Genetic Sex Research Articles

Sources of Individual Differences in Pain.

Pain is an immense clinical and societal challenge, and the key to understanding and treating it is variability. Robust interindividual differences are consistently observed in pain sensitivity, susceptibility to developing painful disorders, and response to analgesic manipulations. This review examines the causes of this variability, including both organismic and environmental sources. Chronic pain development is a textbook example of a gene-environment interaction, requiring both chance initiating events (e.g., trauma, infection) and more immutable risk factors. The focus is on genetic factors, since twin studies have determined that a plurality of the variance likely derives from inherited genetic variants, but sex, age, ethnicity, personality variables, and environmental factors are also considered.

Distinct roles of androgen receptor, estrogen receptor alpha, and BCL6 in the establishment of sex-biased DNA methylation in mouse liver

Sexual dimorphism in gene regulation, including DNA methylation, is the main driver of sexual dimorphism in phenotypes. However, the questions of how and when sex shapes DNA methylation remain unresolved. Recently, using mice with different combinations of genetic and phenotypic sex, we identified sex-associated differentially methylated regions (sDMRs) that depended on the sex phenotype. Focusing on a panel of validated sex-phenotype dependent male- and female-biased sDMRs, we tested the developmental dynamics of sex bias in liver methylation and the impacts of mutations in the androgen receptor, estrogen receptor alpha, or the transcriptional repressor Bcl6 gene. True hermaphrodites that carry both unilateral ovaries and contralateral testes were also tested. Our data show that sex bias in methylation either coincides with or follows sex bias in the expression of sDMR-proximal genes, suggesting that sex bias in gene expression may be required for demethylation at certain sDMRs. Global ablation of AR, ESR1, or a liver-specific loss of BCL6, all alter sDMR methylation, whereas presence of both an ovary and a testis delays the establishment of male-type methylation levels in hermaphrodites. Moreover, the Bcl6-LKO shows dissociation between expression and methylation, suggesting a distinct role of BCL6 in demethylation of intragenic sDMRs.

Female-specific genomic regions and molecular sex identification of the clearhead icefish (Protosalanx hyalocranius)

BackgroundThe clearhead icefish, Protosalanx hyalocranius, is an economically important fishery species in China. Since 1980s, P. hyalocranius was widely introduced into lakes and reservoirs of northern China for aquaculture. However, the lack of a rapid and cost-effective sex identification method based on sex specific genetic markers has hindered study on sex determination mechanisms and breeding applications.ResultsFemale-specific genomic regions were discovered by comparing whole genome re-sequencing data of both males and females. Two female-specific genomic regions larger than 50 bp were identified, and one (598 bp) contained a putative FOXI gene, which was paralogous to another FOXI gene with sex-associated SNPs. The two FOXI sequences displayed significant length difference with nine deletions of total length of 230 bp. This deletion-type structural variation could be easily and efficiently detected by traditional PCR and agarose gel electrophoresis with one 569 bp band for males and two bands (569 and 339 bp) for females, which were validated in 50 females and 40 males with known phenotypic sexes.ConclusionsThe results provided structural genomic evidence for the ZZ/ZW sex determination system in P. hyalocranius discovered in our previous study with association analysis of SNPs. Moreover, the female-specific markers and rapid and cost-effective PCR-based genetic sex identification method should have applications in further studies of sex determination mechanism for this species.

Disparities among infertility patients regarding genetic carrier screening, sex selection, and gene editing.

