Spermatogenesis describes a complex multistep differentiation process to produce millions of mature spermatozoa daily. Spermatogenesis is fueled by spermatogonial stem cells. It comprises a variety of unique genetic and epigenetic mechanisms to eventually generate haploid sperm, which provides half of the genetic material and epigenetic information that is needed to create a new life upon fertilization. Due to its intricacy, germ cell differentiation is error prone and problems at all stages of spermatogenesis might contribute to human infertility. Male infertility accounts for half of all infertility cases and is considered a multifactorial disease with highly heterogeneous phenotype manifestation. The molecular mechanisms causing fertility problems are largely unknown in many cases. At present, epigenetics take center stage in male reproduction since there is increasing evidence that an intact epigenome is required for reproductive health and prevention of paternal disease transmission. Transgenic mouse models represent a valuable tool with which to study the significance of single genes or epimutations for proper germ cell development, though there are some limitations when translating this information from mice to humans. Nevertheless, mouse models greatly enhance our understanding of fertility pathways, which is critical in order to identify genes and epigenetic signatures involved in the pathophysiology of male reproductive disorders and offspring health. This review will provide prominent examples of mouse models with single gene mutations directly affecting spermatogenesis, thereby mimicking primary human infertility. The main focus though will be on mouse models with defects in genes encoding for epigenetic regulators, such as histone-modifying enzymes and DNA methyltransferases, and the consequences for spermatogenesis and offspring health.
In the euchromatic part of the long arm of the human Y chromosome (Yq11) at least 13 Y genes encoding proteins and expressed in male germ cells were found in 3 distinct genomic Y regions frequently deleted in infertile men with idiopathic azoospermia, i.e., for unknown reasons no mature sperm were found in their semen fluid. Accordingly, they were designated as azoospermia factor (AZF) regions: AZFa, AZFb, and AZFc. Additionally, 10 Y genes called "testis-specific transcript Y" (TTTY) genes were mapped in the same AZF intervals. They belong to the long non-coding RNA gene pool in human germ cells because they seem to lack any protein-coding potential. Distinct chromatin regions in Yq11 overlapping with AZFb and AZFc are supposed to be involved in the premeiotic X and Y chromosome pairing and inactivation process controlling male germ cell meiosis. It can thus be assumed that the germ line function of the AZF loci in Yq11 may be not only based on the expression of some germ cell proteins, but also on the expression of some germ cell-specific TTTY transcripts and a locally dynamic and specific chromatin folding structure probably controlled by some germ cell-specific nuclear proteins.
After meiotic divisions, postmeiotic haploid spermatids are faced with the challenge of undergoing a dramatic morphological transformation to form mature, highly specialized spermatozoa. The main processes required for the development of functional spermatozoa include the formation of an acrosome and a flagellum, and compaction of sperm chromatin and nuclear shaping. The haploid differentiation program (spermiogenesis) is governed by the well-coordinated expression of a wide variety of genes required for the morphological and metabolic changes. It is clear that disturbances at any given point of spermiogenesis lead to a reduced ability to conceive offspring due to either a reduced number or abnormal morphology and function of spermatozoa. Defective spermatozoa are often observed in infertile males, including sperm with an abnormal morphology (teratozoospermia), defective motility (asthenozoospermia), or lowered number of sperm in the semen (oligozoospermia). Male infertility is often a multifactorial disorder, which hinders our understanding of the causal factors. However, genetic studies have revealed several genes affected in infertile males with spermiogenic defects. Furthermore, genetically modified mouse models have provided valuable information about the important genes required for haploid germ cell-specific processes.
