Age-Dependent De Novo Mutations During Spermatogenesis and Their Consequences

Cioppi, Francesca; Casamonti, Elena; Krausz, Csilla

doi:10.1007/978-3-030-21664-1_2

Cited by 26 publications

(28 citation statements)

References 155 publications

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“…Germ cells mutations may occur as a result of errors in DNA replication during gametogenesis, inefficient repair of DNA damages or exposure to mutagens during lifetime [61]. Yet we still know little about the role of environmental agents in the etiology of heritable mutations because germ cell mutations are rare (10 −8 per nucleotide) and difficult to detect because of technological limitations [60].…”

Section: Mutagen-induced Cnv In Germlinementioning

confidence: 99%

DNA Copy Number Variations as Markers of Mutagenic Impact

Hovhannisyan

Harutyunyan

Aroutiounian

et al. 2019

IJMS

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DNA copy number variation (CNV) occurs due to deletion or duplication of DNA segments resulting in a different number of copies of a specific DNA-stretch on homologous chromosomes. Implications of CNVs in evolution and development of different diseases have been demonstrated although contribution of environmental factors, such as mutagens, in the origin of CNVs, is poorly understood. In this review, we summarize current knowledge about mutagen-induced CNVs in human, animal and plant cells. Differences in CNV frequencies induced by radiation and chemical mutagens, distribution of CNVs in the genome, as well as adaptive effects in plants, are discussed. Currently available information concerning impact of mutagens in induction of CNVs in germ cells is presented. Moreover, the potential of CNVs as a new endpoint in mutagenicity test-systems is discussed.

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Section: Mutagen-induced Cnv In Germlinementioning

confidence: 99%

DNA Copy Number Variations as Markers of Mutagenic Impact

Hovhannisyan

Harutyunyan

Aroutiounian

et al. 2019

IJMS

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“…Spermatogenesis is a life-long process, and the number of spermatogonial cell divisions prior to spermiogenesis increases from 35 at puberty to more than 600 at 50 years of age [ 4 ]. Genetic mutations occur during each replication cycle every 2–3 weeks; the mutational load continuously increases in the sperm of older males [ 4 – 6 ]. In addition to spontaneous genetic mutations during cell division, the epigenetic modifications must be copied to the daughter cells, and copying of the epigenetic information is much more error-prone than DNA replication [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

High-resolution analyses of human sperm dynamic methylome reveal thousands of novel age-related epigenetic alterations

et al. 2020

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Background Children of aged fathers are at a higher risk of developing mental disorders. Alterations in sperm DNA methylation have been implicated as a potential cause. However, age-dependent modifications of the germ cells’ epigenome remain poorly understood. Our objective was to assess the DNA methylation profile of human spermatozoa during aging. Results We used a high throughput, customized methylC-capture sequencing (MCC-seq) approach to characterize the dynamic DNA methylation in spermatozoa from 94 fertile and infertile men, who were categorized as young, 48 men between 18–38 years or old 46 men between 46–71 years. We identified more than 150,000 age-related CpG sites that are significantly differentially methylated among 2.65 million CpG sites covered. We conducted machine learning using our dataset to predict the methylation age of subjects; the age prediction accuracy based on our assay provided a more accurate prediction than that using the 450 K chip approach. In addition, we found that there are more hypermethylated (62%) than hypomethylated (38%) CpG sites in sperm of aged men, corresponding to 798 of total differential methylated regions (DMRs), of which 483 are hypermethylated regions (HyperDMR), and 315 hypomethylated regions (HypoDMR). Moreover, the distribution of age-related hyper- and hypomethylated CpGs in sperm is not random; the CpG sites that were hypermethylated with advanced age were frequently located in the distal region to genes, whereas hypomethylated sites were near to gene transcription start sites (TSS). We identified a high density of age-associated CpG changes in chromosomes 4 and 16, particularly HyperDMRs with localized clusters, the chr4 DMR cluster overlaps PGC1α locus, a protein involved in metabolic aging and the chr16 DMR cluster overlaps RBFOX1 locus, a gene implicated in neurodevelopmental disease. Gene ontology analysis revealed that the most affected genes by age were associated with development, neuron projection, differentiation and recognition, and behaviour, suggesting a potential link to the higher risk of neurodevelopmental disorders in children of aged fathers. Conclusion We identified thousands of age-related and sperm-specific epigenetic alterations. These findings provide novel insight in understanding human sperm DNA methylation dynamics during paternal aging, and the subsequently affected genes potentially related to diseases in offspring.

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“…Each additional year of the father’s age at conception has been found to increase the germline mutational load of the offspring by one to three de novo mutations. Due to the fact that said process involves recurrent rounds of DNA replication and cell division, random copy-error mutational events are expected to occur mainly in the male germline [ 57 ].…”

Section: Reasons and Consequences Of Genome Instabilitymentioning

confidence: 99%

Idiopathic Infertility as a Feature of Genome Instability

Puzuka

Alksere

Gailīte

et al. 2021

Life

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Genome instability may play a role in severe cases of male infertility, with disrupted spermatogenesis being just one manifestation of decreased general health and increased morbidity. Here, we review the data on the association of male infertility with genetic, epigenetic, and environmental alterations, the causes and consequences, and the methods for assessment of genome instability. Male infertility research has provided evidence that spermatogenic defects are often not limited to testicular dysfunction. An increased incidence of urogenital disorders and several types of cancer, as well as overall reduced health (manifested by decreased life expectancy and increased morbidity) have been reported in infertile men. The pathophysiological link between decreased life expectancy and male infertility supports the notion of male infertility being a systemic rather than an isolated condition. It is driven by the accumulation of DNA strand breaks and premature cellular senescence. We have presented extensive data supporting the notion that genome instability can lead to severe male infertility termed “idiopathic oligo-astheno-teratozoospermia.” We have detailed that genome instability in men with oligo-astheno-teratozoospermia (OAT) might depend on several genetic and epigenetic factors such as chromosomal heterogeneity, aneuploidy, micronucleation, dynamic mutations, RT, PIWI/piRNA regulatory pathway, pathogenic allelic variants in repair system genes, DNA methylation, environmental aspects, and lifestyle factors.

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Age-Dependent De Novo Mutations During Spermatogenesis and Their Consequences

Cited by 26 publications

References 155 publications

DNA Copy Number Variations as Markers of Mutagenic Impact

DNA Copy Number Variations as Markers of Mutagenic Impact

High-resolution analyses of human sperm dynamic methylome reveal thousands of novel age-related epigenetic alterations

Idiopathic Infertility as a Feature of Genome Instability

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