Age-related alterations in the genetics and genomics of the male germ line

Herati, Amin S.; Zhelyazkova, Boryana; Butler, Peter R.; Lamb, Dolores J.

doi:10.1016/j.fertnstert.2016.12.021

Cited by 34 publications

(22 citation statements)

References 42 publications

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“…To take just one example, paternal ageing is associated with a range of epigenetic factors that impact offspring (Jenkins et al 2018), but there are also well-documented effects of paternal age on the male germline that may act as contributory factors (e.g. DNA damage attributable to reaction oxygen species, mutations, DNA fragmentation, chromosomal abnormalities; Herati et al 2017). Strictly, the direct phenotypic consequences of expressing a mutant allele inherited from the father lie outside the definition of a paternal effect.…”

Section: Non-epigenetic Mechanismsmentioning

confidence: 99%

“…These epigenetic marks were associated with exacerbated ageing and reduced longevity of offspring sired by older fathers (Xie et al 2018). Thus, the consequences of advanced paternal age on a range of offspring traits (Table 1) may arise through a range of epigenetic factors (reviewed by Herati et al 2017), but it is important to note that such effects may also be attributable to ageing-related DNA damage (Gunes et al 2016, Bisht et al 2017.…”

Section: Paternal Agementioning

confidence: 99%

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Ejaculate-mediated paternal effects: evidence, mechanisms and evolutionary implications

et al. 2019

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Despite serving the primary objective of ensuring that at least one sperm cell reaches and fertilises an ovum, the male ejaculate (i.e. spermatozoa and seminal fluid) is a compositionally complex ‘trait’ that can respond phenotypically to subtle changes in conditions. In particular, recent research has shown that environmentally and genetically induced changes to ejaculates can have implications for offspring traits that are independent of the DNA sequence encoded into the sperm’s haploid genome. In this review, we compile evidence from several disciplines and numerous taxonomic systems to reveal the extent of such ejaculate-mediated paternal effects (EMPEs). We consider a number of environmental and genetic factors that have been shown to impact offspring phenotypes via ejaculates, and where possible, we highlight the putative mechanistic pathways by which ejaculates can act as conduits for paternal effects. We also highlight how females themselves can influence EMPEs, and in some cases, how maternally derived sources of variance may confound attempts to test for EMPEs. Finally, we consider a range of putative evolutionary implications of EMPEs and suggest a number of potentially useful approaches for exploring these further. Overall, our review confirms that EMPEs are both widespread and varied in their effects, although studies reporting their evolutionary effects are still in their infancy.

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Section: Non-epigenetic Mechanismsmentioning

confidence: 99%

Section: Paternal Agementioning

confidence: 99%

Ejaculate-mediated paternal effects: evidence, mechanisms and evolutionary implications

et al. 2019

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“…De novo mutations in the paternal germline are more common than previously thought. We now know that the risk of mutations in sperm increases with exposure to environmental toxins and with age [ 3 ].…”

Section: What We Know About Mecp2 and Rett Syndromementioning

confidence: 99%

A perspective on “cure” for Rett syndrome

Abdala

2018

Orphanet J Rare Dis

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The reversal of the Rett syndrome disease process in the Mecp2 mouse model of Guy et al. (2007) has motivated families and researchers to work on this condition. The reversibility in adult mice suggests that there is potentially much to be gained from rational treatments applied to patients of any age. However, it may be difficult to strike the right balance between enthusiasm on the one hand and realism on the other. One effect of this has been a fragmentation of the “Rett syndrome community” with some groups giving priority to work aimed at a cure while fewer resources are devoted to medical or therapy-based interventions to enhance the quality of life of affected patients or provide support for their families.Several possible therapeutic approaches are under development that, it is claimed and hoped, may lead to a “cure” for patients with Rett syndrome. While all have a rationale, there are potential obstacles to each being both safe and effective. Furthermore, any strategy that succeeded in restoring normal levels of MECP2 gene expression throughout the brain carries potential pitfalls, so that it will be of crucial importance to introduce any clinical trials of such therapies with great care.Expectations of families for a radical, rational treatment should not be inflated beyond a cautious optimism. This is particularly because affected patients with us now may not be able to reap the full benefits of a “cure”. Thus, interventions aimed at enhancing the quality of life of affected patients should not be forgone and their importance should not be minimised.

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“…Paternal age greater than 50 years is associated with 6-, 8-, and 9.5-fold increases in relative risk for Pfeiffer, Crouzon, and Apert syndromes, respectively (Herati et al, 2017). In 1992, Hall et al described a sixth BSS case and noted a mean paternal age of 36 years (compared to 28 years for the mothers) (Hall et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Report of a Father With Congenital Bilateral Absence of the Vas Deferens Fathering a Child With Beare–Stevenson Syndrome

Ferreira

Dantas

2020

Front. Genet.

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Background: Apert, Pfeiffer, and Crouzon syndromes are autosomal dominant diseases characterized by craniosynostosis. They are paternal age effect disorders. The association between paternal age and Beare-Stevenson syndrome (BSS), a very rare and severe craniosynostosis, is uncertain. Gain-of-function mutations in FGFR2 become progressively enriched in testes as men age and were shown to cause these syndromes. Case report: Here, we describe a child affected with BSS, whose father was 36 years old and had congenital bilateral absence of the vas deferens (CBAVD). The child was heterozygous for the pathogenic FGFR2 variant c.1124A > G p.Tyr375Cys. By reviewing the literature, we found that BSS fathers are older than BSS mothers (mean age in years: 39 ± 10 vs 30 ± 6, p = 0.006). Male age greater than 34 years and CBAVD are both factors associated with poor spermogram parameters, which may represent an additional selective pressure to sperm carrying FGFR2 gain-of-function mutations. Conclusion: These findings are consistent with the hypothesis that BSS is a paternalorigin genetic disorder. Further experimental studies would be needed to confirm this hypothesis.

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Age-related alterations in the genetics and genomics of the male germ line

Cited by 34 publications

References 42 publications

Ejaculate-mediated paternal effects: evidence, mechanisms and evolutionary implications

Ejaculate-mediated paternal effects: evidence, mechanisms and evolutionary implications

A perspective on “cure” for Rett syndrome

Report of a Father With Congenital Bilateral Absence of the Vas Deferens Fathering a Child With Beare–Stevenson Syndrome

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