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 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.

Parental Age and Schizophrenia

1966 ◽  
Vol 112 (490) ◽  
pp. 899-905 ◽  
Author(s):  
K. L. Granville-Grossman
Keyword(s):  
Maternal Age ◽  
Age Effect ◽  
Age Effects ◽  
Paternal Age ◽  
Considerable Importance ◽  
Parental Age ◽  
Advanced Paternal Age ◽  
Older Parents ◽  
Maternal Age Effect ◽  
Environmental Causes

Reports that schizophrenics have older parents than non-schizophrenics (Barry, 1945; Goodman, 1957; Johanson, 1958; Gregory, 1959) are of considerable importance. If valid, they provide evidence for environmental causes of schizophrenia, and by analogy with other conditions where parental age effects have been noted may give some indication of the nature of these causes. There are, however, inconsistencies in these studies: thus Johanson and Gregory found a significant association between advanced paternal age and schizophrenia, but failed to confirm the maternal age effect noted by Barry and Goodman. These differences indicate the need for further investigation and this paper describes such a study.

scholarly journals New observations on maternal age effect on germline de novo mutations

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Wendy S. W. Wong ◽  
Benjamin D. Solomon ◽  
Dale L. Bodian ◽  
Prachi Kothiyal ◽  
Greg Eley ◽  
...  
Keyword(s):  
Maternal Age ◽  
De Novo ◽  
Age Effect ◽  
De Novo Mutations ◽  
Maternal Age Effect

Advancing paternal age and simplex autism

Autism ◽  
2011 ◽  
Vol 16 (4) ◽  
pp. 367-380 ◽  
Author(s):  
Connor Morrow Puleo ◽  
James Schmeidler ◽  
Abraham Reichenberg ◽  
Alexander Kolevzon ◽  
Latha V Soorya ◽  
...  
Keyword(s):  
Risk Factors ◽  
Autism Spectrum Disorder ◽  
Significant Interaction ◽  
Maternal Age ◽  
De Novo ◽  
Autism Spectrum ◽  
Paternal Age ◽  
Family Type ◽  
Simplex Family ◽  
Age And Sex

De novo events appear more common in female and simplex autism spectrum disorder (ASD) cases and may underlie greater ASD risk in older fathers’ offspring. This study examined whether advancing paternal age predicts an increase in simplex ( n = 90) versus multiplex ASD cases ( n = 587) in 677 participants (340 families). Whether or not controlling for maternal age, results support a significant interaction of linear paternal age and sex of the child on simplex family type. Female ASD cases were significantly more likely to be simplex as paternal age increased, but the increase for males was not significant. Findings suggest that ASD arising from non-familial, de novo events may be far less prominent in males than in females, even if more prevalent in males, due to the substantially larger number of male cases attributable to other, more strongly male-biased risk factors.

scholarly journals Older fathers' children have lower evolutionary fitness across four centuries and in four populations

2017 ◽  
Vol 284 (1862) ◽  
pp. 20171562 ◽  
Author(s):  
Ruben C. Arslan ◽  
Kai P. Willführ ◽  
Emma M. Frans ◽  
Karin J. H. Verweij ◽  
Paul-Christian Bürkner ◽  
...  
Keyword(s):  
Reproductive Success ◽  
De Novo ◽  
Age Effects ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Negative Effects ◽  
Older Parents ◽  
Plausible Model ◽  
Large Populations ◽  
Sibling Control

Higher paternal age at offspring conception increases de novo genetic mutations. Based on evolutionary genetic theory we predicted older fathers' children, all else equal, would be less likely to survive and reproduce, i.e. have lower fitness. In sibling control studies, we find support for negative paternal age effects on offspring survival and reproductive success across four large populations with an aggregate N > 1.4 million. Three populations were pre-industrial (1670–1850) Western populations and showed negative paternal age effects on infant survival and offspring reproductive success. In twentieth-century Sweden, we found minuscule paternal age effects on survival, but found negative effects on reproductive success. Effects survived tests for key competing explanations, including maternal age and parental loss, but effects varied widely over different plausible model specifications and some competing explanations such as diminishing paternal investment and epigenetic mutations could not be tested. We can use our findings to aid in predicting the effect increasingly older parents in today's society will have on their children's survival and reproductive success. To the extent that we succeeded in isolating a mutation-driven effect of paternal age, our results can be understood to show that de novo mutations reduce offspring fitness across populations and time periods.

