Sequence-based estimation of minisatellite and microsatellite repeat variability

Abstract

Variable tandem repeats are frequently used for genetic mapping, genotyping, and forensics studies. Moreover, variation in some repeats underlies rapidly evolving traits or certain diseases. However, mutation rates vary greatly from repeat to repeat, and as a consequence, not all tandem repeats are suitable genetic markers or interesting unstable genetic modules. We developed a model, "SERV," that predicts the variability of a broad range of tandem repeats in a wide range of organisms. The nonlinear model uses three basic characteristics of the repeat (number of repeated units, unit length, and purity) to produce a numeric "VARscore" that correlates with repeat variability. SERV was experimentally validated using a large set of different artificial repeats located in the Saccharomyces cerevisiae URA3 gene. Further in silico analysis shows that SERV outperforms existing models and accurately predicts repeat variability in bacteria and eukaryotes, including plants and humans. Using SERV, we demonstrate significant enrichment of variable repeats within human genes involved in transcriptional regulation, chromatin remodeling, morphogenesis, and neurogenesis. Moreover, SERV allows identification of known and candidate genes involved in repeat-based diseases. In addition, we demonstrate the use of SERV for the selection and comparison of suitable variable repeats for genotyping and forensic purposes. Our analysis indicates that tandem repeats used for genotyping should have a VARscore between 1 and 3. SERV is publicly available from

The Rate and Spectrum of Microsatellite Mutation in Caenorhabditis elegans and Daphnia pulex

“…As in previous studies (Wierdl et al 1997;Brinkmann et al 1998;Kayser et al 2000;Beck et al 2003;Whittaker et al 2003;Legendre et al 2007), we find a strong correlation between allele size (repeat number) and mutation rate in C. elegans (Figure 1). In addition, although the variation of repeat numbers among loci sampled in D. pulex does not permit a formal evaluation of length dependence over a large range, as noted above, this organism also exhibits an order of magnitude span in the average mutation rate for small vs. large loci (averaging 21.1 and 38.2 repeats, respectively).…”

“…On a per-generation basis, the mutation rates that we report for C. elegans and D. pulex are much lower than those previously estimated for humans (Heyer et al 1997;Brinkmann et al 1998;Sajantila et al 1999;Kayser et al 2000;Leopoldino and Pena 2003;Dupuy et al 2004;Ballard et al 2005;Gusmao et al 2005;Henke and Henke 2006;Yan et al 2006;Hohoff et al 2007;Lee et al 2007), but much higher than those for yeast (Henderson and Petes 1992;Strand et al 1993;Johnson et al 1996;Sia et al 1997Sia et al , 2001Wierdl et al 1997;Hawk et al 2005;Legendre et al 2007). In principle, such differences could simply arise as a consequence of the pronounced variation in the numbers of germline cell divisions per generation that exists among these species (1, 10, and $200, respectively, in Saccharomyces cerevisiae, C. elegans, and Homo sapiens; Kimble and Ward 1998;Crow 2000).…”

Zinc-finger directed double-strand breaks within CAG repeat tracts promote repeat instability in human cells

“…Length-dependent modifiers of repeat instability are common (32)(33)(34)(35). To explore whether ZFN-induced instability depends on the length of the repeat tract, we transfected the zfGCT nuclease into APRT(CAG) 61 CHO cells and human HPRT(CAG) 68 cells.…”

Of mice and men

“…However, the purity of the repeats is highly correlated with the mutation rate, and even a few mismatches can dramatically enhance the stability of the repeat. 17 Therefore, the FTRs in the mouse Rbl2 gene were predicted to evolve more rapidly than non-repeated DNA sequences, but were likely more stable than perfect tandem repeats.…”

“…We identified three p53 target genes induced by the binding of p53 to clusters of canonical p53 REs within imperfect repeats called "Fuzzy Tandem Repeats" (FTRs). Although FTRs are likely more stable than perfect tandem repeats, 17 the sequences of the FTRs diverged among mammalian species, and the 3 genes were genes belonging to this new class of species-specific target genes: Rbl2, Ncoa1 and Klhl26. Importantly, however, current software programs were not designed to search for imperfectly repeated sequences over entire genomes, and we limited our functional validation of candidate p53 targets to genes that are expressed in MEFs.…”