Accelerated hermaphrodite maturation on male pheromones suggests a general principle of coordination between larval behavior and development.

Environment in general and social signals in particular could alter development. In Caenorhabditis elegans, male pheromones hasten development of hermaphrodite larvae. We show that this involves acceleration of growth and both somatic and germline development during the last larval stage (L4). Larvae exposed to male pheromones spend more time in L3 and less in the quiescent period between L3 and L4. This behavioral alteration improves provision in early L4, likely allowing for faster development. Larvae must be exposed to male pheromones in late L3 for behavioral and developmental effects to occur. Latter portions of other larval stages also contain periods of heightened sensitivity to environmental signals. Behavior during the early part of the larval stages is biased toward exploration, whereas later the emphasis shifts to food consumption. We argue that this organization allows assessment of the environment to identify the most suitable patch of resources, followed by acquisition of sufficient nutrition and salient information for the developmental events in the next larval stage. Evidence from other species indicates that such coordination of behavior and development may be a general feature of larval development.

Towards improved genetic diagnosis of human differences of sex development.

Despite being collectively among the most frequent congenital developmental conditions worldwide, differences of sex development (DSD) lack recognition and research funding. As a result, what constitutes optimal management remains uncertain. Identification of the individual conditions under the DSD umbrella is challenging and molecular genetic diagnosis is frequently not achieved, which has psychosocial and health-related repercussions for patients and their families. New genomic approaches have the potential to resolve this impasse through better detection of protein-coding variants and ascertainment of under-recognized aetiology, such as mosaic, structural, non-coding or epigenetic variants. Ultimately, it is hoped that better outcomes data, improved understanding of the molecular causes and greater public awareness will bring an end to the stigma often associated with DSD.

Discordance in chromosomal and self-reported sex in the UK Biobank: Implications for transgender- and intersex-inclusive data collection.

There is growing need to distinguish between sex and gender. While sex is assigned at birth, gender is socially constructed and may not correspond to one's assigned sex. However, in most research studies, sex or gender is assessed in isolation or the terms are used interchangeably, which has implications for research accuracy and inclusivity. We used data from the UK Biobank to quantify the prevalence of disagreement between chromosomal and self-reported sex and identify potential reasons for discordance. Among approximately 200 individuals with sex discordance, 71% of discordances were potentially explained by the presence of intersex traits or transgender identity. The findings indicate that when describing sex- and/or gender-specific differences in health, researchers may be limited in their ability to draw conclusions regarding specific sex and/or gender health information.

Dioecy and chromosomal sex determination are maintained through allopolyploid speciation in the plant genus Mercurialis.

Polyploidization may precipitate dramatic changes to the genome, including chromosome rearrangements, gene loss, and changes in gene expression. In dioecious plants, the sex-determining mechanism may also be disrupted by polyploidization, with the potential evolution of hermaphroditism. However, while dioecy appears to have persisted through a ploidy transition in some species, it is unknown whether the newly formed polyploid maintained its sex-determining system uninterrupted, or whether dioecy re-evolved after a period of hermaphroditism. Here, we develop a bioinformatic pipeline using RNA-sequencing data from natural populations to demonstrate that the allopolyploid plant Mercurialis canariensis directly inherited its sex-determining region from one of its diploid progenitor species, M. annua, and likely remained dioecious through the transition. The sex-determining region of M. canariensis is smaller than that of its diploid progenitor, suggesting that the non-recombining region of M. annua expanded subsequent to the polyploid origin of M. canariensis. Homeologous pairs show partial sexual subfunctionalization. We discuss the possibility that gene duplicates created by polyploidization might contribute to resolving sexual antagonism.

Genome-wide association study provided insights into the polled phenotype and polled intersex syndrome (PIS) in goats.

BACKGROUND: Breeding polled goats is a welfare-friendly approach for horn removal in comparison to invasive methods. To gain a comprehensive understanding of the genetic basis underlying polledness in goats, we conducted whole-genome sequencing of 106 Xinong Saanen dairy goats, including 33 horned individuals, 70 polled individuals, and 3 polled intersexuality syndrome (PIS) individuals. METHODS: The present study employed a genome-wide association study (GWAS) and linkage disequilibrium (LD) analysis to precisely map the genetic locus underlying the polled phenotype in goats. RESULTS: The analysis conducted in our study revealed a total of 320 genome-wide significant single nucleotide polymorphisms (SNPs) associated with the horned/polled phenotype in goats. These SNPs exhibited two distinct peaks on chromosome 1, spanning from 128,817,052 to 133,005,441 bp and from 150,336,143 to 150,808,639 bp. The present study identified three genome-wide significant SNPs, namely Chr1:129789816, Chr1:129791507, and Chr1:129791577, as potential markers of PIS-affected goats. The results of our LD analysis suggested a potential association between MRPS22 and infertile intersex individuals, as well as a potential association between ERG and the polled trait in goats. CONCLUSION: We have successfully identified three marker SNPs closely linked to PIS, as well as several candidate genes associated with the polled trait in goats. These results may contribute to the development of SNP chips for early prediction of PIS in goats, thereby facilitating breeding programs aimed at producing fertile herds with polled traits.

