Postnatal developmental trajectory of sex-biased gene expression in the mouse pituitary gland

The pituitary gland controls sexually dimorphic processes such as growth, pubertal onset, and lactation. However, the mechanisms underlying sex biases in pituitary gene regulation are not fully understood. To capture pituitary gene regulation dynamics during postnatal development, we ascertained gene and miRNA expression across five postnatal days that span the pubertal transition in mice. Using three prime untranslated region and small RNA sequencing, we observed over 900 instances of sex-biased gene expression, including 18 genes that were putative targets of 5 sex-biased miRNAs. In addition, by combining bulk RNA-seq with scRNA-seq pituitary data, we obtained evidence that cell-type proportion sex differences exist prior to puberty and contribute substantially to the observed sex-biased gene expression post-puberty. This work provides a resource for postnatal mouse pituitary gene regulation and highlights the importance of sex-biases in both cell-type composition and gene regulation when understanding the sexually dimorphic processes regulated by the pituitary gland.

Sex-biased demography modulates male harm across the genome

Recent years have seen an explosion of theoretical and empirical interest in the role that kin selection plays in shaping patterns of sexual conflict, with a particular focus on male harming traits. However, this work has focused solely on autosomal genes, and as such it remains unclear how demography modulates the evolution of male harm loci occurring in other portions of the genome, such as sex chromosomes and cytoplasmic elements. To investigate this, we extend existing models of sexual conflict for application to these different modes of inheritance. We first analyse the general case, revealing how sex-specific relatedness, reproductive value and the intensity of local competition combine to determine the potential for male harm. We then analyse a series of demographically explicit models, to assess how dispersal, overlapping generations, reproductive skew and the mechanism of population regulation affect sexual conflict across the genome, and drive conflict between nuclear and cytoplasmic genes. We then explore the effects of sex biases in these demographic parameters, showing how they may drive further conflicts between autosomes and sex chromosomes. Finally, we outline how different crossing schemes may be used to identify signatures of these intragenomic conflicts.

Sex biases in cancer and autoimmune disease incidence are correlated across human tissues

Cancer occurs more frequently in men while autoimmune diseases (AIDs) occur more frequently in women. To explore whether these sex biases have a common basis, we collected 170 AID incidence studies from many countries for tissues that have both a cancer type and an AID that arise from that tissue. Analyzing a total of 182 country-specific, tissue-matched cancer-AID incidence rate sex bias data pairs, we find that the sex biases observed in the incidence of AIDs and cancers that occur in the same tissue are correlated across human tissues. Among key factors that have been previously associated with sex bias in either AID or cancer incidence, we find that the sex bias in the expression of the 37 genes encoded in the mitochondrial genome and the expression of a few immune pathways stand out as common key factors whose levels across human tissues are strongly associated with these incidence rate sex biases.

Drone Honey Bees (Apis Mellifera) are Disproportionately Sensitive to Abiotic Stressors Despite Expressing High Levels of Stress Response Proteins

Drone honey bees (haploid males) are the obligate sexual partners of queens, and the availability of healthy, high-quality drones directly affects a queen’s fecundity and productivity of her subsequent colony. Yet, our understanding of how stressors affect drone fecundity and physiology is presently limited. We investigated sex biases in susceptibility to abiotic stressors (cold stress, topical imidacloprid exposure, and topical exposure to a realistic cocktail of pesticides), and we found that drones were more sensitive to cold and imidacloprid exposure but the cocktail was not toxic at the concentrations tested. We corroborated this lack of apparent toxicity with in-hive cocktail exposures via pollen feeding. We then used quantitative proteomics to investigate protein expression profiles in the hemolymph of topically exposed workers and drones, and we show that drones express surprisingly high levels of putative stress response proteins relative to workers. Drones apparently invest in strong constitutive expression of damage-mitigating proteins for a wide range of stressors, yet they are still sensitive to stress when challenged. The robust expression of stress-response proteins suggests that drone stress tolerance systems are fundamentally rewired relative to workers, and their susceptibility to stress depends on more than simply gene dose or deleterious recessive alleles.

