Search Results (9)

Sex determination, the developmental process that directs embryos toward male or female fates, is controlled by master sex-determining genes whose origins and evolutionary dynamics remain poorly understood outside of a few model systems. In contrast to the highly differentiated sex chromosomes of mammals, birds, and Drosophila, most anurans (frogs and toads) maintain homomorphic sex chromosomes that exhibit a rapid turnover, even among closely related species. Master sex-determining genes evolve via gene duplication or via allelic diversification, and sex chromosome turnover is driven by gene translocation or novel mutations in the existing genes involved in the sexual developmental pathway. To uncover the mechanisms underlying the emergence of master sex-determining genes and sex chromosome turnover, we analyzed 53 published anuran genomes and one caecilian genome (>200 Mya divergence) and available transcriptomes. We asked how often master sex-determining genes arise by gene duplication, whether and how often gene translocation associates with sex chromosome turnover, and if master sex-determining genes evolve under positive selection. We find that chromosome-level synteny is remarkably conserved, with only a few fusions or fissions and no evidence for translocation of four candidate master sex-determining genes (Dmrt1, Foxl2, Bod1l, and Sox3). Only Dmrt1 duplicated in 3 out of 50 species (excluding tetraploid Xenopus), and it showed strong testis-biased expression in all 8 species with available gonadal expression data. While Dmrt1 has evolved under purifying selection, Dmrt1 duplicates exhibit elevated nonsynonymous substitution rates and tendency towards positive selection. Lineage-specific amino acid changes were observed in the conserved DM domain of Dmrt1. These results demonstrate that, in anurans, master sex-determining genes rarely arise via gene duplication, and more likely evolve via allelic diversification. Sex chromosome turnover is not associated with gene translocation and is more likely driven by mutations on genes involved in sexual developmental pathways. All candidate sex-determining genes were under strong purifying selection, with the exception of duplications which are linked to positive selection. Our results suggest future research on anuran sex determination and sex chromosome evolution should focus on identifying allelic diversification and novel mutations on genes involved in sexual developmental pathways. Full article

Background/Objectives: It is said that genes that escape from X chromosome inactivation (XCI) contribute to gender differences. We analyzed the prognostic role of these genes and identified a gender-biased difference in prognosis according to KDM6A mutation in the immune therapy cohort (IMvigor 210). We also investigate the gender-biased differential effect of KDM6A mutation in several public databases of urothelial carcinoma (UC). Methods: We used AACR GENIE, The Cancer Genome Atlas, International Cancer Genome Consortium, several public databases related to immune therapy, chemotherapy, and BCG treatment. We studied the gender-biased prognostic role of KDM6A mutation in several cohorts and the association between KDM6A mutation and immune-related fractions according to gender. Results: The expression of KDM6A was higher in females than in males in several cohorts. Mutation of KDM6A was observed in about 20–25% of the patients. The rate of KDM6A mutation was higher in females than in males in several cohorts. Kaplan–Meier analysis revealed a gender-biased difference in prognosis between patients with KDM6A mutations and those with the wild-type KDM6A in several cohorts, including the immune therapy cohort. The rate of immune-inflamed type was higher in males than in females in the patients with KDM6A mutation in the IMvigor 210 and UC-GENOME studies. Single-sample Gene Set Enrichment Analysis showed that CD8+ cells and type 1 IFN response fractions and APC co-inhibition fraction were higher in the male than female patients with KDM6A mutation. Similar findings were observed in other immune-related studies (UC-GENOME). Conclusions: The effect of KDM6A mutation on immune therapy varied according to gender, and the status of KDM6A mutation may be a promising biomarker in immune therapy in UC. Full article

Chromatin dysregulation has emerged as a major hallmark of neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorders (ASD). The prevalence of ID and ASD is higher in males compared to females, with unknown mechanisms. Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type (MRXSCJ), is caused by loss-of-function mutations of lysine demethylase 5C (KDM5C), a histone H3K4 demethylase gene. KDM5C escapes X-inactivation, thereby presenting at a higher level in females. Initially, MRXSCJ was exclusively reported in males, while it is increasingly evident that females with heterozygous KDM5C mutations can show cognitive deficits. The mouse model of MRXSCJ, male Kdm5c-hemizygous knockout animals, recapitulates key features of human male patients. However, the behavioral and molecular traits of Kdm5c-heterozygous female mice remain incompletely characterized. Here, we report that gene expression and behavioral abnormalities are readily detectable in Kdm5c-heterozygous female mice, demonstrating the requirement for a higher KDM5C dose in females. Furthermore, we found both shared and sex-specific consequences of a reduced KDM5C dose in social behavior, gene expression, and genetic interaction with the counteracting enzyme KMT2A. These observations provide an essential insight into the sex-biased manifestation of neurodevelopmental disorders and sex chromosome evolution. Full article

