"Selfish spermatogonial selection": a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders

Abstract

There is robust evidence from epidemiological studies that the offspring of older fathers have an increased risk of neurodevelopmental disorders, such as schizophrenia and autism. The authors present a novel mechanism that may contribute to this association. Because the male germ cell undergoes many more cell divisions across the reproductive age range, copy errors taking place in the paternal germline are associated with de novo mutations in the offspring of older men. Recently it has been recognized that somatic mutations in male germ cells that modify proliferation through dysregulation of the RAS protein pathway can lead to within-testis expansion of mutant clonal lines. First identified in association with rare disorders related to paternal age (e.g., Apert syndrome, achondroplasia), this process is known as "selfish spermatogonial selection." This mechanism favors propagation of germ cells carrying pathogenic mutations, increasingly skews the mutational profile of sperm as men age, and enriches de novo mutations in the offspring of older fathers that preferentially affect specific cellular signaling pathways. This mechanism not only offers a parsimonious explanation for the association between advanced paternal age and various neurodevelopmental disorders but also provides insights into the genetic architecture (role of de novo mutations), neurobiological correlates (altered cell cycle), and some epidemiological features of these disorders. The authors outline hypotheses to test this model. Given the secular changes for delayed parenthood in most societies, this hypothesis has important public health implications.

Figure 1

Simplified overview of the receptor tyrosine kinase (RTK)-RAS and RAS-related RHEB signaling pathways. See (5) and 34 for more details on pathways. Germline disorders associated with mutations in specific genes along this pathway are indicated in boxes. The gene products that belong to the paternal age-effect class (as defined in text) are in blue and yellow boxes indicate related disorders. RASopathies include Noonan, Costello, LEOPARD and cardio-facio-cutaneous (CFC) syndromes and are caused by mutations in the RAS/MAPK/ERK pathway. Other proteins in the pathway and associated germline disorders for which evidence of direct involvement in the process of selfish spermatogonial selection/paternal age-effect is still lacking are indicated in black. Known tumor-suppressor genes in cancer are indicated by blue circles. The RAS pathway is involved in many cellular process and some of the consequences of pathway activation of are illustrated in the case of transduction occurring in a mitotically active cell (bottom, middle) or during neurotransmission and/or synaptic plasticity (bottom, left and right). Translocation of phosphorylated forms of ERK (pERK) or AKT (pAKT) into the nucleus of a mitotic cell triggers many different cellular responses such as cell growth, proliferation, differentiation, motility and apoptosis. Within excitatory neurons, a few examples of cellular responses triggered by the RAS orRHEB pathways are illustrated and involve molecules such as ribosomal S6 kinase (S6K and RSK2) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1).

Figure 2

Depiction of the process of selfish spermatogonial selection in the testis and its consequences for the offspring. The pink oval (left) represents the testis of an aging man in which mutations (represented by X or circles) have occurred randomly during the recurrent rounds of replication required for spermatogenesis. In gray (bottom of the diagram), functionally neutral mutations are not enriched in spermatogonial progenitors and are associated with a very low risk of transmission of individual genetic lesions in the offspring. In purple (top of the diagram), the mutant spermatogonial progenitor carries a ‘strong-effect’ mutation that is associated with overt dysregulation of the RTK/RAS pathway – such as a typical oncogenic mutation. These paternal age-effect mutations confer a strong selective advantage (represented by the thickness of the purple arrow) to the mutant spermatogonial stem cell, leading over time to the formation of large clones and relative enrichment in mutant sperm. Upon germline transmission to the offspring, strong paternal age-effect mutations can cause neonatal lethality or disease phenotypes and are eliminated by purifying selection as affected individuals are unlikely to reproduce. In red and orange (middle part of the diagram), are depicted intermediate scenarios for mutations with milder selective advantage (i.e. mutation of variable penetrance, weak gain-of-function) that are enriched over time in spermatogonial stem cells to a lesser extent (>1- to 100-fold). Unlike the strong effect mutations (purple), mildly pathogenic mutations are potentially transmissible over many generations, contributing to genetic heterogeneity and variable expressivity of disease phenotypes.