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In the past decade, several studies have estimated the human per-generation germline mutation rate using large pedigrees. More recently, estimates for various nonhuman species have been published. However, methodological differences among studies in detecting germline mutations and estimating mutation rates make direct comparisons difficult. Here, we describe the many different steps involved in estimating pedigree-based mutation rates, including sampling, sequencing, mapping, variant calling, filtering, and appropriately accounting for false-positive and false-negative rates. For each step, we review the different methods and parameter choices that have been used in the recent literature. Additionally, we present the results from a ‘Mutationathon,’ a competition organized among five research labs to compare germline mutation rate estimates for a single pedigree of rhesus macaques. We report almost a twofold variation in the final estimated rate among groups using different post-alignment processing, calling, and filtering criteria, and provide details into the sources of variation across studies. Though the difference among estimates is not statistically significant, this discrepancy emphasizes the need for standardized methods in mutation rate estimations and the difficulty in comparing rates from different studies. Finally, this work aims to provide guidelines for computational and statistical benchmarks for future studies interested in identifying germline mutations from pedigrees.
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Novel Insights into the Landscape of Crossover and Noncrossover Events in Rhesus Macaques ( Macaca mulatta )
Abstract Meiotic recombination landscapes differ greatly between distantly and closely related taxa, populations, individuals, sexes, and even within genomes; however, the factors driving this variation are yet to be well elucidated. Here, we directly estimate contemporary crossover rates and, for the first time, noncrossover rates in rhesus macaques (Macaca mulatta) from four three-generation pedigrees comprising 32 individuals. We further compare these results with historical, demography-aware, linkage disequilibrium–based recombination rate estimates. From paternal meioses in the pedigrees, 165 crossover events with a median resolution of 22.3 kb were observed, corresponding to a male autosomal map length of 2,357 cM—approximately 15% longer than an existing linkage map based on human microsatellite loci. In addition, 85 noncrossover events with a mean tract length of 155 bp were identified—similar to the tract lengths observed in the only other two primates in which noncrossovers have been studied to date, humans and baboons. Consistent with observations in other placental mammals with PRDM9-directed recombination, crossover (and to a lesser extent noncrossover) events in rhesus macaques clustered in intergenic regions and toward the chromosomal ends in males—a pattern in broad agreement with the historical, sex-averaged recombination rate estimates—and evidence of GC-biased gene conversion was observed at noncrossover sites.
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- PAR ID:
- 10487523
- Editor(s):
- Kosiol, Carolin
- Publisher / Repository:
- Oxford University Press on behalf of Society for Molecular Biology and Evolution
- Date Published:
- Journal Name:
- Genome Biology and Evolution
- Volume:
- 16
- Issue:
- 1
- ISSN:
- 1759-6653
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1093/gbe/evad223
