Conservation, acquisition, and functional impact of sex-biased gene expression in mammals

Sex differences abound in human health and disease, as they do in other mammals used as models. The extent to which sex differences are conserved at the molecular level across species and tissues is unknown. We surveyed sex differences in gene expression in human, macaque, mouse, rat, and dog, across 12 tissues. In each tissue, we identified hundreds of genes with conserved sex-biased expression—findings that, combined with genomic analyses of human height, explain ~12% of the difference in height between females and males. We surmise that conserved sex biases in expression of genes otherwise operating equivalently in females and males contribute to sex differences in traits. However, most sex-biased expression arose during the mammalian radiation, which suggests that careful attention to interspecies divergence is needed when modeling human sex differences.

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Tissue-specific sex differences in human gene expression

Human Molecular Genetics ◽

10.1093/hmg/ddz090 ◽

2019 ◽

Vol 28 (17) ◽

pp. 2976-2986 ◽

Cited By ~ 9

Author(s):

Irfahan Kassam ◽

Yang Wu ◽

Jian Yang ◽

Peter M Visscher ◽

Allan F McRae

Keyword(s):

Gene Expression ◽

Sex Differences ◽

Complex Traits ◽

Tissue Expression ◽

Regulatory Elements ◽

Tissue Specific ◽

Significance Threshold ◽

Expression Of Genes ◽

Causal Variants ◽

Similar Distance

Abstract Despite extensive sex differences in human complex traits and disease, the male and female genomes differ only in the sex chromosomes. This implies that most sex-differentiated traits are the result of differences in the expression of genes that are common to both sexes. While sex differences in gene expression have been observed in a range of different tissues, the biological mechanisms for tissue-specific sex differences (TSSDs) in gene expression are not well understood. A total of 30 640 autosomal and 1021 X-linked transcripts were tested for heterogeneity in sex difference effect sizes in n = 617 individuals across 40 tissue types in Genotype–Tissue Expression (GTEx). This identified 65 autosomal and 66 X-linked TSSD transcripts (corresponding to unique genes) at a stringent significance threshold. Results for X-linked TSSD transcripts showed mainly concordant direction of sex differences across tissues and replicate previous findings. Autosomal TSSD transcripts had mainly discordant direction of sex differences across tissues. The top cis-expression quantitative trait loci (eQTLs) across tissues for autosomal TSSD transcripts are located a similar distance away from the nearest androgen and estrogen binding motifs and the nearest enhancer, as compared to cis-eQTLs for transcripts with stable sex differences in gene expression across tissue types. Enhancer regions that overlap top cis-eQTLs for TSSD transcripts, however, were found to be more dispersed across tissues. These observations suggest that androgen and estrogen regulatory elements in a cis region may play a common role in sex differences in gene expression, but TSSD in gene expression may additionally be due to causal variants located in tissue-specific enhancer regions.

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Transcriptome analysis of the human tibial nerve identifies sexually dimorphic expression of genes involved in pain, inflammation and neuro-immunity

10.1101/450197 ◽

2018 ◽

Author(s):

Pradipta Ray ◽

Jawad Khan ◽

Andi Wangzhou ◽

Diana Tavares-Ferreira ◽

Armen N. Akopian ◽

...

Keyword(s):

Gene Expression ◽

Chronic Pain ◽

Sex Differences ◽

Molecular Mechanisms ◽

Tibial Nerve ◽

Sexually Dimorphic ◽

Pain Mechanisms ◽

Expression Of Genes ◽

Sexually Dimorphic Expression ◽

Insight Into

AbstractSex differences in gene expression are important contributors to normal physiology and mechanisms of disease. This is increasingly apparent in understanding and potentially treating chronic pain where molecular mechanisms driving sex differences in neuronal plasticity are giving new insight into why certain chronic pain disorders preferentially affect women versus men. Large transcriptomic resources are increasingly available and can be used to mine for sex differences and molecular insight using donor cohorts. We analyzed more than 250 human tibial nerve (hTN) transcriptomes from the GTex Consortium project to gain insight into sex-dependent gene expression in the peripheral nervous system (PNS). We discover 149 genes with sex differential expression. Many of the genes upregulated in men are associated with inflammation, and appear to be primarily expressed by glia or immune cells. In women, we find the differentially upregulated transcription factor SP4 that drives a regulatory program, and may impact sex differences in PNS physiology. Many of these 149 DE genes have some previous association with chronic pain but few of them have been explored thoroughly. Additionally, using clinical data in the GTex database, we identify a subset of differentially expressed (DE) genes in diseases associated with chronic pain, arthritis and type II diabetes. Our work identifies sexually dimorphic gene expression in the human PNS with implications for discovery of sex-specific pain mechanisms.