Genetic sex-determination features male (XX/XY) or female heterogamety (ZZ/ZW). To identify similarities and differences in the molecular evolution of sex-linked genes between these systems, we directly compared the sex chromosome systems existing in the frog Glandirana rugosa. The heteromorphic X/Y and Z/W sex chromosomes were derived from chromosomes 7 (2n = 26). RNA-Seq, de novo assembly, and BLASTP analyses identified 766 sex-linked genes. These genes were classified into three different clusters (XW/YZ, XY/ZW, and XZ/YW) based on sequence identities between the chromosomes, probably reflecting each step of the sex chromosome evolutionary history. The nucleotide substitution per site was significantly higher in the Y- and Z-genes than in the X- and W- genes, indicating male-driven mutation. The ratio of nonsynonymous to synonymous nucleotide substitution rates was higher in the X- and W-genes than in the Y- and Z-genes, with a female bias. Allelic expression in gonad, brain, and muscle was significantly higher in the Y- and W-genes than in the X- and Z-genes, favoring heterogametic sex. The same set of sex-linked genes showed parallel evolution across the two distinct systems. In contrast, the unique genomic region of the sex chromosomes demonstrated a difference between the two systems, with even and extremely high expression ratios of W/Z and Y/X, respectively. Full article

Ewsr1 encodes a protein that acts as a multifunctional molecule in a variety of cellular processes. The full-length of Cs-ewsr1-w and Cs-ewsr1-z were cloned in Chinese tongue sole (Cynoglossus semilaevis). The open reading frame (ORF) of Cs-ewsr1-w was 1,767 bp that encoded 589 amino acids, while Cs-ewsr1-z was 1,794 bp that encoded 598 amino acids. Real-time PCR assays showed that Cs-ewsr1-w exhibited significant female-biased expression and could be hardly detected in male. It has the most abundant expression in ovaries among eight healthy tissues. Its expression in ovary increased gradually from 90 d to 3 y with C. semilaevis ovarian development and reached the peak at 3 y. After Cs-ewsr1-w knockdown with siRNA interference, several genes related to gonadal development including foxl2, sox9b and pou5f1 were down-regulated in ovarian cell line, suggesting the possible participation of Cs-ewsr1-w in C. semilaevis ovarian development. The dual-luciferase reporter assay revealed that the -733/-154 bp Cs-ewsr1-w promoter fragment exhibited strong transcription activity human embryonic kidney (HEK) 293T cell line. The mutation of a MAF BZIP Transcription Factor K (Mafk) binding site located in this fragment suggested that transcription factor Mafk might play an important role in Cs-ewsr1-w basal transcription. Our results will provide clues on the gene expression level, transcriptional regulation and knock-down effect of ewsr1 gene during ovarian development in teleost. Full article

Unlike mammals and birds, many fishes have young sex chromosomes, providing excellent models to study sex chromosome differentiation at early stages. Previous studies showed that spotted scat possesses an XX-XY sex determination system. The X has a complete Dmrt3 copy (termed normal) and a truncated copy of Dmrt1 (called Dmrt1b), while the Y has the opposite (normal Dmrt1, which is male-specific, and a truncated Dmrt3 called Dmrt3△-Y). Dmrt1 is the candidate sex determination gene, while the differentiation of other sex-linked genes remains unknown. The spotted scat has proven to be a good model to study the evolution of sex chromosomes in vertebrates. Herein, we sequenced a neighbor gene of this family, Dmrt2, positioned farther from Dmrt1 and closer to Dmrt3 in the spotted scat, and analyzed its sequence variation and expression profiles. The physical locations of the three genes span across an estimated size of >40 kb. The open reading frames of Dmrt2a and its paralog Dmrt2b are 1578 bp and 1311 bp, encoding peptides of 525 and 436 amino acid residues, respectively. Dmrt2a is positioned close to Dmrt3 but farther from Dmrt1 on the same chromosome, while Dmrt2b is not. Sequence analysis revealed several mutations; insertions, and deletions (indels) on Dmrt2a non-coding regions and single-nucleotide polymorphisms (SNPs) on the Dmrt2a transcript. These indels and SNPs are sex-linked and showed high male heterogeneity but do not affect gene translation. The markers designed to span the mutation sites tested on four different populations showed varied concordance with the genetic sexes. Dmrt2a is transcribed solely in the gonads and gills, while Dmrt2b exists in the gonads, hypothalamus, gills, heart, and spleen. The Dmrt2a and Dmrt2b transcripts are profoundly expressed in the male gonads. Analyses of the transcriptome data from five other fish species (Hainan medaka (Oryzias curvinotus), silver sillago (Sillago sihama), Nile tilapia (Oreochromis niloticus), Hong Kong catfish (Clarias fuscus), and spot-fin porcupine fish (Diodon hystrix)) revealed testes-biased expression of Dmrt1 in all, similar to spotted scat. Additionally, the expression of Dmrt2a is higher in the testes than the ovaries in spotted scat and Hainan medaka. The Dmrt2a transcript was not altered in the coding regions as found in Dmrt1 and Dmrt3 in spotted scat. This could be due to the functional importance of Dmrt2a in development. Another possibility is that because Dmrt2a is positioned farther from Dmrt1 and the chromosome is still young, meaning it is only a matter of time before it differentiates. This study undeniably will aid in understanding the functional divergence of the sex-linked genes in fish. Full article