Clinical and gonadal transcriptome analysis of 38,XX disorder of sex development pigs†.

Pigs serve as a robust animal model for the study of human diseases, notably in the context of disorders of sex development (DSD). This study aims to investigate the phenotypic characteristics and molecular mechanisms underlying the reproductive and developmental abnormalities of 38,XX ovotestis-DSD (OT-DSD) and 38,XX testis-DSD (T-DSD) in pigs. Clinical and transcriptome sequencing analyses were performed on DSD and normal female pigs. Cytogenetic and SRY analyses confirmed that OT/T-DSD pigs exhibited a 38,XX karyotype and lacked the SRY gene. The DSD pigs had higher levels of follicle-stimulating hormone, luteinizing hormone, and progesterone, but lower testosterone levels when compared with normal male pigs. The reproductive organs of OT/T-DSD pigs exhibit abnormal development, displaying both male and female characteristics, with an absence of germ cells in the seminiferous tubules. Sex determination and development-related differentially expressed genes shared between DSD pigs were identified in the gonads, including WT1, DKK1, CTNNB1, WTN9B, SHOC, PTPN11, NRG1, and NXK3-1. DKK1 is proposed as a candidate gene for investigating the regulatory mechanisms underlying gonadal phenotypic differences between OT-DSD and T-DSD pigs. Consequently, our findings provide insights into the molecular pathogenesis of DSD pigs and present an animal model for studying into DSD in humans.

Genetic sex determination in three closely related hydrothermal vent gastropods, including one species with intersex individuals.

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.

Clinical utility of early rapid genome sequencing in the evaluation of patients with differences of sex development.

Establishing an early and accurate genetic diagnosis among patients with differences of sex development (DSD) is crucial in guiding the complex medical and psychosocial care they require. Genetic testing routinely utilized in clinical practice for this population is predicated upon physical exam findings and biochemical and endocrine profiling. This approach, however, is inefficient and unstandardized. Many patients with DSD, particularly those with 46,XY DSD, never receive a molecular genetic diagnosis. Rapid genome sequencing (rGS) is gaining momentum as a first-tier diagnostic instrument in the evaluation of patients with DSD given its ability to provide greater diagnostic yield and timely results. We present the case of a patient with nonbinary genitalia and systemic findings for whom rGS identified a novel variant of the WT1 gene and resulted in a molecular diagnosis within two weeks of life. This timeframe of diagnosis for syndromic DSD is largely unprecedented at our institution. Rapid GS expedited mobilization of a multidisciplinary medical team; enabled early understanding of clinical trajectory; informed planning of medical and surgical interventions; and guided individualized psychosocial support provided to the family. This case highlights the potential of early rGS in transforming the evaluation and care of patients with DSD.

SEPA-1 mediates the specific recognition and degradation of P granule components by autophagy in C. elegans.

How autophagy, an evolutionarily conserved intracellular catabolic system for bulk degradation, selectively degrades protein aggregates is poorly understood. Here, we show that several maternally derived germ P granule components are selectively eliminated by autophagy in somatic cells during C. elegans embryogenesis. The activity of sepa-1 is required for the degradation of these P granule components and for their accumulation into aggregates, termed PGL granules, in autophagy mutants. SEPA-1 forms protein aggregates and is also a preferential target of autophagy. SEPA-1 directly binds to the P granule component PGL-3 and also to the autophagy protein LGG-1/Atg8. SEPA-1 aggregates consistently colocalize with PGL granules and with LGG-1 puncta. Thus, SEPA-1 functions as a bridging molecule in mediating the specific recognition and degradation of P granule components by autophagy. Our study reveals a mechanism for preferential degradation of protein aggregates by autophagy and emphasizes the physiological significance of selective autophagy during animal development.

Intersex Pretenders.