The development of spermatozoa from primordial germ cells (PGCs) involves the transition of the genome through a program of sequential epigenetic events, resulting in the genome-wide erasure and subsequent reestablishment of DNA methylation at most loci, along with reprogramming of histone modification profiles and the chromatin remodeling. Following successful fertilization, the epigenetic signatures of the paternal genome are altered during the early embryonic stages compatible with the embryonic developmental program that begins a new life cycle. We highlight the remodeling of the sperm epigenome, beginning from PGCs to the early embryonic stages, preparing for a normal embryonic growth. Additionally, recent studies have shown a significant association between aberrant DNA epigenetic signatures in spermatozoa with idiopathic male infertility and an increased frequency of spontaneous abortions and imprinting disorders. Here we present an overview of the important epigenetic changes that occur to male PGCs until the reprogramming of the preimplantation embryo. In addition, we also highlight the errors in the epigenetic signatures and their consequences.
Male and female infertility affects close to 50 million couples worldwide according to a recent World Health Organization estimate. Many of the 25-30% of couples with idiopathic infertility likely have a genetic etiology for their condition. Next-generation sequencing has identified many new putative causes of infertility in recent years, which are discussed in this chapter. Genetic and genomic causes of infertility can be divided into cytogenetic anomalies, gene defects, and epigenetic aberrances. The discussion of male infertility focuses on genetic factors impairing spermatogenesis and includes numerical chromosomal anomalies such as Klinefelter syndrome, structural chromosomal anomalies such as Y-chromosome microdeletions, certain single gene mutations, syndromic diseases, and epigenetic mutations. The discussion of female infertility includes chromosomal anomalies like Turner syndrome, as well as genetic and epigenetic mutations identified as causes of hypogonadotropic hypogonadism, premature ovarian insufficiency, endometriosis, and polycystic ovarian syndrome. In conclusion, new genetic testing methods have significantly advanced our knowledge of the genetic basis of male and female infertility. However, the list of known candidate abnormalities is not exhaustive, and further research is required to understand how each candidate mutation influences fertility.
The germline is constituted by all cells that have the potential to transmit their genetic information to the next generation. The germline can be considered as a defined sequence of genetic, cellular, and developmental processes recurring in each generation in order to ensure the continuity of a species-specific reproduction program. Although basic mechanisms of germline development in mammals are highly conserved, relatively slight yet relevant modifications of germline development evolved in different groups of mammals to adapt the entire process to the specific requirements of and conditions in each species. This review highlights selected aspects that illustrate germline adaptations and characteristics in primates mainly in comparison to the mouse, which is the best investigated mammalian model organism in reproductive biology.
The establishment of a robust and reliable culture system to study the differentiation of male germ cells in vitro has been a topic in developmental biology and reproductive medicine for over 100 years. Although successful approaches resulting in full mammalian spermatogenesis have been developed for mice, development of a system to elucidate details of the complex process of spermatogenesis in humans is still needed. A huge variety of strategies employing different types of cells, cultured in different conditions, have been investigated so far. However, mostly because of limited access to human gonadal material from healthy donors, crucial information necessary to establish a functioning system remains missing. To picture the current status of information on human spermatogenesis in vitro, this short review mainly focuses on articles published over the last decade. However, important articles published before 2006 have also been included in the absence of more recent studies. A literature search was conducted, including articles written in English and German, cited in PubMed, and references identified in articles, with the focus on in vitro spermatogenesis and its clinical implication for paediatric oncology and haematology patients subjected to gonadotoxic anticancer treatments.
Klinefelter syndrome (KS) is a frequent male sex-chromosomal trisomy (47,XXY) of heterogeneous phenotype (infertility, hypogonadism, gynecomastia, disturbed bone metabolism, diabetes, cognitive deficits and, vascular and cardiac problems) and variable severity. In all patients, germ cell loss and hypergonadotropic hypogonadism is observed. Morbidity and mortality are increased, but so far KS is strongly underdiagnosed. Clinical studies have suggested that changes such as DNA methylation and X-chromosomal and autosomal gene expression are affected. Mouse models resembling the human KS are of great advantage as only few genes escape from X-inactivation, likely causative and sufficient to induce a phenotype closely resembling the human disorder. Here, we report the expression of X-chromosomal escapee genes in 41,XXY* mice which are shared with men (Utx, Kdm5c, Eif2s3x, Ddx3x). A tissue-, gene-, and development-specific expression profile was observed. We discuss the need for improved diagnostics as many patients go undetected. Novel diagnostics and the development of cryobanking with the aim of preserving fertility have recently initiated a debate on prenatal diagnosis and the counselling of patients for tissue storage as a reserve. Diagnosis tools are needed, as evidence indicates that KS should be encountered early has increased.