Patterns and Mechanisms of Sex Ratio Distortion in the Collaborative Cross Mouse Mapping Population

In species with single-locus chromosome-based mechanisms of sex determination, the laws of segregation predict an equal ratio of females to males at birth. Here, we show that departures from this Mendelian expectation are commonplace in the 8-way recombinant inbred Collaborative Cross (CC) mouse population. More than one-third of CC strains exhibit significant sex ratio distortion (SRD) at wean, with twice as many male-biased than female-biased strains. We show that these pervasive sex biases persist across multiple breeding environments, are stable over time, are not fully mediated by maternal effects, and are not explained by sex-biased neonatal mortality. SRD exhibits a heritable component, but QTL mapping analyses and targeted investigations of sex determination genes fail to nominate any large effect loci. These findings, combined with the reported absence of sex ratio biases in the CC founder strains, suggest that SRD manifests from multilocus combinations of alleles only uncovered in recombined CC genomes. We speculate that the genetic shuffling of eight diverse parental genomes during the early CC breeding generations led to the decoupling of sex-linked drivers from their co-evolved suppressors, unleashing complex, multiallelic systems of sex chromosome drive. Consistent with this interpretation, we show that several CC strains exhibit copy number imbalances at co-evolved X- and Y-linked ampliconic genes that have been previously implicated in germline genetic conflict and SRD in house mice. Overall, our findings reveal the pervasiveness of SRD in the CC population and nominate the CC as a powerful resource for investigating sex chromosome genetic conflict in action.

Sexual Dimorphism of the Heart: Genetics, Epigenetics, and Development

The democratization of genomic technologies has revealed profound sex biases in expression patterns in every adult tissue, even in organs with no conspicuous differences, such as the heart. With the increasing awareness of the disparities in cardiac pathophysiology between males and females, there are exciting opportunities to explore how sex differences in the heart are established developmentally. Although sexual dimorphism is traditionally attributed to hormonal influence, expression and epigenetic sex biases observed in early cardiac development can only be accounted for by the difference in sex chromosome composition, i.e., XX in females and XY in males. In fact, genes linked to the X and Y chromosomes, many of which encode regulatory factors, are expressed in cardiac progenitor cells and at every subsequent developmental stage. The effect of the sex chromosome composition may explain why many congenital heart defects originating before gonad formation exhibit sex biases in presentation, mortality, and morbidity. Some transcriptional and epigenetic sex biases established soon after fertilization persist in cardiac lineages, suggesting that early epigenetic events are perpetuated beyond early embryogenesis. Importantly, when sex hormones begin to circulate, they encounter a cardiac genome that is already functionally distinct between the sexes. Although there is a wealth of knowledge on the effects of sex hormones on cardiac function, we propose that sex chromosome-linked genes and their downstream targets also contribute to the differences between male and female hearts. Moreover, identifying how hormones influence sex chromosome effects, whether antagonistically or synergistically, will enhance our understanding of how sex disparities are established. We also explore the possibility that sexual dimorphism of the developing heart predicts sex-specific responses to environmental signals and foreshadows sex-biased health-related outcomes after birth.

The association of sex-biased ATRX mutation in female gastric cancer patients with enhanced immunotherapy-related anticancer immunity

Background Genetic alterations have been proven to be the promising biomarkers for ICI response. However, sex biases in genetic alterations have been often ignored in the field of immunotherapy, which might specially influence the anticancer immunity and immunotherapy efficacy in male or female patients. Here, we have systematically evaluated the effect of the sex biases in somatic mutation of gastric cancer (GC) patients on the anticancer immunity and clinical benefit to immunotherapy. Methods Genomic and transcriptomic data of gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). We also obtained the genomic and clinical data of a MSKCC ICI-treated cohort from cbioportal database. GC male and female-derived tumor somatic mutation profiles were compared by maftools R package. Single sample gene set enrichment analysis (ssGSEA) was conducted to calculate the score of the anticancer immunity indicators including IFN-γ signaling, cytolytic activity (CYT) and antigen presenting machinery (APM). Results ATRX was found to mutate more frequently in female GC patients compared to male patients (FDR = 0.0108). Female GC patients with ATRX mutation manifested significantly more MSI-high subtypes, increased TMB and PDL1 expression as well as higher scores of IFN-γ signaling, CYT and APM. Gene set enrichment analysis (GSEA) has shown that ATRX mutation might enhance the immunogenicity and anticancer immunity through affecting DNA damage repair pathways. In the ICI-treated cohort from MSKCC, GC patients with ATRX mutation were associated with prolonged overall survival. When stratifying the entire ICI-treated cohort by sex, female patients with ATRX mutation obtained significantly better survival benefits than that of ATRX mutant male patients (Female patients, HR of ATRX MT vs WT = 0.636, 95%CI = 0.455–0.890, P = 0.023; Male patients, HR of ATRX MT vs WT = 0.929, 95%CI = 0.596–1.362, P = 0.712). Conclusions ATRX mutation might serve as a potential predictive biomarker for favorable clinical benefit to ICI in female GC patients. ATRX mutation could be applied in combination with other biomarkers of ICI response to better identify the female GC patients who will derive greater benefits from ICI therapy.

