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Amidst a global landscape where transgender individuals face unprecedented challenges in accessing equitable sexual health care, our review breaks new ground by exploring the intricacies of sexual health within the transgender community. Unveiling the critical gaps in current health care practices, our research not only amplifies the voices of those often marginalised in health narratives but also pioneers a comprehensive, culturally sensitive approach to transgender sexual health. The literature review tries to find medical and subsequent legal justifications for PRO and CONS of participation of transgender and intersex athletes in the category of the opposite sex. It tries to analyse which differences in life can be relevant in defining competitive advantages, which nowadays lead to very controversial, often politically motivated conclusions. The opinions of the professional and sports public do not go along with some decisions of sports associations and authorities. It therefore also deals with the recent decision of the European Court of Human Rights in the case of Caster Semenya, as well as the participation of athletes across different sports disciplines and categories. It does not ignore the question of the adequacy of anti-discrimination measures. Furthermore, it evaluates the impact of such participation on the integrity and fairness of competitive sports, highlighting the need for a balanced approach that respects the rights of all athletes. This study stands at the forefront of transforming sexual health care for transgender individuals worldwide.

46, XX male syndrome is a rare disorder of sex development, which usually has a 46, XX chromosome karyotype and positive sex-determining region Y gene (SRY), normal external genitalia and male phenotype. Most of them come to hospital due to adult infertility. The patients with SRY negative 46, XX male syndrome are often accompanied by external genital malformations, and most of them seek the treatment because of abnormal sexual development at young age. A case of SRY negative 46, XX male syndrome was reported in this paper. The development of external genitalia and secondary sexual characteristics in this patient were normal male type. The chromosome karyotype was 46, XX, while SRY was negative and AZF region was deleted. The hypergonadotropin hypogonadism and azoospermia were diagnosed. As for the fertility requirement of this patient, artificial insemination by donor was recommended. [ABSTRACT FROM AUTHOR]

Sex chromosomes are classically predicted to stop recombining in the heterogametic sex, thereby enforcing linkage between sex-determining (SD) and sex-antagonistic (SA) genes. With the same rationale, a pre-existing sex asymmetry in recombination is expected to affect the evolution of heterogamety, for example, a low rate of male recombination might favor transitions to XY systems, by generating immediate linkage between SD and SA genes. Furthermore, the accumulation of deleterious mutations on nonrecombining Y chromosomes should favor XY-to-XY transitions (which discard the decayed Y), but disfavor XY-to-ZW transitions (which fix the decayed Y as an autosome). Like many anuran amphibians, Hyla tree frogs have been shown to display drastic heterochiasmy (males only recombine at chromosome tips) and are typically XY, which seems to fit the above expectations. Instead, here we demonstrate that two species, H. sarda and H. savignyi, share a common ZW system since at least 11 Ma. Surprisingly, the typical pattern of restricted male recombination has been maintained since then, despite female heterogamety. Hence, sex chromosomes recombine freely in ZW females, not in ZZ males. This suggests that heterochiasmy does not constrain heterogamety (and vice versa), and that the role of SA genes in the evolution of sex chromosomes might have been overemphasized.

Dioecy, the separation of reproductive organs on different individuals, has evolved repeatedly in different plant families. Several evolutionary paths to dioecy have been suggested, but the mechanisms behind sex determination is not well understood. The diploid dioecious Amaranthus palmeri represents a well-suited model system to study sex determination in plants. Despite the agricultural importance of the species, the genetic control and evolutionary state of dioecy in A. palmeri is currently unknown. Early cytogenetic experiments did not identify heteromorphic chromosomes. Here, we used whole-genome sequencing of male and female pools from 2 independent populations to elucidate the genetic control of dioecy in A. palmeri. Read alignment to a close monoecious relative and allele frequency comparisons between male and female pools did not reveal significant sex-linked genes. Consequently, we employed an alignment-free k-mer comparison which enabled us to identify a large number of male-specific k-mers. We assembled male-specific contigs comprising a total of almost 2 Mb sequence, proposing a XY sex-determination system in the species. We were able to identify the potential Y chromosome in the A. palmeri draft genome sequence as 90% of our male-specific sequence aligned to a single scaffold. Based on our findings, we suggest an intermediate evolutionary state of dioecy with a young Y chromosome in A. palmeri. Our findings give insight into the evolution of sex chromosomes in plants and may help to develop sustainable strategies for weed management.

BackgroundParasitoid wasps have fascinating life cycles and play an important role in trophic networks, yet little is known about their genome content and function. Parasitoids that infect aphids are an important group with the potential for biological control. Their success depends on adapting to develop inside aphids and overcoming both host aphid defenses and their protective endosymbionts.ResultsWe present the de novo genome assemblies, detailed annotation, and comparative analysis of two closely related parasitoid wasps that target pest aphids: Aphidius ervi and Lysiphlebus fabarum (Hymenoptera: Braconidae: Aphidiinae). The genomes are small (139 and 141 Mbp) and the most AT-rich reported thus far for any arthropod (GC content: 25.8 and 23.8%). This nucleotide bias is accompanied by skewed codon usage and is stronger in genes with adult-biased expression. AT-richness may be the consequence of reduced genome size, a near absence of DNA methylation, and energy efficiency. We identify missing desaturase genes, whose absence may underlie mimicry in the cuticular hydrocarbon profile of L. fabarum. We highlight key gene groups including those underlying venom composition, chemosensory perception, and sex determination, as well as potential losses in immune pathway genes.ConclusionsThese findings are of fundamental interest for insect evolution and biological control applications. They provide a strong foundation for further functional studies into coevolution between parasitoids and their hosts. Both genomes are available at https://bipaa.genouest.org.

The laboratory mouse is the most widely used animal model for biomedical research, due in part to its well-annotated genome, wealth of genetic resources, and the ability to precisely manipulate its genome. Despite the importance of genetics for mouse research, genetic quality control (QC) is not standardized, in part due to the lack of cost-effective, informative, and robust platforms. Genotyping arrays are standard tools for mouse research and remain an attractive alternative even in the era of high-throughput whole-genome sequencing. Here, we describe the content and performance of a new iteration of the Mouse Universal Genotyping Array (MUGA), MiniMUGA, an array-based genetic QC platform with over 11,000 probes. In addition to robust discrimination between most classical and wild-derived laboratory strains, MiniMUGA was designed to contain features not available in other platforms: (1) chromosomal sex determination, (2) discrimination between substrains from multiple commercial vendors, (3) diagnostic SNPs for popular laboratory strains, (4) detection of constructs used in genetically engineered mice, and (5) an easy-to-interpret report summarizing these results. In-depth annotation of all probes should facilitate custom analyses by individual researchers. To determine the performance of MiniMUGA, we genotyped 6899 samples from a wide variety of genetic backgrounds. The performance of MiniMUGA compares favorably with three previous iterations of the MUGA family of arrays, both in discrimination capabilities and robustness. We have generated publicly available consensus genotypes for 241 inbred strains including classical, wild-derived, and recombinant inbred lines. Here, we also report the detection of a substantial number of XO and XXY individuals across a variety of sample types, new markers that expand the utility of reduced complexity crosses to genetic backgrounds other than C57BL/6, and the robust detection of 17 genetic constructs. We provide preliminary evidence that the array can be used to identify both partial sex chromosome duplication and mosaicism, and that diagnostic SNPs can be used to determine how long inbred mice have been bred independently from the relevant main stock. We conclude that MiniMUGA is a valuable platform for genetic QC, and an important new tool to increase the rigor and reproducibility of mouse research.

