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

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.

Impact of Paternal Age at Conception on Human Health

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.

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

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.

Epigenetic inheritance of telomere length in wild birds

Telomere length (TL) predicts health and lifespan in humans and other organisms, making the identification of the causes of TL variation of interest. At conception, zygotes inherit genes that regulate TL during early development, but at the same time already express a phenotype, which is the TL of the parental gametes that formed the zygote. Whether the effect of gamete TL is transient or affects TL for life depends on the extent to which regulatory genes compensate for gamete TL variation during early development. A carry-over effect of parental TL, resulting in epigenetic inheritance, has been suggested to explain the observed relationship between parental age and offspring TL in humans and other species. However, reports of parental age effects are based on cross-sectional data, and age at reproduction has numerous confounds. Furthermore, parental age may affect offspring telomere dynamics between conception and sampling, which could also explain the paternal age effect. Using longitudinal telomere data of jackdaw parents and their chicks, we show that chicks hatched with shorter telomeres as individual fathers aged, whereas mother age had no effect. By cross-fostering eggs, we confirmed the paternal age effect to be independent of paternal care after conception. The epigenetic effect accounted for 34% of the variance in offspring TL that was explained by paternal telomere length; the remaining 66% we ascribe to a combination of environmental and additive genetic effects. Thus, our results strongly indicate epigenetic inheritance of TL, with potential consequences for offspring fitness prospects.Significance statementTelomeres are DNA-protein structures at chromosome ends and their length predicts remaining lifespan in humans and other organisms. Variation in telomere length is thought to be largely of genetic origin, but telomere inheritance may be unusual because a fertilised cell already has a telomere length (most traits are first expressed later in life). Telomeres shorten with age, and, using long-term individual-based data of jackdaw families, we show that as fathers aged, they produced chicks with shorter telomeres. This shows that paternal telomere length directly affects offspring telomere length, i.e. is inherited genetically but without the involvement of genes. This is known as an epigenetic effect and explained a large part (≥34%) of the telomere resemblance between fathers and their offspring.

Mutation rates and the evolution of germline structure

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'.