It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure. I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance. I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research.

/pdf/dna-methylation-age-of-human-tissues-and-cell-types-528gzlrlkl.pdf

DNA methylation age of human tissues and cell types

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

WHO laboratory manual for the examination and processing of human semen

Numerous reports have recently focused on various aspects of adverse trends in male reproductive health, such as the rising incidence of testicular cancer; low and probably declining semen quality; high and possibly increasing frequencies of undescended testis and hypospadias; and an apparently growing demand for assisted reproduction. Due to specialization in medicine and different ages at presentation of symptoms, reproductive problems used to be analysed separately by various professional groups, e.g. paediatric endocrinologists, urologists, andrologists and oncologists. This article summarizes existing evidence supporting a new concept that poor semen quality, testis cancer, undescended testis and hypospadias are symptoms of one underlying entity, the testicular dysgenesis syndrome (TDS), which may be increasingly common due to adverse environmental influences. Experimental and epidemiological studies suggest that TDS is a result of disruption of embryonal programming and gonadal development during fetal life. Therefore, we recommend that future epidemiological studies on trends in male reproductive health should not focus on one symptom only, but be more comprehensive and take all aspects of TDS into account. Otherwise, important biological information may be lost.

Testicular dysgenesis syndrome ; an increasingly common developmental disorder with environmental aspects

Human mitochondrial DNA is widely used as tool in many fields including evolutionary anthropology and population history, medical genetics, genetic genealogy, and forensic science. Many applications require detailed knowledge about the phylogenetic relationship of mtDNA variants. Although the phylogenetic resolution of global human mtDNA diversity has greatly improved as a result of increasing sequencing efforts of complete mtDNA genomes, an updated overall mtDNA tree is currently not available. In order to facilitate a better use of known mtDNA variation, we have constructed an updated comprehensive phylogeny of global human mtDNA variation, based on both coding- and control region mutations. This complete mtDNA tree includes previously published as well as newly identified haplogroups, is easily navigable, will be continuously and regularly updated in the future, and is online available at http://www.phylotree.org. © 2008 Wiley-Liss, Inc.

/pdf/updated-comprehensive-phylogenetic-tree-of-global-human-448qrnrzdo.pdf

Updated Comprehensive Phylogenetic Tree of Global Human Mitochondrial DNA Variation

Need for standardization and confirmation of STS deletions on the Y chromosome.

Virilization of gender-incongruent subjects to whom were assigned the female gender at birth (AFAB) is achieved through testosterone administration. Inter-individual differences in the timing and acquisition of phenotypic characteristics, even if the same hormone preparations and regimens are used, are frequently observed. Polymorphisms of sex hormone receptors and methylation of their gene promoters, as well of several imprinted genes as H19, may underlie the differential response to treatment. Thus, the aim of this study was to examine the possible relationship between the CpG methylation profile of the estrogen receptor 2 gene (ESR2) and H19 promoters and their influence on phenotype modifications in a cohort of AFAB people at baseline (T0) and after 6 mo (T6) and 12 mo (T12) of testosterone therapy (testosterone enanthate, 250 mg i.m. every 28 d). A total of 13 AFAB subjects (mean age 29.3 ± 12.6) were recruited. The percentage of methylation of the ESR2 promoter significantly increased at T6 (adj. p = 0.001) and T12 (adj. p = 0.05), while no difference was detected for H19 (p = 0.237). Methylation levels were not associated with androgen receptor (AR)/estrogen receptor beta (ERβ) polymorphisms nor hormone levels at baseline and after six months of treatment. On the other hand, total testosterone level and patient age resulted in being significantly associated with ESR2 methylation after twelve months of treatment. Finally, the difference in ESR2 promoter methylation between T6 and baseline was significantly associated with the number of CA repeats of the ERβ receptor, adjusted vs. all considered variables (R2 = 0.62, adj. R2 = 0.35). No associations were found with CAG repeats of the AR, age, and estradiol and testosterone levels. Despite the small sample size, we can hypothesize that treatment with exogenous testosterone can modify the ESR2 methylation pattern. Our data also indicated that epigenetic changes may be regulated, suggesting that the modulation of estrogen signaling is relevant shortly after the beginning of the treatment up to T6, with no further significant modification at T12. Furthermore, estrogen receptor methylation appears to be associated with the age of the subjects and exogenous testosterone administration, representing a marker of androgenic treatment. Nonetheless, it will be necessary to increase the number of subjects to evaluate how epigenetic regulation might play a relevant role in the modulation of phenotypical changes after testosterone treatment.

