Gender and the Genome

Sex chromosome gene dosage compensation is required to ensure equivalent levels of X-linked gene expression between males (46, XY) and females (46, XX). To achieve similar expression, X-chromosome inactivation (XCI) is initiated in female cells during early stages of embryogenesis. Within each cell, either the maternal or paternal X chromosome is selected for whole chromosome transcriptional silencing, which is initiated and maintained by epigenetic and chromatin conformation mechanisms. With the emergence of small-molecule epigenetic inhibitors for the treatment of disease, such as cancer, the epigenetic mechanism underlying XCI may be inadvertently targeted. Here, we test 2 small-molecule epigenetic inhibitors being used clinically, GSK126 (a histone H3 lysine 27 methyltransferase inhibitor) and suberoylanilide hydroxamic acid (a histone deacetylase inhibitor), on their effects of the inactive X (Xi) in healthy human female fibroblasts. The combination of these modifiers, at subcancer therapeutic levels, leads to the inability to detect the repressive H3K27me3 modification characteristic of XCI in the majority of the cells. Importantly, genes positioned near the X-inactivation center (Xic), where inactivation is initiated, exhibit robust expression with treatment of the inhibitors, while genes located near the distal ends of the X chromosome intriguingly exhibit significant downregulation. These results demonstrate that small-molecule epigenetic inhibitors can have profound consequences on XCI in human cells, and they underscore the importance of considering gender when developing and clinically testing small-molecule epigenetic inhibitors, in particular those that target the well-characterized mechanisms of X inactivation.

Who is the determining factor for the sex of the offspring—mother, father, or both parents? This fundamental hypothesis proposes a new model of sex determination, challenging the existing dogma that the male Y chromosome of the father is the sole determinant of the sex of the offspring. According to modern science, the 3 X chromosomes (male XY and female XX) are assumed to be similar, and the sex of the offspring is determined after the zygote is formed. In contrast to this, the new hypothesis based on theoretical research proposes that the 3 X chromosomes can be differentiated, based on the presence of Barr bodies. The first X in female XX chromosomes and X in male XY chromosomes are similar as they lack Barr body and are hereby denoted as ‘X’ and referred to as ancestral chromosomes. The second X chromosome in the female cells which is a Barr body, denoted as X, is different. This X chromosome along with the Y chromosome are referred to as parental chromosomes. Sperm with a Y chromosome can only fuse with an ovum containing the ‘X’ chromosome. Similarly, sperm with the ‘X’ chromosome can only fuse with an ovum containing the X chromosome. Cell biology models of gametogenesis and fertilization were simulated with the new hypothesis model and assessed. Only chromosomes that participated in recombination could unite to form the zygote. This resulted in a paradigm shift in our understanding of sex determination, as both parents were found to be equally responsible for determining the sex of the offspring. The gender of the offspring is determined during the prezygotic stage itself and is dependent on natural selection. A new dimension has been given to inheritance of chromosomes. This new model also presents a new nomenclature for pedigree charts. This work of serendipity may contribute to future research in cell biology, gender studies, genome analysis, and genetic disorders including cancer.

Prevalence estimates of obstructive sleep apnea (OSA) continue to rise, partially due to better recognition of and screening for the disease, in part due to increase in obesity and in part due to changes in definitions of obstructive hypopneas. Despite increasing knowledge of the deleterious impact of OSA on health, underrecognition continues to be a major concern, especially in women. A middle-aged man that snores and is sleepy has been the accepted “textbook” picture of OSA; women may present with more atypical symptoms and excessive sleepiness that are not reflected on sleepiness scale questionnaires. Even when presenting with snoring and sleepiness, and in the presence of comorbidities, women are less likely to be evaluated for OSA. Symptom burden and poor health outcomes have been documented in women with OSA and treatment improves their health. In this article, we explore possible causes for this underrecognition of OSA in women, including gender bias and healthcare inequity, and propose solutions.