The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a cAMP-activated Cl- and HCO3- channel, which is widely expressed in epithelial cells of th
The androgen testosterone has an essential trophic role in the development of male physiology and in adult spermatogenesis and fertility. Testosterone mainly exerts its effect through the androgen receptor (AR), a ligand-activated transcription factor that is activated by binding the androgens testosterone or dihydrotestosterone. Mutations in AR can result in the genetic disorder androgen insensitivity syndrome, which results in a feminised phenotype and developmental problems, including cryptorchidism and disrupted spermatogenesis, thus complicating the investigation of the role of AR in adulthood. Transgenic mouse models of conditional AR inactivation have helped to define cell-specific roles for AR in the testis and the wider male reproductive system, and revealed a complex paracrine signalling network that controls fertility through several cell types and differing mechanisms.
Age-related hearing loss (ARHL) is a complex multifactorial disease. It is highly prevalent in older adults and has significant adverse impact on communication, mental health and quality of life. Severity and onset of ARHL varies substantially between individuals, and heritability estimates of ARHL range up to 75%. Understanding the genetics of ARHL may allow targeted treatment or prevention. We review the current research in humans on genetic susceptibility to ARHL related to (1) cell adhesion, cell shape and epithelial development, (2) neurotransmission, (3) oxidative stress, (4) immune response/apoptosis, and (5) other functions. (C) 2016 S. Karger AG, Basel
Since the publication of the first draft of the human genome sequence in 2001, there has been an explosion in the number of genes associated with human genetic diseases, including those involved in human deafness. Clinical studies, genome-wide association studies, and exome resequencing have all added to the ever-expanding candidate list of genes with a role in hearing. Because human genetic data is primarily correlative, this explosion of data has increased the need for more efficient approaches to confirm these candidate genes in a model system. In addition, as our understanding of stem cells and genome editing advances, the potential for restoring hearing through regenerative medicine increases. This review highlights the role zebrafish can play as a model for human deafness, and also its potential role in discovering regenerative medicine therapies to restore lost hearing.
Hearing loss is a common neurosensory disorder. Mutations of many genes are associated with hearing loss, and there are a great variety of reasons for phenotypic variability, including environmental causes such as loud noise and exposure to ototoxic drugs. Additionally, there are genetic modifiers that can play a pivotal role in modulating the severity and/or the rate of hearing loss. In vertebrates including humans, genetic modifiers have been identified that affect hearing ability. Further characterization of these enhancers and suppressors of mutated genes associated with profound deafness should provide new insights into the complex molecular and functional networks essential for sound transduction and might reveal novel targets for potential therapeutic interventions to circumvent hearing loss. (C) 2016 S. Karger AG, Basel
This chapter presents a cross-disciplinary overview of genetics and deafness from the perspective of 3 deaf academics employed in tenured or tenure-track positions at American and Canadian universities. We present a collective examination of the science of genetics and deafness using perspectives gained through disciplinary-specific research in bioethics, deaf and disability studies, education, linguistics, and philosophy. Specifically, we analyze the relationship between genetic patterning and language diversity, and then move to an analysis of bioethical issues related to deaf people and social policy. (C) 2016 S. Karger AG, Basel
There has been considerable progress in identifying the mutations primarily associated with congenital hearing loss caused by a single gene. The next challenge is the discovery of genes and mutations associated with common acquired hearing loss in the human population such as age-related hearing loss (AHL) and presbyacusis, which occur through the effects of environmental risk factors and several quantitative trait loci, namely, genetic modifiers. One approach to identify novel modifier genes is an unbiased genomic strategy that utilizes mouse models, which are investigated in a controlled environment. Here, we describe the genetic modifiers that contribute to hearing loss susceptibility and resistance in inbred mice and the genetic approaches used to identify the modifiers in the genetic background, with emphasis on the AHL mutation of the cadherin 23 gene Cdh23ahl. Cdh23ahl is the mutation responsible for hearing loss in multiple inbred strains and impacts mice hearing phenotypes as a genetic modifier. We then discuss the AHL-resistance effect in the presence of Cdh23ahl identified using a chromosomal substitution (consomic) strain. Finally, we propose future directions for identifying genetic modifiers using forward and reverse genetics approaches.