Background. Every year, approximately 500,000 children in the world are born with congenital abnormalities of the urinary system and kidneys. Therefore, pediatricians and urologists must understand the normal processes that lead to male sexual differentiation. Objective. The aim of this study was to describe in detail the process that occurs during masculinization of the fetus, which leads to the formation of male structures under normal conditions. Methods. Fifty-four fetuses with gestation periods between four and 18 weeks were collected, which were considered normal, did not have any signs of external anatomic abnormalities or any alteration in their development, and were a product of spontaneous abortions and tubal pregnancies. The urogenital sinus region was collected and prepared for scanning electron microscopy and high-resolution optical microscopy to observe the cellular characteristics of the urogenital fold during external development in male embryos. Results. This work shows the formation of the glans and spongy urethra in a detailed manner from the eighth week of embryonic development, carefully describing the role of the labioscrotal folds and the fusion of the walls of the urogenital fold during the subsequent stages of development to form the proximal part of the urinary tract. Conclusion. The formation of the penile urethra from the urethral fold and its posterior fusion have a probable role of ectodermal cells, in addition to the endodermal origin established previously. [ABSTRACT FROM AUTHOR]

In many reptiles, including the red-eared slider turtle Trachemys scripta elegans (T. scripta), sex is determined by ambient temperature during embryogenesis. We previously showed that the epigenetic regulator Kdm6b is elevated at the male-producing temperature and essential to activate the male pathway. In this work, we established a causal link between temperature and transcriptional regulation of Kdm6b We show that signal transducer and activator of transcription 3 (STAT3) is phosphorylated at the warmer, female-producing temperature, binds the Kdm6b locus, and represses Kdm6b transcription, blocking the male pathway. Influx of Ca2+, a mediator of STAT3 phosphorylation, is elevated at the female temperature and acts as a temperature-sensitive regulator of STAT3 activation.

Gametes constitute a critical stage of the plant life cycle during which the genome undergoes reprogramming in preparation for embryogenesis. Here, we examined genome-wide distributions of small RNAs in the sperm and egg cells of rice. We found that 24-nt siRNAs, which are a hallmark of RNA-directed DNA methylation (RdDM) in plants, were depleted from heterochromatin boundaries in both gametes relative to vegetative tissues, reminiscent of siRNA patterns in DDM1-type nucleosome remodeler mutants. In sperm cells, 24-nt siRNAs were spread across heterochromatic regions, while in egg cells, 24-nt siRNAs were concentrated at a smaller number of heterochromatic loci throughout the genome, especially at loci which also produced siRNAs in other tissues. In both gametes, patterns of CHH methylation, typically a strong indicator of RdDM, were similar to vegetative tissues, although lower in magnitude. These findings indicate that the small RNA transcriptome undergoes large-scale redistribution in both male and female gametes, which is not correlated with recruitment of DNA methyltransferases in gametes and suggestive of unexplored regulatory activities of gamete small RNAs.

Fetal mammalian testes secrete Anti-Müllerian hormone (Amh), which inhibits female reproductive tract (Müllerian duct) development. Amh also derives from mature mammalian ovarian follicles, which marks oocyte reserve and characterizes polycystic ovarian syndrome. Zebrafish (Danio rerio) lacks Müllerian ducts and the Amh receptor gene amhr2 but, curiously, retains amh To discover the roles of Amh in the absence of Müllerian ducts and the ancestral receptor gene, we made amh null alleles in zebrafish. Results showed that normal amh prevents female-biased sex ratios. Adult male amh mutants had enormous testes, half of which contained immature oocytes, demonstrating that Amh regulates male germ cell accumulation and inhibits oocyte development or survival. Mutant males formed sperm ducts and some produced a few offspring. Young female mutants laid a few fertile eggs, so they also had functional sex ducts. Older amh mutants accumulated nonvitellogenic follicles in exceedingly large but sterile ovaries, showing that Amh helps control ovarian follicle maturation and proliferation. RNA-sequencing data partitioned juveniles at 21 days postfertilization (dpf) into two groups that each contained mutant and wild-type fish. Group21-1 upregulated ovary genes compared to Group21-2, which were likely developing as males. By 35 dpf, transcriptomes distinguished males from females and, within each sex, mutants from wild types. In adult mutants, ovaries greatly underexpressed granulosa and theca genes, and testes underexpressed Leydig cell genes. These results show that ancestral Amh functions included development of the gonadal soma in ovaries and testes and regulation of gamete proliferation and maturation. A major gap in our understanding is the identity of the gene encoding a zebrafish Amh receptor; we show here that the loss of amhr2 is associated with the breakpoint of a chromosome rearrangement shared among cyprinid fishes.

Evolution of genetic mechanisms of sex determination led to two processes causing sex differences in somatic phenotypes: gonadal differentiation and sex chromosome dosage inequality. In species with heteromorphic sex chromosomes, the sex of the individual is established at the time of formation of the zygote, leading to inherent sex differences in expression of sex chromosome genes beginning as soon as the embryonic transcriptome is activated. The inequality of sex chromosome gene expression causes sexual differentiation of the gonads and of non-gonadal tissues. The difference in gonad type in turn causes lifelong differences in gonadal hormones, which interact with unequal effects of X and Y genes acting within cells. Separating the effects of gonadal hormones and sex chromosomes has been possible using mouse models in which gonadal determination is separated from the sex chromosomes, allowing comparison of XX and XY mice with the same type of gonad. Sex differences caused by gonadal hormones and sex chromosomes affect basic physiology and disease mechanisms in most or all tissues.

