000;Lai and Sun 2003;Kelkar et al 2008) and (ii) varies greatly across loci, which is partly due to the variable nature of the repeat motif itself (Kelkar et al 2008).…”

A new set of markers for human identification based on 32 polymorphic Alu insertions

“…3,[5][6][7] Initially, the most commonly used human genotypic systems were based on STRs, each of them having multiple alleles with different population frequencies. These markers possess a very strong discrimination power but have a higher mutation rate as compared with SNP or RE 3,27 and laborious and expensive allele identification. The acquisition of data on human SNPs has resulted in systems based on this type of MGMs.…”

Analysis of Simple and Imperfect Microsatellites in Ebolavirus Species and Other Genomes of Filoviridae Family

“…To determine the impact of dMAX, incidence of compound microsatellites of the seven genomes with increasing dMAX was studied by analyzing cSSRs percentage (13). It is important to mention that the dMAX value can only be set between 0 and 50 for IMEx (24).…”

“…Their role in gene regulation, transcription and protein function has been elucidated in a few cases (9,10). Genome features such as size and GC content influence the incidence and polymorphic nature of microsatellites (11)(12)(13). However, owing to the absence of a universal correlation per se, a single priority rule cannot be forged for predicting their occurrence and density.…”