Selective mutation accumulation: a computational model of the paternal age effect

Whelan, Eoin C; Nwala, Alexander C.; Osgood, C.; Olariu, Stephan

doi:10.1093/bioinformatics/btw528

Cited by 5 publications

(6 citation statements)

References 46 publications

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“…In deeper evolutionary view, as it was established by Lewis et al () there are links between sperm competition and a range of issues not directly related to reproduction including SGE that are responsible of several epigenetic pathologies in offspring. As reported by Whelan, Nwala, Osgood, and Olariu, (), these SGE present selective advantage in the testis of the father despite a deleterious effect in offspring.…”

Section: Discussionsupporting

confidence: 66%

“…Indeed, APA patients present an increased 5‐mc and 5‐hmc levels (methylated forms of cytosine) by 1.76% every year and causing evident gene silencing risk. This issue was proved to be consequence of several diseases as angelman Syndrome (neurogenetic disorder associated with both developmental and intellectual disability), Bechwith‐Wiedmann Syndrome (genetic disorder which is usually associated with overgrowth and increased risk of childhood cancer), Apert's syndrome and achondroplasia diseases (Sharma et al, ; Whelan, Nwala, Osgood, & Olariu, ). Moreover, an accumulation of some sperm de novo point mutations and methylation alterations caused by APA, are specifically touching some genes related to neuropsychiatric disorders in offspring as Pex7 related to autism (Katz‐Jaffe et al, ), DRD4, RDMR_2, TBKBP1, TNXB, and DMPK related to schizophrenia and bipolar disorder as well as many others (Timothy et al, ).…”

Section: Discussionmentioning

confidence: 99%

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Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years

Kaarouch

Bouamoud

Madkour

et al. 2018

Molecular Reproduction Devel

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This study assessed sperm quality declining on relation to paternal age and its impact on in vitro fertilization (IVF) outcomes in order to estimate the APA (Advanced Paternal Age) cutoff. For this, 83 couples undergoing IVF treatment for male factor infertility were enrolled. The women age was ≤39 years, whereas the men were divided in two groups: APA (n = 41; age ≥ 40 years) and young (Y) (n = 42; age < 40 years). Conventional semen parameters (volume, concentration, motility, vitality, and morphology) were analyzed in the collected sperm samples. Furthermore, sperm genome decays (SGD) was assessed by TUNEL assay (DNA fragmentation), aniline blue staining (chromatin decondensation), and fluorescent in situ hybridization (aneuploidy). No significant difference was found concerning the conventional semen parameters between APA and Y groups. Conversely, SGD analysis showed increased DNA fragmentation; chromatin decondensation and sperm aneuploidy rates in the APA group (respectively, 41%, 43%, and 14% vs. 25%, 23%, and 4% in Y group). IVF outcomes also were affected by paternal age as indicated by the rates of cancelled embryo transfers, clinical pregnancy and miscarriage in the two groups APA and Y (29%, 17%, and 60% vs. 10%, 32%, and 42%). Finally, statistical analysis of the results suggests that the age of 40 should be considered as the APA cutoff during ART attempts.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years

Kaarouch

Bouamoud

Madkour

et al. 2018

Molecular Reproduction Devel

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“…Use of Markov chain models along with mutation assays of donor sperm have been used to confirm a direct connection between PAE-associated birth defects and SSC dysfunction that can be traced to sperm carrying a variety of FGFR/RAS/MAPK pathway mutations. In other words, the mutations which confer selective advantages to certain SSCs in their deteriorating niche come at a cost: the genes affected are the same ones that drive PAEs in offspring conceived with sperm carrying those mutations ( Goriely and Wilkie, 2012 ; Whelan et al, 2016 ). The prognostic value of the Markov chain modeling approach is striking in that its use predicts incidence rates for Apert syndrome, Costello syndrome, and thanatophoric dysplasia that are extremely close to the actual observed values ( Whelan et al, 2016 ).…”

Section: Selfish Selection In Spermatogonial Stem Cellsmentioning

confidence: 99%

“…In other words, the mutations which confer selective advantages to certain SSCs in their deteriorating niche come at a cost: the genes affected are the same ones that drive PAEs in offspring conceived with sperm carrying those mutations ( Goriely and Wilkie, 2012 ; Whelan et al, 2016 ). The prognostic value of the Markov chain modeling approach is striking in that its use predicts incidence rates for Apert syndrome, Costello syndrome, and thanatophoric dysplasia that are extremely close to the actual observed values ( Whelan et al, 2016 ). Taken together, these findings support a crucial role for selfish clonal selection in SSCs as a principal contributing factor to aging-associated testicular dysfunction and spermatogenic defects, as well as the prognostic value of screening spermatozoa prior to use in assisted human reproductive technologies for transmissible gene mutations that would be detrimental to offspring development ( Breuss et al, 2022 ).…”

Section: Selfish Selection In Spermatogonial Stem Cellsmentioning

confidence: 99%

Non-neutral clonal selection and its potential role in mammalian germline stem cell dysfunction with advancing age

Stolzenbach

Woods

Tilly

2022

Front. Cell Dev. Biol.