Dioecy has evolved numerous times in plants, but heteromorphic sex chromosomes are apparently rare. Sex determination has been studied in multiple Salix and Populus (Salicaceae) species, and P. trichocarpa has an XY sex determination system on chromosome 19, while S. suchowensis and S. viminalis have a ZW system on chromosome 15. Here we use whole genome sequencing coupled with quantitative trait locus mapping and a genome-wide association study to characterize the genomic composition of the non-recombining portion of the sex determination region. We demonstrate that Salix purpurea also has a ZW system on chromosome 15. The sex determination region has reduced recombination, high structural polymorphism, an abundance of transposable elements, and contains genes that are involved in sex expression in other plants. We also show that chromosome 19 contains sex-associated markers in this S. purpurea assembly, along with other autosomes. This raises the intriguing possibility of a translocation of the sex determination region within the Salicaceae lineage, suggesting a common evolutionary origin of the Populus and Salix sex determination loci.

Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S-transferase genes that are important for insecticide resistance. Using high-resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector.

The canonical model of sex-chromosome evolution predicts that, as recombination is suppressed along sex chromosomes, gametologs will progressively differentiate, eventually becoming heteromorphic. However, there are numerous examples of homomorphic sex chromosomes across the tree of life. This homomorphy has been suggested to result from frequent sex-chromosome turnovers, yet we know little about which forces drive them. Here, we describe an extremely fast rate of turnover among 28 species of Ranidae. Transitions are not random, but converge on several chromosomes, potentially due to genes they harbour. Transitions also preserve the ancestral pattern of male heterogamety, in line with the hot-potato model of sex-chromosome transitions, suggesting a key role for mutation-load accumulation in non-recombining genomic regions. The importance of mutation-load selection in frogs might result from the extreme heterochiasmy they exhibit, making frog sex chromosomes differentiate immediately from emergence and across their entire length.

Sex separation methods are critical for genetic sexing systems in commercial insect production and sterile insect techniques. Integration of selectable marker genes into a sex chromosome is particularly useful in insects with a heterogametic sex determination system. Here, we describe targeted gene integration of fluorescent marker expression cassettes into a randomly amplified polymorphic DNA (RAPD) marker region in the W chromosome of the lepidopteran model insect Bombyx mori using transcriptional activator-like effector nuclease (TALEN)-mediated genome editing. This silkworm strain shows ubiquitous female-specific red or green fluorescence from the embryonic to adult stages. Furthermore, we developed a binary, female-specific, embryonic lethality system combining the TALEN and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology. This system includes one strain with TALEN-mediated, W-specific Cas9 expression driven by the silkworm germ cell-specific nanos (nos) promoter and another strain with U6-derived single-guide RNA (sgRNA) expression targeting transformer 2 (tra2), an essential gene for silkworm embryonic development. Filial 1 (F1) hybrids exhibit complete female-specific lethality during embryonic stages. Our study provides a promising approach for B. mori genetic sexing and sheds light on developing sterile insect techniques in other insect species, especially in lepidopteran pests with WZ/ZZ sex chromosome systems.

The use of a site-specific homing-based gene drive for insect pest control has long been discussed, but the easy design of such systems has become possible only with the recent establishment of CRISPR/Cas9 technology. In this respect, novel targets for insect pest management are provided by new discoveries regarding sex determination. Here, we present a model for a suppression gene drive designed to cause an all-male population collapse in an agricultural pest insect. To evaluate the molecular details of such a sex conversion-based suppression gene drive experimentally, we implemented this strategy in Drosophila melanogaster to serve as a safe model organism. We generated a Cas9-based homing gene-drive element targeting the transformer gene and showed its high efficiency for sex conversion from females to males. However, nonhomologous end joining increased the rate of mutagenesis at the target site, which resulted in the emergence of drive-resistant alleles and therefore curbed the gene drive. This confirms previous studies that simple homing CRISPR/Cas9 gene-drive designs will be ineffective. Nevertheless, by performing population dynamics simulations using the parameters we obtained in D. melanogaster and by adjusting the model for the agricultural pest Ceratitis capitata, we were able to identify adequate modifications that could be successfully applied for the management of wild Mediterranean fruit fly populations using our proposed sex conversion-based suppression gene-drive strategy.

The use of a site-specific homing-based gene drive for insect pest control has long been discussed, but the easy design of such systems has become possible only with the recent establishment of CRISPR/Cas9 technology. In this respect, novel targets for insect pest management are provided by new discoveries regarding sex determination. Here, we present a model for a suppression gene drive designed to cause an all-male population collapse in an agricultural pest insect. To evaluate the molecular details of such a sex conversion-based suppression gene drive experimentally, we implemented this strategy in Drosophila melanogaster to serve as a safe model organism. We generated a Cas9-based homing gene-drive element targeting the transformer gene and showed its high efficiency for sex conversion from females to males. However, nonhomologous end joining increased the rate of mutagenesis at the target site, which resulted in the emergence of drive-resistant alleles and therefore curbed the gene drive. This confirms previous studies that simple homing CRISPR/Cas9 gene-drive designs will be ineffective. Nevertheless, by performing population dynamics simulations using the parameters we obtained in D. melanogaster and by adjusting the model for the agricultural pest Ceratitis capitata, we were able to identify adequate modifications that could be successfully applied for the management of wild Mediterranean fruit fly populations using our proposed sex conversion-based suppression gene-drive strategy.

Sex determination is a hierarchically-regulated process with high diversity in different organisms including insects. The W chromosome-derived Fem piRNA has been identified as the primary sex determination factor in the lepidopteran insect, Bombyx mori, revealing a distinctive piRNA-mediated sex determination pathway. However, the comprehensive mechanism of silkworm sex determination is still poorly understood. We show here that the silkworm PIWI protein BmSiwi, but not BmAgo3, is essential for silkworm sex determination. CRISPR/Cas9-mediated depletion of BmSiwi results in developmental arrest in oogenesis and partial female sexual reversal, while BmAgo3 depletion only affects oogenesis. We identify three histone methyltransferases (HMTs) that are significantly down-regulated in BmSiwi mutant moths. Disruption one of these, BmAsh2, causes dysregulation of piRNAs and transposable elements (TEs), supporting a role for it in the piRNA signaling pathway. More importantly, we find that BmAsh2 mutagenesis results in oogenesis arrest and partial female-to-male sexual reversal as well as dysregulation of the sex determination genes, Bmdsx and BmMasc. Mutagenesis of other two HMTs, BmSETD2 and BmEggless, does not affect piRNA-mediated sex determination. Histological analysis and immunoprecipitation results support a functional interaction between the BmAsh2 and BmSiwi proteins. Our data provide the first evidence that the HMT, BmAsh2, plays key roles in silkworm piRNA-mediated sex determination.

