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Reviews and Overviews   |    
“Selfish Spermatogonial Selection”: A Novel Mechanism for the Association Between Advanced Paternal Age and Neurodevelopmental Disorders
Anne Goriely, Ph.D.; John J. McGrath, M.D., Ph.D.; Christina M. Hultman, Ph.D.; Andrew O.M. Wilkie, D.M., F.R.C.P.; Dolores Malaspina, M.D., M.S.P.H.
Am J Psychiatry 2013;170:599-608. doi:10.1176/appi.ajp.2013.12101352
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Dr. McGrath reports receiving research support from Eli Lilly and honoraria for educational talks from AstraZeneca and Lundbeck. The other authors report no financial relationships with commercial interests.

Supported by Wellcome Trust grant 091182 to Drs. Goriely and Wilkie, Australian National Health and Medical Research Council grant APP569528 to Dr. McGrath, NIMH grants RC1 MH-088843 and K24-5K24 MH-001699 to Dr. Malaspina, and Swedish Research Council grant 2011-4659 to Dr. Hultman.

From the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, U.K.; the Queensland Brain Institute, University of Queensland, St. Lucia, Australia; the Queensland Centre for Mental Health Research, Park Centre for Mental Health, Richlands, Australia; the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; and the Departments of Psychiatry and Environmental Medicine, New York University, New York.

Address correspondence to Dr. McGrath (j.mcgrath@uq.edu.au).

Copyright © 2013 by the American Psychiatric Association

Received October 25, 2012; Revised January 15, 2013; Accepted January 18, 2013.

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.

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FIGURE 1. Cellular Signaling Pathways Affected by Gene Mutations Due to Greater Paternal Agea,b

a Abbreviations: AKT, a serine/threonine-specific protein kinase, also known as protein kinase B (PKB); AR, adrenergic receptor; BRAF, a member of the RAF (rapidly accelerated fibrosarcoma) kinase family; CBL, protein encoded by Cbl gene (named after Casitas B-lineage lymphoma); CFC, cardiofaciocutaneous syndrome; CRAF, a member of the RAF (rapidly accelerated fibrosarcoma) kinase family; 4E-BP1, 4E binding protein 1; ERK, extracellular-signal-regulated kinase; FGFR, fibroblast growth factor receptor gene; GDP, guanosine 5′-diphosphate; GEF, guanine nucleotide exchange factor; GluR, glutamate receptor; GluT, glutamate transporter; GTP, guanosine 5′-triphosphate; HRAS, enzyme encoded by the Harvey RAS-1 gene; KRAS, protein encoded by the Kirsten RAS oncogene; MAPK, mitogen-activated protein kinase; MEK, a protein kinase (“mitogen-activated protein kinase/extracellular-signal-regulated kinase”); MEN, multiple endocrine neoplasia; MR, mineralocorticoid receptor; mTOR, mammalian target of rapamycin (a serine/threonine protein kinase); NMDAR, N-methyl-d-aspartate receptor; NRAS, enzyme encoded by the NRAS gene, which is associated with neuroblastoma; pAKT, phosphorylated form of AKT; PDK, phosphoinositide-dependent kinase; pERK, phosphorylated form of ERK; PI3K, phosphatidylinositide 3-kinase; PIP, prolactin-inducible protein; PKB, protein kinase B; PTEN, protein encoded by the phosphatase and tensin homolog gene; RAS, a family of proteins involved in intracellular signal transmission (from “rat sarcoma”); RET, “rearranged during transfection” gene; RHEB, RAS homolog enriched in brain; RSK2, ribosomal S6 kinase; RTK, receptor tyrosine kinase; S6K, S6 kinase; SHOC, protein encoded by “suppressor of clear homolog in C. elegans” gene; SHP2, cytosolic SH2 domain containing protein tyrosine phosphatase; SOS, protein encoded by “son of sevenless” gene; TD, thanatophoric dysplasia; TRKB, tyrosine-related kinase B; TSC, tuberous sclerosis complex. LEOPARD is a mnemonic of characteristic features.

b See references 5 and 32 for more details on these pathways. Germline disorders associated with mutations in specific genes along these pathways are indicated in boxes. The gene products that belong to the class affected by paternal age (as defined in text) are in blue, and yellow boxes indicate related disorders. Congenital disorders associated with the RAS family are known as “RASopathies.” They include the Noonan, Costello, LEOPARD, and CFC syndromes and are caused by mutations in the RTK/RAS and MAPK pathways. Other proteins in the pathway and associated germline disorders for which evidence of direct involvement in the process of selfish spermatogonial selection and paternal age effect is still lacking are indicated in black. Known tumor-suppressor genes in cancer are indicated by blue ovals. The RAS pathway is involved in many cellular processes, and some of the consequences of pathway activation 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 or RHEB pathway are illustrated and involve molecules such as ribosomal S6 kinase (S6K and RSK2) and eukaryotic translation initiation factor 4E-BP1.

FIGURE 2. Process of Selfish Spermatogonial Selection in the Testis and Its Consequences for the Offspringa,b

a Abbreviations: RAS, a family of proteins involved in intracellular signal transmission (from “rat sarcoma”); RTK, receptor tyrosine kinase. A “private” variant is a mutational hit that is likely to be serendipitous and therefore is anticipated to be essentially unique.

b 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 the gray section (bottom of 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 the red section (top of 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 red 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. The orange and yellow sections (middle of the diagram) depict 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 mutations with strong effects (red), mildly pathogenic mutations are potentially transmissible over many generations, contributing to genetic heterogeneity and variable expressivity of disease phenotypes.

+

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With respect to age-related mutations, the key difference between male and female gamete production is:
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