The purpose of this study is to evaluate the perspectives of infertility patients regarding genetic carrier screening, embryo sex selection, embryo research, and gene editing. An anonymous 32-question survey was distributed electronically to all patients who seen at a single academic fertility center for at least one visit between June 2018 and September 2019. Survey questions evaluated patient perspectives on genetic carrier screening, embryo sex selection, embryo research, and gene editing. There were 1460 survey responses (32.0% response rate). There were significant differences in the proportion of respondents receiving genetic carrier screening between racial groups, 73.1% of White, 45.5% of Black, 49.4% of Hispanic, and 62.8% of Asian respondents. The likelihood of having genetic carrier screening was also significantly influenced by respondent income, insurance status, and religion. Religion significantly influenced the acceptance of embryonic research and embryonic sex selection. While only 8.9% felt that genetically modifying embryos for physical traits should be allowed, 74.1% felt that genetic modification to correct disease should be allowed. Racial, religious, and socioeconomic factors significantly impacted respondents' likelihood to have genetic carrier screening and views on embryo sex selection, embryo research, and gene editing. These findings highlight the importance of tailoring genetic counseling to the individual, acknowledging individual and cultural differences in agreement with genetic testing and emerging genetic therapies.

A rapid and reliable method for genetic sex identification in sea cucumber, Apostichopus japonicus

Identification of sex-specific markers has important implications for genetic breeding and sex control breeding in aquaculture. Sea cucumber (Apostichopus japonicus) is one of the most important mariculture species in China. Although a substantial difference in immunocompetence has been observed between male and female sea cucumbers, the sex-specific marker remains unclear. Moreover, there is no reliable method for genetic sex identification in sea cucumbers. In this study, we first applied a 2b-RAD-seq method and identified two male-specific 2b-RAD-tags. This includes a 313 bp male-specific fragment that was mapped to scaffold MRZV01000576.1 of the male genome of A. japonicus. Several genes associated with the centromere, such as tesin-a-like gene, centromere-associated gene, reverse transcriptase gene, were also annotated within this scaffold. By designing three different sex-specific primers, we characterized genetic sex of sea cucumbers in different culture populations and the wild population. Using a fast and low-cost alkaline lysis method for DNA extraction, a reliable PCR amplification-mediated genetic sex identification method was developed. Hence, the sex-specific markers provide a solid basis to reveal the sex determination mechanism and the origin of sex-determining regions in sea cucumber. Furthermore, this study will improve the efficiency of genetic and sex control breeding in sea cucumbers.

Understanding and Addressing Disparities in Patients With Hematologic Malignancies: Approaches for Clinicians.

Approximately 185,840 individuals will be diagnosed with hematologic malignancies in the United States in 2020. Disparities in disease incidence, prevalence, burden, mortality, and survivorship have been identified among this patient population. Contributing factors include genetic ancestry, race/ethnicity, sex, socioeconomic status, and geographic region. Historically, these inequities have been understudied. Addressing these disparities requires a systems-level approach, improving access to care and reducing biases in the clinical setting. Additional research is needed to construct comprehensive, multilevel models to explore systematic observational studies and perform strategic intervention trials to overcome these disparities.

Effect of the genetic structure and sex local Iraqi chicken and Brahman in some hematological treaties

This study conducted in the Physiological Laboratory of the Department of Animal Production/College of Agriculture/Tikrit University, with the aim of finding out the effect of the genotype and sex of local chickens and Brahma chickens on some hematological traits. Used 24 blood samples, twelve samples from local chickens and Brahma chicken, with six samples for both sexes. After performing the hematological analyzes, the following results showed A significant effect of the genotype was observed in the TCH, HB, MCV and MCH. Moreover, it showed a significant increasing for domestic chickens compared to Brahma chickens. The total number of red and white blood cells did not significantly affect the genotype. Sex had a significant effect on most of the studied traits (HCT, HB, RBC, MCV, and, MCHC), where males significantly outperformed females. The interaction between genotype and sex had a noteworthy impact (p≤ 0.05) on most ofthe considered characteristics, and it by and large demonstrated a noteworthy diminish within the examined characteristics in female Brahma chickens compared to male and female residential chickens and indeed male Brahma. However, not effect in WBC count. From the results local chickens recorded to exceed expectations in most of the physiological characteristics and for both genders, the immune status of both genetic structure was rise to, and this may show the versatility of the Brahma chickens to the Iraqi airspace.