Sex-specific glycosylation of secreted immunomodulatory proteins in the filarial nematode Brugia malayi

The extended persistence of filarial nematodes within a host suggests immunomodulatory mechanisms that allow the parasites to resist or evade the host immune response. There is increasing evidence for immunomodulatory glycans expressed by a diversity of parasitic worms. In this study, we integrate multiple layers of the host-parasite interface to investigate the glycome of a model filarial parasite, Brugia malayi. We report a significant overrepresentation of terminal GalNAc moieties in adult female worms coupled with an overall upregulation in O-glycosylation, T-antigen expression, and a bias for galactose containing glycans. Adult males preferentially displayed a bias for terminal GlcNAc containing glycans, and fucosylated epitopes. Subsequent proteomic analysis confirmed sex-biases in protein glycosylation and highlighted the sex-specific glycosylation of well characterized immunomodulators expressed and secreted by B. malayi. We identify sex-specific effectors at that interface and suggest approaches to selectively interfere with the parasitic life cycle and potentially control transmission.

Using strontium isotopes to determine philopatry and dispersal in primates: a case study from Kibale National Park

Strontium isotope ratios ( 87 Sr/ 86 Sr) allow researchers to track changes in mobility throughout an animal's life and could theoretically be used to reconstruct sex-biases in philopatry and dispersal patterns in primates. Dispersal patterns are a life-history variable that correlate with numerous aspects of behaviour and socio-ecology that are elusive in the fossil record. The present study demonstrates that the standard archaeological method used to differentiate between ‘local’ and ‘non-local’ individuals, which involves comparing faunal isotopic ratios with environmental isotopic minima and maxima, is not always reliable; aspects of primate behaviour, local environments, geologic heterogeneity and the availability of detailed geologic maps may compromise its utility in certain situations. This study instead introduces a different methodological approach: calculating offset values to compare 87 Sr/ 86 Sr of teeth with that of bone or local environments. We demonstrate this method's effectiveness using data from five species of primates, including chimpanzees, from Kibale National Park, Uganda. Tooth-to-bone offsets reliably indicate sex-biases in dispersal for primates with small home ranges while tooth-to-environment offset comparisons are more reliable for primates with larger home ranges. Overall, tooth-to-environment offsets yield the most reliable predictions of species' sex-biases in dispersal.

The Association of Sex-biased ATRX Mutation in Female Gastric Cancer Patients With Enhanced Immunotherapy-related Anticancer Immunity

Background: Genetic alterations have been proven to be the promising biomarkers for ICI response. However, sex biases in genetic alterations have been often ignored in the field of immunotherapy, which might specially influence the anticancer immunity and immunotherapy efficacy in male or female patients. Here, we have systematically evaluated the effect of the sex biases in somatic mutation of gastric cancer (GC) patients on the anticancer immunity and clinical benefit to immunotherapy. Methods: Genomic and transcriptomic data of gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). We also obtained the genomic and clinical data of a MSKCC ICI-treated cohort from cbioportal database. GC male and female-derived tumor somatic mutation profiles were compared by maftools R package. Single sample gene set enrichment analysis (ssGSEA) was conducted to calculate the score of the anticancer immunity indicators including IFN-γ signaling, cytolytic activity (CYT) and antigen presenting machinery (APM). Results: ATRX was found to mutate more frequently in female GC patients compared to male patients (FDR = 0.0108). Female GC patients with ATRX mutation manifested significantly more MSI-high subtypes, increased TMB and PDL1 expression as well as higher scores of IFN-γ signaling, CYT and APM. Gene set enrichment analysis (GSEA) has shown that ATRX mutation might enhance the immunogenicity and anticancer immunity through affecting DNA damage repair pathways. In the ICI-treated cohort from MSKCC, GC patients with ATRX mutation were associated with prolonged overall survival. When stratifying the entire ICI-treated cohort by sex, female patients with ATRX mutation obtained significantly better survival benefits than that of ATRX mutant male patients (Female patients, HR of ATRX MT vs WT = 0.636, 95%CI = 0.455-0.890, P = 0.023; Male patients, HR of ATRX MT vs WT = 0.929, 95%CI = 0.596-1.362, P = 0.712). Conclusions: ATRX mutation might serve as a potential predictive biomarker for favorable clinical benefit to ICI in female GC patients. ATRX mutation could be applied in combination with other biomarkers of ICI response to better identify the female GC patients who will derive greater benefits from ICI therapy.