Methylation Levels at Selected CpG Sites in the Factor VIII and FGFR3 Genes, in Mature Female and Male Germ Cells: Implications for Male-Driven Evolution

El‐Maarri, Osman; Olek, Alexander; Balaban, Başak; Montag, Markus; Ven, H. van der; Urman, Bülent; Olek, K.; Çağlayan, S. Hande; Walter, Jörn; Oldenburg, Johannes

doi:10.1086/302065

Cited by 38 publications

(24 citation statements)

References 37 publications

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“…The cytosine at base pair 1138 is highly methylated in sperm (data not shown and ref. 28). A single sperm with a G͞T mismatch would produce PCR product in our assay.…”

Section: Discussionmentioning

confidence: 99%

The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect

Tiemann‐Boege

Navidi²,

Grewal³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

152

133

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The lifelong spermatogonial stem cell divisions unique to male germ cell production are thought to contribute to a higher mutation frequency in males. The fact that certain de novo human genetic conditions (e.g., achondroplasia) increase in incidence with the age of the father is consistent with this idea. Although it is assumed that the paternal age effect is the result of an increasing frequency of mutant sperm as a man grows older, no direct molecular measurement of the germ-line mutation frequency has been made to confirm this hypothesis. Using sperm DNA from donors of different ages, we determined the frequency of the nucleotide substitution in the fibroblast growth factor receptor 3 (FGFR3) gene that causes achondroplasia. Surprisingly, the magnitude of the increase in mutation frequency with age appears insufficient to explain why older fathers have a greater chance of having a child with this condition. A number of alternatives may explain this discrepancy, including selection for sperm that carry the mutation or an age-dependent increase in premutagenic lesions that remain unrepaired in sperm and are inefficiently detected by the PCR assay.

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“…The cytosine at base pair 1138 is highly methylated in sperm (data not shown and ref. 28). A single sperm with a G͞T mismatch would produce PCR product in our assay.…”

Section: Discussionmentioning

confidence: 99%

The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect

Tiemann‐Boege

Navidi²,

Grewal³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

152

133

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“…However, only sperm, (rather than self-renewing spermatogonia or female germline tissues) were examined. A very small number of human CpG sites in disease gene coding sequences have been studied in the germline130: analysis of a total of 33 CpG sites at the Factor VIII and FGFR3 genes130 showed little difference in CpG methylation levels in mature oocytes relative to mature sperm.…”

Section: Sex Differences In Mutationmentioning

confidence: 99%

“…For diseases where most mutations arise at CpG sites outside of CpG islands, the expected α value (~2) would make it difficult to detect a PAE (for example see144, 146) other than in an exceptionally large epidemiological study. However, in achondroplasia, where all new mutations arise at the same CpG site (shown to be methylated in mature sperm130), the observed exponential PAE is likely due to selection acting on SrAp cells carrying the mutation. Overall, most diseases arise from a mixture of different genetic events, some of which show a strong male- and others a strong female-bias (see above).…”

Section: Age Effects On Mutation Frequenciesmentioning

confidence: 99%

Understanding what determines the frequency and pattern of human germline mutations

2009

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Surprising findings about human germline mutation come from applying new technologies to detect rare mutations in germline DNA and from analyzing DNA sequence divergence between human and closely related species as well as human polymorphic variation. In this Review we discuss how these approaches affect our current understanding of the roles that sex, age, mutation hot spots, germline selection and genomic factors play in determining human base substitution mutation patterns and frequencies. To enhance progress, more extensive molecular data on the human germline with regard to mutation origin, DNA repair, epigenetic status and the consequences to gamete development of newly arisen mutations are needed.

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“…Although two previous studies investigated epigenetic 5meCpG changes in the F8 gene, they were not in the context of inhibitor’s development. The first study (El-Maarri et al, 1998) explored the fact that transitional mutations at CpG dinucleotides account for approximately a third of all germline point mutations, which arise through spontaneous deamination of 5meCpG as a sort of causative point mutation in index patients with unknown mutations. Using F8 gene-based BS-Seq, the authors screened for such mutations occurring at the F8 gene in mature male and female germ cells.…”

Section: Discussionmentioning

confidence: 99%

A Differentially Methylated CpG Site in theIL4Gene Associated with Anti-FVIII Inhibitor Antibody Development in Hemophilia A

Souza

Ferreira

et al. 2019

Preprint

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40Hemophilia A is the most common clotting disorder in humans. It affects one in five 41 thousand live-born children. Mutations in the X-chromosome linked F8 gene lead to the 42 deficiency of circulating factor VIII (FVIII). The defect is characterized by severe 43 bleeding. The standard therapy is to replace the deficient factor intravenously. The main 44 adverse event of the therapy is the development of anti-FVIII inhibitor antibodies that 45 impair coagulation and result in increased complications and risk of death. Several risk 46 factors have been described for the development of inhibitor antibodies, among them 47 age, type of FVIII administered, ethnicity, and variant alleles in immune response 48 genes. Epigenetic risks factors have not yet been explored. This work aimed to evaluate 49 2 the methylation statuses at thirteen CpG sites (5meCpG) in regulatory regions of the 50 IL1B, IL2, IL4, IL6, IL10, TNF, IFNG, CTLA4, CD28, and CST7 immune regulation 51 genes in hemophilia A affected males on replacement therapy who develop or do not 52 develop inhibitor antibodies. At each of the thirteen specific CpG sites, we observed one 53 of three possible statuses: hypermethylated, hypomethylated or intermediate 54 methylated. We found a statistically significant (p = 0.04) decrease in the methylation 55 level at one CpG site in the IL4 intron 1 (CpG-3) in the affected group of patients 56 presenting with anti-FVIII inhibitors as compared with the group of patients without 57 inhibitors. The differential 5meCpG-3 maps within a predicted enhancer region in IL4 58 intron 1 that overlaps DNase I hypersensitive chromatin region of the Th2 IL5, IL13, 59 and IL4 cytokine gene cluster and, therefore, permissive for gene expression. Six-bp 60 upstream of the differentially 5meCpG-3 is the rs2227282 cis expression quantitative 61 trait locus that influences the transcript levels of the PDLIM4, SLC22A4, SLC22A5, 62 RAD50, IL4, KIF3A, SEPT8 genes. We consider the IL4 (CpG-3) site a promising lead 63 epigenetic mark, the potential value of which must be appraised in a larger group of 64 patients. The methodology employed also allowed to evaluate the distribution of the IL6 65 rs35081782 insertion/deletion variant, associated with white blood cell count traits in 66 genome-wide association studies, and which showed no difference in distribution 67 between the groups of patients. 68 69 90 91Risk factors for inhibitor development are classified into non-genetic and genetic. 92Among non-genetic risks, the age at the replacement therapy, the type of hemorrhage 93 and the factor administered have been described (Ragni et al., 2009). Among the genetic 94 risk factors, the most well-described factor is the type of causative mutation. Mutations 95 that associate with a higher risk of developing inhibitors are linked to significant 96 functional alterations or complete absence of FVIII. About 40% of patients with large 97 deletions develop inhibitors, while nonsense mutations account for up to 30% of 98

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Methylation Levels at Selected CpG Sites in the Factor VIII and FGFR3 Genes, in Mature Female and Male Germ Cells: Implications for Male-Driven Evolution

Cited by 38 publications

References 37 publications

The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect

The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect

Understanding what determines the frequency and pattern of human germline mutations

A Differentially Methylated CpG Site in theIL4Gene Associated with Anti-FVIII Inhibitor Antibody Development in Hemophilia A

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