No evidence for genetic sex determination in Daphnia magna.

Mechanisms of sex determination (SD) differ widely across the tree of life. In genotypic sex determination (GSD), genetic elements determine whether individuals are male or female, while in environmental sex determination (ESD), external cues control the sex of the offspring. In cyclical parthenogens, females produce mostly asexual daughters, but environmental stimuli such as crowding, temperature or photoperiod may cause them to produce sons. In aphids, sons are induced by ESD, even though GSD is present, with females carrying two X chromosomes and males only one (X0 SD system). By contrast, although ESD exists in Daphnia, the two sexes were suggested to be genetically identical, based on a 1972 study on Daphnia magna (2n=20) that used three allozyme markers. This study cannot, however, rule out an X0 system, as all three markers may be located on autosomes. Motivated by the life cycle similarities of Daphnia and aphids, and the absence of karyotype information for Daphnia males, we tested for GSD (homomorphic sex chromosomes and X0) systems in D. magna using a whole-genome approach by comparing males and females of three genotypes. Our results confirm the absence of haploid chromosomes or haploid genomic regions in D. magna males as well as the absence of sex-linked genomic regions and sex-specific single-nucleotide polymorphisms. Within the limitations of the three studied populations here and the methods used, we suggest that our results make the possibility of genetic differences among sexes in the widely used Daphnia model system very unlikely.

Sex reversal and ontogeny under climate change and chemical pollution: are there interactions between the effects of elevated temperature and a xenoestrogen on early development in agile frogs?

Anthropogenic environmental change poses a special threat to species in which genetic sex determination can be overwritten by the thermal and chemical environment. Endocrine disrupting chemicals as well as extreme temperatures can induce sex reversal in such species, with potentially wide-ranging consequences for fitness, demography, population viability and evolution. Despite accumulating evidence suggesting that chemical and thermal effects may interact in ecological contexts, little is known about their combined effects on sex reversal. Here we assessed the simultaneous effects of high temperature (female-to-male sex-reversing agent) and 17α-ethinylestradiol (EE2), a widespread xenoestrogen (male-to-female sex-reversing agent), on sexual development and fitness-related traits in agile frogs (Rana dalmatina). We exposed tadpoles to a six-days heat wave (30 °C) and/or an ecologically relevant concentration of EE2 (30 ng/L) in one of three consecutive larval periods, and diagnosed sex reversals two months after metamorphosis using species-specific markers for genetic sexing. We found that high temperature induced female-to-male sex reversal, decreased survival, delayed metamorphosis, decreased body mass at metamorphosis, and increased the proportion of animals that had no fat bodies, while EE2 had no effect on these traits. Simultaneous exposure to heat and EE2 had non-additive effects on juvenile body mass, which were dependent on treatment timing and further complicated by a negative effect of sex reversal on body mass. These results show that environmentally relevant exposure to EE2 does not diminish the female-to-male sex-reversing effects of high temperature. Instead, our findings on growth suggest that climate change and chemical pollution may have complex consequences for individual fitness and population persistence in species with environment-sensitive sex determination.

Verification of an efficient genetic sex identification method in Portunus trituberculatus: Applied to study sex ratios in full-sib families

Portunus trituberculatus is one of the main mariculture crabs in China and has obvious sexual dimorphism. The development of a genetic sex identification method is key to clarifying the mechanisms of sex determination. Based on an insertion-deletion (inDel) marker closely linked to the sex of P. trituberculatus, we successfully established a sex identification method with the advantages of high efficiency, low cost and low false-positive rates using conventional PCR and agarose gel electrophoresis. Based on the method, the sex ratio of seven full-sib families at different developmental stages were analyzed, including zoea, megalopa and II juvenile crab. Our results showed that the sex ratio of P. trituberculatus in early development stages approximated the theoretical sex ratio (1:1) of the XY sex determination system, although there were three families with sex ratio deviations from 1:1 at the juvenile stage. This study is important for detailing the mechanisms of sex determination, and is also conducive to the development of sex-control technologies in this species.