Genetic forms of sensorineural deafness account for almost half of all patients with congenital hearing loss (HL). Increasing knowledge of the underlying molecular and genetic mechanisms that lead to HL raises the possibility for novel therapeutics, such as those based on gene transfer and related methods that influence gene expression in affected tissues. Over the past decade, there has been renewed interest in cochlear gene therapy for the treatment of a variety of causes of HL. The last several years have seen significant advances in gene therapy for HL in mouse models of deafness that further supports the promise of gene therapy approaches to improving hearing health. These studies document that both replacing an absent gene and downregulating a dominant mutated gene can restore hearing. It is thus reasonable to predict that the successful treatment approaches increasingly being reported in mouse models of HL will establish a framework for developing gene replacement therapies in humans. Here, we review the most recent advances in cochlear gene therapy. This review will cover the animal models used in these studies, the most widely employed viral vectors, potential routes of delivery into the inner ear, and an overview of several genetic deficiencies in mouse models that have been successfully addressed. Lastly, this review elaborates on research directed towards spiral ganglion neuronal preservation and regeneration. (C) 2016 S. Karger AG, Basel
Hereditary hearing loss is a classic genetically heterogeneous condition with nearly 100 nonsyndromic hearing loss genes currently described and many more awaiting discovery. Priorities in the field with potentially rapid clinical application are the identification of all genes involved in the biological mechanisms of hearing and understanding their coordinated molecular interplay for normal auditory and nervous system functioning. Much of this momentum has been hindered by the inherent complexities of the genetics underlying deafness, as well as constraints such as requirements of large families for successful positional cloning. Major technological advancements in the past decade have empowered high-throughput next-generation sequencing approaches that have already facilitated the recognition of over 30 genes since 2010 and shifted hurdles away from achieving economical and time-efficient data toward accurate variant prioritization. Progress in the field of molecular genetics has never occurred at such a remarkable pace or been at such an exciting crossroad for expedited identification of the genes involved in hearing loss. (C) 2016 S. Karger AG, Basel
Hearing loss is the most common sensory deficit in humans. Untreated hearing loss will affect speech and language development and lead to impaired cognitive and social skills. Early detection and intervention have proven critical to successful rehabilitation and help individuals with hearing loss to reach their full potential. Since the adoption of universal newborn hearing screening in the United States and other parts of the world, many infants with congenital hearing loss have received a diagnosis shortly after birth and benefited from early intervention programs by 6 months of age, the critical period for language acquisition. However, traditional screening methods have their limitations, including high false positive and false negative rates, difficulty to distinguish transient versus permanent hearing loss, inability to prevent hearing loss presymptomatically, and no etiological explanations. New advances in next-generation sequencing and computing technologies have enabled rapid discoveries of genetic causes of hearing loss. Targeted therapeutic strategies hold the promise for precision medicine to treat hearing loss. Next-generation newborn hearing screening will incorporate comprehensive genomic analyses, which is expected to offer improved sensitivity, specificity, precise etiology, and an earlier window of opportunity for treatment to patients, and to reduce healthcare costs and disparities in society. (C) 2016 S. Karger AG, Basel
