Dataset Information

Quantifying Microsatellite Mutation Rates from Intestinal Stem Cell Dynamics in Msh2-Deficient Murine Epithelium.

ABSTRACT: Microsatellite sequences have an enhanced susceptibility to mutation, and can act as sentinels indicating elevated mutation rates and increased risk of cancer. The probability of mutant fixation within the intestinal epithelium is dictated by a combination of stem cell dynamics and mutation rate. Here, we exploit this relationship to infer microsatellite mutation rates. First a sensitive, multiplexed, and quantitative method for detecting somatic changes in microsatellite length was developed that allowed the parallel detection of mutant [CA]_n sequences from hundreds of low-input tissue samples at up to 14 loci. The method was applied to colonic crypts in Mus musculus, and enabled detection of mutant subclones down to 20% of the cellularity of the crypt (∼50 of 250 cells). By quantifying age-related increases in clone frequencies for multiple loci, microsatellite mutation rates in wild-type and Msh2-deficient epithelium were established. An average 388-fold increase in mutation per mitosis rate was observed in Msh2-deficient epithelium (2.4 × 10^-2) compared to wild-type epithelium (6.2 × 10^-5).

SUBMITTER: Christopher J

PROVIDER: S-EPMC6614890 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Quantifying Microsatellite Mutation Rates from Intestinal Stem Cell Dynamics in Msh2-Deficient Murine Epithelium.

Christopher Joseph J Thorsen Ann-Sofie AS Abujudeh Sam S Lourenço Filipe C FC Kemp Richard R Potter Paul K PK Morrissey Edward E Hazelwood Lee L Winton Douglas J DJ

Genetics 20190524 3

Microsatellite sequences have an enhanced susceptibility to mutation, and can act as sentinels indicating elevated mutation rates and increased risk of cancer. The probability of mutant fixation within the intestinal epithelium is dictated by a combination of stem cell dynamics and mutation rate. Here, we exploit this relationship to infer microsatellite mutation rates. First a sensitive, multiplexed, and quantitative method for detecting somatic changes in microsatellite length was developed th ...[more]

PMID: 31126976

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Project description:Microsatellite loci play an important role as markers for identification, disease gene mapping, and evolutionary studies. Mutation rate, which is of fundamental importance, can be obtained from interspecies comparisons, which, however, are subject to ascertainment bias. This bias arises, for example, when a locus is selected on the basis of its large allele size in one species (cognate species 1), in which it is first discovered. This bias is reflected in average allele length in any noncognate species 2 being smaller than that in species 1. This phenomenon was observed in various pairs of species, including comparisons of allele sizes in human and chimpanzee. Various mechanisms were proposed to explain observed differences in mean allele lengths between two species. Here, we examine the framework of a single-step asymmetric and unrestricted stepwise mutation model with genetic drift. Analysis is based on coalescent theory. Analytical results are confirmed by simulations using the simuPOP software. The mechanism of ascertainment bias in this model is a tighter correlation of allele sizes within a cognate species 1 than of allele sizes in two different species 1 and 2. We present computations of the expected average allele size difference, given the mutation rate, population sizes of species 1 and 2, time of separation of species 1 and 2, and the age of the allele. We show that when the past demographic histories of the cognate and noncognate taxa are different, the rate and directionality of mutations affect the allele sizes in the two taxa differently from the simple effect of ascertainment bias. This effect may exaggerate or reverse the effect of difference in mutation rates. We reanalyze literature data, which indicate that despite the bias, the microsatellite mutation rate estimate in the ancestral population is consistently greater than that in either human or chimpanzee and the mutation rate estimate in human exceeds or equals that in chimpanzee with the rate of allele length expansion in human being greater than that in chimpanzee. We also demonstrate that population bottlenecks and expansions in the recent human history have little impact on our conclusions.

Dataset Information

Quantifying Microsatellite Mutation Rates from Intestinal Stem Cell Dynamics in Msh2-Deficient Murine Epithelium.

Publications

Quantifying Microsatellite Mutation Rates from Intestinal Stem Cell Dynamics in Msh2-Deficient Murine Epithelium.

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