Genetics of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a psychiatric disorder with multiple symptom dimensions (e.g. contamination, symmetry). OCD clusters in families and decades of twin studies clearly demonstrate an important role for genetics in the etiology of the disorder. In this review, we summarize the genetic epidemiology and molecular genetic studies of OCD and obsessive-compulsive symptoms. OCD is a heritable, polygenic disorder with contributions from both common and rare variants, including de novo deleterious variations. Multiple studies have provided reliable support for a large additive genetic contribution to liability to OCD, with discrete OCD symptom dimensions having both shared and unique genetic risks. Genome-wide association studies have not produced significant results yet, likely because of small sample sizes, but larger meta-analyses are forthcoming. Both twin and genome-wide studies show that OCD shares genetic risk with its comorbid conditions (e.g. Tourette syndrome and anorexia nervosa). Despite significant efforts to uncover the genetic basis of OCD, the mechanistic understanding of how genetic and environmental risk factors interact and converge at the molecular level to result in OCD's heterogeneous phenotype is still mostly unknown. Future investigations should increase ancestral genetic diversity, explore age and/or sex differences in genetic risk for OCD and expand the study of pharmacogenetics, gene expression, gene × environment interactions and epigenetic mechanisms for OCD.

Development and validation of SNP genotyping assays to identify genetic sex in the swimming crab Portunus trituberculatus

The swimming crab Portunus trituberculatus is an economically vital aquaculture species in China and South East Asia. Monosex female culture has been identified as a key priority due to their increased market value, consumer preference and enhanced growth performance. However, the lack of a rapid and reliable sex-linked marker panel has hampered the application of sex control and understanding of the sex determination in the species. In this study, two sex-linked SNPs obtained from our simplified genomic data were validated by sequencing and then converted into competitive allele-specific PCR assays. The results showed high consistency between the genetic and phenotypic sex providing therefore a rapid test sex identification. Moreover, heterogametic genotypes in males provided a significant genetic evidence to support an XX/XY sex determination system in the P. trituberculatus.

Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease.

ObjectiveParkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex‐specific manner.MethodsIn an effort to study sex‐specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta‐analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases.ResultsIn total, 19 genomewide significant regions were identified and no sex‐specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%).InterpretationWe did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. ANN NEUROL 2021;90:41–48

Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods.

Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation constants, leading to diverse responses in biological processes. Enantioselectivity can be observed in drugs pharmacodynamics and in pharmacokinetic (absorption, distribution, metabolism, and excretion), especially in metabolic profile and in toxicity mechanisms. The stereoisomers of a drug can undergo to different metabolic pathways due to different enzyme systems, resulting in different types and/or number of metabolites. The configuration of enantiomers can cause unexpected effects, related to changes as unidirectional or bidirectional inversion that can occur during pharmacokinetic processes. The choice of models for pharmacokinetic studies as well as the subsequent data interpretation must also be aware of genetic factors (such as polymorphic metabolic enzymes), sex, patient age, hepatic diseases, and drug interactions. Therefore, the pharmacokinetics and toxicity of a racemate or an enantiomerically pure drug are not equal and need to be studied. Enantioselective analytical methods are crucial to monitor pharmacokinetic events and for acquisition of accurate data to better understand the role of the stereochemistry in pharmacokinetics and toxicity. The complexity of merging the best enantioseparation conditions with the selected sample matrix and the intended goal of the analysis is a challenge task. The data gathered in this review intend to reinforce the importance of the enantioselectivity in pharmacokinetic processes and reunite innovative enantioselective analytical methods applied in pharmacokinetic studies. An assorted variety of methods are herein briefly discussed.

