The impact of sex on gene expression across human tissues. Oliva, M., Muñoz-Aguirre, M., Kim-Hellmuth, S., Wucher, V., Gewirtz, A. D. H., Cotter, D. J., Parsana, P., Kasela, S., Balliu, B., Viñuela, A., Castel, S. E., Mohammadi, P., Aguet, F., Zou, Y., Khramtsova, E. A., Skol, A. D., Garrido-Martín, D., Reverter, F., Brown, A., Evans, P., Gamazon, E. R., Payne, A., Bonazzola, R., Barbeira, A. N., Hamel, A. R., Martinez-Perez, A., Soria, J. M., Consortium§, G., Pierce, B. L., Stephens, M., Eskin, E., Dermitzakis, E. T., Segrè, A. V., Im, H. K., Engelhardt, B. E., Ardlie, K. G., Montgomery, S. B., Battle, A. J., Lappalainen, T., Guigó, R., & Stranger, B. E. Science, September, 2020. Publisher: American Association for the Advancement of Science Section: Research Article
The impact of sex on gene expression across human tissues [link]Paper  doi  abstract   bibtex   
The role of sex in the human transcriptome In humans, the inheritance of the XX or XY set of sex chromosomes is responsible for most individuals developing into adults expressing male or female sex-specific traits. However, the degree to which sex-biased gene expression occurs in tissues, especially those that do not contribute to characteristic sexually dimorphic traits. is unknown. Oliva et al. examined Genotype-Tissue Expression (GTEx) project data and found that 37% of genes in at least one of the 44 tissues studied exhibit a tissue-specific, sex-biased gene expression. They also identified a sex-specific variation in cellular composition across tissues. Overall, the effects of sex on gene expression were small, but they were genome-wide and mostly mediated through transcription factor binding. With sex-biased gene expression associated with loci identified in genome-wide association studies, this study lays the groundwork for identifying the molecular basis of male- and female-based diseases. Science, this issue p. eaba3066 Structured Abstract INTRODUCTIONMany complex human phenotypes, including diseases, exhibit sex-differentiated characteristics. These sex differences have been variously attributed to hormones, sex chromosomes, genotype × sex effects, differences in behavior, and differences in environmental exposures; however, their mechanisms and underlying biology remain largely unknown. The Genotype-Tissue Expression (GTEx) project provides an opportunity to investigate the prevalence and genetic mechanisms of sex differences in the human transcriptome by surveying many tissues that have not previously been characterized in this manner. RATIONALETo characterize sex differences in the human transcriptome and its regulation, and to discover how sex and genetics interact to influence complex traits and disease, we generated a catalog of sex differences in gene expression and its genetic regulation across 44 human tissue sources surveyed by the GTEx project (v8 data release), analyzing 16,245 RNA-sequencing samples and genotypes of 838 adult individuals. We report sex differences in gene expression levels, tissue cell type composition, and cis expression quantitative trait loci (cis-eQTLs). To assess their impact, we integrated these results with gene function, transcription factor binding annotation, and genome-wide association study (GWAS) summary statistics of 87 GWASs. RESULTSSex effects on gene expression are ubiquitous (13,294 sex-biased genes across all tissues). However, these effects are small and largely tissue-specific. Genes with sex-differentiated expression are not primarily driven by tissue-specific gene expression and are involved in a diverse set of biological functions, such as drug and hormone response, embryonic development and tissue morphogenesis, fertilization, sexual reproduction and spermatogenesis, fat metabolism, cancer, and immune response. Whereas X-linked genes with higher expression in females suggest candidates for escape from X-chromosome inactivation, sex-biased expression of autosomal genes suggests hormone-related transcription factor regulation and a role for additional transcription factors, as well as sex-differentiated distribution of epigenetic marks, particularly histone H3 Lys27 trimethylation (H3K27me3).Sex differences in the genetic regulation of gene expression are much less common (369 sex-biased eQTLs across all tissues) and are highly tissue-specific. We identified 58 gene-trait associations driven by genetic regulation of gene expression in a single sex. These include loci where sex-differentiated cell type abundances mediate genotype-phenotype associations, as well as loci where sex may play a more direct role in the underlying molecular mechanism of the association. For example, we identified a female-specific eQTL in liver for the hexokinase HKDC1 that influences glucose metabolism in pregnant females, which is subsequently reflected in