In Europe as well as the United States, nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is strongly associated with obesity and type 2 diabetes mellitus (T2DM). Nonalcoholic fatty liver disease is defined as a hepatic manifestation of the metabolic syndrome. Being a very powerful and independent cardiovascular risk factor, NAFLD increases cardiovascular and overall mortality to a significant degree. The purpose of this review was to determine sex- and gender-specific differences in the prevalence and pathogenesis of NAFLD and delineate the specific characteristics of NAFLD as a systemic disease in men and women. Postmenopausal women and women with endocrine disorders such as the polycystic ovarian syndrome are at high risk of developing NAFLD. The increasing incidence of female NAFLD after menopause appears to be related to reduced estrogen and increased testosterone levels, as well as changes in the distribution of fatty tissue. Finally, the role of gender-specific nutrition patterns in the pathogenesis of NAFLD will be discussed. Fructose consumption from industrialized products is a promoter of NAFLD, depending on the total daily calorie intake of macronutrients. A higher level of health literacy and conscious food behavior have been noted among women of all age groups compared to males, which could play a role in the pathogenesis of NAFLD. Health professionals are confronted with the challenges of early diagnosis by the use of sensitive, reliable, and noninvasive diagnostic tools, including screening algorithms for high-risk persons and providing gender-specific nutritional support as a crucial element of treatment and disease prevention.

With the advent of gene-editing tools, changes to sequences encoding genes or regulatory elements can be made with relative ease compared to prior technologies. The development and anticipated commercialization of new applications using gene-editing technologies may span the gamut from therapeutic interventions to agricultural applications to cosmetic or enhancement procedures. Although objections have been raised about the purpose and on whom gene editing should be performed, limiting its uses in the absence of demonstrated harm may be difficult and unwise at this time, even at this early stage of development. The fledgling field may benefit from a review of the history of plastic and cosmetic surgery that underwent a similarly rocky start and continues to evolve to this day. From this brief comparative historical analysis, we may gain some insight about the path forward regarding the use of gene-editing tools for cosmetic purposes.

There is increasing interest in and tolerance of the lay public for variations in human sexuality. In contrast, the molecular biology that underlies gender identity, the development of gonadal and genital anatomy, and the factors that define sexual behavior is proving unexpectedly complex and is still incompletely understood. It is now evident that humans cannot be characterized as member of 1 of 2 clearly defined units: male or female. In fact, individuals exist on a continuum: those who do not conform unequivocally to the dyadic view of human sex in terms of anatomy, gender identity, and/or sexual behavior should be characterized as having variations in rather than disorders of sexual development. Such individuals can no longer be regarded as anomalies to be rejected, condemned, and, if possible, “corrected” either psychologically or anatomically.

Telomere length is a biomarker of cell aging that is hypothesized to contribute to women’s greater longevity. Although most previous studies have found no sex difference in telomere length at birth, it is well established that females have longer average telomere length than males during adulthood. Proposed biological mechanisms underlying sex differences in adult telomere length include differences in sex steroid hormones and body size, which emerge during the pubertal transition. The purpose of this study was to examine the total effect of sex on telomere length during early adolescence and to examine estradiol, total testosterone, and body surface area (BSA; a measure of body size) as potential mediators of sex differences in telomere length. Data were from a population-based sample of 126 female and 109 male Hispanic adolescents aged 8 to 14 years from the Early Life Exposures in Mexico to ENvironmental Toxicants (ELEMENT) study. Relative telomere length (T/S ratio) was measured by the quantitative polymerase chain reaction method; sex steroid hormones were measured using an automated chemiluminescent immunoassay, and BSA was calculated using measured height and weight. Adjusting for age and pubertal status, we found that girls had significantly longer telomeres than boys (β = .13; P < .01), but there were no significant indirect effects of sex on telomere length through any of the proposed mediators. We conclude that sex differences in telomere length are evident during early adolescence but are not explained by cross-sectional differences in sex steroid hormones or body size.