Analysis of a sex-biased sequence in sex determination region and exploitation of a fast sex detection method in Litopenaeus vannamei

In order to understand the characteristics of the sex determination region in Litopenaeus vannamei, genome walking was performed based on the existing sex-linked Marker19299. A fragment of 2630 bp sequence was obtained for the genomic DNA of females, which contains two contigs, contig 122401 and contig 4497889. On contig 122401, the sequence showed a sex-biased amplification between females and males, the target band for males was much weaker than that for females. Copy number analysis showed that the female DNA contained more copies of contig 122401 sequence than that of males. Besides, the females contained an extra 9 bp insertion and a 205 bp repeat on contig 4497889 in comparison with males. These results not only provide further evidence for the ZZ/ZW sex determination system in Litopenaeus vannamei, but also suggest a novel hypothesis that the sex determination in L.vannamei might be controlled by the existence of the differences both in DNA sequence and genome structure. According to the above characteristics, a fast detection method to distinguish genetic sex of L.vannamei was developed. This research will not only provide useful information for the fine mapping of the sex determination region in L.vannamei, but also accelerate studies about the sex determination mechanism in shrimp.

A simple and rapid method for fish sex identification based on recombinase-aided amplification and its use in Cynoglossus semilaevis

Fish sex identification is a basic technique of great importance for both fish genetic studies and fisheries. Due to the sexual reversal phenomenon in many fish species, a simple and rapid molecular identification method for fish genetic sex is urgently needed to suit versatile detection scenarios, such as point-of-need applications. In this study, we took Cynoglossus semilaevis as an example, established a recombinase-aided amplification (RAA)-based method for sex identification, and combined the RAA-detection with two result visualization approaches with distinct features, capillary electrophoresis (CE) and lateral flow dipstick (LFD). Specific primers and probe were designed to specifically detect the sex chromosome W of C. semilaevis in order to distinguish the genetic sex between males, pseudo-males and females. To evaluate the performance of our methods, the genetic sex for twenty-eight males, sixty-eight pseudo-males and fifty-four females were examined with the RAA-based method and classical PCR-based genotyping method, demonstrating the consistent results of sex identification between both methods. The RAA-LFD method is operationally simple, rapid (~ 30 min) and holds great potential for point-of-need applications of fish sex identification, including fishery fields. The method presented here could be effective for identifying fish gender with the ZW karyotype.

The Drosophila melanogaster Levodopa-Induced Depression Model Exhibits Negative Geotaxis Deficits and Differential Gene Expression in Males and Females.

More than 320 million people live with depression in the world, a disorder that severely limits psychosocial functioning and diminishes quality of life. The prevalence of major depression is almost two times higher in women than in men. However, the molecular mechanisms of its sex-specific pathophysiology are still poorly understood. Drosophila melanogaster is an established model for neurobiological research of depression-like states, as well as for the study of molecular and genetic sex differences in the brain. Here, we investigated sex-specific effects on forced-climbing locomotion (negative geotaxis) and gene expression of a fly model of depression-like phenotypes induced by levodopa administration, which was previously shown to impair normal food intake, mating frequency, and serotonin concentration. We observed that both males and females show deficits in the forced-climbing paradigm; however, modulated by distinct gene expression patterns after levodopa administration. Our results suggest that Drosophila models can be a valuable tool for identifying the molecular mechanisms underlying the difference of depressive disorder prevalence between men and women.

The Pitfalls of in vivo Cardiac Physiology in Genetically Modified Mice - Lessons Learnt the Hard Way in the Creatine Kinase System.

In order to fully understand gene function, at some point, it is necessary to study the effects in an intact organism. The creation of the first knockout mouse in the late 1980’s gave rise to a revolution in the field of integrative physiology that continues to this day. There are many complex choices when selecting a strategy for genetic modification, some of which will be touched on in this review, but the principal focus is to highlight the potential problems and pitfalls arising from the interpretation of in vivo cardiac phenotypes. As an exemplar, we will scrutinize the field of cardiac energetics and the attempts to understand the role of the creatine kinase (CK) energy buffering and transport system in the intact organism. This story highlights the confounding effects of genetic background, sex, and age, as well as the difficulties in interpreting knockout models in light of promiscuous proteins and metabolic redundancy. It will consider the dose-dependent effects and unintended consequences of transgene overexpression, and the need for experimental rigour in the context of in vivo phenotyping techniques. It is intended that this review will not only bring clarity to the field of cardiac energetics, but also aid the non-expert in evaluating and critically assessing data arising from in vivo genetic modification.

