Parent-of-origin-specific signatures of de novo mutations

Goldmann, Jakob M.; Wong, Wendy S. W.; Pinelli, Michele; Farrah, Terry; Bodian, Dale L.; Stittrich, Anna Barbara; Glusman, Gustavo; Vissers, Lisenka E.L.M.; Hoischen, Alexander; Roach, Jared C.; Vockley, Joseph G.; Veltman, Joris A.; Solomon, Benjamin D.; Gilissen, Christian; Niederhuber, John E.

doi:10.1038/ng.3597

Cited by 305 publications

(438 citation statements)

References 40 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: 76%

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: 76%

The rate of meiotic gene conversion varies by sex and age

et al. 2016

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“…There is generally a higher mutation rate in males (e.g. [19]), and paternal X-linked mutations are not transmitted to sons; however, germ-line rstb.royalsocietypublishing.org Phil. Trans.…”

Section: (B) X-linked Mutationsmentioning

confidence: 99%

When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

Carrel

Brown

2017

Phil. Trans. R. Soc. B

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A tribute to Mary Lyon was held in October 2016. Many remarked about Lyon's foresight regarding many intricacies of the X-chromosome inactivation process. One such example is that a year after her original 1961 hypothesis she proposed that genes with Y homologues should escape from X inactivation to achieve dosage compensation between males and females. Fifty-five years later we have learned many details about these escapees that we attempt to summarize in this review, with a particular focus on recent findings. We now know that escapees are not rare, particularly on the human X, and that most lack functionally equivalent Y homologues, leading to their increasingly recognized role in sexually dimorphic traits. Newer sequencing technologies have expanded profiling of primary tissues that will better enable connections to sex-biased disorders as well as provide additional insights into the X-inactivation process. Chromosome organization, nuclear location and chromatin environments distinguish escapees from other X-inactivated genes. Nevertheless, several big questions remain, including what dictates their distinct epigenetic environment, the underlying basis of species differences in escapee regulation, how different classes of escapees are distinguished, and the roles that local sequences and chromosome ultrastructure play in escapee regulation.

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“…The putative numbers of paternal mutations per generation were then divided by 629 the estimated number of cell divisions per generation (62 in mice, 401 in 630 humans) 8 . 631…”

Section: Average Mutation Rates 612 613mentioning

confidence: 99%

“…Most germline mutations in humans (75-80%) are paternal in origin, and 42 increasing paternal age is the major factor determining variation in numbers of 43 mutations per offspring in humans 2, 8,9 with an average increase of 1-2 paternal 44 de novo mutations (DNMs) per year. Recently a more modest effect of maternal 45 age has been reported, equating to an additional 0.24-0.5 DNMs per year 10 .…”

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confidence: 99%

Striking differences in patterns of germline mutation between mice and humans

Rahbari

Kaplanis

et al. 2016

Preprint

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Summary 11 12Little is known about differences in germline mutation processes between 13 extant mammals. We analysed genome sequences of mouse and human 14 pedigrees to investigate mutational differences between these species. We found 15 that while the generational mutation rate in mice is 40% of that in humans, the 16 annual mutation rate is 16 times higher, and the mutation rate per cell division is 17 two-fold higher. We classified mutations into four temporal strata reflecting the 18 timing of the mutation within the lineage from zygote to gamete. The earliest 19 embryonic cell divisions are the most mutagenic in both species, but these 20 earliest mutations account for a much higher proportion of all mutations in mice 21 (~25%) than in humans (~5%). We observed a strong sex bias in the number of 22 mutations arising in subsequent cell divisions in the early embryo in mice, but not 23 in humans. Finally, we reconstructed partial genealogies of murine parental 24 gametes that suggest markedly unequal contributions from founding primordial 25 germ cells.

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Parent-of-origin-specific signatures of de novo mutations

Cited by 305 publications

References 40 publications

The rate of meiotic gene conversion varies by sex and age

The rate of meiotic gene conversion varies by sex and age

When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

Striking differences in patterns of germline mutation between mice and humans

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