The ‘faulty male’ hypothesis for sex-biased mutation and disease

Hahn, Matthew W.; Peña-Garcia, Yadira; Wang, Richard J.

doi:10.1016/j.cub.2023.09.028

Cited by 5 publications

References 75 publications

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Characterization and distribution of de novo mutations in the zebra finch

Liang,

Yang,

Wang

et al. 2024

Commun Biol

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Germline de novo mutations (DNMs) provide the raw material for evolution. The DNM rate varies considerably between species, sexes and chromosomes. Here, we identify DNMs in the zebra finch ( Taeniopygia guttata ) across 16 parent-offspring trios using two genome assemblies of different quality. Using an independent genotyping assay, we validate 82% of the 150 candidate DNMs. DNM rates are consistent between both assemblies, with estimates of 6.14 × 10 –9 and 6.36 × 10 –9 per site per generation. We observe a strong paternal bias in DNM rates (male-to-female ratio ɑ ≈ 4), but this bias is in transition mutations only, leading to a transition-to-transversion ratio of 3.18 and 3.57. Finally, we find that DNMs tend to be randomly distributed across chromosomes, not associated with recombination hotspots or genic regions. However, the sex chromosome chrZ shows a roughly fourfold increased DNM rate compared to autosomes, which is more than the expected increase due to chrZ spending two-thirds of its time in males. Overall, our results further enhance our understanding of DNMs in passerine songbirds.

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Characterization and distribution of de novo mutations in the zebra finch

Liang,

Yang,

Wang

et al. 2024

Commun Biol

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Paternal age, de novo mutations, and offspring health? New directions for an ageing problem

Aitken

2024

Human Reproduction

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This Directions article examines the mechanisms by which a father’s age impacts the health and wellbeing of his children. Such impacts are significant and include adverse birth outcomes, dominant genetic conditions, neuropsychiatric disorders, and a variety of congenital developmental defects. As well as age, a wide variety of environmental and lifestyle factors are also known to impact offspring health via changes mediated by the male germ line. This picture of a dynamic germ line responsive to a wide range of intrinsic and extrinsic factors contrasts with the results of trio studies indicating that the incidence of mutations in the male germ line is low and exhibits a linear, monotonic increase with paternal age (∼two new mutations per year). While the traditional explanation for this pattern of mutation has been the metronomic plod of replication errors, an alternative model pivots around the ‘faulty male’ hypothesis. According to this concept, the genetic integrity of the male germ line can be dynamically impacted by age and a variety of other factors, and it is the aberrant repair of such damage that drives mutagenesis. Fortunately, DNA proofreading during spermatogenesis is extremely effective and these mutant cells are either repaired or deleted by apoptosis/ferroptosis. There appear to be only two mechanisms by which mutant germ cells can escape this apoptotic fate: (i) if the germ cells acquire a mutation that by enhancing proliferation or suppressing apoptosis, permits their clonal expansion (selfish selection hypothesis) or (ii) if a genetically damaged spermatozoon manages to fertilize an oocyte, which then fixes the damage as a mutation (or epimutation) as a result of defective DNA repair (oocyte collusion hypothesis). Exploration of these proposed mechanisms should not only help us better understand the aetiology of paternal age effects but also inform potential avenues of remediation.

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A modeling of complex trait phenotypic variance determinants

Hussain

2024

PNAS Nexus

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Studies have now shown that the heritability of some complex traits, such as human height, can be virtually fully captured via potential use of sufficiently powered approaches that can collectively characterize the associated common- and rare-variant additive genetic architecture. However, for other traits, including complex disease traits, full recovery of the predicted narrow sense heritability would still likely fall far short of respective heritability estimates yielded from pedigree-based analyses such as twin studies. Here, it is proposed that such traits may also involve additional types of relevant architecture and underlying genetic mechanism, such that interaction of somatic variants with heritable variants may represent an underappreciated component. The theoretical model suggested predicts that some relevant heritability estimates are systematically inflated by twin studies, and that instead a significant proportion of the phenotypic variances may be explained by specialized types of heritable genotype by environment interaction.

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The ‘faulty male’ hypothesis for sex-biased mutation and disease

Cited by 5 publications

References 75 publications

Characterization and distribution of de novo mutations in the zebra finch

Characterization and distribution of de novo mutations in the zebra finch

Paternal age, de novo mutations, and offspring health? New directions for an ageing problem

A modeling of complex trait phenotypic variance determinants

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