The impact of genetic background and sex on the phenotype of IL-23 induced murine spondyloarthritis.

BackgroundOverexpression of IL-23 in adult mice by means of hydrodynamic tail vein injection of IL-23 minicircles has been reported to result in spondyloarthritis-like disease. The impact of genetic background and sex on the disease phenotype in this model has not been investigated.MethodsWe compared male B10.RIII mice with male C57BL/6 mice, and male with female B10.RIII mice after hydrodynamic injection of IL-23 enhanced episomal vector (EEV) at 8–12 weeks of age. We monitored clinical arthritis scores, paw swelling, and body weight. Animals were euthanized after two weeks and tissues were harvested for histology, flow cytometry and gene expression analysis. Serum cytokine levels were determined by ELISA.FindingsMale B10.RIII mice developed arthritis in the forepaws and feet within 6 days after IL-23 EEV injection; they also exhibited psoriasis-like skin disease, colitis, weight loss, and osteopenia. In contrast to previous reports, we did not observe spondylitis or uveitis. Male C57BL/6 mice injected with IL-23 EEV had serum IL-23 levels comparable with B10.RIII mice and developed skin inflammation, colitis, weight loss, and osteopenia but failed to develop arthritis. Female B10.RIII mice had more severe arthritis than male B10.RIII mice but did not lose weight.ConclusionsThe phenotype of IL-23 induced disease in mice is controlled by genetic background and sex of the animals. The development of extra-articular manifestations but absence of arthritis in C57BL/6 mice suggests that organ-specificity of IL-23 driven inflammation is genetically determined. The mechanisms behind the strain-specific differences and the sexual dimorphism observed in this study may be relevant for human spondyloarthritis and warrant further exploration.

Adult and adolescent C57BL/6J and DBA/2J mice are differentially susceptible to fear learning deficits after acute ethanol or MK-801 treatment

Ethanol and other drugs of abuse disrupt learning and memory processes, creating problems associated with drug use and addiction. Understanding individual factors that determine susceptibility to drug-induced cognitive deficits, such as genetic background, age, and sex, is important for prevention and treatment. Comparison of adolescent and adult mice of both sexes across inbred mouse strains can reveal age, sex, and genetic contributions to phenotypes. We treated adolescent and adult, male and female, C57BL/6J and DBA/2J inbred mice with ethanol (1 g/kg or 1.5 g/kg) or MK-801 (0.05 mg/kg or 0.1 mg/kg), an NMDA receptor antagonist, prior to fear conditioning training. Contextual and cued fear retention were tested one day and eight or nine days after training. After ethanol exposure, adult C57BL/6J mice experienced greater deficits in contextual learning than adult DBA/2J mice. C57BL/6 J adolescents were less susceptible to ethanol-induced contextual learning disruptions than C57BL/6J adults, and adolescent males of both strains exhibited greater ethanol-induced contextual learning deficits than adolescent females. After MK-801 exposure, adolescent C57BL/6J mice experienced more severe contextual learning deficits than adolescent DBA/2J mice. Both ethanol and MK-801 had greater effects on contextual learning than cued learning. Collectively, we demonstrate that genetic background contributes to contextual and cued learning outcomes after ethanol or MK-801 exposure. Further, we report age-dependent drug sensitivities that are strain-, sex-, and drug-specific, suggesting that age, sex, and genetic background interact to determine contextual and cued learning impairments after ethanol or MK-801 exposure.