Microsatellite evolution inferred from human– chimpanzee genomic sequence alignments

Abstract

Most studies of microsatellite evolution utilize long, highly mutable loci, which are unrepresentative of the majority of simple repeats in the human genome. Here we use an unbiased sample of 2,467 microsatellite loci derived from alignments of 5.1 Mb of genomic sequence from human and chimpanzee to investigate the mutation process of tandemly repetitive DNA. The results indicate that the process of microsatellite evolution is highly heterogeneous, exhibiting differences between loci of different lengths and motif sizes and between species. We find a highly significant tendency for human dinucleotide repeats to be longer than their orthologues in chimpanzees, whereas the opposite trend is observed in mononucleotide repeat arrays. Furthermore, the rate of divergence between orthologues is significantly higher at longer loci, which also show significantly greater mutability per repeat number. These observations have important consequences for understanding the molecular mechanisms of microsatellite mutation and for the development of improved measures of genetic distance.T he human genome is composed of 40-50% repetitive DNA, an important class being simple tandem repeats or microsatellite DNA sequences (1). Microsatellites are iterations of short (1-6 bp) sequence motifs, repeat numbers generally being less than 30 (2). They are spread over the genome with an estimated average density of one locus per 2-30 kb, the frequency being dependent on the criteria used for defining a microsatellite locus (1, 3). Similar microsatellite densities have also been documented for other eukaryotic genomes (4). Microsatellites are instrumental as genetic linkage markers in genome mapping projects (5) and have also found widespread use for evolutionary and population genetics studies in many species (6, 7), including humans (8).Microsatellites differ from most other DNA sequences in their high degree of polymorphism, with heterozygosities commonly exceeding 70%. As they generally seem to be free of selective constraints, it is evident that the extensive degree of genetic variability requires a high underlying mutation rate. Estimates of the human genomic mutation rate are in the range of 10 Ϫ4 to 10 Ϫ2 per meiosis (9), several orders of magnitude higher than that of unique DNA sequences (10, 11). It is commonly assumed that microsatellite mutations arise from replication slippage (slipped strand mispairing), a process thought to result in the gain or loss of one or a few repeat units (12)(13)(14). A microsatellite locus may initially evolve from the random occurrence of a few repeat units embedded within unique sequence and subsequently, after several steps of repeat expansion, reach a stage of an appreciable number of repeats. In theory, such expansion can proceed indefinitely in the absence of selection unless there are mechanisms that direct mutations toward contractions (15)(16)(17) or that make loci collapse (e.g., point mutations or large deletions; ref. 18).Based on the assumption that replication slippage is the main cause...

Segmenting the human genome based on states of neutral genetic divergence

“…These subgenomes were delineated in humanorangutan-macaque BLASTZ alignments broken into nonoverlapping 1-Mb windows based on human coordinates. For nucleotides belonging to each subgenome in each window, we computed human-specific insertion and deletion rates, human-specific nucleotide substitution rates (using the Jukes-Cantor model) (55), and human-orangutan pairwise microsatellite mutability (56). The latter was obtained for mononucleotide microsatellites with ≥9 repeats that were sufficiently abundant per 1 Mb and for repeat number bins of size four-e.g., microsatellites with 9-12 repeats formed one bin, etc.…”

Models of Microsatellite Evolution

“…Despite accounting for this ascertainment bias, Cooper, Rubinsztein, and Amos [9] found that human dinucleotide microsatellites are significantly longer than their chimpanzee orthologues. Webster, Smith, and Ellegren [51] considered many more microsatellites and concurred with [9]'s findings. They also found that human mononucleotide microsatellites are more likely to be shorter than their chimpanzee counterparts.…”

“…The estimated parameters imply microsatellites shorter than eighteen repeat units have a bias towards expansions, while longer microsatellites have a bias towards contractions. When they relaxed the assumption that the same model parameters applied in both the human and chimpanzee lineages, they found that this focal length increased to twentyone repeats in humans while remaining at eighteen repeats in chimpanzees, further confirming the findings in [9] and [51].…”

“…Since longer microsatellites are more mutable and hence more useful to experimentalists, when microsatellites are selected in one species and then compared in another species there is an ascertainment bias. Two studies that avoid this problem are Cooper, Rubinsztein, and Amos [9] and Webster, Smith, and Ellegren [51]. Despite accounting for this ascertainment bias, Cooper, Rubinsztein, and Amos [9] found that human dinucleotide microsatellites are significantly longer than their chimpanzee orthologues.…”

“…They also found that human mononucleotide microsatellites are more likely to be shorter than their chimpanzee counterparts. Webster, Smith, and Ellegren [51] selected an unbiased sample of AC dinucleotide microsatellites from a region of genomic DNA and compared the orthologues in humans and chimpanzees. Sainudiin [40] followed this strategy and used the AIC scoring system to compare slippage models of the form in equation (9).…”