Frequency of mosaicism points towards mutation-prone early cleavage cell divisions in cattle

It has recently become possible to directly estimate the germ-line de novo mutation (dnm) rate by sequencing the whole genome of father-mother-offspring trios, and this has been conducted in human1–5, chimpanzee6, mice7, birds8 and fish9. In these studies dnm’s are typically defined as variants that are heterozygous in the offspring while being absent in both parents. They are assumed to have occurred in the germ-line of one of the parents and to have been transmitted to the offspring via the sperm cell or oocyte. This definition assumes that detectable mosaïcism in the parent in which the mutation occurred is negligible. However, instances of detectable mosaïcism or premeiotic clusters are well documented in humans and other organisms, including ruminants10–12. We herein take advantage of cattle pedigrees to show that as much as ∼30% to ∼50% of dnm’s present in a gamete may occur during the early cleavage cell divisions in males and females, respectively, resulting in frequent detectable mosaïcism and a high rate of sharing of multiple dnm’s between siblings. This should be taken into account to accurately estimate the mutation rate in cattle and other species.

Clusters of Identical New Mutations Can Account for the “Overdispersed” Molecular Clock

Germ-cell mutations may occur during meiosis, giving rise to independent mutant gametes in a Poisson process, or before meiosis, giving rise to multiple copies of identical mutant gametes at a much higher probability than the Poisson expectation. We report that the occurrence of these early premeiotic clusters of new identical mutant alleles increases the variance-to-mean ratio of mutation rate (R(u) > 1). This leads to an expected variance-to-mean ratio (R(t)) of the molecular clock that is always greater than one and may cover the observed range of R(t) values. Hence, the molecular clock may not be overdispersed based on this new mutational model that includes clusters. To get a better estimation of R(u) and R(t), one needs measurements of the intrageneration variation of reproductive success (Ni/Ne(i)), population dynamics (k‒i), and the proportion of new mutations that occur in clusters (rc), especially those formed before germ-cell differentiation.