Sex differences in the brain are prominent features across the animal kingdom. Understanding the anatomical and regulatory mechanisms behind these differences is critical for both explaining sexually dimorphic behaviors and developing sex-targeted treatments for neurological disorders. Clinical studies considering sex biases and basic research on animal models have provided much evidence for the existence of sex differences in the brain and, in a larger sense, sexual dimorphisms in the nervous system. However, due to the complexity of structure and dimorphic behaviors, it is yet unclear precisely how neuronal sexual dimorphisms are regulated on a molecular or cellular level. This commentary reviews available tools for investigating sexual dimorphisms using a simple model organism, the roundworm Caenorhabditis elegans (C. elegans), which enables one to study gene regulation at single-cell resolution with a number of cutting-edge molecular and genetic technologies. I highlight the doublesex/mab-3 family of transcription factors, first discovered in invertebrates, and their roles in a potentially universal regulatory mechanism underlying neuronal sexual dimorphisms. Studies of these transcription factors using C. elegans, fruit flies, and vertebrates will promote our understanding of fundamental mechanisms behind sex differences in the brain.

Epidemiologic studies demonstrate significant gender-specific differences in immune system function. Males are more prone to infection and malignancies, while females are more vulnerable to autoimmune diseases. These differences are thought to be due to the action of gonadal hormones: Estrogen increases the inflammatory response and testosterone dampens it. More specifically, estrogen stimulation induces inflammatory cytokine production including interferon γ, interleukin (IL) 6, and tumor necrosis factor α, while testosterone induces IL-10, IL-4, and transforming growth factor β. More recent studies demonstrate threshold effects of estrogen stimulation on immune cell function: physiologic doses of estrogen (approximately 0.5 nmol/L) stimulate inflammatory cytokine production, but superphysiologic dosages (above 50 nmol/L) can result in decreased inflammatory cytokine production. This review reports findings concerning the impact of estrogen on CD8⁺ cytotoxic T cells and the overall immune response in the tumor microenvironment. Variables examined include dosage of hormone, the diversity of immune cells involved, and the nature of the immune response in cancer. Collective review of these points may assist in future hypotheses and studies to determine sex-specific differences in immune responses that may be used as targets in disease prevention and treatment.

Scientific misconduct does not only relate to falsifying scientific data or plagiarism but may also include improper handling of authorship. A researcher may be cited as author of a manuscript without having contributed to the scientific work involved, another who has fulfilled the requirements of authorship is omitted or his/her name does not appear in the order, which would have been appropriate. All these may reflect various degrees of dishonesty and improper scientific conduct. There are even more severe cases, in which scientific research is sponsored, conducted, and sometimes even published by employees of vested parties who prefer their involvement not being disclosed, using proxy authors instead. This form of ghost authorship may sometimes amount to felony. As chair of the Ethics Committee (M.G.) and Dean (E.G.), both at the Sackler Medical School, Tel Aviv University, we report on our insights related to authorship and present 2 representative cases.

Early childhood is an important developmental period, which lays the foundation for future learning, behaviour, physical and mental health and gene expression. The most vulnerable children in society are often referred to and receive services from the child welfare system because of a concern of abuse and neglect and/or a poor developmental trajectory. This paper presents an organizing framework for how the child welfare system, in concert with allied partners, can support interventions for young children and families by acknowledging its crucial role in improving their development and well-being. The framework is informed by research amassed from numerous disciplines, including child welfare, development, neuroscience, neurobiology and epigenetics. Although the notions of protection and well-being are central considerations in child welfare legislation in Ontario, Canada, the operationalization of wellbeing has proven challenging in child welfare practice, policy and research. The framework proposes ten key indicators and priorities for identifying and promoting optimal child development. Findings from the 2013 cycle of the Ontario Incidence Study of Reported Child Abuse and Neglect (OIS-2013), the only provincial source of aggregated child welfare investigation data, are presented to articulate the divide between the environmental context of a population of at-risk children and the conditions that both protect children and increase the likelihood that they will thrive in adulthood. This paper argues there are different points of entry and intervention across sectors and provides a foundation for further discussion on how to promote well-being for society's most vulnerable children.

