Increased paternal age may give rise to disease in the new generation

By Bhavana KunkalikarNov 8 2022Reviewed by Aimee Molineux

In a recent study published in the Fertility and Sterility journal, researchers assessed the effects of paternal age on novel mutations and diseases in the next generation.

Background

Studies have revealed that older parents are at a higher risk of bearing children having genetic diseases. The relationship between higher maternal age and congenital abnormalities in children has drawn much attention. However, a growing body of research shows that elevated paternal age is related to problems in conceiving, pregnancy complications, and increased vulnerability of offspring to several illnesses, regardless of maternal age.

Therefore, it is becoming increasingly important to assess the effect of increased paternal age on genetic vulnerability and comprehend its origins and consequences for individual couples and public health recommendations.

Origins of new mutations in humans

In the present study, researchers determined how de novo point mutations (DNMs), a major cause of genetic disease, are affected by paternal age.

The whole-exome sequencing (WES) or whole-genome sequencing (WGS) of mother-father child families involves the sequencing of a child's and both biological parents' coding sections (WES) or entire genomes (WGS). These technologies have greatly advanced the understanding of DNM biology. These investigations have conclusively demonstrated that a newborn has an average of 60 new point mutations, which places the mean human germline mutation rate at nearly 1.2×10^-8 per nucleotide in each generation. Overall, as parental age increases, the number of DNMs grows consistently and nearly monotonically. Approximately 80% of all DNMs are present on the paternally-derived allele, and the father's age predominantly influences the number of DNMs in a child at conception.

Molecular evidence derived from large WGS data is consistent with spermatogonial stem cell (SSCs) replications being the predominant factor influencing the parental bias in DNM origin and the paternal age effect (PAE) of DNMs. For example, large WGS mutation datasets have been used to derive ‘‘mutational signatures’’. This approach shows that the most common signatures observed in DNMs are similar to those associated with spontaneous preneoplastic somatic mutations. This supports the idea that stem cell cycling is the main mutational process operative in the germline and the principal contributor to DNM.

DNMs and genetic diseases

Data on DNMs from WGS/WES research of large family trios and/or testicular tissues revealed that all humans receive a small but constant amount of novel mutations at each generation. The team also noted a strong paternal bias concerning DNM origin, with most DNMs exhibiting mutational signatures. This suggested that these DNMs occur as copy errors during the process of stem cell cycling. Additionally, paternal age was the main contributing factor in a child's DNM count, with most cases displaying a linear association. Furthermore, the predominance of spontaneous developmental diseases exhibited a correlation with paternal age that was similar to that noted for the number of DNMs across a genome.

Together, these results provide strong evidence in favor of the hypothesis that for most genetic illnesses caused by DNMs, the impact of paternal age on the prevalence of diseases was causally related to the gradual buildup of DNMs in SSCs. Despite numerous other adverse reproductive outcomes, including preterm birth, poor Apgar scores, low birth weight, and elevated morbidity exhibiting similar linear increase with paternal age, the association of these conditions with DNM accumulation in SSCs is still unclear.

Selfish selection

Being able to measure and visualize the mutations present within the tissue from which they originate, for instance, testis or sperm, has facilitated a mechanism via which DNMs are frequently detected in the population. This mechanism is called 'selfish selection.'

In selfish selection, SSCs present in the seminiferous tubule of the testis of an adult human spontaneously experience rare, specific point mutations that impart functional characteristics to encoded proteins. These mutations confer the mutant SSCs with a competitive advantage and cause them to clonally expand as the age of the man increases. In turn, this leads to a sharp increase in the relative mutation abundance in sperm over time and an increased likelihood of fertilization by a mutant sperm, resulting in Mendelian disorder in the offspring. This process is equivalent to clonal growth observed in tumorigenesis; however, it occurs in the germline rather than the somatic tissues. Hence, selfish mutations have consequences not only for the individual in which they occur, causing a rare benign testicular tumor, but also for the next generation.

Overall, the individual disease risk to offspring owing to advanced paternal age remains small; however, its impact on population health is non-negligible. Moreover, the consequences of raising the age of fatherhood may need to be considered over several generations.