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Differential Sex-Dependent Regulation of the Alveolar Macrophage miRNome of SP-A2 and co-ex (SP-A1/SP-A2) and Sex Differences Attenuation after 18 h of Ozone Exposure

Antioxidants ◽

10.3390/antiox9121190 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1190

Author(s):

Nithyananda Thorenoor ◽

David S. Phelps ◽

Joanna Floros

Keyword(s):

Gene Expression ◽

Sex Differences ◽

Alveolar Macrophage ◽

Genetic Variants ◽

Target Gene ◽

Single Gene ◽

Ozone Exposure ◽

Delayed Response ◽

Expression Of Genes ◽

Males And Females

Background: Human SP-A1 and SP-A2, encoded by SFTPA1 and SFTPA2, and their genetic variants differentially impact alveolar macrophage (AM) functions and regulation, including the miRNome. We investigated whether miRNome differences previously observed between AM from SP-A2 and SP-A1/SP-A2 mice are due to continued qualitative differences or a delayed response of mice carrying a single gene. Methods: Human transgenic (hTG) mice, carrying SP-A2 or both SP-A genes, and SP-A-KO mice were exposed to filtered air (FA) or ozone (O3). AM miRNA levels, target gene expression, and pathways determined 18 h after O3 exposure. RESULTS: We found (a) differences in miRNome due to sex, SP-A genotype, and exposure; (b) miRNome of both sexes was largely downregulated by O3, and co-ex had fewer changed (≥2-fold) miRNAs than either group; (c) the number and direction of the expression of genes with significant changes in males and females in co-ex are almost the opposite of those in SP-A2; (d) the same pathways were found in the studied groups; and (e) O3 exposure attenuated sex differences with a higher number of genotype-dependent and genotype-independent miRNAs common in both sexes after O3 exposure. Conclusion: Qualitative differences between SP-A2 and co-ex persist 18 h post-O3, and O3 attenuates sex differences.

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Differential Response Of Leukemic Blasts To Dexamethasone and Prednisone Occurs At Sub-Saturating Doses

Blood ◽

10.1182/blood.v122.21.4915.4915 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4915-4915

Author(s):

Miles A. Pufall ◽

Hongxing Yang ◽

Dawne N. Shelton

Keyword(s):

Gene Expression ◽

Cell Lines ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Cell Type ◽

Cell Precursor ◽

Expression Of Genes ◽

The Difference ◽

Genomic Response ◽

Differential Expression Of Genes

Abstract Dexamethasone (dex) and prednisone (pred) are highly related glucocorticoids that are used in the treatment of leukemias and lymphomas. Recently it was shown that dex produces better outcomes in children with high-risk B cell precursor acute lymphoblastic leukemia than pred. Although this result was consistent with the accepted potencies of the two drugs, the reason for this difference is not well understood. Glucocorticoids work primarily by binding and activating the glucocorticoid receptor, which, when bound, associates with genomic response elements to orchestrate gene expression programs. We hypothesized that dex regulates key genes that drive apoptosis in BCP-ALL more strongly. To test this we used microarrays to measure the differential expression of genes in response to saturating doses of dex and pred in three cell lines. Dex and pred induced very similar patterns of gene expression in each cell type, with an overlap of about 60%. Surprisingly, when we compared the 40% of genes that were regulated by dex or pred alone in each cell line, there were no commonly regulated genes among all cell lines. Further, for the 150 genes commonly regulated by both dex and pred in all three cell lines, there were no differences in the magnitude of response, suggested that the difference might lie at a lower, more functional doses. We tested this using RNA sequencing at five concentrations of both dex and pred in a primary patient sample. Consistent with their potency, the average regulated gene required eight times more pred than dex. Interestingly, when we performed unsupervised clustering of regulated genes by concentration, we found more modest differences in the concentration required for the onset of regulation, and that pred selectively suppressed expression of a block of genes at lower concentrations. These data suggest that rather than specific genes being regulated by dex, or simply a more potent response of the same genes, that the difference in apoptosis induction may be due to surprisingly different responses at sub-saturating concentrations. Disclosures: No relevant conflicts of interest to declare.

