Paternal Age Explains a Major Portion of De Novo Germline Mutation Rate Variability in Healthy Individuals

Abstract Why are more genes expressed in the testis than in any other organ in mammals? The recently proposed transcriptional scanning hypothesis posits that transcription alleviates mutagenesis through transcription-coupled repair so has been selected in the testis to modulate the germline mutation rate in a gene-specific manner. Here, we show that this hypothesis is theoretically untenable because the selection would be too weak to have an effect in mammals. Furthermore, the analysis purported to support the hypothesis did not control known confounding factors and inappropriately excluded genes with no observed de novo mutations. After remedying these problems, we find the human germline mutation rate of a gene to rise with its testis expression level. This trend also exists for inferred coding strand-originated mutations, suggesting that it arises from transcription-associated mutagenesis. Furthermore, the testis expression level of a gene robustly correlates with its overall expression in other organs, nullifying the need to explain the testis silencing of a minority of genes by adaptive germline mutagenesis. Taken together, our results demonstrate that human testis transcription increases the germline mutation rate, rejecting the transcriptional scanning hypothesis of extensive gene expressions in the mammalian testis.

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The germline mutational process in rhesus macaque and its implications for phylogenetic dating

10.1101/2020.06.22.164178 ◽

2020 ◽

Author(s):

Lucie A. Bergeron ◽

Søren Besenbacher ◽

Jaco Bakker ◽

Jiao Zheng ◽

Panyi Li ◽

...

Keyword(s):

Rhesus Macaque ◽

Mutation Rate ◽

De Novo ◽

Rhesus Macaques ◽

Average Rate ◽

Paternal Age ◽

Divergence Times ◽

Sequencing Coverage ◽

Parental Bias ◽

Mutational Process

AbstractUnderstanding the rate and pattern of germline mutations is of fundamental importance for understanding evolutionary processes. Here we analyzed 19 parent-offspring trios of rhesus macaques (Macaca mulatta) at high sequencing coverage of ca. 76X per individual, and estimated an average rate of 0.77 × 10−8de novo mutations per site per generation (95 % CI: 0.69 × 10−8 - 0.85 × 10−8). By phasing 50 % of the mutations to parental origins, we found that the mutation rate is positively correlated with the paternal age. The paternal lineage contributed an average of 81 % of the de novo mutations, with a trend of an increasing male contribution for older fathers. About 3.5 % of de novo mutations were shared between siblings, with no parental bias, suggesting that they arose from early development (postzygotic) stages. Finally, the divergence times between closely related primates calculated based on the yearly mutation rate of rhesus macaque generally reconcile with divergence estimated with molecular clock methods, except for the Cercopithecidae/Hominoidea molecular divergence dated at 52 Mya using our new estimate of the yearly mutation rate.

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Inference of candidate germline mutator loci in humans from genome-wide haplotype data

10.1101/089623 ◽

2016 ◽

Author(s):