Psychological stress, a subjective perception of an adverse environmental change, is a hallmark of modern society. Although psychological stress has previously been established as a risk factor for cardiovascular disease (CVD), it is unclear whether stress influences cardiovascular risk differently in men versus women. Gender disparities exist in the prevalence of stress as well as in the prevalence and prognosis of CVD; therefore, associations between stress and CVD risk and mortality may vary by sex. The purpose of this review was to summarize the evidence from recent and landmark studies on gender differences in the associations of stress with CVD risk factors and end points and to highlight clinical and public health implications as well as future research directions in this field. Taken together, research to date indicates that while stress is associated with poorer cardiovascular health metrics in both men and women, the influence of stress on measures of glucose regulation and dyslipidemia and on overall CVD risk may be stronger among women. However, men may be more susceptible to the influence of stress on body adiposity, blood pressure, and CVD mortality. In terms of behavioral risk factors for CVD, associations between stress and diet quantity and quality appear to be stronger among women, but the influence of stress on sedentary behaviors and sleep may be stronger among men. Given that gender disparities exist in the prevalence of overall and different types of stress (eg, financial stress, caregiving stress, and occupational stress), future studies should decipher the potential differential associations between types of stress and cardiovascular risk among men and women to identify vulnerable populations and develop targeted interventions.

Discoveries in molecular genetics over the last two decades have broadened our information about the genomics of complex microbial communities. As in all other fields of medicine, there is an undeniable need to explore the microbiome and the way it is impacted by biological sex. A number, although small, of recent studies have demonstrated that women and men have striking differences in the species that constitute their microbiomes. This effects pathological physiology in fields such as hepatology, oncology, autoimmune disease (most notably diabetes mellitus), autism, and obstetrics. There is still an unfortunate lack of research being done on the “microgenderome”: the interaction between microbiota, sex hormones, and the immune system. This review will highlight some of the main areas to be affected by microgenderome physiology, with an in depth focus on obstetrics.

The prevalence of obesity has been increasing globally, with important implications for cardiovascular morbidity and mortality. Obesity is linked to changes in cardiac morphology that collectively play a role in the development of heart failure in this population, as hemodynamic and metabolic alterations lead to cardiac hypertrophy and chamber enlargement. Over time subclinical abnormalities in contractile function occur and could progress to overt clinical heart failure. Understanding the relationship between obesity and alterations in cardiac structure and function has important implications for the development of lifestyle and pharmacologic interventions targeting this modifiable risk factor. There is also a growing awareness of the importance of understanding gender differences in obesity. Gender-specific patterns of adiposity and fat distribution in addition to the distinctive hormonal environments of men and women may lead to sex-specific differences in the degree of cardiometabolic risk associated with obesity. Imaging studies have shown that ventricular remodeling in response to obesity differs among the sexes, and these differences may play a role in the female predominance of heart failure with a preserved ejection fraction.

Cardiac arrhythmias are an important clinical problem since it increases risk of stroke, heart failure, and overall morbidity. Treatment of arrhythmias may include blood thinners, rhythm control, as well as surgical ablation. In this review, we discuss the differences in diagnosis, prognosis and treatment of cardiac arrhythmias in men and women. Further understanding of the gender specific differences of cardiac arrhythmias may be helpful to achieve success and more delivery of more personalized medicine.

Stress cardiomyopathy, also known as “Takotsubo syndrome” (TS), is a complex disease that typically affects postmenopausal women. The pathophysiology is still largely unknown, but evidence of a frequent association between TS and stressful events has evoked the hypothesis of a pathophysiologic role of sympathetic overdrive in the myocardial dysfunction. However, despite several studies, the role gender plays in TS onset remains unclear because stress cardiomyopathy also has been described in young women and in men. Moreover, although several cases of a familial cluster of TS have been reported, no responsible gene mutations or polymorphisms have been clearly identified so far, and neither the modality of transmission or the true impact of genetic background. In this review, we discuss the role of gender in the onset, course, and outcomes of TS and we report the available data about polymorphisms and gene mutations so far investigated, trying to critically analyze the evidence reported in the literature.