scholarly journals Mutation rates and the evolution of germline structure

2015 ◽  
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.

scholarly journals Mutation rates and the evolution of germline structure

2016 ◽  
Vol 371 (1699) ◽  
pp. 20150137 ◽  
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'.

scholarly journals Model for de novo mutation propagation depending on paternal age at conception and associated neurological disorders

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 358
Author(s):  
Johannes Lawen ◽  
Ena Wang
Keyword(s):  
Neurological Disorders ◽  
De Novo ◽  
Demographic Data ◽  
Age Effect ◽  
Age Effects ◽  
Paternal Age ◽  
De Novo Mutation ◽  
Mutation Rates ◽  
Mitigating Factors ◽  
Paternal Age Effect

This paper presents a computational model for simulating the propagation of de novo mutations and paternal age effects in populations. The model uses data for paternal de novo mutation rates depending on age and demographic data such as age distributions, birth distributions versus age, varying life expectancy, and correlations with fertility. The number of paternal de novo mutations in children increases with the paternal age at conception. This might be of interest considering that the average paternal age has risen significantly in many societies throughout the last century. The model introduced below can superimpose and extrapolate different effects based on demographic dynamics. This includes the assessment of statistically associated neurological disorders in offspring, particularly IQ decay depending on the paternal age and other medical phenotypes which constitute paternal age effects. Yearly paternal mutation rates and correlations with paternal age were used to simulate both, de novo mutation propagation and probabilities for correlating conditions such as IQ decay. The extrapolated effect after several generations of persistently elevated paternal age appears to be drastic. To account for possibly mitigating factors, the paternal age effect has been super-positioned with the Flynn effect in simulated cases. The model automatically generates distributions for varying paternal ages, not just single cases, in convenient 3D distributions. The model simulates each person’s individual reproductive incidents through a particle type approach which is more rigorous than insufficiently adaptive, continuum models based on partial differential equations. The model is not only applicable to humans and yields many valuable conclusions for a wide array of topics including the paternal age effect, correlations with intelligence, evolution, bottlenecks in evolution, as well as the role of de novo mutation.

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

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.

scholarly journals Reproductive longevity predicts mutation rates in primates

2018 ◽  
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.

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

PLoS ONE ◽  
2016 ◽  
Vol 11 (10) ◽  
pp. e0164212 ◽  
Author(s):  
Simon L. Girard ◽  
Cynthia V. Bourassa ◽  
Louis-Philippe Lemieux Perreault ◽  
Marc-André Legault ◽  
Amina Barhdadi ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Germline Mutation ◽  
De Novo ◽  
Paternal Age ◽  
Major Portion ◽  
Healthy Individuals

scholarly journals De novo mutations across 1,465 diverse genomes reveal novel mutational insights and reductions in the Amish founder population

2019 ◽  
Author(s):  
Michael D. Kessler ◽  
Douglas P. Loesch ◽  
James A. Perry ◽  
Nancy L. Heard-Costa ◽  
Brian E. Cade ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Mutation Rate ◽  
De Novo ◽  
Population Level ◽  
Mutation Rates ◽  
Founder Population ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Nucleotide Mutation ◽  
Rare Genetic Variation

Abstractde novo Mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) program, we directly estimate and analyze DNM counts, rates, and spectra from 1,465 trios across an array of diverse human populations. Using the resulting call set of 86,865 single nucleotide DNMs, we find a significant positive correlation between local recombination rate and local DNM rate, which together can explain up to 35.5% of the genome-wide variation in population level rare genetic variation from 41K unrelated TOPMed samples. While genome-wide heterozygosity does correlate weakly with DNM count, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, interestingly, we do find significantly fewer DNMs in Amish individuals compared with other Europeans, even after accounting for parental age and sequencing center. Specifically, we find significant reductions in the number of T→C mutations in the Amish, which seems to underpin their overall reduction in DNMs. Finally, we calculate near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by non-additive genetic effects and/or the environment, and that a less mutagenic environment may be responsible for the reduced DNM rate in the Amish.SignificanceHere we provide one of the largest and most diverse human de novo mutation (DNM) call sets to date, and use it to quantify the genome-wide relationship between local mutation rate and population-level rare genetic variation. While we demonstrate that the human single nucleotide mutation rate is similar across numerous human ancestries and populations, we also discover a reduced mutation rate in the Amish founder population, which shows that mutation rates can shift rapidly. Finally, we find that variation in mutation rates is not heritable, which suggests that the environment may influence mutation rates more significantly than previously realized.