the birth weight of the offspring. CONCLUSIONBy integrating sex-aware analyses of GTEx data with gene function and transcription factor binding annotations, we describe tissue-specific and tissue-shared drivers and mechanisms contributing to sex differences in the human transcriptome and eQTLs. We discovered multiple sex-differentiated genetic effects on gene expression that colocalize with complex trait genetic associations, thereby facilitating the mechanistic interpretation of GWAS signals. Because the causative tissue is unknown for many phenotypes, analysis of the diverse GTEx tissue collection can serve as a powerful resource for investigations into the basis of sex-biased traits. This work provides an extensive characterization of sex differences in the human transcriptome and its genetic regulation. \textlessimg class="fragment-image" aria-describedby="F1-caption" src="https://science.sciencemag.org/content/sci/369/6509/eaba3066/F1.medium.gif"/\textgreater Download high-res image Open in new tab Download Powerpoint Sex affects gene expression and its genetic regulation across tissues.Sex effects on gene expression were measured in 44 GTEx human tissue sources and integrated with genotypes of 838 subjects. Sex-biased expression is present in numerous biological pathways and is associated to sex-differentiated transcriptional regulation. Sex-biased expression quantitative trait loci in cis (sex-biased eQTLs) are partially mediated by cellular abundances and reveal gene-trait associations. TT, AT, and AA are genotypes for a single-nucleotide polymorphism; TF, transcription factor. Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation. Sex differences in the human transcriptome are widespread and tissue specific, and they contribute to complex traits. Sex differences in the human transcriptome are widespread and tissue specific, and they contribute to complex traits.
@article{oliva_impact_2020,
	title = {The impact of sex on gene expression across human tissues},
	volume = {369},
	copyright = {Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. https://www-sciencemag-org.stanford.idm.oclc.org/about/science-licenses-journal-article-reuseThis is an article distributed under the terms of the Science Journals Default License.},
	issn = {0036-8075, 1095-9203},
	url = {http://science.sciencemag.org/content/369/6509/eaba3066},
	doi = {10.1126/science.aba3066},
	abstract = {The role of sex in the human transcriptome
In humans, the inheritance of the XX or XY set of sex chromosomes is responsible for most individuals developing into adults expressing male or female sex-specific traits. However, the degree to which sex-biased gene expression occurs in tissues, especially those that do not contribute to characteristic sexually dimorphic traits. is unknown. Oliva et al. examined Genotype-Tissue Expression (GTEx) project data and found that 37\% of genes in at least one of the 44 tissues studied exhibit a tissue-specific, sex-biased gene expression. They also identified a sex-specific variation in cellular composition across tissues. Overall, the effects of sex on gene expression were small, but they were genome-wide and mostly mediated through transcription factor binding. With sex-biased gene expression associated with loci identified in genome-wide association studies, this study lays the groundwork for identifying the molecular basis of male- and female-based diseases.
Science, this issue p. eaba3066
Structured Abstract
INTRODUCTIONMany complex human phenotypes, including diseases, exhibit sex-differentiated characteristics. These sex differences have been variously attributed to hormones, sex chromosomes, genotype × sex effects, differences in behavior, and differences in environmental exposures; however, their mechanisms and underlying biology remain largely unknown. The Genotype-Tissue Expression (GTEx) project provides an opportunity to investigate the prevalence and genetic mechanisms of sex differences in the human transcriptome by surveying many tissues that have not previously been characterized in this manner.
RATIONALETo characterize sex differences in the human transcriptome and its regulation, and to discover how sex and genetics interact to influence complex traits and disease, we generated a catalog of sex differences in gene expression and its genetic regulation across 44 human tissue sources surveyed by the GTEx project (v8 data release), analyzing 16,245 RNA-sequencing samples and genotypes of 838 adult individuals. We report sex differences in gene expression levels, tissue cell type composition, and cis expression quantitative trait loci (cis-eQTLs). To assess their impact, we integrated these results with gene function, transcription factor binding annotation, and genome-wide association study (GWAS) summary statistics of 87 GWASs.
