The impact of paternal age on new mutations and disease in the next generation

Abstract

Advanced paternal age is associated with an increased risk of fathering children with genetic disorders and other adverse reproductive consequences. However, the mechanisms underlying this phenomenon remain largely unexplored. In this review, we focus on the impact of paternal age on de novo mutations that are an important contributor to genetic disease and can be studied both indirectly through large-scale sequencing studies and directly in the tissue in which they predominantly arise-the aging testis. We discuss the recent data that have helped establish the origins and frequency of de novo mutations, and highlight experimental evidence about the close link between new mutations, parental age, and genetic disease. We then focus on a small group of rare genetic conditions, the so-called "paternal age effect" disorders that show a strong association between paternal age and disease prevalence, and discuss the underlying mechanism ("selfish selection") and implications of this process in more detail. More broadly, understanding the causes and consequences of paternal age on genetic risk has important implications both for individual couples and for public health advice given that the average age of fatherhood is steadily increasing in many developed nations.

Keywords: Paternal age effect; complex disorders; rare disorders; selfish selection; spermatogonial stem cells.

Figure 1

Origins of de novo mutations: (A) Sequencing of the whole genome or whole exome of both biological parents and a child (trio sequencing) allows identification of new mutations only present in the child. Such studies have shown that each newborn acquires ∼30–90 de novo mutations (DNMs), depending on parental age at conception. (B) Determination of the parental origin of a DNM by haplotype phasing. When an informative heterozygous SNP - for example, the SNP is AA (purple) in the mother and BB (blue) in the father - is present in the vicinity of a DNM (green star) in the child, it can be used to distinguish the maternally- and paternally-derived alleles and determine the parent of origin of the DNM. (C) Gametogenesis and origins of DNMs. In humans, segregation of PGCs from somatic lineages occurs after ∼10 mitoses, just before gastrulation takes place. Embryonic germ cells then undergo a few more replications (∼22 in females and ∼30 in males). After birth, oocytes do not undergo any further mitotic divisions. However, throughout adulthood, spermatogonial stem cells SSCs actively replicate to sustain sperm production, dividing every ∼16 days (∼23 divisions per year). It can be estimated that the sperm produced from a 25-year old male has undergone ∼350 replications, while ∼750 SSC replications would have taken place to sustain sperm production in a 45-year old male. These differences in germ cell biology likely account for the observed 80:20 ratio of paternal to maternal DNMs observed in offspring, the majority of which arise from copying errors during SSC cycling, with the number of DNMs doubling with every additional 20 years of paternal age. Lightning bold represents a mutational event. Figures created with BioRender.com. PGC = primordial germ cell; SNP = single nucleotide polymorphism; SSC = spermatogonial stem cell.

Figure 2

Selfish spermatogonial selection (A) In selfish selection, rare specific mutations occur in genes involved in the homeostatic regulation of spermatogonial stem cells (SSCs), conferring gain-of-function properties to the encoded protein. This provides the SSCs with a selective advantage over the wild-type neighbors and results in their clonal expansion within individual seminiferous tubules. As a consequence of clonal growth, the relative proportion of mutant sperm increases over the course of time. Fertilization of an oocyte by a sperm carrying a selfish mutation results in a genetic disorder in the offspring. This process is akin to tumorigenesis but occurs in the germline with consequences for the next generation. (B) Single-cell transcriptomics has allowed the key signaling pathways active in SSCs to be identified. To date, all known selfishly selected genes (highlighted in red) cluster within the Receptor Tyrosine Kinase (RTK)-RAS-MAPK pathway (red box). Deciphering the role of these pathways/genes in controlling proliferation, growth and survival of SSCs allows us to focus on new promising candidates for selfishly selected genes within the testes. Note that most of these genes cause genetic disease when mutated. Adapted from refs 74-75. Figures created with BioRender.com. SSC = spermatogonial stem cell.