Cathal Seoighe ◽

Aylwyn Scally

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Mutation Rate ◽

Germline Mutation ◽

De Novo ◽

1000 Genomes Project ◽

1000 Genomes ◽

A Genome ◽

Haplotype Data ◽

Candidate Loci

AbstractThe rate of germline mutation varies widely between species but little is known about the extent of variation in the germline mutation rate between individuals of the same species. Here we demonstrate that an allele that increases the rate of germline mutation can result in a distinctive signature in the genomic region linked to the affected locus, characterized by a number of haplotypes with a locally high proportion of derived alleles, against a background of haplotypes carrying a typical proportion of derived alleles. We searched for this signature in human haplotype data from phase 3 of the 1000 Genomes Project and report a number of candidate mutator loci, several of which are located close to or within genes involved in DNA repair or the DNA damage response. To investigate whether mutator alleles remained active at any of these loci, we used de novo mutation counts from human parent-offspring trios in the 1000 Genomes and Genome of the Netherlands cohorts, looking for an elevated number of de novo mutations in the offspring of parents carrying a candidate mutator haplotype at each of these loci. We found some support for two of the candidate loci, including one locus just upstream of the BRSK2 gene, which is expressed in the testis and has been reported to be involved in the response to DNA damage.Author SummaryEach time a genome is replicated there is the possibility of error resulting in the incorporation of an incorrect base or bases in the genome sequence. When these errors occur in cells that lead to the production of gametes they can be incorporated into the germline. Such germline mutations are the basis of evolutionary change; however, to date there has been little attempt to quantify the extent of genetic variation in human populations in the rate at which they occur. This is particularly important because new spontaneous mutations are thought to make an important contribution to many human diseases. Here we present a new way to identify genetic loci that may be associated with an elevated rate of germline mutation and report the application of this method to data from a large number of human genomes, generated by the 1000 Genomes Project. Several of the candidate loci we report are in or near genes involved in DNA repair and some were supported by direct measurement of the mutation rate obtained from parent-offspring trios.

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Mutation rates and the evolution of germline structure

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2015.0137 ◽

2016 ◽

Vol 371 (1699) ◽

pp. 20150137 ◽

Cited By ~ 30

Author(s):

Aylwyn Scally

Keyword(s):

Mutation Rate ◽

De Novo ◽

Active Role ◽

Paternal Age ◽

State Transitions ◽

De Novo Mutations ◽

Evolutionary Changes ◽

Sequencing Studies ◽

Paternal Age Effect ◽

Stem Cell State

Genome sequencing studies of de novo mutations in humans have revealed surprising incongruities in our understanding of human germline mutation. In particular, the mutation rate observed in modern humans is substantially lower than that estimated from calibration against the fossil record, and the paternal age effect in mutations transmitted to offspring is much weaker than expected from our long-standing model of spermatogenesis. I consider possible explanations for these discrepancies, including evolutionary changes in life-history parameters such as generation time and the age of puberty, a possible contribution from undetected post-zygotic mutations early in embryo development, and changes in cellular mutation processes at different stages of the germline. I suggest a revised model of stem-cell state transitions during spermatogenesis, in which ‘dark’ gonial stem cells play a more active role than hitherto envisaged, with a long cycle time undetected in experimental observations. More generally, I argue that the mutation rate and its evolution depend intimately on the structure of the germline in humans and other primates. This article is part of the themed issue ‘Dating species divergences using rocks and clocks'.

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Nucleosome positioning stability is a significant modulator of germline mutation rate variation across the human genome

10.1101/494914 ◽

2018 ◽

Cited By ~ 3

Author(s):

Cai Li ◽

Nicholas M. Luscombe

Keyword(s):

Human Genome ◽

Genome Evolution ◽

Mutation Rate ◽

Germline Mutation ◽

De Novo ◽

Mutation Rates ◽

Rate Variation ◽

Nucleosome Organization ◽

Local Sequence ◽

Mutation Rate Variation

AbstractUnderstanding the patterns and genesis of germline de novo mutations is important for studying genome evolution and human diseases. Nucleosome organization is suggested to be a contributing factor to mutation rate variation across the genome. However, the small number of published de novo mutations and the low resolution of earlier nucleosome maps limited our understanding of how nucleosome organization affects germline mutation rates in the human genome. Here, we systematically investigated the relationship between nucleosome organization and fine-scale mutation rate variation by analyzing >300,000 de novo mutations from whole-genome trio sequencing and high-resolution nucleosome maps in human. We found that de novo mutation rates are elevated around strong, translationally stable nucleosomes, a previously under-appreciated aspect. We confirmed this observation having controlled for local sequence context and other potential confounding factors. Analysis of the underlying mutational processes suggests that the increased mutation rates around strong nucleosomes are shaped by a combination of low-fidelity replication, frequent DNA damage and insufficient/error-prone repair in these regions. Interestingly, strong nucleosomes are preferentially located in young SINE/LINE elements, implying frequent nucleosome re-positioning (i.e. shifting of dyad position) and their contribution to hypermutation at new retrotransposons during evolution. These findings provide novel insights into how chromatin organization affects germline mutation rates and have important implications in human genetics and genome evolution.

