Toward understanding de novo germline mutations in mammals

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Germline mutations are the root source of all sequence variation between populations and species. Although DNA replication fidelity in the cells of wild-type mammals is adequately high, some level of mutation still occurs in every generation. A longstanding interest for many geneticists has been to understand the rate and spectra of de novo mutations (DNMs) in germline cells. Because the process of mutagenesis is the first step in molecular evolution, factors that control mutagenesis are important determinants of the species-specific genomic landscape. Furthermore, a better understanding of the causes of human genetic diseases can be gained by elucidating the mechanisms of mutagenesis.

Since recent advances in sequencing technology have enabled the detection of DNMs by direct comparison of DNA sequences between parents and offspring, human DNM data have accumulated rapidly. Nevertheless, the causes of, and the mechanisms that generate, germline DNMs remain elusive. To date, the rate of human germline DNM has been reported to average 1.2 × 10⁻⁸ per nucleotide per generation and is affected by parental age. Furthermore, over two thirds of DNMs detected in children have been shown to originate from a paternal allele. Although this observation has generally been explained by the difference in DNA replication frequency between spermatogenesis and oogenesis, other underlying mechanisms may also be involved. The origin of mutation varies according to cell state: for example, mitotically increasing cells acquire mutations that are more likely to originate from replication errors or DNA damage; in contrast, in post- or non-replicative cells, such as oocytes in the meiotic prophase stage, the major processes for acquiring DNMs are DNA damage and DNA repair-mediated mutagenesis. These new observations from a vast amount of human genome data raise new questions, such as when and how do DNMs arise in germ cell development? How do age, gender, genetic variation and environment affect DNM rate and spectra? What are the factors controlling mutagenesis? Do they differ across populations and species? Despite the importance and necessity of experimental approaches using animal models to answer these questions, there is much less germline DNM data available for non-human animals than for humans.

In this issue of Genes and Genetic Systems, two reviews on germline mutation are presented. In the first, Dr. Kunihiko Sakumi (Kyushu University) introduces basic information on spontaneous mutations and the definition of de novo germline mutations, along with previous data for germline DNMs from our research group. In the second, I review recent germline mutation studies in humans and mice, focusing on the causes and the mechanisms of spontaneous mutations and discussing the issues that remain to be addressed. In addition, evidence that oxidatively damaged bases are the ultimate source of spontaneous DNMs, which was demonstrated by our experimental study using genetically engineered DNA repair-deficient mouse lines, is introduced in this review.