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The concept of natural selection, or "survival of the fittest", refers to an evolutionary process in nature whereby traits emerge in individuals of a population through random gene alterations that enable those individuals to better adapt to changing environmental conditions. This genetic variance allows certain members of the population to gain an advantage over others in the same population to survive and reproduce in greater numbers under new environmental pressures, with the perpetuation of those advantageous traits in future progeny. Here we present that the behavior of adult stem cells in a tissue over time can, in many respects, be viewed in the same manner as evolution, with each stem cell clone being representative of an individual within a population. As stem cells divide or are subjected to cumulative oxidative damage over the lifespan of the organism, random genetic alterations are introduced into each clone that create variance in the population. These changes may occur in parallel to, or in response to, aging-associated changes in microenvironmental cues perceived by the stem cell population. While many of these alterations will be neutral or silent in terms of affecting cell function, a small fraction of these changes will enable certain clones to respond differently to shifts in microenvironmental conditions that arise with advancing age. In some cases, the same advantageous genetic changes that support survival and expansion of certain clones over others in the population (viz. non-neutral competition) could be detrimental to the downstream function of the differentiated stem cell descendants. In the context of the germline, such a situation would be devastating to successful propagation of the species across generations. However, even within a single generation, the “evolution” of stem cell lineages in the body over time can manifest into aging-related organ dysfunction and failure, as well as lead to chronic inflammation, hyperplasia, and cancer. Increased research efforts to evaluate stem cells within a population as individual entities will improve our understanding of how organisms age and how certain diseases develop, which in turn may open new opportunities for clinical detection and management of diverse pathologies.

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“…The fibroblast growth factor (FGF) family plays an important role in the maintenance of SSCs. In humans, dysregulation of signalling pathways involved in SSC regulation by FGF receptor mutations produces a striking paternal age effect through disproportionate self‐renewal of harbouring cells increasing the proportion of mutant spermatozoa 5‐7 . FGF2 is required for normal spermatogenesis and is typically included in germ cell culture media as it increases SSC proliferation 8‐11 .…”

Section: Introductionmentioning

confidence: 99%

FGF9 promotes mouse spermatogonial stem cell proliferation mediated by p38 MAPK signalling

et al. 2020

Self Cite

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Objectives Fibroblast growth factor 9 (FGF9) is expressed by somatic cells in the seminiferous tubules, yet little information exists about its role in regulating spermatogonial stem cells (SSCs). Materials and Methods Fgf9 overexpression lentivirus was injected into mouse testes, and PLZF immunostaining was performed to investigate the effect of FGF9 on spermatogonia in vivo. Effect of FGF9 on SSCs was detected by transplanting cultured germ cells into tubules of testes. RNA‐seq of bulk RNA and single cell was performed to explore FGF9 working mechanisms. SB203580 was used to disrupt p38 MAPK pathway. p38 MAPK protein expression was detected by Western blot and qPCR was performed to determine different gene expression. Small interfering RNA (siRNA) was used to knock down Etv5 gene expression in germ cells. Results Overexpression of Fgf9 in vivo resulted in arrested spermatogenesis and accumulation of undifferentiated spermatogonia. Exposure of germ cell cultures to FGF9 resulted in larger numbers of SSCs over time. Inhibition of p38 MAPK phosphorylation negated the SSC growth advantage provided by FGF9. Etv5 and Bcl6b gene expressions were enhanced by FGF9 treatment. Gene knockdown of Etv5 disrupted the growth effect of FGF9 in cultured SSCs along with downstream expression of Bcl6b. Conclusions Taken together, these data indicate that FGF9 is an important regulator of SSC proliferation, operating through p38 MAPK phosphorylation and upregulating Etv5 and Bcl6b in turn.

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Selective mutation accumulation: a computational model of the paternal age effect

Abstract: C ++/R source codes and documentation including compilation instructions are available under GNU license at https://github.com/anwala/NicheSimulation CONTACT: ewhel001@odu.eduSupplementary information: Supplementary data are available at Bioinformatics online.

Cited by 5 publications

References 46 publications

Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years

Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years

Non-neutral clonal selection and its potential role in mammalian germline stem cell dysfunction with advancing age

FGF9 promotes mouse spermatogonial stem cell proliferation mediated by p38 MAPK signalling

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