RESULTSSex effects on gene expression are ubiquitous (13,294 sex-biased genes across all tissues). However, these effects are small and largely tissue-specific. Genes with sex-differentiated expression are not primarily driven by tissue-specific gene expression and are involved in a diverse set of biological functions, such as drug and hormone response, embryonic development and tissue morphogenesis, fertilization, sexual reproduction and spermatogenesis, fat metabolism, cancer, and immune response. Whereas X-linked genes with higher expression in females suggest candidates for escape from X-chromosome inactivation, sex-biased expression of autosomal genes suggests hormone-related transcription factor regulation and a role for additional transcription factors, as well as sex-differentiated distribution of epigenetic marks, particularly histone H3 Lys27 trimethylation (H3K27me3).Sex differences in the genetic regulation of gene expression are much less common (369 sex-biased eQTLs across all tissues) and are highly tissue-specific. We identified 58 gene-trait associations driven by genetic regulation of gene expression in a single sex. These include loci where sex-differentiated cell type abundances mediate genotype-phenotype associations, as well as loci where sex may play a more direct role in the underlying molecular mechanism of the association. For example, we identified a female-specific eQTL in liver for the hexokinase HKDC1 that influences glucose metabolism in pregnant females, which is subsequently reflected in the birth weight of the offspring.
CONCLUSIONBy integrating sex-aware analyses of GTEx data with gene function and transcription factor binding annotations, we describe tissue-specific and tissue-shared drivers and mechanisms contributing to sex differences in the human transcriptome and eQTLs. We discovered multiple sex-differentiated genetic effects on gene expression that colocalize with complex trait genetic associations, thereby facilitating the mechanistic interpretation of GWAS signals. Because the causative tissue is unknown for many phenotypes, analysis of the diverse GTEx tissue collection can serve as a powerful resource for investigations into the basis of sex-biased traits. This work provides an extensive characterization of sex differences in the human transcriptome and its genetic regulation. {\textless}img class="fragment-image" aria-describedby="F1-caption" src="https://science.sciencemag.org/content/sci/369/6509/eaba3066/F1.medium.gif"/{\textgreater} Download high-res image Open in new tab Download Powerpoint Sex affects gene expression and its genetic regulation across tissues.Sex effects on gene expression were measured in 44 GTEx human tissue sources and integrated with genotypes of 838 subjects. Sex-biased expression is present in numerous biological pathways and is associated to sex-differentiated transcriptional regulation. Sex-biased expression quantitative trait loci in cis (sex-biased eQTLs) are partially mediated by cellular abundances and reveal gene-trait associations. TT, AT, and AA are genotypes for a single-nucleotide polymorphism; TF, transcription factor.
Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37\% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.
Sex differences in the human transcriptome are widespread and tissue specific, and they contribute to complex traits.
Sex differences in the human transcriptome are widespread and tissue specific, and they contribute to complex traits.},
	language = {en},
	number = {6509},
	urldate = {2020-09-10},
	journal = {Science},
	author = {Oliva, Meritxell and Muñoz-Aguirre, Manuel and Kim-Hellmuth, Sarah and Wucher, Valentin and Gewirtz, Ariel D. H. and Cotter, Daniel J. and Parsana, Princy and Kasela, Silva and Balliu, Brunilda and Viñuela, Ana and Castel, Stephane E. and Mohammadi, Pejman and Aguet, François and Zou, Yuxin and Khramtsova, Ekaterina A. and Skol, Andrew D. and Garrido-Martín, Diego and Reverter, Ferran and Brown, Andrew and Evans, Patrick and Gamazon, Eric R. and Payne, Anthony and Bonazzola, Rodrigo and Barbeira, Alvaro N. and Hamel, Andrew R. and Martinez-Perez, Angel and Soria, José Manuel and Consortium§, GTEx and Pierce, Brandon L. and Stephens, Matthew and Eskin, Eleazar and Dermitzakis, Emmanouil T. and Segrè, Ayellet V. and Im, Hae Kyung and Engelhardt, Barbara E. and Ardlie, Kristin G. and Montgomery, Stephen B. and Battle, Alexis J. and Lappalainen, Tuuli and Guigó, Roderic and Stranger, Barbara E.},
	month = sep,
	year = {2020},
	note = {Publisher: American Association for the Advancement of Science
Section: Research Article},
}
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