The identification of sex chromosomes is fundamental for exploring the mechanism and evolution of sex determination. Platichthys stellatus , a species exhibiting clear sexual dimorphism and homomorphic chromosome pairs, has received limited research concerning its sex determination mechanisms. Clarifying the sex chromosome of P. stellatus will enhance our understanding of sex chromosome evolution in Pleuronectiformes. This study employed whole-genome resequencing to investigate the sex chromosome and sex determination system in P. stellatus . Notably, Chr23 was identified as the sex chromosome in P. stellatus , with the sex-determining region (SDR) occupying 48.1% of the chromosome and featuring an XX/XY system. Sex chromosome turnover was observed within Pleuronectiformes, with P. stellatus , Verasper variegatus , and Hippoglossus hippoglossus sharing a common ancestral karyotype. No inversions were detected within the SDR of P. stellatus , although chromosomal rearrangements between sex chromosomes and autosomes were identified. Additionally, a sex-specific marker for P. stellatus was ascertained, enabling genetic sex identification, with significant implications for improving breeding programs and aquaculture practices.

Water temperature governs physiological functions such as growth, energy allocation, and sex determination in ectothermic species. The European sea bass (Dicentrarchus labrax) is a major species in European aquaculture, exhibiting early dimorphic growth favoring females. The species has a polygenic sex determination system that interacts with water temperature to determine an individual's sex, with two periods during development that are sensitive to temperature. The current study investigated the influence of water temperature on energy allocation and sex-biased genes during sex determination and differentiation periods. RNA-Sequencing and qPCR analyses were conducted in two separate experiments, of either constant water temperatures typical of aquaculture conditions or natural seasonal thermal regimes, respectively. We focused on eight key genes associated with energy allocation, growth regulation, and sex determination and differentiation. In Experiment 1, cold and warm temperature treatments favored female and male proportions, respectively. The RNA-seq analysis highlighted sex-dependent energy allocation transcripts, with higher levels of nucb1 and pomc1 in future females, and increased levels of egfra and spry1 in future males. In Experiment 2, a warm thermal regime favored females, while a cold regime favored males. qPCR analysis in Experiment 2 revealed that ghrelin and nucb1 were down-regulated by warm temperatures. A significant sex-temperature interaction was observed for pank1a with higher and lower expression for males in the cold and warm regimes respectively, compared to females. Notably, spry1 displayed increased expression in future males at the all-fins stage and in males undergoing molecular sex differentiation in both experimental conditions, indicating that it provides a novel, robust, and consistent marker for masculinization. Overall, our findings emphasize the complex interplay of genes involved in feeding, energy allocation, growth, and sex determination in response to temperature variations in the European sea bass., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Fisher's general principle for sex allocation holds that population sex ratios are typically balanced because parents producing the rare sex are benefited and the rare sex alternates over time. In species that have temperature-dependent sex determination (TSD), thermal reaction norms need to be adjusted at the population level to avoid extremely biased sex ratios and extinction. Extant species with TSD experienced drastic climatic changes in the geological past and must necessarily have mechanisms of adaptation. I propose here a conceptual framework to explain how TSD curves could be adjusted by means of natural selection, based on Fisher's equilibrium sex-ratio principle. Through a process that alternatively favors mothers that tend to produce the rare sex under new temperatures, sex ratios eventually return toward a theoretical equilibrium. Prerequisites for this model are variability among mothers in the tendency to produce a particular sex at a given temperature (i.e., variability in the thermal reaction norm), inheritance of this trend, and higher fitness of the rare sex. This straightforward mechanism could facilitate thermal adaptation in species with TSD over multiple generations., (© 2024 John Wiley & Sons Ltd.)

In reptiles, such as the red-eared slider turtle ( Trachemys scripta elegans ), gonadal sex determination is highly dependent on the environmental temperature during embryonic stages. This complex process, which leads to differentiation into either testes or ovaries, is governed by the finely tuned expression of upstream genes, notably the testis-promoting gene Dmrt1 and the ovary-promoting gene Foxl2 . Recent studies have identified epigenetic regulation as a crucial factor in testis development, with the H3K27me3 demethylase KDM6B being essential for Dmrt1 expression in T. s. elegans. However, whether KDM6B alone can induce testicular differentiation remains unclear. In this study, we found that overexpression of Kdm6b in T. s. elegans embryos induced the male development pathway, accompanied by a rapid increase in the gonadal expression of Dmrt1 at 31°C, a temperature typically resulting in female development. Notably, this sex reversal could be entirely rescued by Dmrt1 knockdown. These findings demonstrate that Kdm6b is sufficient for commitment to the male pathway, underscoring its role as a critical epigenetic regulator in the sex determination of the red-eared slider turtle.

Ovarian development was traditionally recognized as a "default" sexual outcome and therefore received much less scientific attention than testis development. In turtles with temperature-dependent sex determination (TSD), how the female pathway is initiated to induce ovary development remains unknown. In this study, we have found that phosphorylation of the signal transducer and activator of transcription 3 (pSTAT3) and Foxl2 exhibit temperature-dependent sexually dimorphic patterns and tempo-spatial coexpression in early embryos of the red-eared slider turtle ( Trachemys scripta elegans ). Inhibition of pSTAT3 at a female-producing temperature of 31 °C induces 64.7% female-to-male sex reversal, whereas activation of pSTAT3 at a male-producing temperature of 26 °C triggers 75.6% male-to-female sex reversal. In addition, pSTAT3 directly binds to the locus of the female sex-determining gene Foxl2 and promotes Foxl2 transcription. Overexpression or knockdown of Foxl2 can rescue the sex reversal induced by inhibition or activation of pSTAT3. This study has established a direct genetic link between warm temperature-induced STAT3 phosphorylation and female pathway initiation in a TSD system, highlighting the critical role of pSTAT3 in the cross talk between female and male pathways., Competing Interests: Competing interests statement:The authors declare no competing interest.

A sex change phenomenon was reported in some free-living, non-sessile coral species of the Family Fungiidae. However, there are no reports describing sex change in sessile colonial species. Timing and cellular processes of sex change are also unclear in corals. Here, we report sex change of the colonial coral, Fimbriaphyllia ancora, and its cellular process. Of 26 colonies monitored at Nanwan Bay, southern Taiwan, about 70% changed their sex every year after annual spawning for least 3-4 consecutive years, i.e., colonies that were male two years ago became female last year, and male again this year. The remaining 30% were permanently male or female. Sex-change and non-sex-change colonies grew in close proximity or even side-by-side. No significant differences were found in colony size between sex-change and non-sex-change colonies. Histological analysis showed that, in female-to-male sex change, small oocytes were present up to 3 months in some gonads after spawning and disappeared by 5 months. This suggests that sex change occurred 4-5 months after spawning. In contrast, in male-to-female sex change, oocytes appeared weeks after sperm release and in most gonads by 3 months, suggesting that male-to-female sex change occurred 0-3 months after sperm release., (© 2024. The Author(s).)