False claims of having an intersex condition have been observed in print, video, Internet media, and in live presentations. Claims of being intersexed in publicly accessible media were examined and evidence that they were false was considered sufficiently conclusive in 37 cases. Falsity was most often detected due to medical implausibility and/or inconsistency, but sometimes also using information from third-party or published sources. The majority, 26/37, of cases were natal males; 11/37 were natal females. Almost all (34/37) were transgendered, living, or aspiring to live, in their non-natal sex or as socially intergender. The most commonly claimed diagnosis was ovotesticular disorder ("true hermaphroditism") due to chimerism, an actually uncommon cause of authentic intersexuality. Motivations for pretending to be intersexed were inferred from statements and behaviors and were varied. Some such pretenders appear to be avoiding the external or internalized stigma of an actual transgendered condition. Some appear, similarly to persons with factitious disorder, to be seeking attention and/or the role of a sick, disadvantaged, or victimized person. Some showed evidence of paraphilia, most frequently autogynephilia, and, in several cases, paraphilic diaperism. For some cases, such claims had been accepted as authentic by journalists or social scientists and repeated as true in published material.

Recommendations for 46,XX Congenital Adrenal Hyperplasia Across Two Decades: Insights from the North American Differences of Sex Development Clinician Survey.

Several aspects of clinical management of 46,XX congenital adrenal hyperplasia (CAH) remain unsettled and controversial. The North American Disorders/Differences of Sex Development (DSD) Clinician Survey investigated changes, over the last two decades, in clinical recommendations by specialists involved in the management of newborns with DSD. Members of the (Lawson Wilkins) Pediatric Endocrine Society and the Societies for Pediatric Urology participated in a web-based survey at three timepoints: 2003-2004 (T1, n = 432), 2010-2011 (T2, n = 441), and 2020 (T3, n = 272). Participants were presented with two clinical case scenarios-newborns with 46,XX CAH and either mild-to-moderate or severe genital masculinization-and asked for clinical recommendations. Across timepoints, most participants recommended rearing the newborn as a girl, that parents (in consultation with physicians) should make surgical decisions, performing early genitoplasty, and disclosing surgical history at younger ages. Several trends were identified: a small, but significant shift toward recommending a gender other than girl; recommending that adolescent patients serve as the genital surgery decision maker; performing genital surgery at later ages; and disclosing surgical details at younger ages. This is the first study assessing physician recommendations across two decades. Despite variability in the recommendations, most experts followed CAH clinical practice guidelines. The observation that some of the emerging trends do not align with expert opinion or empirical evidence should serve as both a cautionary note and a call for prospective studies examining patient outcomes associated with these changes.

Sex Reassignment Surgery, Marriage, and Reproductive Rights of Intersex and Transgender People in Sunni Islam.

The traditional gender binary constitutes an integral aspect of Islamic social ethics, which has a pivotal role in shaping religious obligations, legal proceedings, and interpersonal judgments within Muslim communities. Within the familial sphere, this gender binary underscores fundamental responsibilities encompassing parenthood, filial duties, and inheritance rights. Recent years have witnessed a growing challenge to the traditional concept of the gender binary within Islamic societies. This shift is driven by increasing social libertarianism that emphasizes gender fluidity and individual choice. Hence, this article aims to critically scrutinize evolving discussions and controversies about the rights of intersex and transgender individuals, particularly issues relating to sex reassignment or gender-affirming surgery, marriage, and reproduction, from the perspective of the Sunni tradition of Islam. To support the various interpretations and insights presented here, a comprehensive and rigorous analysis is carried out on various religious texts and scholarly sources to elucidate the theological and jurisprudential positions on gender issues. It is thus concluded that Shariah offers greater flexibility in the treatment of intersex individuals compared to those with gender dysphoria because the intersex condition is viewed as a physical impairment that is not the choice of the afflicted individual. By contrast, in the case of individuals with gender dysphoria, they are willfully attempting to change their recognized biological sex, that God had naturally given to them at birth. Therefore, it is recommended that such transgender individuals deserve respectful psychological and social rehabilitation with help and guidance from religious authorities, their families, and communities.

Unusual sex chromosomal DSD in a domestic Shorthair cat with a 37,X/38,XY mosaic karyotype.

