The Research Institute of the Hospital de Sant Pau – IIB Sant Pau participates in a study published in the journal Science that reveals that biological sex has a small but widespread influence on the gene expression of almost every type of human tissue. Genes that are estimated to be expressed at different levels in adult women and men are involved in many different biological processes, including response to medication, control of blood glucose levels during pregnancy, and cancer.
Reference article: https://doi.org/10.1126/science.aba3066
The study is part of a set of articles (4 to Science, 1 to Cell and 8 in other scientific journals) published by the Consortium Genotype-Tissue Expression (GTEx), and is the culmination of a 10-year effort funded by the U.S. National Institutes of Health (NIH). The GTEx project is an international initiative that aims to build a comprehensive public repository for studying gene expression and its specific regulation in tissues.
Sex has a minor but relevant effect on the genetic contribution to gene regulation. The research team has discovered previously unreported connections between genes and complex attributes, including birth weight and body fat percentage. Therefore, these discoveries highlight the importance of considering sex as a biological variant in human genetics and genetic studies. If there are specific genes or genetic variants that differentially contribute to a particular attribute in men and women, gender-specific (or differentiated) biomarkers, therapies, drug doses, etc. could be considered. In the future, this knowledge may become a critical component of personalized medicine or may reveal the underlying biology of the disease that remains hidden when men and women are considered as a single group.
Sex differences have previously been attributed to hormones, sex chromosomes, differences in behavior and environmental factors, but the underlying molecular mechanisms of biology are largely unknown.
In this study, led by Barbara E. Stranger of the University of Chicago and Northwestern University, both in Illinois, USA, a scientific team from the Research Institute of the Hospital de Sant Pau-IIB Sant Pau, led by José Manuel Soria, from the Center for Genomic Regulation (CRG), specifically from Roderic Guigó’s group, and the University of Barcelona, and teams from other international centers, investigated the sexual differences in the transcriptome, which is the sum of all single-cell RNA transcripts, in 44 healthy human tissue types belonging to 838 people.
“Our work is a catalog of sex-differentiated effects to the human transcriptome that can serve as a reference when performing more extensive analyses to explore the role of sex in biology,” says Manuel Muñoz-Aguirre, co-author and researcher at the Center for Genomic Regulation. “We believe that this work can be useful to other scientific teams that wish to evaluate sex bias in diseases, which could eventually be transferred to clinical practice”.
José Manuel Soria, co-author of the article and head of the Complex Diseases Genomics Unit at the Sant Pau Hospital Research Institute – IIB Sant Pau, adds: “The implications of our study in Biomedicine are enormous. We must take into account that the risk of suffering from complex diseases (such as osteoporosis, endocrine diseases or stroke, among others), with an important genetic basis, is different between men and women. We also respond differently to medication if you are male or female. Thanks to our study we have a map of genetic expression that will allow us to know which genetic factors are responsible for these differential traits between the sexes. This information will be essential to establish models of disease prediction or response to drugs that affect men and women differently, which will improve their prevention, diagnosis and treatment in a personalized way (Personalized Medicine) “.
Gender differences in gene expression are reported in at least one tissue type in approximately one third of all human genes (37%). While not abundant, sexual effects on gene expression are mostly small. The number of sexually biased genes and their effects on dimensions are not dominated by either sex.
Sexually biased genes represent a diversity of molecular and biological functions, including genes relevant to some diseases and clinical phenotypes, many of which had not previously been associated with sexual differences at the molecular level. For example, the gene CYP450, associated with drug metabolism in humans in the liver, was found to be expressed differentially by sex across multiple tissues. The target genes of the epigenetic marker H3K27me3, associated with the sex-differentiated secretion of pituitary hormone for growth and development of the placenta, were also expressed differentially by sex in multiple tissues.
The scientific team also studied the genetic regulation of gene expression. Here sex had much less impact, with most of the uncovered effects observed to breast tissue, followed by shoulder, skin, and fat tissue. When they cross-referenced this data with results from 87 genome-wide association studies (GWAS) representing 74 different complex attributes, the team discovered 58 associations between genes and attributes that would have been lost through analysis that did not take sex into account, underlining the importance of considering sex as a biological variable in genomic analysis.
“These results suggest that sex differences in complex human attributes may derive, in part, from sexual differences in gene regulation. In the future, this knowledge could contribute to personalized medicine, in which we consider biological sex as one of the relevant components of a person’s characteristics,” stated Barbara E. Stranger, lead author of the study at Northwestern University, in Chicago, USA.
In women, the genetic regulation of CCDC88 is strongly linked to the progression of breast cancer, and HKDC1 to birth weight, possibly through the alteration of glucose metabolism in the liver of a pregnant woman. In men, genetic regulation of DPYSL4 was associated with body fat percentage and CLDN7 with birth weight. The scientific team also identified links between an uncharacterized gene, C9orf66, and the pattern of hair loss in men.
“Our study reveals links between genes and attributes that would have been lost through other analyses that did not take into account the sexual factor, which underlines the importance of considering sex as a biological variable in genomic analyses. In the near future, we believe that innovative, single-cell transcriptome-based methods that take sex into account may play an important role in fitting the pieces of the transcriptome to sex more extensively,” says Mertixell Oliva, co-first author of the study at the University of Chicago, USA, and a former researcher at the Center for Genomic Regulation.
It is important to highlight that the research team shows that despite the discovery of wide sexual differences at the transcriptome level, these effects are very small and their distribution between men and women overlapped. In fact, they highlight that most of the biology at all phenotypic levels between men and women is shared. They also highlight that the study has several limitations. The findings are based on a snapshot of mostly older people. The analyses also have not considered sexual differences that occur at developmental stages, in specific environmental situations, or in specific disease states.
The CRG authors of this study have also contributed to two other studies in the set of articles published by Consorcio GTEx. In the main article published by the GTEx Consortium, and in another manuscript, cell type composition was identified as a key factor in understanding the mechanisms of gene regulation in human tissues. They also discovered that the abundance of each cell type in human tissues is associated with specific features of the genome. The CRG scientific team has contributed to these articles by testing statistical methods to identify the presence of specific cell types in tissues based on gene expression.
Reference: Oliva M, Muñoz-Aguirre M, Guigó R and Stranger BE. “The impact of sex on gene expression across human tissues.” Science 369, eaba3066 (2020). DOI: https://doi.org/10.1126/science.aba3066
The GTEx Consortium. “The GTEx Consortium atlas of genetic regulatory effects across human tissues”. Science, Sep 11, 2020. DOI: https://doi.org/10.1126/science.aaz1776
Kim-Hellmuth et al. (including Muñoz-Aguirre M, Wucher V, Garrido-Martín D and Guigó R from CRG). “Cell type-specific genetic regulation of gene expression across human tissues”. Science 369, eaaz8528 (2020). DOI: https://doi.org/10.1126/science.aaz8528