Sex determination in animals is not only determined by karyotype but can also be modulated by environmental cues like temperature via unclear transduction mechanisms. Moreover, in contrast to earlier views that sex may exclusively be determined by either karyotype or temperature, recent observations suggest that these factors rather co-regulate sex, posing another mechanistic mystery. Here, we discovered that certain wild-isolated and mutant C. elegans strains displayed genotypic germline sex determination (GGSD), but with a temperature-override mechanism. Further, we found that BiP, an ER chaperone, transduces temperature information into a germline sex-governing signal, thereby enabling the coexistence of GGSD and temperature-dependent germline sex determination (TGSD). At the molecular level, increased ER protein-folding requirements upon increased temperatures lead to BiP sequestration, resulting in ERAD-dependent degradation of the oocyte fate-driving factor, TRA-2, thus promoting male germline fate. Remarkably, experimentally manipulating BiP or TRA-2 expression allows to switch between GGSD and TGSD. Physiologically, TGSD allows C. elegans hermaphrodites to maintain brood size at warmer temperatures. Moreover, BiP can also influence germline sex determination in a different, non-hermaphroditic nematode species. Collectively, our findings identify thermosensitive BiP as a conserved temperature sensor in TGSD, and provide mechanistic insights into the transition between GGSD and TGSD., (© 2024. The Author(s).)

Sex chromosomes evolved from autosomes many times across the eukaryote phylogeny. Several models have been proposed to explain this transition, some involving male and female sterility mutations linked in a region of suppressed recombination between X and Y (or Z/W, U/V) chromosomes. Comparative and experimental analysis of a reference genome assembly for a double haploid YY male garden asparagus (Asparagus officinalis L.) individual implicates separate but linked genes as responsible for sex determination. Dioecy has evolved recently within Asparagus and sex chromosomes are cytogenetically identical with the Y, harboring a megabase segment that is missing from the X. We show that deletion of this entire region results in a male-to-female conversion, whereas loss of a single suppressor of female development drives male-to-hermaphrodite conversion. A single copy anther-specific gene with a male sterile Arabidopsis knockout phenotype is also in the Y-specific region, supporting a two-gene model for sex chromosome evolution.

The American alligator, Alligator mississippiensis, like all crocodilians, has temperature-dependent sex determination, in which the sex of an embryo is determined by the incubation temperature of the egg during a critical period of development. The lack of genetic differences between male and female alligators leaves open the question of how the genes responsible for sex determination and differentiation are regulated. Insight into this question comes from the fact that exposing an embryo incubated at male-producing temperature to estrogen causes it to develop ovaries. Because estrogen response elements are known to regulate genes over long distances, a contiguous genome assembly is crucial for predicting and understanding their impact. We present an improved assembly of the American alligator genome, scaffolded with in vitro proximity ligation (Chicago) data. We use this assembly to scaffold two other crocodilian genomes based on synteny. We perform RNA sequencing of tissues from American alligator embryos to find genes that are differentially expressed between embryos incubated at male- versus female-producing temperature. Finally, we use the improved contiguity of our assembly along with the current model of CTCF-mediated chromatin looping to predict regions of the genome likely to contain estrogen-responsive genes. We find that these regions are significantly enriched for genes with female-biased expression in developing gonads after the critical period during which sex is determined by incubation temperature. We thus conclude that estrogen signaling is a major driver of female-biased gene expression in the post-temperature sensitive period gonads.

The dmrt1 (doublesex and mab-3 related transcription factor 1) gene is a key regulator of sex determination and/or gonadal sex differentiation across metazoan animals. This is unusual given that sex determination genes are typically not well conserved. The mechanisms by which zebrafish sex is determined have remained elusive due to the lack of sex chromosomes and the complex polygenic nature of sex determination in domesticated strains. To investigate the role of dmrt1 in zebrafish sex determination and gonad development, we isolated mutations disrupting this gene. We found that the majority of dmrt1 mutant fish develop as fertile females suggesting a complete male-to-female sex reversal in mutant animals that would have otherwise developed as males. A small percentage of mutant animals became males, but were sterile and displayed testicular dysgenesis. Therefore zebrafish dmrt1 functions in male sex determination and testis development. Mutant males had aberrant gonadal development at the onset of gonadal sex-differentiation, displaying reduced oocyte apoptosis followed by development of intersex gonads and failed testis morphogenesis and spermatogenesis. By contrast, female ovaries developed normally. We found that Dmrt1 is necessary for normal transcriptional regulation of the amh (anti-Müllerian hormone) and foxl2 (forkhead box L2) genes, which are thought to be important for male or female sexual development respectively. Interestingly, we identified one dmrt1 mutant allele that co-operates with a linked segregation distorter locus to generate an apparent XY sex determination mechanism. We conclude that dmrt1 is dispensable for ovary development but necessary for testis development in zebrafish, and that dmrt1 promotes male development by transcriptionally regulating male and female genes as has been described in other animals. Furthermore, the strong sex-ratio bias caused by dmrt1 reduction-of-function points to potential mechanisms through which sex chromosomes may evolve.

Manipulation of sex determination pathways in insects provides the basis for a wide spectrum of strategies to benefit agriculture and public health. Furthermore, insects display a remarkable diversity in the genetic pathways that lead to sex differentiation. The silkworm, Bombyx mori, has been cultivated by humans as a beneficial insect for over two millennia, and more recently as a model system for studying lepidopteran genetics and development. Previous studies have identified the B. mori Fem piRNA as the primary female determining factor and BmMasc as its downstream target, while the genetic scenario for male sex determination was still unclear. In the current study, we exploite the transgenic CRISPR/Cas9 system to generate a comprehensive set of knockout mutations in genes BmSxl, Bmtra2, BmImp, BmImpM, BmPSI and BmMasc, to investigate their roles in silkworm sex determination. Absence of Bmtra2 results in the complete depletion of Bmdsx transcripts, which is the conserved downstream factor in the sex determination pathway, and induces embryonic lethality. Loss of BmImp or BmImpM function does not affect the sexual differentiation. Mutations in BmPSI and BmMasc genes affect the splicing of Bmdsx and the female reproductive apparatus appeared in the male external genital. Intriguingly, we identify that BmPSI regulates expression of BmMasc, BmImpM and Bmdsx, supporting the conclusion that it acts as a key auxiliary factor in silkworm male sex determination.