BACKGROUND: Sex chromosome abnormalities associated with disorders of sexual development (DSD) are rarely described in cats, mainly due to the lack of chromossome studies that precisely reveal the condition. Genetic approaches are therefore required in order to detect sex chromossomes abnormalities as variations in the number and structure of chromosomes, or the presence of a second cell line as mosaicim or chimerism. CASE PRESENTATION: A male Shorthair cryptorchid cat was presented with clinical signs of anorexia, tenesmus and hyperthermia. Ultrasonography revealed a fluid-filled structure, with approximately 1 cm in diameter, adjacent to the descending colon. Computed tomography evidenced a tubular structure, ventral to the descending colon and caudal to the bladder, which extended cranially, through two branches. Histopathological evaluation confirmed the presence of two atrophic uterine horns and one hypoplastic testicle with epididymis at the end of one of the uterine horns. The end of the other uterine horn was attached to a structure composed by a mass of adipocytes. Cytogenetic analysis revealed a mosaic 37,X/38,XY karyotype. The two cell lines were found in 15% and 85% of the lymphocytes, respectively. Genetic analysis confirmed the presence of SRY and ZFY genes in blood and hair bulbs, and revealed a marked reduction in SRY expression in the testicle. Additionally, this case presented exceptionally rare features, such as a Leydig' cell tumour and a chronic endometritis in both uterine horns. CONCLUSIONS: Complete imaging workup, cytogenetic analysis and SRY gene expression should be systematically realized, in order to properly classify disorders of sexual development (DSD) in cats.

Arguments for a ban on pediatric intersex surgery: A dis/analogy with Jehovah witness blood transfusion.

This article argues for a ban on the performance of medically unnecessary genital normalizing surgeries as part of assigning a binary sex/gender to infants with intersex conditions on the basis of autonomy, regardless of etiology. It does this via a dis/analogy with the classic case in bioethics of Jehovah Witness (JW) parents' inability to refuse life-saving blood transfusions for their minor children. Both cases address ethical medical practice in situations where parents are making irreversible medical decisions on the basis of values strongly held, identity, and relationship-shaping values-such as religious beliefs or beliefs regarding the inherent value of binary sex/gender-amidst ethical pluralism. Furthermore, it takes seriously-as we must in the intersex case-that the restriction of parents' right to choose will likely result in serious harms to potentially large percentage of patients, their families, and their larger communities. I address the objection that parents' capacity to choose is restricted in the JW case on the basis of the harm principle or a duty to nonmaleficence, given that the result of parent choice would be death. I provide evidence that this is mistaken from how we treat epistemic uncertainty in the JW case and from cases in which clinicians are ethically obligated to restrict the autonomy of nonminor patients. I conclude that we restrict the parents' right to choose in the JW case-and should in the case of pediatric intersex surgery-to secure patient's future autonomy.

Evaluation and medical care of intersex and gender diverse youth.

While there is considerable overlap in the treatment of patients with intersex traits and differences in sex development (I/DSD) with transgender and gender diverse (TGD) youth, the initial medical evaluation varies significantly. I/DSD youth often present due to differences in genitalia development in infancy or pubertal development in adolescence, and this leads to comprehensive biochemical, radiologic, and genetic evaluation. TGD youth, however, tend to have typical development noted at birth and during puberty, but present with a gender identity that does not align with their sex assigned at birth and do not require evaluation for underlying pathology. For both I/DSD and TGD youth, the mainstays of treatment are to better align one's physical appearance to their gender identity. This review discusses the non-medical and medical interventions utilized in gender affirming care. A multidisciplinary team of mental health providers, pediatric medical providers, and surgeons is recommended for providing gender affirming care to both I/DSD youth and TGD youth and their families. Radiologists have an important role in initial evaluation of I/DSD youth and in ongoing monitoring of growth and bone mineral density during puberty induction in I/DSD and TGD youth.

Overview of gender-affirming surgery.

This publication will discuss the diversity of procedures that are common to those with intersex traits,/differences of sex development (I/DSD), and transgender and gender diverse (TGD) patients. It will address how these procedures are performed, and common after care and long-term considerations which are relevant to the pediatric radiologist. Some surgeries offered to these patient populations have shared surgical approaches and radiographic considerations. With the growth of TGD procedures as a field, more pediatric subspecialties are performing these procedures, and the approaches are informing the surgical care of the growing number of I/DSD individuals who are seeking surgery in adolescence and young adulthood. Surgeries discussed will include procedures to masculinize or feminize breast/chest tissue, facial bony contours, as well as internal and external genital structures. Patients are diverse and this includes their embodiment goals. As such, not all TGD and I/DSD patients will desire to undergo these procedures. It is important for radiologists to have a foundational understanding of this heterogenous set of procedures so they can provide optimal care for these patient populations.

Peri-surgical imaging of intersex and gender diverse youths.