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Sex differences in gene expression in the human fetal brain

10.1101/483636 ◽

2018 ◽

Cited By ~ 3

Author(s):

Heath E. O’Brien ◽

Eilis Hannon ◽

Aaron R. Jeffries ◽

William Davies ◽

Matthew J. Hill ◽

...

Keyword(s):

Gene Expression ◽

Sex Differences ◽

Human Brain ◽

Brain Development ◽

Developmental Disorders ◽

Fetal Brain ◽

Human Fetal Brain ◽

Human Brain Development ◽

Early Human ◽

Sex Biases

ABSTRACTWidespread structural, chemical and molecular differences have been reported between the male and female human brain. Although several neurodevelopmental disorders are more commonly diagnosed in males, little is known regarding sex differences in early human brain development. Here, we used RNA sequencing data from a large collection of human brain samples from the second trimester of gestation (N = 120) to assess sex biases in gene expression within the human fetal brain. In addition to 43 genes (102 Ensembl transcripts) transcribed from the Y-chromosome in males, we detected sex differences in the expression of 2558 autosomal genes (2723 Ensembl transcripts) and 155 genes on the X-chromosome (207 Ensembl transcripts) at a false discovery rate (FDR) < 0.1. Genes exhibiting sex-biased expression in human fetal brain are enriched for high-confidence risk genes for autism and other developmental disorders. Male-biased genes are enriched for expression in neural progenitor cells, whereas female-biased genes are enriched for expression in Cajal-Retzius cells and glia. All gene- and transcript-level data are provided as an online resource (available at http://fgen.psycm.cf.ac.uk/FBSeq1) through which researchers can search, download and visualize data pertaining to sex biases in gene expression during early human brain development.

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Sex differences in the expression of lipid oxidation and glucose uptake genes in muscles of fasted mice

Vavilov Journal of Genetics and Breeding ◽

10.18699/vj19.462 ◽

2019 ◽

Vol 23 (1) ◽

pp. 62-66

Author(s):

N. A. Feofanova ◽

T. V. Yakovleva ◽

E. N. Makarova ◽

N. M. Bazhan

Keyword(s):

Gene Expression ◽

Body Weight ◽

Sex Differences ◽

Lipid Oxidation ◽

Blood Plasma ◽

Glucose Uptake ◽

Plasma Levels ◽

Fibroblast Growth Factor 21 ◽

Mrna Levels ◽

Expression Of Genes

Fasting has become increasingly popular for treatment and prevention of obesity. Sex differences in the mechanisms of adaptation to fasting may contribute to choosing a therapeutic strategy for correction of metabolic disorders. Hepatokine fibroblast growth factor 21 (FGF21) is involved in the adaptation to fasting. Muscles are assumed to be the main energy-consuming tissue in the body, as muscle metabolism plays an important role in the adaptation to nutritional deficit. However, there is still little information on sex differences in muscle and FGF21 physiological response to fasting. Our aim was to find out whether there were sex differences in hormonal regulation and the expression of genes controlling glucose and lipid metabolism in skeletal muscles in response to fasting. We estimated the effect of 24-hour fasting on the expression of genes involved in lipid (Ucp3, Cpt1) and carbohydrate (Slc2a4) metabolism in muscles and evaluated changes in body weight and blood plasma levels of glucose, insulin, free fatty acids (FFA), adiponectin, and FGF21 in male and female C57BL/6J mice. None of the genes studied (Ucp3, Cpt1 and Slc2a4) showed sex-related changes at mRNA levels in control groups, but females exposed to fasting demonstrated a significant increase in the expression of all genes as compared to control. Fasting significantly decreased body weight and glucose blood plasma levels in animals of both sexes but exerted no effect on the levels of insulin or FFA. The adiponectin and FGF21 levels were increased in response to fasting, the increase in females being significant. We were first to show sex dimorphism in muscle gene expression and FGF21 blood level in response to fasting. In females, the greater increase in FGF21 and adiponectin blood levels was positively associated with the greater upregulation of lipid oxidation and glucose uptake gene expression.