Sexual dimorphisms are prevalent in development, physiology and diseases in humans. Currently, the contributions of the genes on the male-specific region of the Y chromosome (MSY) in these processes are uncertain. Using a transgene activation system, the human sex-determining gene hSRY is activated in the single-cell embryos of the mouse. Pups with hSRY activated (hSRYON) are born of similar sizes as those of non-activated controls. However, they retard significantly in postnatal growth and development and all die of multi-organ failure before two weeks of age. Pathological and molecular analyses indicate that hSRYON pups lack innate suckling activities, and develop fatty liver disease, arrested alveologenesis in the lung, impaired neurogenesis in the brain and occasional myocardial fibrosis and minimized thymus development. Transcriptome analysis shows that, in addition to those unique to the respective organs, various cell growth and survival pathways and functions are differentially affected in the transgenic mice. These observations suggest that ectopic activation of a Y-located SRY gene could exert male-specific effects in development and physiology of multiple organs, thereby contributing to sexual dimorphisms in normal biological functions and disease processes in affected individuals.

Insects harbor a tremendous diversity of sex determining mechanisms both within and between groups. For example, in some orders such as Hymenoptera, all members are haplodiploid, whereas Diptera contain species with homomorphic as well as male and female heterogametic sex chromosome systems or paternal genome elimination. We have established a large database on karyotypes and sex chromosomes in insects, containing information on over 13000 species covering 29 orders of insects. This database constitutes a unique starting point to report phylogenetic patterns on the distribution of sex determination mechanisms, sex chromosomes, and karyotypes among insects and allows us to test general theories on the evolutionary dynamics of karyotypes, sex chromosomes, and sex determination systems in a comparative framework. Phylogenetic analysis reveals that male heterogamety is the ancestral mode of sex determination in insects, and transitions to female heterogamety are extremely rare. Many insect orders harbor species with complex sex chromosomes, and gains and losses of the sex-limited chromosome are frequent in some groups. Haplodiploidy originated several times within insects, and parthenogenesis is rare but evolves frequently. Providing a single source to electronically access data previously distributed among more than 500 articles and books will not only accelerate analyses of the assembled data, but also provide a unique resource to guide research on which taxa are likely to be informative to address specific questions, for example, for genome sequencing projects or large-scale comparative studies.

The DM domain genes, doublesex (dsx) in insects, or their structural homologs, male abnormal 3 (mab-3) in nematodes and Dmrt1 (doublesex and mab-3-related transcription factor 1) in mammals, are downstream regulators of the sex determination pathway that control sexually dimorphic development. Despite the functional importance of dsx and its potential applications in sterile insect technologies (SITs), the mechanisms by which it controls sexually dimorphic traits and the subsequent developmental gene networks in insects are poorly understood. Phylogenetic analyses indicate that insect dsx genes have sex-specific alternative splicing isoforms, whereas other taxa do not. We exploited genome editing and transgenesis technologies to induce mutations in either the male-specific isoform (dsxM) or common region (dsxC) of dsx in the somatic tissues of the lepidopteran model insect Bombyx mori. Disruptions of gene function produced either male-specific sexually-dimorphic defects or intersexual phenotypes; these results differ from those observed in other insects, including Drosophila melanogaster. Our data provide insights into the divergence of the insect sex determination pathways related to the most conserved downstream component dsx.

In many taxa, sex chromosomes are heteromorphic and largely non-recombining. Evolutionary models predict that spread of recombination suppression on the Y chromosome is fueled by the accumulation of sexually antagonistic alleles in close linkage to the sex determination region. However, empirical evidence for the existence of sexually antagonistic alleles is scarce. In the mosquito Aedes aegypti, the sex-determining chromosomes are homomorphic. The region of suppressed recombination, which surrounds the male-specific sex-determining gene, remains very small, despite ancient origin of the sex chromosomes in the Aedes lineage. We conducted a genetic analysis of the A. aegypti chromosome region tightly linked to the sex locus. We used a strain with an enhanced green fluorescent protein (EGFP)-tagged transgene inserted near the male-determining gene to monitor crossing-over events close to the boundary of the sex-determining region (SDR), and to trace the inheritance pattern of the transgene in relation to sex. In a series of crossing experiments involving individuals with a recombinant sex chromosome we found developmental abnormalities leading to 1:2 sex biases, caused by lethality of half of the male or female progeny. Our results suggest that various factors causing sex-specific lethal effects are clustered within the neighborhood of the SDR, which in the affected sex are likely lost or gained through recombination, leading to death. These may include genes that are recessive lethal, vital for development and/or sexually antagonistic. The sex chromosome fragment in question represents a fascinating test case for the analysis of processes that shape stable boundaries of a non-recombining region.

Cell lineages of the early human gonad commit to one of the two mutually antagonistic organogenetic fates, the testis or the ovary. Some individuals with a 46,XX karyotype develop testes or ovotestes (testicular or ovotesticular disorder of sex development; TDSD/OTDSD), due to the presence of the testis-determining gene, SRY Other rare complex syndromic forms of TDSD/OTDSD are associated with mutations in pro-ovarian genes that repress testis development (e.g. WNT4); however, the genetic cause of the more common non-syndromic forms is unknown. Steroidogenic factor-1 (known as NR5A1) is a key regulator of reproductive development and function. Loss-of-function changes in NR5A1 in 46,XY individuals are associated with a spectrum of phenotypes in humans ranging from a lack of testis formation to male infertility. Mutations in NR5A1 in 46,XX women are associated with primary ovarian insufficiency, which includes a lack of ovary formation, primary and secondary amenorrhoea as well as early menopause. Here, we show that a specific recurrent heterozygous missense mutation (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated with variable degree of testis development in 46,XX children and adults from four unrelated families. Remarkably, in one family a sibling raised as a girl and carrying this NR5A1 mutation was found to have a 46,XY karyotype with partial testicular dysgenesis. These unique findings highlight how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals and represents the first missense mutation causing isolated, non-syndromic 46,XX testicular/ovotesticular DSD in humans.

The patterns of sex determination and sex differentiation have been shown to differ among geographic populations of common frogs. Notably, the association between phenotypic sex and linkage group 2 (LG2) has been found to be perfect in a northern Swedish population, but weak and variable among families in a southern one. By analyzing these populations with markers from other linkage groups, we bring two new insights: (1) the variance in phenotypic sex not accounted for by LG2 in the southern population could not be assigned to genetic factors on other linkage groups, suggesting an epigenetic component to sex determination; (2) a second linkage group (LG7) was found to co-segregate with sex and LG2 in the northern population. Given the very short timeframe since post-glacial colonization (in the order of 1000 generations) and its seemingly localized distribution, this neo-sex chromosome system might be the youngest one described so far. It does not result from a fusion, but more likely from a reciprocal translocation between the original Y chromosome (LG2) and an autosome (LG7), causing their co-segregation during male meiosis. By generating a strict linkage between several important genes from the sex-determination cascade (Dmrt1, Amh and Amhr2), this neo-sex chromosome possibly contributes to the 'differentiated sex race' syndrome (strictly genetic sex determination and early gonadal development) that characterizes this northern population.

