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

Anne Goriely, John J. McGrath, Christina M. Hultman, Andrew O.M. Wilkie, Dolores Malaspina

Research output: Contribution to journalReview articlepeer-review

69 Scopus citations

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 themale germcell 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." Thismechanism favors propagation of germ cells carrying pathogenic mutations, increasingly skews themutational profile of spermasmen 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.

Original languageEnglish
Pages (from-to)599-608
Number of pages10
JournalAmerican Journal of Psychiatry
Volume170
Issue number6
DOIs
StatePublished - 1 Jun 2013
Externally publishedYes

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