/pdf/epigenetic-effects-of-gender-affirming-hormone-treatment-a-3bl41qo0.pdf

Epigenetic Effects of Gender-Affirming Hormone Treatment: A Pilot Study of the ESR2 Promoter’s Methylation in AFAB People

On estime a pres de 10 % la frequence du phenotype d'infertilite masculine dans la population humaine [1]. L'existence d'anomalies chromosomiques et de cas familiaux montre qu'un defaut genetique peut etre a l'origine de certains cas d'infertilite [2-4]. Mises a part les azoospermies obstructives ou excretoires, la sterilite secretoire, par deficit primaire dans la production de spermatozoides, touche environ 2 % des hommes dans le monde et, dans un nombre non negligeable de cas, une cause genetique peut etre avancee. Meme si, le plus souvent, l'origine de l'anomalie n'est pas identifiee, plusieurs regions du genome sont candidates, particulierement sur le chromosome Y en raison de l'existence d'anomalies cytogenetiques specifiques (aneuploidies, deletions, microdeletions, translocations...) liees a la sterilite masculine [5-21]. Cet article presente une analyse des donnees actuelles concernant le controle genetique de la spermatogenese en precisant le role des genes portes par le chromosome Y et l'implication d'un nombre croissant d'autres genes, autosomiques ou lies a l'X, connus grâce aux modeles animaux.

[Genetic control of spermatogenesis: Y chromosome and male infertility]

Bien que de nombreux arguments sont en faveur d’un défaut génétique à l’origine de certains cas d’infertilité, pour le moment très peu de gènes impliqués dans l’infertilité masculine ont été identifiés. Parmi les arguments en faveur d’une origine génétique de l’infertilité les suivants ont été mentionnés : 1) des réarrangements chromosomiques sont retrouvés avec une fréquence supérieure à la normale chez des hommes infertiles [11]. Ces réarrangements pourraient être responsables d’une anomalie mécanique de la meïose mais aussi de l’inactivation d’un gène crucial pour la spermatogenèse ; 2) des cas familiaux de stérilité ont été décrits dans la littérature, où plusieurs membres d’une fratrie bien sont atteints, ou plusieurs individus infertiles sur plusieurs générations de la même famille (oncle-neveu par exemple) [5, 19, 33] ; 3) la présence de consanguinité chez les parents de certains patients stériles laisse supposer une transmission récessive d’un gène muté impliqué dans la spermatogenèse ; 4) des modèles animaux, montrent que des mutations géniques spontanées ou induites, sont responsables d’infertilité. On estime sur la base de l’extrapolation des données obtenues à partir de l’étude du génome de la drosophile ou de la souris à l’homme, que les gènes impliqués dans le bon déroulement de la spermatogenèse sont plusieurs centaines, voire milliers. En outre, on sait que le testicule est un site important d’expression de nombreux gènes, parfois d’isoformes issues d’un épissage alternatif spécifique du testicule. Il est donc fort probable que des mutations dans ces gènes aient des répercussions sur la spermatogenèse.

Chromosome Y et l'infertilité chez l'homme

We performed a survey among European semen banks enquiring safety protocols during the COVID-19 pandemic. We report the experience from a center searching SARS-CoV-2 mRNA in semen of patients undergoing cryopreservation from May 2020 to January 2021.A questionnaire was submitted to accredited semen banks of the European Academy of Andrology (EAA) and the Italian Society of Andrology and Sexual Medicine (SIAMS). A total of 22 centers answered to the survey. SARS-CoV-2 mRNA in semen was evaluated by RT-PCR in 111 subjects banking in the Semen Bank of Careggi University Hospital (Florence, Italy).No particularly drastic safety measures were adopted by the majority of the centers to prevent the risk of contamination or transmission of the virus. The most common strategy (77.3%) was the administration of an anamnestic questionnaire. About half of the centers request a negative nasopharyngeal swab (NPS) before cryopreservation. Few centers use a quarantine tank, in case of late response of NPS, and only 4 store in a dedicated tank in case of infection. SARS-CoV-2 mRNA was not found in 111 semen samples cryopreserved in the Florentine bank.European semen banks use different measures to handle semen samples for cryopreservation during COVID-19 pandemic. The request of NPS is advised to better manage couples undergoing ART and to protect the personnel operating in the bank/ART center. Finally, due to the areas of uncertainties of an almost unknown virus, it is absolutely recommended the use of safe devices for sample handling and storage. 

/pdf/safety-issues-in-semen-banks-during-the-covid-19-pandemic-1ktb4m1m.pdf

Csilla Krausz

Papers

Need for standardization and confirmation of STS deletions on the Y chromosome.

Epigenetic Effects of Gender-Affirming Hormone Treatment: A Pilot Study of the ESR2 Promoter’s Methylation in AFAB People

[Genetic control of spermatogenesis: Y chromosome and male infertility]

Chromosome Y et l'infertilité chez l'homme

Safety issues in semen banks during the COVID-19 pandemic: data from a European survey