Although the zebrafish is a major model organism, how they determine sex is not well understood. In domesticated zebrafish, sex determination appears to be polygenic, being influenced by multiple genetic factors that may vary from strain to strain, and additionally can be influenced by environmental factors. However, the requirement of germ cells for female sex determination is well documented: animals that lack germ cells, or oocytes in particular, develop exclusively as males. Recently, it has been determined that oocytes are also required throughout the adult life of the animal to maintain the differentiated female state. How oocytes control sex differentiation and maintenance of the sexual phenotype is unknown. We therefore generated targeted mutations in genes for two oocyte produced signaling molecules, Bmp15 and Gdf9 and here report a novel role for Bmp15 in maintaining adult female sex differentiation in zebrafish. Females deficient in Bmp15 begin development normally but switch sex during the mid- to late- juvenile stage, and become fertile males. Additionally, by generating mutations in the aromatase cyp19a1a, we show that estrogen production is necessary for female development and that the function of Bmp15 in female sex maintenance is likely linked to the regulation of estrogen biosynthesis via promoting the development of estrogen-producing granulosa cells in the oocyte follicle.

The non-Mendelian transmission of sex chromosomes during gametogenesis carries significant implications, influencing sex ratios and shaping evolutionary dynamics. Here we focus on known mechanisms that drive non-Mendelian inheritance of X chromosomes during spermatogenesis and their impact on population dynamics in species with different breeding systems. In Drosophila and mice, X-linked drivers targeting Y-bearing sperm for elimination or limiting their fitness, tend to confer unfavourable effects, prompting the evolution of suppressors to mitigate their impact. This leads to a complex ongoing evolutionary arms race to maintain an equal balance of males and females. However, in certain insects and nematodes with XX/X0 sex determination, the preferential production of X-bearing sperm through atypical meiosis yields wild-type populations with highly skewed sex ratios, suggesting non-Mendelian transmission of the X may offer selective advantages in these species. Indeed, models suggest X-meiotic drivers could bolster population size and persistence under certain conditions, challenging the conventional view of their detrimental effects. Furthering our understanding of the diverse mechanisms and evolutionary consequences of non-Mendelian transmission of X chromosomes will provide insights into genetic inheritance, sex determination, and population dynamics, with implications for fundamental research and practical applications., (© 2024 The Author(s).)

Most land plants alternate between generations of sexual gametophytes and asexual sporophytes. Unlike seed plants, fern gametophytes are free living and grow independently of their sporophytes. In homosporous ferns such as Ceratopteris, gametophytes derived from genetically identical spores exhibit sexual dimorphism, developing as either males or hermaphrodites. Males lack meristems and promote cell differentiation into sperm-producing antheridia. In contrast, hermaphrodites initiate multicellular meristems that stay undifferentiated, sustain cell division and prothallus expansion, and drive the formation of egg-producing archegonia. Once initiating the meristem, hermaphrodites secrete the pheromone antheridiogen, which triggers neighboring slower-growing gametophytes to develop as males, while the hermaphrodites themselves remain insensitive to antheridiogen. This strategy promotes outcrossing and prevents all individuals in the colony from becoming males. This study reveals that an evolutionarily conserved GRAS-domain transcriptional regulator (CrHAM), directly repressed by Ceratopteris microRNA171 (CrmiR171), promotes meristem development in Ceratopteris gametophytes and determines the male-to-hermaphrodite ratio in the colony. CrHAM preferentially accumulates within the meristems of hermaphrodites but is excluded from differentiated antheridia. CrHAM sustains meristem proliferation and cell division through conserved hormone pathways. In the meantime, CrHAM inhibits the antheridiogen-induced conversion of hermaphrodites to males by suppressing the male program expression and preventing meristem cells from differentiating into sperm-producing antheridia. This finding establishes a connection between meristem indeterminacy and sex determination in ferns, suggesting both conserved and diversified roles of meristem regulators in land plants., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sex chromosomes display remarkable diversity and variability among vertebrates. Compared with research on the X/Y and Z/W chromosomes, which have long evolutionary histories in mammals and birds, studies on the sex chromosomes at early evolutionary stages are limited. Here, we precisely assembled the genomes of homozygous XX female and YY male Lanzhou catfish (Silurus lanzhouensis) derived from an artificial gynogenetic family and a self-fertilized family, respectively. Chromosome 24 (Chr24) was identified as the sex chromosome based on resequencing data. Comparative analysis of the X and Y chromosomes showed an approximate 320 kb Y-specific region with a Y-specific duplicate of anti-Mullerian hormone type II receptor (amhr2y), which is consistent with findings in 2 other Silurus species but on different chromosomes (Chr24 of Silurus meridionalis and Chr5 of Silurus asotus). Deficiency of amhr2y resulted in male-to-female sex reversal, indicating that amhr2y plays a male-determining role in S. lanzhouensis. Phylogenetic analysis and comparative genomics revealed that the common sex-determining gene amhr2y was initially translocated to Chr24 of the Silurus ancestor along with the expansion of transposable elements. Chr24 was maintained as the sex chromosome in S. meridionalis and S. lanzhouensis, whereas a sex-determining region transition triggered sex chromosome turnover from Chr24 to Chr5 in S. asotus. Additionally, gene duplication, translocation, and degeneration were observed in the Y-specific regions of Silurus species. These findings present a clear case for the early evolutionary trajectory of sex chromosomes, including sex-determining gene origin, repeat sequence expansion, gene gathering and degeneration in sex-determining region, and sex chromosome turnover., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

DNA methylation plays a critical role in the modulation of gene expression. The role of DNA methylation in sex determination was investigated in spinach. The differentiated cytosine CpG methylation profiles of CCGG motifs were assessed with methylation sensitivity amplification polymorphism (MSAP) in spinach. Among 442 DNA fragments from four plants, 134 methylated fragments were found. Relative proportions of methylation sites were 28.8% in male plants and 31.8% in female plants. At the same time, cytosine methylation levels were higher in females than in males in CCGG motifs of genomes in the spinach. These findings suggest that methylation of CG islands is involved in sex determination and differentiation in spinach., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Lunar rhythms shape spawning phenology and subsequent risks and rewards for early life-history stages in the sea. Here, we consider a perplexing spawning phenology of the sixbar wrasse ( Thalassoma hardwicke ), in which parents spawn disproportionately around the new moon, despite the low survival of these larvae. Because primary sex determination in this system is highly plastic and sensitive to social environments experienced early in development, we ask whether this puzzling pattern of spawning is explained by fitness trade-offs associated with primary sexual maturation. We used otoliths from 871 fish to explore how spawning on different phases of the moon shapes the environments and phenotypes of settling larvae. Offspring that were born at the new moon were more likely to settle (i) before other larvae, (ii) at a larger body size, (iii) at an older age, (iv) to the best quality sites, and (v) as part of a social group-all increasing the likelihood of primary maturation to male. Selection of birthdates across life stage transitions suggests that the perplexing spawning phenology of adults may reflect an evolutionarily stable strategy that includes new moon spawning for compensatory benefits later in life, including preferential production of primary males at certain times.