This publication provides an overview of current imaging indications and practices for patients undergoing gender-affirming surgery, with an emphasis on the importance of tailored, patient-specific care. Gender-affirming surgeries are performed with personalized approaches at various stages of life for those with intersex traits or differences in sex development (I/DSD) and transgender and gender diverse (TGD) individuals. For I/DSD patients, ultrasound, genitography, or MRI occurs during infancy and puberty to evaluate genital and gonadal anatomy. Facial harmonization involves bony and soft tissue modifications, guided by maxillofacial computerized tomography (CT) with three-dimensional reconstruction. Ultrasound is the main modality in assessing hormone-related and post-surgical changes in the chest. Imaging for genital reconstruction uses cross-sectional images and fluoroscopy to assess neoanatomy and complications.

Knockout of the HMG domain of the porcine SRY gene causes sex reversal in gene-edited pigs.

The sex-determining region on the Y chromosome (SRY) is thought to be the central genetic element of male sex development in mammals. Pathogenic modifications within the SRY gene are associated with a male-to-female sex reversal syndrome in humans and other mammalian species, including rabbits and mice. However, the underlying mechanisms are largely unknown. To understand the biological function of the SRY gene, a site-directed mutational analysis is required to investigate associated phenotypic changes at the molecular, cellular, and morphological level. Here, we successfully generated a knockout of the porcine SRY gene by microinjection of two CRISPR-Cas ribonucleoproteins, targeting the centrally located "high mobility group" (HMG), followed by a frameshift mutation of the downstream SRY sequence. This resulted in the development of genetically male (XY) pigs with complete external and internal female genitalia, which, however, were significantly smaller than in 9-mo-old age-matched control females. Quantitative digital PCR analysis revealed a duplication of the SRY locus in Landrace pigs similar to the known palindromic duplication in Duroc breeds. Our study demonstrates the central role of the HMG domain in the SRY gene in male porcine sex determination. This proof-of-principle study could assist in solving the problem of sex preference in agriculture to improve animal welfare. Moreover, it establishes a large animal model that is more comparable to humans with regard to genetics, physiology, and anatomy, which is pivotal for longitudinal studies to unravel mammalian sex determination and relevant for the development of new interventions for human sex development disorders.

Clinical and genetic characteristics of disorders of sex development in Sudanese patients

Given the scarce data on DSD in Sudan, we aimed to characterize DSD's clinical and genetic profile in Sudanese patients. We studied 60 patients with DSD using clinical data, cytogenetics, and PCR for the SRY gene. The results showed that 65% grew up as females and 35% as males. There was a high percentage of consanguineous parents (85%). Female genital mutilation (FGM) was performed in 75% of females. Patients who presented after pubertal age were 63%, with ambiguous genitalia in 61.7%, followed by primary amenorrhea (PA) in 30%. The SRY gene was positive in 3.3% of patients with 46,XX karyotype and negative in 6.7% of patients with 46,XY karyotype. 5αR2D-DSD was seen in 43.3%, gonadal dysgenesis in 21.7%, Ovotesticular syndrome in 6.7%, Swyer and Turner syndrome in 5% each, and Androgen Insensitivity Syndrome (AIS) in 3.3%. In conclusion, DSD in Sudan has a distinct profile with late presentation, dominated by 5αR2D-DSD due to the increased consanguineous marriage, and FGM represents a significant risk for DSD patients.

Compte tenu du peu de données sur le DSD au Soudan, nous avons cherché à caractériser le profil clinique et génétique du DSD chez les patients soudanais. Nous avons étudié 60 patients atteints de DSD en utilisant des données cliniques, cytogénétiques et PCR pour le gène SRY. Les résultats ont montré que 65 % ont grandi en tant que femmes et 35 % en tant qu'hommes. Il y avait un pourcentage élevé de parents consanguins (85 %). Des mutilations génitales féminines (MGF) ont été pratiquées chez 75 % des femmes. Les patientes qui se sont présentées après l'âge pubertaire étaient 63 %, avec des organes génitaux ambigus dans 61,7 %, suivis d'une aménorrhée primaire (AP) dans 30 %. Le gène SRY était positif chez 3,3 % des patients de caryotype 46,XX et négatif chez 6,7 % des patients de caryotype 46,XY. Le 5αR2D-DSD a été observé dans 43,3 %, la dysgénésie gonadique dans 21,7 %, le syndrome ovotesticulaire dans 6,7 %, le syndrome de Swyer et Turner dans 5 % chacun et le syndrome d'insensibilité aux androgènes (AIS) dans 3,3 %. En conclusion, le DSD au Soudan présente un profil distinct avec une présentation tardive, dominé par le 5αR2D-DSD en raison de l'augmentation des mariages consanguins, et les MGF représentent un risque important pour les patients DSD.