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The knowledge of chromosomal sex is important for large-scale analysis of gene expression

Reports of the National Academy of Sciences of Ukraine ◽

10.15407/dopovidi2021.01.100 ◽

2021 ◽

pp. 100-109

Author(s):

O.K. Lykhenko ◽

◽

M.Yu. Obolenskaya ◽

Keyword(s):

Gene Expression ◽

Gene Expression Data ◽

Large Scale ◽

Differentially Expressed ◽

Expression Data ◽

X Chromosomes ◽

Large Scale Analysis ◽

Expression Of Genes ◽

The Difference ◽

In Pregnancy

The aim of the study was to determine the sex of the fetus in gene expression data lacking this information using expression of the Y-linked genes, and to elucidate the difference between sex-chromosomal-linked gene expression between placental samples with XX and XY genotypes during pregnacy. We have detected 27 differentially expressed sex-chromosomes-linked genes. We have shown that, in most cases, the expression of genes from X-chromosomes in pregnancy carrying baby girls is higher than in pregnancy carrying baby boys, but there are exceptions to this pattern, which must be taken into account in large-scale studies of gene expression. The nature of the difference in gene expression during pregnancy carrying baby girls and boys (positive or ne gative difference) persists during pregnancy, but the magnitude of the difference may remain unchanged or decrease from the first to the third trimester. Taking sex dimorphism into account when analyzing large-scale gene expression data between trimesters of pregnancy increases the number of differentially expressed genes, which improves the informative value of the study and is important for elucidating the pathogenesis of pregnancy complications associated with placental dysfunction.

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Honey bee (Apis mellifera) larval pheromones regulate gene expression related to foraging task specialization

10.1101/587113 ◽

2019 ◽

Author(s):

R Ma ◽

J Rangel ◽

CM Grozinger

Keyword(s):

Gene Expression ◽

Honey Bee ◽

Foraging Behavior ◽

Behavioral Plasticity ◽

Molecular Level ◽

Social Signals ◽

Task Specialization ◽

Brain Gene Expression ◽

Expression Of Genes ◽

Foraging Task

AbstractBackgroundForaging behavior in honey bees (Apis mellifera) is a complex phenotype which is regulated by physiological state and social signals. How these factors are integrated at the molecular level to modulate foraging behavior has not been well-characterized. The transition of worker bees from nursing to foraging behavior is mediated by large-scale changes in brain gene expression, which are influenced by pheromones produced by the queen and larvae. Larval pheromones can also stimulate foragers to leave the colony to collect pollen, but the mechanisms underpinning this rapid behavioral plasticity are unknown. Furthermore, the mechanisms through which foragers specialize on collecting nectar or pollen, and how larval pheromones impact these different behavioral states, remains to be determined. Here, we investigated the patterns of gene expression related to rapid behavioral plasticity and task allocation among honey bee foragers exposed to two larval pheromones, brood pheromone (BP) and (E)-beta-ocimene (EBO).ResultsWe hypothesized that both pheromones would alter expression of genes in the brain related to foraging and would differentially impact expression of genes in the brains of pollen compared to nectar foragers. Combining data reduction, clustering, and network analysis methods, we found that foraging preference (nectar vs. pollen) and pheromone exposure are each associated with specific brain gene expression profiles. Furthermore, pheromone exposure has a strong transcriptional effect on genes that are preferentially expressed in nectar foragers. Representation factor analysis between our study and previous landmark honey bee transcriptome studies revealed significant overlaps for both pheromone communication and foraging task specialization.ConclusionsSocial signals (i.e. pheromones) may invoke foraging-related genes to upregulate pollen foraging at both long and short time scales. These results provide new insights into how social signals integrate with task specialization at the molecular level and highlights the important role that brain gene expression plays in behavioral plasticity across time scales.