In honey bees, complementary sex determiner (csd) is the primary signal of sex determination. Its allelic composition is heterozygous in females, and hemizygous or homozygous in males. To explore the transcriptome differences after sex differentiation between males and females, with genetic differences excluded, csd in fertilized embryos was knocked out by CRISPR/Cas9. The diploid mutant males at 24 h, 48 h, 72 h, and 96 h after egg laying (AEL) and the mock-treated females derived from the same fertilized queen were investigated through RNA-seq. Mutations were detected in the target sequence in diploid mutants. The diploid mutant drones had typical male morphological characteristics and gonads. Transcriptome analysis showed that several female-biased genes, such as worker-enriched antennal (Wat), vitellogenin (Vg), and some venom-related genes, were down-regulated in the diploid mutant males. In contrast, some male-biased genes, such as takeout and apolipophorin-III-like protein (A4), had higher expressions in the diploid mutant males. Weighted gene co-expression network analysis (WGCNA) indicated that there might be interactions between csd and fruitless (fru), feminizer (fem) and hexamerin 70c (hex70c), transformer-2 (tra2) and troponin T (TpnT). The information provided by this study will benefit further research on the sex dimorphism and development of honey bees and other insects in Hymenoptera. Full article

The liver is a vital organ that sustains multiple functions beneficial for the whole organism. It is sexually dimorphic, presenting sex-biased gene expression with implications for the phenotypic differences between males and females. Estrogens are involved in this sex dimorphism and their actions in the liver of several reptiles, fishes, amphibians, and birds are discussed. The liver participates in reproduction by producing vitellogenins (yolk proteins) and eggshell proteins under the control of estrogens that act via two types of receptors active either mainly in the cell nucleus (ESR) or the cell membrane (GPER1). Estrogens also control hepatic lipid and lipoprotein metabolisms, with a triglyceride carrier role for VLDL from the liver to the ovaries during oogenesis. Moreover, the activation of the vitellogenin genes is used as a robust biomarker for exposure to xenoestrogens. In the context of liver diseases, high plasma estrogen levels are observed in fatty liver hemorrhagic syndrome (FLHS) in chicken implicating estrogens in the disease progression. Fishes are also used to investigate liver diseases, including models generated by mutation and transgenesis. In conclusion, studies on the roles of estrogens in the non-mammalian oviparous vertebrate liver have contributed enormously to unveil hormone-dependent physiological and physiopathological processes. Full article

The irradiation of dry seeds is the most widely-used irradiation method for improving seed-propagated crops; however, the irradiation of other tissues also has useful effects. The irradiation of plant reproductive organs, rather than seeds, for mutation breeding has advantages, such as producing non-chimeric progeny. However, the mutation frequency and spectrum produced using this method have not been analyzed on a genome-wide level. We performed a genotype-by-sequencing analysis to determine the frequencies of single-base substitutions and small (1–2 bp) insertions and deletions in hot pepper (Capsicum annuum L.) plants derived from crosses using gamma-irradiated female or male gametophytes. The progeny of irradiated gametophytes showed similar or higher DNA mutation frequencies, which were dependent on the irradiation dose and irradiated tissue, and less biased single base substitutions than progeny of irradiated seeds. These characteristics were expected to be beneficial for development of mutation population with a high frequency of small DNA mutations and performing reverse-genetics-based mutation screening. We also examined the possible use of this irradiation method in manipulating the meiotic recombination frequency; however, no statistically significant increase was detected. Our results provide useful information for further research and breeding using irradiated gametophytes. Full article