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 Paternal-age-related de novo mutations and risk for five disorders

2017 ◽  
Author(s):  
Jacob L. Taylor ◽  
Jean-Christophe P.G. Debost ◽  
Sarah U. Morton ◽  
Emilie M. Wigdor ◽  
Henrike O. Heyne ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
National Registry ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Single Nucleotide Variants ◽  
Advanced Paternal Age ◽  
Age Related ◽  
Rate Ratios

AbstractBackgroundThere are well-established epidemiologic associations between advanced paternal age and increased offspring risk for several psychiatric and developmental disorders. These associations are commonly attributed to age-related de novo mutations. However, the actual magnitude of risk conferred by age-related de novo mutations in the male germline is unknown. Quantifying this risk would clarify the clinical and public health significance of delayed paternity.MethodsUsing results from large, parent-child trio whole-exome-sequencing studies, we estimated the relationship between paternal-age-related de novo single nucleotide variants (dnSNVs) and offspring risk for five disorders: autism spectrum disorders (ASD), congenital heart disease (CHD), neurodevelopmental disorders with epilepsy (EPI), intellectual disability (ID), and schizophrenia (SCZ). Using Danish national registry data, we then investigated the degree to which the epidemiologic association between each disorder and advanced paternal age was consistent with the estimated role of de novo mutations.ResultsIncidence rate ratios comparing dnSNV-based risk to offspring of 45 versus 25-year-old fathers ranged from 1.05 (95% confidence interval 1.01–1.13) for SCZ to 1.29 (95% CI 1.13-1.68) for ID. Epidemiologic estimates of paternal age risk for CHD, ID and EPI were consistent with the dnSNV effect. However, epidemiologic effects for ASDs and SCZ significantly exceeded the risk that could be explained by dnSNVs alone (p<2e-4 for both comparisons).ConclusionIncreasing dnSNVs due to advanced paternal age confer a small amount of offspring risk for psychiatric and developmental disorders. For ASD and SCZ, epidemiologic associations with delayed paternity largely reflect factors that cannot be assumed to increase with age.

scholarly journals Older fathers' children have lower evolutionary fitness across four centuries and in four populations

2016 ◽  
Author(s):  
Ruben C. Arslan ◽  
Kai P. Willführ ◽  
Emma Frans ◽  
Karin J. H. Verweij ◽  
Mikko Myrskylä ◽  
...  
Keyword(s):  
De Novo ◽  
Child Survival ◽  
Genetic Load ◽  
Age Effects ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Delayed Reproduction ◽  
Large Populations ◽  
Sibling Control ◽  
Control Study

Higher paternal age at offspring conception increases de novo genetic mutations (Kong et al., 2012). Based on evolutionary genetic theory we predicted that the offspring of older fathers would be less likely to survive and reproduce, i.e. have lower fitness. In a sibling control study, we find clear support for negative paternal age effects on offspring survival, mating and reproductive success across four large populations with an aggregate N > 1.3 million in main analyses. Compared to a sibling born when the father was 10 years younger, individuals had 4-13% fewer surviving children in the four populations. Three populations were pre-industrial (1670-1850) Western populations and showed a pattern of paternal age effects across the offspring's lifespan. In 20th-century Sweden, we found no negative paternal age effects on child survival or marriage odds. Effects survived tests for competing explanations, including maternal age and parental loss. To the extent that we succeeded in isolating a mutation-driven effect of paternal age, our results can be understood to show that de novo mutations reduce offspring fitness across populations and time. We can use this understanding to predict the effect of increasingly delayed reproduction on offspring genetic load, mortality and fertility.

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