Past Issues

Widespread transcriptional scanning in the testis modulates gene evolution rates

Librarian's Comment : Almost 90% of all protein coding genes are expressed, at least at the RNA level, during human spermatogenesis. Why do developing male germ cells express so many genes is a long-standing mystery in Andrology. This widespread expression is typically considered a consequence of the extreme remodeling sperm DNA is subjected to during spermatogenesis. Such remodeling has been shown to be essential for the differentiation of functionally competent mature gametes, and defects in this process can lead to male infertility. Yet, in this paper, an intriguing new possibility is put forward to explain why developing germ cells express so many genes. According to the Authors, male germ cells use this widespread expression to correct lesions in their DNA and, therefore, avoid the transmission of harmful mutations to the next generation. This process, previously described in other cellular contexts, is called transcription-coupled repair, and allows developing sperm cells to use their gene expression machinery to scan for DNA damage and trigger its efficient repair. Yet, like so many processes in nature, this one also seems to require a very precise balance: in genes expressed at very high levels during spermatogenesis, repair is surprisingly ineffective as it cannot compensate for the damage introduced by the underlying elevated expression. These thought-provoking observations will certainly add to the on-going debate of why fathers are the preferential source of new mutations in human populations.

Published in : Biorxiv

Authors : Bo Xia,Yun Yan,Maayan Baron,Florian Wagner, Dalia Barkley, Marta Chiodin,Sang Y. Kim, David L. Keefe, Joseph P. Alukal,Jef D. Boeke,Itai Yanai

Abstract : The testis expresses the largest number of genes of any mammalian organ, a finding that has long puzzled molecular biologists. Analyzing our single-cell transcriptomic maps of human and mouse spermatogenesis, we provide evidence that this widespread transcription serves to maintain DNA sequence integrity in the male germline by correcting DNA damage through 'transcriptional scanning'. Supporting this model, we find that genes expressed during spermatogenesis display lower mutation rates on the transcribed strand and have low diversity in the population. Moreover, this effect is fine-tuned by the level of gene expression during spermatogenesis. The unexpressed genes, which in our model do not benefit from transcriptional scanning, diverge faster over evolutionary time-scales and are enriched for sensory and immune-defense functions. Collectively, we propose that transcriptional scanning modulates germline mutation rates in a gene-specific manner, maintaining DNA sequence integrity for the bulk of genes but allowing for fast evolution in a specific subset.

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Molecular support for heterogonesis resulting in sesquizygotic twinning

Librarian's Comment : Don’t blame the ultrasound: it is possible (albeit extremely rare) that twins can share the same placenta but have different genders. This extraordinary event can result from the simultaneous fertilization of a single oocyte by two (!) sperm cells. Nature is extremely efficient at ruling out such possibility, but sometimes the unexpected does happen. In the case reported in this study, the resulting embryo managed to correctly assort the genetic material coming from 3 sources: one oocyte and, most likely, two different sperm cells (one carrying an X chromosome, the other a Y). But wait, it gets even more amazing: the resulting embryo likely divided into two, with one of the fetuses developing as male, the other as female, despite both having genetic material coming from the X and Y-carrying sperm cells. This was possible because the twinned embryos had a slightly different genetic constitution reflecting differences in overall DNA content coming from the two sperm cells. More specifically, the twins (which are now healthy children) are genetically identical to each other with respect to the mother’s DNA, but differ in regards to the percentage of the DNA they inherited from each of the two sperm cells. This intermediate state between monozygosis and dizygosis is refered to as sesquizygosis. Although the original report was still published in a paywalled journal, you can find more information on this remarkable story from several freely available sources (such as: https://www.sciencedaily.com/releases/2019/02/190227173108.htm).

Published in : New England Journal of Medicine

Authors : Michael T. Gabbett, Johanna Laporte, Renuka Sekar, Adayapalam Nandini, Pauline McGrath, Yadav Sapkota, Peiyong Jiang, Haiqiang Zhang, Trent Burgess, Grant W. Montgomery, Rossa Chiu, and Nicholas M. Fisk.