scholarly journals Impact of Paternal Age at Conception on Human Health

2019 ◽  
Vol 65 (1) ◽  
pp. 146-152 ◽  
Author(s):  
Mathieu Simard ◽  
Catherine Laprise ◽  
Simon L Girard
Keyword(s):  
Maternal Age ◽  
De Novo ◽  
Autism Spectrum ◽  
Age Effect ◽  
Age Effects ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Brain Functions ◽  
Offspring Health ◽  
Paternal Age Effect

Abstract BACKGROUND The effect of maternal age at conception on various aspects of offspring health is well documented and often discussed. We seldom hear about the paternal age effect on offspring health, although the link is now almost as solid as with maternal age. The causes behind this, however, are drastically different between males and females. CONTENT In this review article, we will first examine documented physiological changes linked to paternal age effect. We will start with all morphological aspects of the testis that have been shown to be altered with aging. We will then move on to all the parameters of spermatogenesis that are linked with paternal age at conception. The biggest part of this review will focus on genetic changes associated with paternal age effects. Several studies that have established a strong link between paternal age at conception and the rate of de novo mutations will be reviewed. We will next discuss paternal age effects associated with telomere length and try to better understand the seemingly contradictory results. Finally, severe diseases that affect brain functions and normal development have been associated with older paternal age at conception. In this context, we will discuss the cases of autism spectrum disorder and schizophrenia, as well as several childhood cancers. SUMMARY In many Western civilizations, the age at which parents have their first child has increased substantially in recent decades. It is important to summarize major health issues associated with an increased paternal age at conception to better model public health systems.

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

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.

scholarly journals Highly accelerated rates of heritable large-scale mutations under prolonged exposure to a metal mixture of copper and nickel

2018 ◽  
Author(s):  
Frédéric J.J. Chain ◽  
Jullien M. Flynn ◽  
James K. Bull ◽  
Melania E. Cristescu
Keyword(s):  
Mutation Rate ◽  
Large Scale ◽  
Prolonged Exposure ◽  
De Novo ◽  
Multiple Stressors ◽  
Copy Number Variations ◽  
Environmental Stressors ◽  
Mutation Rates ◽  
Rate Variation ◽  
Mutational Load

AbstractMutation rate variation has been under intense investigation for decades. Despite these efforts, little is known about the extent to which environmental stressors accelerate mutation rates and influence the genetic load of populations. Moreover, most studies have focused on point mutations rather than large-scale deletions and duplications (copy number variations or “CNVs”). We estimated mutation rates inDaphnia pulexexposed to low levels of environmental stressors as well as the effect of selection onde novomutations. We conducted a mutation accumulation (MA) experiment in which selection was minimized, coupled with an experiment in which a population was propagated under competitive conditions in a benign environment. After an average of 103 generations of MA propagation, we sequenced 60 genomes and found significantly accelerated rates of deletions and duplications in MA lines exposed to ecologically relevant concentrations of metals. Whereas control lines had gene deletion and duplication rates comparable to other multicellular eukaryotes (1.8 × 10−6per gene per generation), a mixture of nickel and copper increased rates fourfold. The realized mutation rate under selection was reduced to 0.4x that of control MA lines, providing evidence that CNVs contribute to mutational load. Our CNV breakpoint analysis revealed that nonhomologous recombination associated with regions of DNA fragility is the primary source of CNVs, plausibly linking metal-induced DNA strand breaks with higher CNV rates. Our findings suggest that environmental stress, in particular multiple stressors, can have profound effects on large-scale mutation rates and mutational load of populations.

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

2018 ◽  
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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