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Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans

10.1101/108290 ◽

2017 ◽

Cited By ~ 10

Author(s):

Jedidiah Carlson ◽

Adam E Locke ◽

Matthew Flickinger ◽

Matthew Zawistowski ◽

Shawn Levy ◽

...

Keyword(s):

Mutation Rate ◽

Germline Mutation ◽

De Novo ◽

Gc Content ◽

Mutation Rates ◽

Rate Heterogeneity ◽

Genomic Features ◽

Genome Wide ◽

Wide Variability ◽

Nucleotide Context

AbstractA detailed understanding of the genome-wide variability of single-nucleotide germline mutation rates is essential to studying human genome evolution. Here we use ∼36 million singleton variants from 3,560 whole-genome sequences to infer fine-scale patterns of mutation rate heterogeneity. Mutability is jointly affected by adjacent nucleotide context and diverse genomic features of the surrounding region, including histone modifications, replication timing, and recombination rate, sometimes suggesting specific mutagenic mechanisms. Remarkably, GC content, DNase hypersensitivity, CpG islands, and H3K36 trimethylation are associated with both increased and decreased mutation rates depending on nucleotide context. We validate these estimated effects in an independent dataset of ∼46,000 de novo mutations, and confirm our estimates are more accurate than previously published estimates based on ancestrally older variants without considering genomic features. Our results thus provide the most refined portrait to date of the factors contributing to genome-wide variability of the human germline mutation rate.

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Striking differences in patterns of germline mutation between mice and humans

10.1101/082297 ◽

2016 ◽

Cited By ~ 10

Author(s):

Sarah J. Lindsay ◽

Raheleh Rahbari ◽

Joanna Kaplanis ◽

Thomas Keane ◽

Matthew E. Hurles

Keyword(s):

Mutation Rate ◽

Germline Mutation ◽

Purifying Selection ◽

Germline Mutations ◽

Spermatogonial Stem Cell ◽

Paternal Age ◽

Effective Population ◽

Population Sizes ◽

Species Specific ◽

Biological Differences

SummaryRecent whole genome sequencing (WGS) studies have estimated that the human germline mutation rate per basepair per generation (∼1.2−10−8) 1,2 is substantially higher than in mice (3.5-5.4−10−9) 3,4, which has been attributed to more efficient purifying selection due to larger effective population sizes in mice compared to humans.5,6,7. In humans, most germline mutations are paternal in origin and the numbers of mutations per offspring increase markedly with paternal age 2,8,9 and more weakly with maternal age 10. Germline mutations can arise at any stage of the cellular lineage from zygote to gamete, resulting in mutations being represented in different proportion and types of cells, with the earliest embryonic mutations being mosaic in both somatic and germline cells. Here we use WGS of multi-sibling mouse and human pedigrees to show striking differences in germline mutation rate and spectra between the two species, including a dramatic reduction in mutation rate in human spermatogonial stem cell (SSC) divisions, which we hypothesise was driven by selection. The differences we observed between mice and humans result from both biological differences within the same stage of embryogenesis or gametogenesis and species-specific differences in cellular genealogies of the germline.

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Mutation rates and the evolution of germline structure

10.1101/034298 ◽

2015 ◽

Cited By ~ 3

Author(s):

Aylwyn Scally

Keyword(s):

Mutation Rate ◽

De Novo ◽

Active Role ◽

Paternal Age ◽

Mutation Rates ◽

State Transitions ◽

Evolutionary Changes ◽

Sequencing Studies ◽

Paternal Age Effect ◽

Stem Cell State

AbstractGenome sequencing studies of de novo mutations in humans have revealed surprising incongruities with our understanding of human germline mutation. In particular, the mutation rate observed in modern humans is substantially lower than that estimated from calibration against the fossil record, and the paternal age effect in mutations transmitted to offspring is much weaker than expected from our longstanding model of spermatogenesis. I consider possible explanations for these discrepancies, including evolutionary changes in life history parameters such as generation time and the age of puberty, a possible contribution from undetected post-zygotic mutations early in embryo development, and changes in cellular mutation processes at different stages of the germline. I suggest a revised model of stem cell state transitions during spermatogenesis, in which ‘dark’ gonial stem cells play a more active role than hitherto envisaged, with a long cycle time undetected in experimental observations. More generally I argue that the mutation rate and its evolution depend intimately on the structure of the germline in humans and other primates.