Abstract : Sesquizygotic multiple pregnancy is an exceptional intermediate between monozygotic and dizygotic twinning. We report a monochorionic twin pregnancy with fetal sex discordance. Genotyping of amniotic fluid from each sac showed that the twins were maternally identical but chimerically shared 78% of their paternal genome, which makes them genetically in between monozygotic and dizygotic; they are sesquizygotic. We observed no evidence of sesquizygosis in 968 dizygotic twin pairs whom we screened by means of pangenome single-nucleotide polymorphism genotyping. Data from published repositories also show that sesquizygosis is a rare event. Detailed genotyping implicates chimerism arising at the juncture of zygotic division, termed heterogonesis, as the likely initial step in the causation of sesquizygosis.

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From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia.

Librarian's Comment : This is an original paper by Krausz et al suggesting new insights in the diagnostics of non-obstructive azoospermia (NOA), which in the vast majority of cases is stated as idiopathic, probably due to a not yet identified genetic defect. In about 10% of patients with Fanconi anemia (FA), the diagnosis may be delayed until adulthood, when it is often suggested by typical FA-related cancers ("occult" or "Late-onset" FA). The study by Krausz et al, reports for the first time, the diagnosis of "occult" FA in the context of genetic analyses of NOA patients. In particular, a subset of patients with NOA and histology of SCOS plus suggestive hematological parameters (borderline/low number of platelets, relatively high MCV) might be further evaluated, in order to rule out "occult" FA, providing a timely diagnosis before the appearance of a FA related malignancy.

Published in : Genetics in medicine : official journal of the American College of Medical Genetics

Authors : Krausz C, Riera-Escamilla A, Chianese C, Moreno-Mendoza D, Ars E, Rajmil O, Pujol R, Bogliolo M, Blanco I, Rodríguez I, Badell I, Ruiz-Castañé E, Surrallés J

Abstract : PURPOSE: In about 10% of patients affected by Fanconi anemia (FA) the diagnosis is delayed until adulthood, and the presenting symptom in these "occult" FA cases is often a solid cancer and cancer treatment-related toxicity. Highly predictive clinical parameter(s) for diagnosing such an adult-onset cases are missing. METHODS: (1) Exome sequencing (ES), (2) Sanger sequencing of FANCA, (3) diepoxybutane (DEB)-induced chromosome breakage test. RESULTS: ES identified a pathogenic homozygous FANCA variant in a patient affected by Sertoli cell-only syndrome (SCOS) and in his azoospermic brother. Although they had no overt anemia, chromosomal breakage test revealed a reverse somatic mosaicism in the former and a typical FA picture in the latter. In 27 selected SCOS cases, 1 additional patient showing compound heterozygous pathogenic FANCA variants was identified with positive chromosomal breakage test. CONCLUSION: We report an extraordinarily high frequency of FA in a specific subgroup of azoospermic patients (7.1%). The screening for FANCA pathogenic variants in such patients has the potential to identify undiagnosed FA before the appearance of other severe clinical manifestations of the disease. The definition of this high-risk group for "occult" FA, based on specific testis phenotype with mild/borderline hematological alterations, is of unforeseen clinical relevance.

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The CATCH checklist to investigate adult-onset hypogonadism.

Librarian's Comment : This is an interesting narrative review by Defeudis et al. summarizing the key points in screening and diagnosing adult-onset hypogonadism (AOH) in men, a clinical entity which is often overlooked. Several challenges in establishing the diagnosis of AOH exist and the present work provide the clinicians with a handy tool in order to facilitate them run a comprehensive workup and reach a safe diagnosis. This tool consists of a checklist labeled with the acronym (CATCH), which derives from the words:

Clinical features [symptoms] and Causes,
Age,
Testosterone level,
Comorbidities, and
Hormones,

making thus easier for clinicians to remember and increasing the possibilities of detecting cases of AOH in the community.