Molluscs have undergone many transitions between separate sexes and hermaphroditism, which is of interest in studying the evolution of sex determination and differentiation. Here, we combined multi-locus genotypes obtained from restriction site-associated DNA (RAD) sequencing with anatomical observations of the gonads of three deep-sea hydrothermal vent gastropods of the genus Alviniconcha living in the southwest Pacific. We found that all three species (Alviniconcha boucheti, Alviniconcha strummeri, and Alviniconcha kojimai) share the same male-heterogametic XY sex-determination system but that the gonads of XX A. kojimai individuals are invaded by a variable proportion of male reproductive tissue. The identification of Y-specific RAD loci (found only in A. boucheti) and the phylogenetic analysis of three sex-linked loci shared by all species suggested that X-Y recombination has evolved differently within each species. This situation of three species showing variation in gonadal development around a common sex-determination system provides new insights into the reproductive mode of poorly known deep-sea species and opens up an opportunity to study the evolution of recombination suppression on sex chromosomes and its association with mixed or transitory sexual systems., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Evolutionary Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

African cichlid fishes are known for their high rates of phenotypic evolution. A rapid rate of diversification is apparent also in the diversity of their sex chromosomes. To date, sex determiners have been identified on 18 of 22 chromosomes in the standard karyotype. Here, we use whole-genome sequencing to characterize the sex chromosomes of seven populations of basal haplochromines, focusing on the genus Pseudocrenilabrus. We identify six new sex chromosome systems, including the first report of a cichlid sex-determining system on linkage group 12. We then quantify the rates and patterns of sex chromosome turnover in this clade. Finally, we test whether some autosomes become sex chromosomes in East African cichlids more often than expected by chance., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

The evolution of separate sexes from cosexuality requires at least two mutations: a feminizing allele to cause female development and a masculinizing allele to cause male development. Classically, the double mutant is assumed to be sterile, which leads to two-factor sex determination where male and female sex chromosomes differ at two loci. However, several species appear to have one-factor sex determination where sexual development depends on variation at a single locus. We show that one-factor sex determination evolves when the double mutant develops as a male or a female. The feminizing allele fixes when the double mutant is male, and the masculinizing allele fixes when the double mutant is female. The other locus then gives XY or ZW sex determination based on dominance: for example, a dominant masculinizer becomes a Y chromosome. Although the resulting sex determination system differs, the conditions required for feminizers and masculinizers to spread are the same as in classical models, with the important difference that the two alleles do not need to be linked. Thus, we reveal alternative pathways for the evolution of sex determination and discuss how they can be distinguished using new data on the genetics of sex determination.

Although evolution is driven by changes in how regulatory pathways control development, we know little about the molecular details underlying these transitions. The TRA-2 domain that mediates contact with TRA-1 is conserved in Caenorhabditis. By comparing the interaction of these proteins in two species, we identified a striking change in how sexual development is controlled. Identical mutations in this domain promote oogenesis in Caenorhabditis elegans but promote spermatogenesis in Caenorhabditis briggsae. Furthermore, the effects of these mutations involve the male-promoting gene fem-3 in C. elegans but are independent of fem-3 in C. briggsae. Finally, reciprocal mutations in these genes show that C. briggsae TRA-2 binds TRA-1 to prevent expression of spermatogenesis regulators. By contrast, in C. elegans TRA-1 sequesters TRA-2 in the germ line, allowing FEM-3 to initiate spermatogenesis. Thus, we propose that the flow of information within the sex determination pathway has switched directions during evolution. This result has important implications for how evolutionary change can occur., (Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution 2024.)

Sex determination in animals and fungi is regulated by specific sex-determining genes. The Aspergillus nidulans mating type gene matA and the human SRY (Sex-Determining Region Y) encode proteins containing a single HMG (high-mobility group) domain. Analysis of the amino-acid sequence of MatA and SRY transcription factors revealed significant structural similarity. The human SRY protein is able to functionally replace MatA and drives the sexual cycle in the fungus A. nidulans. Functional studies indicate that SRY drives early fruiting body development, and hybrid MatA protein carrying the SRY HMG box is fully capable of driving both early and late stages of sexual development, including gametogenesis. Our data suggest that SRY and MatA are both structurally and functionally related and conserved in regulating sexual processes. The fundamental mechanisms driving evolution of the genetic pathways underlying sex determination, sex chromosomes and sexual reproduction in eukaryotes appear similar.

To identify novel genomic regions that regulate sex determination, we utilized the powerful C57BL/6J-Y(POS) (B6-Y(POS)) model of XY sex reversal where mice with autosomes from the B6 strain and a Y chromosome from a wild-derived strain, Mus domesticus poschiavinus (Y(POS)), show complete sex reversal. In B6-Y(POS), the presence of a 55-Mb congenic region on chromosome 11 protects from sex reversal in a dose-dependent manner. Using mouse genetic backcross designs and high-density SNP arrays, we narrowed the congenic region to a 1.62-Mb genomic region on chromosome 11 that confers 80% protection from B6-Y(POS) sex reversal when one copy is present and complete protection when two copies are present. It was previously believed that the protective congenic region originated from the 129S1/SviMJ (129) strain. However, genomic analysis revealed that this region is not derived from 129 and most likely is derived from the semi-inbred strain POSA. We show that the small 1.62-Mb congenic region that protects against B6-Y(POS) sex reversal is located within the Sox9 promoter and promotes the expression of Sox9, thereby driving testis development within the B6-Y(POS) background. Through 30 years of backcrossing, this congenic region was maintained, as it promoted male sex determination and fertility despite the female-promoting B6-Y(POS) genetic background. Our findings demonstrate that long-range enhancer regions are critical to developmental processes and can be used to identify the complex interplay between genome variants, epigenetics, and developmental gene regulation.

In this commentary, Michelle Arbeitman et al., examine the topic of the Genetics of Sex as explored in this month's issues of GENETICS and G3: Genes|Genomes|Genetics. These inaugural articles are part of a joint Genetics of Sex collection (ongoing) in the GSA journals.

Dosage compensation, which regulates the expression of genes residing on the sex chromosomes, has provided valuable insights into chromatin-based mechanisms of gene regulation. The nematode Caenorhabditis elegans has adopted various strategies to down-regulate and even nearly silence the X chromosomes. This article discusses the different chromatin-based strategies used in somatic tissues and in the germline to modulate gene expression from the C. elegans X chromosomes and compares these strategies to those used by other organisms to cope with similar X-chromosome dosage differences.