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De novo mutations in domestic cat are consistent with an effect of reproductive longevity on both the rate and spectrum of mutations

10.1101/2021.04.06.438608 ◽

2021 ◽

Author(s):

Richard J Wang ◽

Muthuswamy Raveendran ◽

R Alan Harris ◽

William J Murphy ◽

Leslie A Lyons ◽

...

Keyword(s):

Mutation Rate ◽

Sexual Maturity ◽

De Novo ◽

Age Effect ◽

Domestic Cat ◽

Reproductive Age ◽

Paternal Age ◽

De Novo Mutations ◽

The Difference ◽

Paternal Age Effect

The mutation rate is a fundamental evolutionary parameter with direct and appreciable effects on the health and function of individuals. Here, we examine this important parameter in the domestic cat, a beloved companion animal as well as a valuable biomedical model. We estimate a mutation rate of 0.86 × 10-8 per bp per generation for the domestic cat (at an average age of 3.8 years). We find evidence for a strong paternal age effect, with more mutations transmitted by older sires. Our analyses suggest that the cat and the human have accrued similar numbers of mutations in the germline before reaching sexual maturity. The per-generation mutation rate in the cat is slightly lower than what has been observed in humans, but consistent with the shorter generation time in the cat. Using a model of reproductive longevity, which takes into account differences in the reproductive age and time to sexual maturity, we are able to explain much of the difference in per-generation rates between species. We further apply our reproductive longevity model in a novel analysis of mutation spectra and find that the spectrum for the cat resembles the human mutation spectrum at a younger age of reproduction. Together, these results implicate changes in life-history as a driver of mutation rate evolution between species. As the first direct observation of the paternal age effect outside of primates, our results also suggest a phenomenon that may be universal among mammals.

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Reproductive longevity predicts mutation rates in primates

10.1101/327627 ◽

2018 ◽

Cited By ~ 1

Author(s):

Gregg W.C. Thomas ◽

Richard J. Wang ◽

Arthi Puri ◽

R. Alan Harris ◽

Muthuswamy Raveendran ◽

...

Keyword(s):

Mutation Rate ◽

De Novo ◽

Paternal Age ◽

Mutation Rates ◽

Specific Mutation ◽

Genetic Constraints ◽

Wide Range ◽

Owl Monkeys ◽

Species Specific ◽

Multicellular Organisms

AbstractMutation rates vary between species across several orders of magnitude, with larger organisms having the highest per-generation mutation rates. Hypotheses for this pattern typically invoke physiological or population-genetic constraints imposed on the molecular machinery preventing mutations1. However, continuing germline cell division in multicellular eukaryotes means that organisms with longer generation times and of larger size will leave more mutations to their offspring simply as a by-product of their increased lifespan2,3. Here, we deeply sequence the genomes of 30 owl monkeys (Aotus nancymaae) from 6 multi-generation pedigrees to demonstrate that paternal age is the major factor determining the number of de novo mutations in this species. We find that owl monkeys have an average mutation rate of 0.81 × 10−8 per site per generation, roughly 32% lower than the estimate in humans. Based on a simple model of reproductive longevity that does not require any changes to the mutational machinery, we show that this is the expected mutation rate in owl monkeys. We further demonstrate that our model predicts species-specific mutation rates in other primates, including study-specific mutation rates in humans based on the average paternal age. Our results suggest that variation in life history traits alone can explain variation in the per-generation mutation rate among primates, and perhaps among a wide range of multicellular organisms.

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