A threshold size for microsatellite expansion.

When is a DNA repeat sequence a microsatellite? Microsatellites are tandem arrays of short (1–5 bp) repeats, characterized by rapid expansion and contraction through a process of ‘‘dynamic mutation’’ (Sutherland and Richards 1995). Despite their importance in modern genetic analyses (Bruford and Wayne 1993; Dib et al. 1996) and association with several human genetic diseases (Mandel 1994), little is known about the initial conditions necessary for dynamic mutation to occur— the evolutionary origin of a microsatellite. Here, we use data on the frequency of large arrays in the genome of Saccharomyces cerevisiae to demonstrate the existence of a minimum threshold size necessary for a repeat sequence to undergo dynamic mutation. The existence of this threshold provides an important insight into the evolutionary properties of repeat arrays in the genome. The major component of the dynamic mutation process is thought to be polymerase slippage during replication (Strand et al. 1993), resulting in an increase or decrease in array size of one repeat unit. Estimates of slippage mutation rates range from 1025 to 1022, values which are orders of magnitude greater than point nucleotide substitution rates (Edwards et al. 1992; Mahtani and Willard 1993). Large in vivo studies of pedigrees show a 2:1 bias in favor of gain of repeats (Weber and Wong 1993; Banchs et al. 1994), and, coupled with high mutation rates, this suggests that microsatellites show a tendency to rapidly increase in size over time. Phylogenetic analysis of two putative primate microsatellite loci further suggests that dynamic mutation may only affect arrays with a certain minimum number of repeat units (Messier, Li, and Stewart 1996). Thus, an understanding of the rapid evolutionary dynamics of microsatellites is developing, but both in vivo and phylogenetic studies are limited by the large amount of data which must be accumulated in order to observe a few mutation events. Large-scale genome sequencing projects allow a novel approach to the analysis of slippage mutation and the evolutionary origins of microsatellites. We present a study of the size distribution of short tandem repeats in the genome of yeast (S. cerevisiae) to illustrate the mutational processes acting on these arrays. We assume a null hypothesis in which there is no dynamic mutation, and repeat units (i.e., CA, AT, AGAT, etc.) are randomly distributed within the genome. This null hypothsesis is consistent with a simple model of genome evolution in