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Sex-Biased Expression of Genes Allocated in the Autosomal Chromosomes: Lc-ms/ms Protein Profiling in Healthy Subjects

10.21203/rs.3.rs-353208/v1 ◽

2021 ◽

Author(s):

Hayder Ahmed Giha ◽

Rabab Asghar Abdulwahab ◽

Jaafar Abbas ◽

Zakia Shinwari ◽

Ayodele Alaiya

Keyword(s):

Gene Expression ◽

Protein Profiling ◽

Sex Hormone Binding Globulin ◽

Gene Localization ◽

Sex And Gender ◽

Serum Samples ◽

Expression Of Genes ◽

Bioinformatics Databases ◽

Health And Disease ◽

And Gender

Abstract Sex and gender has large impact in human health and disease prediction. Men differ from women by a limited number of genes in Y chromosome while their phenotypes differ markedly. In this study, serum samples from healthy Bahraini men and women were analyzed by LC-MS/MS. Bioinformatics databases were used for proteins/peptides (PPs) identification and their gene localization. Results revealed that, the PPs which differed significantly (p<0.05 ANOVA) in abundance with fold change (FC) of ³1.5, were twenty, 11 were up-regulated in women (up to 8-folds), and 9 were up-regulated in men but with much lower FC, however, all PPs are encoded by genes located in autosomal chromosomes, indicative of sex-biased gene expression. The only PP related to sex, the sex hormone-binding globulin, was up-regulated in women. The remaining PPs were involved in immunity (6), lipid metabolism (5), gene expression (3) connective tissue (3), and others. The identified PPs were discussed within their physiological and pathological context, in relation to sex e.g. Apo-B100 (pathological cholesterol) was unregulated in men while the inflammatory/immunity related PPs, including Alpha-1-acid glycoproteins, were up-regulated in women. Finally, we propose proteomic as an ideal complementary tool for study of the molecular basis of the sex-biased gene expression.

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Sex Differences in Rumen Fermentation and Microbiota of Tibetan Goat

10.21203/rs.3.rs-1070699/v1 ◽

2021 ◽

Author(s):

Xinyu Guo ◽

Yuzhu Sha ◽

Weibing Lv ◽

Xiaoning Pu ◽

Xiu Liu ◽

...

Keyword(s):

Sex Differences ◽

Gut Microbiota ◽

Rumen Fermentation ◽

Rumen Microbiota ◽

Rumen Epithelium ◽

Expression Of Genes ◽

Composition And Structure ◽

The Difference ◽

Fermentation Parameters ◽

And Function

Abstract Background: Gut microbiota play an important role in maintaining host metabolism, immune system and health, while sex, genotype, diet and health have certain effects on composition of gut microbiota. Therefore, in order to explore the sex differences in the structure and function of rumen microbiota in Tibetan goat, the study analyzed the sex differences in rumen fermentation parameters, rumen microbiota and the expression of genes related to VFAs transport in Tibetan goat. Results: The results showed that the content of acetic acid in the rumen of rams was significantly higher than that of ewes (P <0.05), and propionic acid and butyric acid were higher than that of ewes, but the difference was not significant (P >0.05); The expression of VFAs transport related genes DRA, AE2, MCT-1, NHE1, NHE2 in rumen epithelium of ewes was significantly higher than that of rams. Analysis of the composition and structure of rumen microbiota showed that there were significant sex differences in structure of rumen microbiota, and the abundance of rumen microbiota in ewes was higher than that in rams (P>0.05). At the phylum level, Firmicutes and Bacteroidetes were the dominant phyla of Tibetan goat, while Firmicutes was significantly higher in ewes than in rams (P<0.05). At the genus level, the relative abundance of Fibrobacter, Ruminococcus_1 and Pyramidobacter in ewes was significantly higher than that in rams (P<0.05). The function prediction results showed that Replication, recombination and repair, RNA processing and modification were mainly enriched in ewes (P<0.05). Conclusions: Correlation analysis revealed significant associations of some rumen microbiota with the fermentation product VFAs and VFAs transport-related genes. It is concluded that rams and ewes have a strong ability for fermenting and metabolizing when adapting to the plateau environment, which provides a certain sex reference basis for Tibetan goat adaptation to the plateau environment.

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