Variation in genome-wide mutation rates within and between human families

Abstract

J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female 1. Diverse studies have supported Haldane’s contention of a higher average mutation rate in the male germline in a variety of mammals, including humans (e.g. 2,3). Here we present the first direct comparative analysis of male and female germline mutation rates from complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell-lines from which DNA was derived. Most strikingly, in one family we observed that 92% of germline DNMs were from the paternal germline, while, in complete contrast, in the other family 64% of DNMs were from the maternal germline. These observations reveal considerable variation in mutation rates within and between families.

Clock-like mutational processes in human somatic cells

“…Moreover, a combination of signatures 1 and 5 also recapitulates the pattern of de novo mutations found in the human germline (data from refs. [12][13][14], and this de novo germline pattern cannot be parsimoniously generated by other combinations of known mutational signatures (Supplementary Figure 6).…”

Whole-Exome Sequencing and Whole-Genome Sequencing in Critically Ill Neonates Suspected to Have Single-Gene Disorders

“…Although inherited changes can be recessive or dominant in nature, de novo changes that result in an observable phenotype are typically dominant. Although mutation rates vary (Conrad et al 2011), it is estimated that each individual's genome has about 74 de novo germline single nucleotide variants (Kondrashov 2003;Veltman and Brunner 2012; Genome of the Netherlands Consortium 2014) and that, if associated with dominantly expressed phenotypes, they tend to be more deleterious than other inherited variants caused by the absence of evolutionary selection (Crow 2000;EyreWalker and Keightley 2007). The vast majority of the 5 million de novo and inherited nucleotide variants and tens of millions of structural variant nucleotides in each individual genome, however, are not in coding regions or functional motifs, nor pathogenic but present a substantial signal-to-noise challenge when attempting to establish the molecular cause of a likely genetic disease.…”

Preconception exposure to mutagens: medical and other exposures to radiation and chemicals

“…One future direction for germ cell mutagenesis lies in combining a genomics approach with the present clinical studies. To be more specific, it has now been shown, as proof of principle, that a family of four can be totally sequenced (Roach et al 2010;Conrad et al 2011). A strategy for the future would be to sequence the cancer survivor (or other environmentally exposed individual), as well as his or her biological children and their other parent, to seek sequence abnormalities that seem de novo.…”