Paternal age, de novo mutations, and offspring health? New directions for an ageing problem

Abstract

This Directions article examines the mechanisms by which a father's age impacts the health and wellbeing of his children. Such impacts are significant and include adverse birth outcomes, dominant genetic conditions, neuropsychiatric disorders, and a variety of congenital developmental defects. As well as age, a wide variety of environmental and lifestyle factors are also known to impact offspring health via changes mediated by the male germ line. This picture of a dynamic germ line responsive to a wide range of intrinsic and extrinsic factors contrasts with the results of trio studies indicating that the incidence of mutations in the male germ line is low and exhibits a linear, monotonic increase with paternal age (∼two new mutations per year). While the traditional explanation for this pattern of mutation has been the metronomic plod of replication errors, an alternative model pivots around the 'faulty male' hypothesis. According to this concept, the genetic integrity of the male germ line can be dynamically impacted by age and a variety of other factors, and it is the aberrant repair of such damage that drives mutagenesis. Fortunately, DNA proofreading during spermatogenesis is extremely effective and these mutant cells are either repaired or deleted by apoptosis/ferroptosis. There appear to be only two mechanisms by which mutant germ cells can escape this apoptotic fate: (i) if the germ cells acquire a mutation that by enhancing proliferation or suppressing apoptosis, permits their clonal expansion (selfish selection hypothesis) or (ii) if a genetically damaged spermatozoon manages to fertilize an oocyte, which then fixes the damage as a mutation (or epimutation) as a result of defective DNA repair (oocyte collusion hypothesis). Exploration of these proposed mechanisms should not only help us better understand the aetiology of paternal age effects but also inform potential avenues of remediation.

Keywords: antioxidant therapy; epigenetic mutation; genetic mutation; male ageing; oxidative stress; sperm DNA damage.

Graphical Abstract

Pathologies associated with male ageing and their possible resolution with androgen replacement and/or antioxidant therapy.

Figure 1.

A proposed framework for understanding the impact of paternal age on offspring health. Within the ageing germ cell population (i) the progressive buildup of intrinsic replication errors and (ii) accumulated DNA damage inflicted by a lifetime’s exposure to extrinsic environmental and lifestyle stressors, combined with (iii) age-dependent declines in the efficacy of DNA repair and antioxidant availability lead to an increase in genetic damage. Such damage is usually addressed by effective DNA repair (particularly the BER pathway) and, if the damage is too great, the extremely rapid and efficient induction of apoptosis. Programmed cell death operates at all stages of germ cell development including spermatogonia, spermatocytes, spermatids and even spermatozoa and effectively removes around 75–80% of these damaged cells from the germinal epithelium. The combination of DNA repair and apoptosis ensures that the mutational load carried by the male germ line is low and only increases slowly with paternal age. There are only two ways in which germ cells can avoid this apoptotic fate. (A) The occurrence of germ line mutations in signal transduction pathways that result in either an increase in cell proliferation and/or a decrease in apoptosis (selfish selection). These mutations lead to a clonal expansion of the mutated cells that become enriched in the seminiferous tubules of ageing males. For example, lesions in the RTK-RAS-MAPK pathway are known to be involved in a wide range of genetic diseases (achondroplasia, Apert syndrome etc.) but other pathways are theoretically possible including the PTEN-PI3K-AKT signal transduction cascade. (B) Spermatozoa possessing high levels of DNA damage may escape apoptosis and retain sufficient functionality to be rescued by fertilization. At this point, the DNA damage is either repaired by the oocyte or, if this process is compromised, becomes fixed as a genetic or epigenetic mutation in the embryo (oocyte collusion). These pathways finally converge to generate a wide range of paternally-mediated pathologies in the offspring including congenital birth defects, neuropsychiatric disorders, cancers and miscarriage. BER, base excision repair; SSC, spermatogonial stem cell.