Published in : Andrology

Authors : Defeudis G, Mazzilli R, Gianfrilli D, Lenzi A, Isidori AM

Abstract : Adult-onset hypogonadism is a syndrome often underdiagnosed, undertreated, or incompletely explored. There are various reasons for this: firstly, undefined age range of men in whom testosterone levels should be investigated and then no definitive serum cutoff point for the diagnosis of hypogonadism; and finally, variable and non-specific signs and symptoms; men and physicians do not pay adequate attention to sexual health. All these factors make the diagnostic criteria for hypogonadism controversial. The evaluation of the clinical features and causes of this syndrome, its link with age, the role of testosterone and other hormone levels, and the presence of any comorbidities are all useful factors in the investigation of this population. The purpose of this manuscript, after an accurate analysis of current literature, is to facilitate the diagnosis of hypogonadism in men through the use of the CATCH acronym and a checklist to offer a practical diagnostic tool for daily clinical practice. A narrative review of the relevant literature regarding the diagnosis of late-onset hypogonadism or adult-onset hypogonadism was performed. PubMed database was used to retrieve articles published on this topic. A useful new acronym CATCH (Clinical features [symptoms] and Causes, Age, Testosterone level, Comorbidities, and Hormones) and a practical checklist to facilitate the evaluation of hypogonadism in aging men were used. The evaluation of the clinical features and causes of hypogonadism, the link with age, the role of Testosterone and other hormones, and the evaluation of comorbidities are important in investigating adult-onset hypogonadism. The CATCH checklist could be helpful for clinicians for an early diagnosis of both hypogonadism and associated comorbidities. We suggest the use of this acronym to advocate the investigation of declining testosterone in aging men.

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Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline

Librarian's Comment : On March 17 the Endocrine Society released an update of the Guidelines for Testosterone Therapy in Men with Hypogonadism, which has been much awaited since the last version of 2010. The current guidelines were cosponsored by the European Society of Endocrinology and endorsed by the European Academy of Andrology and although they are largely congruent with the 2010 version, they have incorporated the new scientific evidence gathered from recent RCTs (e.g. Testosterone Trials) and meta-analyses. Moreover, much effort has been devoted to address growing public concerns about the recent increase in “off label” testosterone (T) prescribing and the subsequent warning of US Food and Drug Administration regarding possible increased risks for myocardial infarction and stroke with testosterone replacement therapy (TRT).

Published in : The Journal of Clinical Endocrinology & Metabolism

Authors : Shalender Bhasin Juan P Brito Glenn R Cunningham Frances J HayesHoward N Hodis Alvin M Matsumoto Peter J Snyder Ronald S Swerdloff Frederick C WuMaria A Yialamas

Abstract : Objective To update the “Testosterone Therapy in Men With Androgen Deficiency Syndromes” guideline published in 2010. Participants The participants include an Endocrine Society–appointed task force of 10 medical content experts and a clinical practice guideline methodologist. Evidence This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process One group meeting, several conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees and members and the cosponsoring organization were invited to review and comment on preliminary drafts of the guideline. Conclusions We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) deficiency and unequivocally and consistently low serum T concentrations. We recommend measuring fasting morning total T concentrations using an accurate and reliable assay as the initial diagnostic test. We recommend confirming the diagnosis by repeating the measurement of morning fasting total T concentrations. In men whose total T is near the lower limit of normal or who have a condition that alters sex hormone–binding globulin, we recommend obtaining a free T concentration using either equilibrium dialysis or estimating it using an accurate formula. In men determined to have androgen deficiency, we recommend additional diagnostic evaluation to ascertain the cause of androgen deficiency. We recommend T therapy for men with symptomatic T deficiency to induce and maintain secondary sex characteristics and correct symptoms of hypogonadism after discussing the potential benefits and risks of therapy and of monitoring therapy and involving the patient in decision making. We recommend against starting T therapy in patients who are planning fertility in the near term or have any of the following conditions: breast or prostate cancer, a palpable prostate nodule or induration, prostate-specific antigen level > 4 ng/mL, prostate-specific antigen > 3 ng/mL in men at increased risk of prostate cancer (e.g., African Americans and men with a first-degree relative with diagnosed prostate cancer) without further urological evaluation, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia. We suggest that when clinicians institute T therapy, they aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost. Clinicians should monitor men receiving T therapy using a standardized plan that includes: evaluating symptoms, adverse effects, and compliance; measuring serum T and hematocrit concentrations; and evaluating prostate cancer risk during the first year after initiating T therapy.

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