New observations on maternal age effect on germline de novo mutations

Wong, Wendy S. W.; Solomon, Benjamin D.; Bodian, Dale L.; Kothiyal, Prachi; Eley, Greg; Huddleston, Kathi; Baker, Robin; Thach, Dzung C.; Iyer, Ramaswamy K.; Vockley, Joseph G.; Niederhuber, John E.

doi:10.1038/ncomms10486

Cited by 178 publications

(237 citation statements)

References 23 publications

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“…Our results and others 12,13,20 show that gene conversions are biased towards GC base-pairs, while mutations are biased towards AT base-pairs and increase with age in both sexes 46,47 , but more strongly with father's age 48 . Now it is clear that gene conversions increase with mothers' age.…”

Section: Discussionsupporting

confidence: 77%

The rate of meiotic gene conversion varies by sex and age

et al. 2016

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Meiotic recombination involves a combination of gene conversion and crossover events that along with mutations produce germline genetic diversity. Here, we report the discovery of 3,176 SNP and 61 indel gene conversions. Our estimate of the non-crossover (NCO) gene conversion rate (G) is 7.0 for SNPs and 5.8 for indels per Mb per generation, and the GC bias is 67.6%. For indels we demonstrate a 65.6% preference for the shorter allele. NCO gene conversions from mothers are longer than those from fathers and G is 2.17 times greater in mothers. Notably, G increases with the age of mothers, but not fathers. A disproportionate number of NCO gene conversions in older mothers occur outside double strand break (DSB) regions and in regions with relatively low GC content. This points to age-related changes in the mechanisms of meiotic gene conversions in oocytes.

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Section: Discussionsupporting

confidence: 77%

The rate of meiotic gene conversion varies by sex and age

et al. 2016

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“…The only assumption made by the method we use is that replication fork velocity is nearly constant throughout the genome Baker et al 2012), and this assumption has been confirmed experimentally Baker et al 2012). Still, the strand asymmetry of TpCpW→K de novo mutations in a larger joined data set (Francioli et al 2015;Wong et al 2016) yielded a significant 1.17-fold difference between strands (Pvalue = 0.0174). This is in line with the approximately 1.15-fold asymmetry observed for rare SNPs.…”

Section: Wwwgenomeorgmentioning

confidence: 68%

“…Notably, C→G is among the most frequent mutations in de novo mutational clusters (Francioli et al 2015). We investigated C→G mutations in more detail in two recently published whole-genome data sets on human trios (Francioli et al 2015;Wong et al 2016) and found that within 23 pairs of C→G mutations at distances of up to 20 kb from each other, 18 were strand coordinated, which is more than expected if they were independent (P = 0.01) (Fig. 4A).…”

Section: An Unknown Mechanism Produces Clusters Of Heritable Npcpt→gmentioning

confidence: 83%

“…We thank Wendy Wong, Shamil Sunyaev, Ruslan Soldatov, and Nadezhda Terekhanova for useful discussion and Wendy Wong for help with data retrieving from the study by Wong et al (2016). This work was performed in IITP RAS and supported by the Russian Science Foundation (grant no.…”

Section: Acknowledgmentsmentioning

confidence: 99%

“…Recent studies have shown that different numbers of de novo mutations are inherited from the father and from the mother, with the contribution of paternal mutations being two to four times higher (Kong et al 2012;Francioli et al 2015;Wong et al 2016;Yuen et al 2016). Additionally, the number of de novo mutations strongly depends on the father's age at conception (Kong et al 2012;Francioli et al 2015;Wong et al 2016;Yuen et al 2016) and, to a lesser extent, on the mother's age at conception (Goldmann et al 2016;Wong et al 2016).…”

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confidence: 99%

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APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context

2016

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APOBEC3A/B cytidine deaminase is responsible for the majority of cancerous mutations in a large fraction of cancer samples. However, its role in heritable mutagenesis remains very poorly understood. Recent studies have demonstrated that both in yeast and in human cancerous cells, most APOBEC3A/B-induced mutations occur on the lagging strand during replication and on the nontemplate strand of transcribed regions. Here, we use data on rare human polymorphisms, interspecies divergence, and de novo mutations to study germline mutagenesis and to analyze mutations at nucleotide contexts prone to attack by APOBEC3A/B. We show that such mutations occur preferentially on the lagging strand and on nontemplate strands of transcribed regions. Moreover, we demonstrate that APOBEC3A/B-like mutations tend to produce strandcoordinated clusters, which are also biased toward the lagging strand. Finally, we show that the mutation rate is increased 3 ′ of C→G mutations to a greater extent than 3 ′ of C→T mutations, suggesting pervasive trans-lesion bypass of the APOBEC3A/B-induced damage. Our study demonstrates that 20% of C→T and C→G mutations in the TpCpW context-where W denotes A or T, segregating as polymorphisms in human population-or 1.4% of all heritable mutations are attributable to APOBEC3A/B activity.

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