The Impact of DNA Methylation Dynamics on the Mutation Rate During Human Germline Development

Zhou, Yangjie; He, Funan; Pu, Weilin; Gu, Xun; Wang, Jiucun; Su, Zhixi

doi:10.1534/g3.120.401511

Cited by 26 publications

(32 citation statements)

References 48 publications

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“…The cytosine in the CpG site is often methylated to form 5-methylcytosine, which undergoes deamination as a result of spontaneous oxidation 18 , 23 . It has been suggested that higher methylation levels are associated with higher mutation rates of CpG dinucleotides during germline development 37 . Therefore, a FD diet could lead to a globally lower methylation level and fewer genome-wide G:C>A:T transitions.…”

Section: Discussionmentioning

confidence: 99%

Parental folate deficiency induces birth defects in mice accompanied with increased de novo mutations

Zhao

Chen

Tang³

et al. 2022

Cell Discov

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Dietary folate deficiency (FD) is associated with the occurrence of birth defects. However, the mechanisms underlying this association remain elusive. In particular, how FD affects genome stability is unknown. To examine whether a folate-deficient diet can affect genome stability, C57BL/6 mice were maintained on a synthetic diet lacking of folic acid (FA) for two generations. F0 mice received the FD diet beginning at 3 weeks of age, and their offspring (F1) began the FD diet after weaning. Both male and female F1 mice fed the FD diet were intentionally crossed with F1 mice fed the normal diet to produce F2 mice. F2 embryos were dissected and collected at E14.5 and E18.5. The malformation ratio was significantly increased in F2 embryos fed the FD diet for two generations compared to those fed the normal diet. Whole-genome sequencing of multiple sibship with F1 males on the FD diet showed that the de novo mutation (DNM) rate in F2 embryos was three times of the reported spontaneous rate in mice. Furthermore, many DNMs observed in the F2 mice exhibited an allele ratio of 1:3 instead of 2:2, suggesting that these mutations are likely to accumulate in gamete cells as a form of mismatch in the DNA duplex. Our study indicated that FD for two generations significantly enhances DNM accumulation during meiosis, which might contribute to the increased negative birth outcomes among F2 mice. Not only maternal but also paternal FA supplementation is probably also necessary and beneficial to prevent birth defects.

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Section: Discussionmentioning

confidence: 99%

Parental folate deficiency induces birth defects in mice accompanied with increased de novo mutations

Zhao

Chen

Tang³

et al. 2022

Cell Discov

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“…Our understanding of the effects of DNA methylation on mutation varies widely. The risk of spontaneous oxidative deamination of 5mC to T (or C to U) is relatively well understood, and has been documented to occur in organisms ranging from bacteria ( 46 ) to humans ( 47 ). However, our focus here has been on the effects of 5mC methylation on the binding of specific proteins, and on how that protein binding modulates the mutation rate.…”

Section: Discussionmentioning

confidence: 99%

Preferential CEBP binding to T:G mismatches and increased C-to-T human somatic mutations

Yang

Horton

Akdemir

et al. 2021

Nucleic Acids Research

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DNA cytosine methylation in mammals modulates gene expression and chromatin accessibility. It also impacts mutation rates, via spontaneous oxidative deamination of 5-methylcytosine (5mC) to thymine. In most cases the resulting T:G mismatches are repaired, following T excision by one of the thymine DNA glycosylases, TDG or MBD4. We found that C-to-T mutations are enriched in the binding sites of CCAAT/enhancer binding proteins (CEBP). Within a CEBP site, the presence of a T:G mismatch increased CEBPβ binding affinity by a factor of >60 relative to the normal C:G base pair. This enhanced binding to a mismatch inhibits its repair by both TDG and MBD4 in vitro. Furthermore, repair of the deamination product of unmethylated cytosine, which yields a U:G DNA mismatch that is normally repaired via uracil DNA glycosylase, is also inhibited by CEBPβ binding. Passage of a replication fork over either a T:G or U:G mismatch, before repair can occur, results in a C-to-T mutation in one of the daughter duplexes. Our study thus provides a plausible mechanism for accumulation of C-to-T human somatic mutations.

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“…One such genomic feature is the spontaneous deamination of 5-methyl cytosine at CpG sites, which has been suggested to cause C to T transitions. The recent development of CpG maps in human germ cells, including primordial germ cells [60] , [61] , have facilitated both cell-type and site-specific analyses of mutations rates and provide support for evidence that the methylation status at CpGs correlate with C to T mutations [62] .…”

Section: Genome Stability In Primordial Germ Cells and Other Proliferative Germ Cellsmentioning

confidence: 91%

Genome diversity and instability in human germ cells and preimplantation embryos

Shukla

Høffding

Hoffmann

2021

Seminars in Cell & Developmental Biology

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Genome diversity is essential for evolution and is of fundamental importance to human health. Generating genome diversity requires phases of DNA damage and repair that can cause genome instability. Humans have a high incidence of de novo congenital disorders compared to other organisms. Recent access to eggs, sperm and preimplantation embryos is revealing unprecedented rates of genome instability that may result in infertility and de novo mutations that cause genomic imbalance in at least 70% of conceptions. The error type and incidence of de novo mutations differ during developmental stages and are influenced by differences in male and female meiosis. In females, DNA repair is a critical factor that determines fertility and reproductive lifespan. In males, aberrant meiotic recombination causes infertility, embryonic failure and pregnancy loss. Evidence suggest germ cells are remarkably diverse in the type of genome instability that they display and the DNA damage responses they deploy. Additionally, the initial embryonic cell cycles are characterized by a high degree of genome instability that cause congenital disorders and may limit the use of CRISPR-Cas9 for heritable genome editing.

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The Impact of DNA Methylation Dynamics on the Mutation Rate During Human Germline Development

Cited by 26 publications

References 48 publications

Parental folate deficiency induces birth defects in mice accompanied with increased de novo mutations

Parental folate deficiency induces birth defects in mice accompanied with increased de novo mutations

Preferential CEBP binding to T:G mismatches and increased C-to-T human somatic mutations

Genome diversity and instability in human germ cells and preimplantation embryos

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