The Influence of Premeiotic Clusters of Mutation on Indirect Estimations of Mutation Rate

Abstract

Based on the hypothesis that rare alleles are in mutation and random loss equilibrium, mutation rate can be indirectly estimated by measuring the number of rare variants and the average existing time of a mutant allele. This method can be applied to estimate the mutation rate in humans. However, this estimation of mutation rate is affected by the presence of premeiotic clusters of mutation. Mutation clusters change both the number of initial mutants and the average existing time of a mutant allele. As a result, the formula indirectly estimating mutation rate should be modified. The influence of premeiotic clusters is more obvious when the population size is small or the average cluster size is big. For example, if the population size is 3,000 and average cluster size is two, instead of one, the mutation rate is increased by about 9.4%.

Parent of Origin, Mosaicism, and Recurrence Risk: Probabilistic Modeling Explains the Broken Symmetry of Transmission Genetics

“…24 Other studies have considered the consequences of mosaicism (also called ''premeiotic clusters'') but were directed more toward the study of population genetics. 3,25,26 Our model predictions are consistent with the unexplained observation of increased recurrence risk among X-linked recessive diseases. This elevated recurrence risk is not a feature of a special choice of parameters in our model but is instead a result of the structural difference in gametogenesis between the sexes.…”

“…1 Importantly, these mutations can be present in the germline of parents and can be potentially recurrently transmitted to future offspring. [2][3][4] Unexpected recurrences can occur, as evidenced by multiple affected children harboring the same apparently de novo variation. The birth of a single child with a severe genetic disease presents considerable psychological, social, and economic challenges; consequently, recurrence of the same disorder in a second child is a situation many couples prefer to avoid.…”

Adaptation from Leaps in the Dark

“…Because of their potential effect on the gene pool when they occur, a cluster of mutant alleles cannot be ignored or be counted as a single mutation. All members of a cluster should be counted in the determination of mutation rates (Auerbach 1962;Muller et al 1963;Drost and Lee 1995;Drake et al 1998;Neel 1998;Selby 1998;Thompson et al 1998;Fu and Huai 2003;Gong et al 2005).…”

Recurrent Cystic Hygroma and Poor Pregnancy Outcomes in a Single Patient.

“…A review of literature suggests that recurrent CH may have a familial link or possibly arise from germline mosaicism. Unfortunately, parents with germline mosaicism have mutations in their gonads which will not show up on routine genetic carrier testing that are done through blood or saliva testing 11,12 .…”