Cellular correlates of selfish spermatogonial selection

Maher, Geoffrey J.; Meyts, Ewa Rajpert‐De; Goriely, Anne

doi:10.1111/andr.12185

Cited by 11 publications

(6 citation statements)

References 16 publications

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“…One of the recent concepts about de novo mutations -different from the idea of accumulation of copy errors only -is the 'selfish spermatogonial selection' hypothesis. It suggests that de novo mutations in genes for tyrosine kinase receptors, such as the fibroblast growth factor receptor 2 (FGFR2; found in patients with Apert syndrome) or its paralog FGFR3 (found in cases of achondroplasia) offer a selective advantage to spermatogonia carrying this mutation, causing their clonal expansion (Goriely et al 2009, Maher et al 2016.…”

Section: R91mentioning

confidence: 99%

Healthy ageing and spermatogenesis

et al. 2021

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Delayed family planning and increased parental age increases the risk for infertility and impaired offspring health. While the impact of ageing on oogenesis is well studied, on spermatogenesis this is less understood. Assessing ageing effects on the male germline presents the challenge of differentiating between the effects of ageing-associated morbidities, infertility, and “pure” ageing. However, understanding the impact of ageing on male germ cells requires a separation of age from other factors. In this review we therefore discuss the current knowledge on healthy ageing and spermatogenesis. Male ageing has been previously associated with declining sperm parameters, disrupted hormone secretion, and increased time-to-pregnancy, among others. However, recent data show that healthy ageing does not deteriorate testicular function in terms of hormone production and spermatogenic output. In addition, intrinsic, age-dependent, highly specific processes occur in ageing germ cells that are clearly distinct from somatic ageing. Changes in spermatogonial stem cell populations indicate a compensation for stem cell exhaustion. Alterations in the stem cell niche and molecular ageing signatures in sperm can be observed in ageing fertile men. DNA fragmentation rates as well as changes of DNA methylation patterns and increased telomere length are hallmarks of ageing sperm. Taken together, we propose a putative link between the re-activation of quiescent Adark spermatogonia and molecular changes in aged sperm descending from these activated spermatogonia. We suggest a baseline of “pure” age effects in male germ cells which can be used for subsequent studies in which the impact of infertility or co-morbidities will be studied.

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Section: R91mentioning

confidence: 99%

Healthy ageing and spermatogenesis

et al. 2021

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“…B 371: 20150137 that parameters can be inferred under one model or another, but the fact that including an active role for the A d cells allows models which are compatible both with long-standing observations of the seminiferous epithelium and with recent measurements of the paternal age effect. More sophisticated models might also include feedback or global regulation mechanisms other than cell death [52,55], age-related changes in cell-division mutation rate and spermiogenetic efficiency, and perhaps phenomena such as selfish spermatogonial selection [65]. At present, experimental data are limited, but more extensive data including trio sequencing on population-wide scales will provide a better basis for exploration of spermatogenetic models along these or similar lines.…”

Section: Changes In the Structure Of Spermatogenesismentioning

confidence: 99%

Mutation rates and the evolution of germline structure

Scally¹

2016

Phil. Trans. R. Soc. B

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Genome sequencing studies of de novo mutations in humans have revealed surprising incongruities in our understanding of human germline mutation. In particular, the mutation rate observed in modern humans is substantially lower than that estimated from calibration against the fossil record, and the paternal age effect in mutations transmitted to offspring is much weaker than expected from our long-standing model of spermatogenesis. I consider possible explanations for these discrepancies, including evolutionary changes in life-history parameters such as generation time and the age of puberty, a possible contribution from undetected post-zygotic mutations early in embryo development, and changes in cellular mutation processes at different stages of the germline. I suggest a revised model of stem-cell state transitions during spermatogenesis, in which ‘dark’ gonial stem cells play a more active role than hitherto envisaged, with a long cycle time undetected in experimental observations. More generally, I argue that the mutation rate and its evolution depend intimately on the structure of the germline in humans and other primates.This article is part of the themed issue ‘Dating species divergences using rocks and clocks'.

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“…According to this model, spermatogonia carrying specific pathogenic mutations gain a selection/growth advantage over non‐mutated spermatogonia which leads to an increased number of mutated spermatogonia in the testis. Consequently, with increasing age, more mutated spermatozoa are produced, and thus, it becomes more likely to pass such mutations to the offspring (Goriely & Wilkie, ; Maher et al ., ). These ageing‐associated clonal drift models in which advantageous (e.g.…”

Section: Introductionmentioning

confidence: 97%

Ageing in men with normal spermatogenesis alters spermatogonial dynamics and nuclear morphology in Sertoli cells

et al. 2019

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Background: Ageing in men is believed to be associated with fertility decline and elevated risk of congenital disorders for the offspring. The previous studies also reported reduced germ and Sertoli cell numbers in older men. However, it is not clear whether ageing in men with normal spermatogenesis affects the testis and germ cell population dynamics in a way sufficient for transmitting adverse age effects to the offspring. Objectives: We examined men with normal spermatogenesis at different ages concerning effects on persisting testicular cell types, that is the germ line and Sertoli cells, as these cell populations are prone to be exposed to age effects. Material and methods: Ageing was assessed in testicular biopsies of 32 patients assigned to three age groups: (i) 28.8 AE 2.7 years; (ii) 48.1 AE 1 years; and (iii) 70.9 AE 6.2 years, n = 8 each, with normal spermatogenesis according to the Bergmann-Kliesch score, and in a group of meiotic arrest patients (29.9 AE 3.8 years, n = 8) to decipher potential links between different germ cell types. Besides morphometry of seminiferous tubules and Sertoli cell nuclei, we investigated spermatogenic output/efficiency, and dynamics of spermatogonial populations via immunohistochemistry for MAGE A4, PCNA, CREM and quantified A-pale/A-dark spermatogonia. Results: We found a constant spermatogenic output (CREM-positive round spermatids) in all age groups studied. In men beyond their mid-40s (group 2), we detected increased nuclear and nucleolar size in Sertoli cells, indirectly indicating an elevated protein turnover. From the 7th decade (group 3) of life onwards, testes showed increased proliferation of undifferentiated spermatogonia, decreased spermatogenic efficiency and elevated numbers of proliferating A-dark spermatogonia. Discussion and conclusion: Maintaining normal sperm output seems to be an intrinsic determinant of spermatogenesis. Ageing appears to affect this output and might provoke compensatory proliferation increase in A spermatogonia which, in turn, might hamper germ cell integrity.

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Cellular correlates of selfish spermatogonial selection

Cited by 11 publications

References 16 publications

Healthy ageing and spermatogenesis

Healthy ageing and spermatogenesis

Mutation rates and the evolution of germline structure

Ageing in men with normal spermatogenesis alters spermatogonial dynamics and nuclear morphology in Sertoli cells

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