The Impact of Paternal Age on New Mutations and Disease in the Next Generation

Overview

Journal Fertil Steril

Specialty Reproductive Medicine

Date 2022 Nov 9

PMID 36351856

Authors

Katherine A Wood

Anne Goriely

Affiliations

Soon will be listed here.

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.

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References

British Andrology Society . British Andrology Society guidelines for the screening of semen donors for donor insemination (1999). Hum Reprod. 1999; 14(7):1823-6. DOI: 10.1093/humrep/14.7.1823. View

Chan P, Robaire B . Advanced Paternal Age and Future Generations. Front Endocrinol (Lausanne). 2022; 13:897101. PMC: 9218097. DOI: 10.3389/fendo.2022.897101. View

Wong W, Solomon B, Bodian D, Kothiyal P, Eley G, Huddleston K . New observations on maternal age effect on germline de novo mutations. Nat Commun. 2016; 7:10486. PMC: 4735694. DOI: 10.1038/ncomms10486. View

Frans E, McGrath J, Sandin S, Lichtenstein P, Reichenberg A, Langstrom N . Advanced paternal and grandpaternal age and schizophrenia: a three-generation perspective. Schizophr Res. 2011; 133(1-3):120-4. PMC: 3660090. DOI: 10.1016/j.schres.2011.09.027. View

Pinson A, Xing L, Namba T, Kalebic N, Peters J, Eugster Oegema C . Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals. Science. 2022; 377(6611):eabl6422. DOI: 10.1126/science.abl6422. View

Qin J, Calabrese P, Tiemann-Boege I, Shinde D, Yoon S, Gelfand D . The molecular anatomy of spontaneous germline mutations in human testes. PLoS Biol. 2007; 5(9):e224. PMC: 1951783. DOI: 10.1371/journal.pbio.0050224. View

Goriely A, McVean G, van Pelt A, ORourke A, Wall S, de Rooij D . Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia. Proc Natl Acad Sci U S A. 2005; 102(17):6051-6. PMC: 1087921. DOI: 10.1073/pnas.0500267102. View

Toriello H, Meck J . Statement on guidance for genetic counseling in advanced paternal age. Genet Med. 2008; 10(6):457-60. PMC: 3111019. DOI: 10.1097/GIM.0b013e318176fabb. View

Yeager M, Machiela M, Kothiyal P, Dean M, Bodelon C, Suman S . Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident. Science. 2021; 372(6543):725-729. PMC: 9398532. DOI: 10.1126/science.abg2365. View

10.

Urhoj S, Andersen P, Mortensen L, Davey Smith G, Nybo Andersen A . Advanced paternal age and stillbirth rate: a nationwide register-based cohort study of 944,031 pregnancies in Denmark. Eur J Epidemiol. 2017; 32(3):227-234. DOI: 10.1007/s10654-017-0237-z. View

11.

Jonsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E . Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017; 549(7673):519-522. DOI: 10.1038/nature24018. View

12.

Maher G, Ralph H, Ding Z, Koelling N, Mlcochova H, Giannoulatou E . Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes. Genome Res. 2018; 28(12):1779-1790. PMC: 6280762. DOI: 10.1101/gr.239186.118. View

13.

Murray L, McCarron P, Bailie K, Middleton R, Davey Smith G, Dempsey S . Association of early life factors and acute lymphoblastic leukaemia in childhood: historical cohort study. Br J Cancer. 2002; 86(3):356-61. PMC: 2375228. DOI: 10.1038/sj.bjc.6600012. View

14.

Petersen L, Mortensen P, Pedersen C . Paternal age at birth of first child and risk of schizophrenia. Am J Psychiatry. 2010; 168(1):82-8. DOI: 10.1176/appi.ajp.2010.10020252. View

15.

Green R, Devine O, Crider K, Olney R, Archer N, Olshan A . Association of paternal age and risk for major congenital anomalies from the National Birth Defects Prevention Study, 1997 to 2004. Ann Epidemiol. 2010; 20(3):241-9. PMC: 2824069. DOI: 10.1016/j.annepidem.2009.10.009. View

16.

. Guidelines for sperm donation. Fertil Steril. 2004; 82 Suppl 1:S9-12. DOI: 10.1016/j.fertnstert.2004.06.020. View

17.

Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L . Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014; 94(5):677-94. PMC: 4067558. DOI: 10.1016/j.ajhg.2014.03.018. View

18.

Guo J, Grow E, Yi C, Mlcochova H, Maher G, Lindskog C . Chromatin and Single-Cell RNA-Seq Profiling Reveal Dynamic Signaling and Metabolic Transitions during Human Spermatogonial Stem Cell Development. Cell Stem Cell. 2017; 21(4):533-546.e6. PMC: 5832720. DOI: 10.1016/j.stem.2017.09.003. View

19.

Tiemann-Boege I, Navidi W, Grewal R, Cohn D, Eskenazi B, Wyrobek A . The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect. Proc Natl Acad Sci U S A. 2002; 99(23):14952-7. PMC: 137526. DOI: 10.1073/pnas.232568699. View

20.

Jonsson H, Sulem P, Arnadottir G, Palsson G, Eggertsson H, Kristmundsdottir S . Multiple transmissions of de novo mutations in families. Nat Genet. 2018; 50(12):1674-1680. DOI: 10.1038/s41588-018-0259-9. View