Germline De Novo Mutation Clusters Arise During Oocyte Aging in Genomic Regions With High Double-Strand-Break Incidence

Goldmann, Jakob M.; Seplyarskiy, Vladimir B.; Wong, Wendy S. W.; Vilboux, Thierry; Neerincx, Pieter; Bodian, Dale L.; Solomon, Benjamin D.; Veltman, Joris A.; Deeken, John F.; Gilissen, Christian; Niederhuber, John E.

doi:10.1097/ogx.0000000000000604

Cited by 7 publications

(23 citation statements)

References 40 publications

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“…This deficit of de novo mutations in the oocytes was taken as a proof that most mutations occurred in the male lineage. This observation was later connected to the higher evolutionary point mutation rates reported for Y than for X (3)(4)(5) and more recently to direct counting of de-novo mutations in humans (6)(7)(8)(9)(10)(11)(12), chimpanzees (13) and rodents (14).…”

Section: Introductionmentioning

confidence: 97%

The quiescent X, the replicative Y and the Autosomes

Achaz¹,

Gangloff²,

Arcangioli³

2018

Preprint

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From the analysis of the mutation spectrum in the 2,504 sequenced human genomes from the 1000 genomes project (phase 3), we show that sexual chromosomes (X and Y) exhibit a different proportion of indel mutations than autosomes (A), ranking them X>A>Y. We further show that X chromosomes exhibit a higher ratio of deletion/insertion when compared to autosomes. This simple pattern shows that the recent report that nondividing quiescent yeast cells accumulate relatively more indels (and particularly deletions) than replicating ones also applies to metazoan cells, including humans. Indeed, the X chromosomes display more indels than the autosomes, having spent more time in quiescent oocytes, whereas the Y chromosomes are solely present in the replicating spermatocytes. From the proportion of indels, we have inferred that de novo mutations arising in the maternal lineage are twice more likely to be indels than mutations from the paternal lineage. Our observation, consistent with a recent trio analysis of the spectrum of mutations inherited from the maternal lineage, is likely a major component in our understanding of the origin of anisogamy.

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Section: Introductionmentioning

confidence: 97%

The quiescent X, the replicative Y and the Autosomes

Achaz¹,

Gangloff²,

Arcangioli³

2018

Preprint

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“…Analysis of de novo mutations within these regions reveals that they are dramatically enriched in mutations of maternal origin (Table S2). Several genomic regions with high prevalence of maternal mutations, many of them occurring in clusters, have been reported by the original trio sequencing studies (29,30). Spikes of process 6/7 include all these regions and many previously unreported regions, also strongly enriched in individual and clustered mutations of maternal origin (Table S2 and Table S3).…”

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confidence: 86%

“…Alternative mutation mechanisms should involve either DNA damage or resolution of double strand breaks outside of S-phase. The latter is favored by the current literature (29,30). This is an appealing explanation in light of mutation clusters and the striking maternal age dependency resembling the impact of age on structural variants (32).…”

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confidence: 97%

Population sequencing data reveal a compendium of mutational processes in human germline

Seplyarskiy

Soldatov

McGinty

et al. 2020

Preprint

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Mechanistic processes underlying human germline mutations remain largely unknown. Variation in mutation rate and spectra along the genome is informative about the biological mechanisms. We statistically decompose this variation into separate processes using a blind source separation technique. The analysis of a large-scale whole genome sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. Seven of these processes lend themselves to a biological interpretation. One process is driven by bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes independently track direction of replication fork and replication timing. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions. We also demonstrate that a recently discovered mutagenic process specific to oocytes can be localized solely from population sequencing data. This process is spread across all chromosomes and is highly asymmetric with respect to the direction of transcription, suggesting a major role of DNA damage.

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“…Furthermore, tumors greatly vary in their mutation spectrum [34,9,35], reflecting particular differences among cell types in repair and mutagenic mechanisms, while germline variation is mainly driven by CpG transitions [36]. Our estimates of exonic and intronic mutation rate of, respectively, 1.38 × 10 −8 and 1.11 × 10 −8 mutations per site per generation, obtained from the representative Goldmann dataset [23], are consistent with the previously reported whole-genome based rate of 1.2 × 10 −8 estimated by Millholland et al [26].…”

Section: Figure 2amentioning

confidence: 99%

“…site is the number of sites (in our case 13,632,264 exonic sites and 177,729,369 flanking intronic sites) and N gen is the number of generations. For the largest healthy dataset(Goldmann et al 2018)[23], N gen = 2,582 gametogeneses, while N gen = 22,474 gametogeneses in the pooled dataset. Mutation spectrum across nine mutation classes for all analyzed DNMdatasets.…”

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confidence: 99%

Germlinede novomutation rates on exons versus introns in humans

Rodriguez-Galindo

Casillas

Weghorn

et al. 2019

Preprint

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A main assumption of molecular population genetics is that genomic mutation rate does not depend on sequence function. Challenging this assumption, a recent study has found a reduction in the mutation rate in exons compared to introns in somatic cells. This reduction was ascribed to an enhanced exonic mismatch repair system activity. If this reduction happens also in the germline, it can compromise studies of population genomics, including the detection of the footprint of selection when using introns as proxies of neutrality. Here we compiled and analyzed published germline de novo mutation (DNM) data to test if the exonic mutation rate is also reduced in germ cells. We detected ascertainment bias in studies using DNM data from diseased probands and investigated the impact of extended nucleotide context on de novo mutation rate. After controlling for these factors, we found no reduction in the mutation rate in exons compared to introns in the germline genome, in contrast to what has been previously described in somatic cells. Therefore, there is no evidence of an enhanced mismatch repair system activity in exons with respect to adjacent introns in germline cells. 1One of the most general and widely accepted predictions of the neutral theory of molecular evolution is that "the more sequence conservation, the more functional (selective) constraint on the sequence" [1]. This principle explains why different functional regions in the genome have different levels of polymorphism and divergence, such as the lower variation at nonsynonymous vs synonymous sites in protein-coding genes or in exonic vs intronic sequences [2]. This relationship between constraint and variation constitutes one of the most powerful approaches in the current search for functional regions in the genome and the detection of natural selection at the molecular level. An integral part of estimating constraint, or purifying selection, on functional genomic regions is the comparison of the observed number of mutations to the expectation under neutral evolution. In genes, this neutral expectation is usually estimated from putatively non-functional regions or sites, including intronic sequence [3,4]. A main requirement for the validation of this assumption is that mutation rate on exons and introns does not correlate with that sequence function.Mutation rates can vary strongly across the human genome, with positional differences up to 3-fold in the germline [5] and up to 5-fold in tumor cells [6]. It is influenced by several factors, including replication time, chromatin state, and expression level [7,8,6]. A priori, none of these factors are expected to correlate directly with genic sequence function (exonic vs intronic). Another important determinant of mutation rate is DNA sequence composition. Recent studies have addressed mutational processes and their associated sequence-dependent "signatures", both in the soma and the germline [9,10,11,12]. Germline and many cancer tumor signatures exhibit a higher relative rate of C>T transitions for single nu...

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Germline De Novo Mutation Clusters Arise During Oocyte Aging in Genomic Regions With High Double-Strand-Break Incidence

Abstract: Germline de novo mutation clusters arise during oocyte aging in genomic regions with high double-strand-break incidence.

Cited by 7 publications

References 40 publications

The quiescent X, the replicative Y and the Autosomes

The quiescent X, the replicative Y and the Autosomes

Population sequencing data reveal a compendium of mutational processes in human germline

Germlinede novomutation rates on exons versus introns in humans

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