Sex-biased genetic effects on gene regulation in humans

Human regulatory variation, reported as expression quantitative trait loci (eQTLs), contributes to differences between populations and tissues. The contribution of eQTLs to differences between sexes, however, has not been investigated to date. Here we explore regulatory variation in females and males and demonstrate that 12%-15% of autosomal eQTLs function in a sex-biased manner. We show that genes possessing sex-biased eQTLs are expressed at similar levels across the sexes and highlight cases of genes controlling sexually dimorphic and shared traits that are under the control of distinct regulatory elements in females and males. This study illustrates that sex provides important context that can modify the effects of functional genetic variants.

[1]  Kui Liu,et al.  Expression and localization of the serine proteases high-temperature requirement factor A1, serine protease 23, and serine protease 35 in the mouse ovary. , 2008, Endocrinology.

[2]  E. Dermitzakis,et al.  Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic Associations , 2010, PLoS genetics.

[3]  John D. Storey,et al.  A Genome-Wide Gene Expression Signature of Environmental Geography in Leukocytes of Moroccan Amazighs , 2008, PLoS genetics.

[4]  S. Hunt,et al.  Genome-Wide Associations of Gene Expression Variation in Humans , 2005, PLoS genetics.

[5]  M. Olivier.  A haplotype map of the human genome , 2003, Nature.

[6]  Judy H. Cho,et al.  Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease , 2008, Nature Genetics.

[7]  R. J. McFarlane,et al.  Biological roles of translin and translin-associated factor-X: RNA metabolism comes to the fore. , 2010, The Biochemical journal.

[8]  G. Churchill,et al.  Influence of sex and diet on quantitative trait loci for HDL cholesterol levels in an SM/J by NZB/BlNJ intercross population Published, JLR Papers in Press, March 1, 2004. DOI 10.1194/jlr.M300460-JLR200 , 2004, Journal of Lipid Research.

[9]  P. Deloukas,et al.  Patterns of Cis Regulatory Variation in Diverse Human Populations , 2012, PLoS genetics.

[10]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[11]  S. L. Wong,et al.  Towards a proteome-scale map of the human protein–protein interaction network , 2005, Nature.

[12]  H. Lehrach,et al.  A Human Protein-Protein Interaction Network: A Resource for Annotating the Proteome , 2005, Cell.

[13]  Philippe Rigault,et al.  A novel, high-performance random array platform for quantitative gene expression profiling. , 2004, Genome research.

[14]  Yoav Gilad,et al.  The effects of EBV transformation on gene expression levels and methylation profiles. , 2011, Human molecular genetics.

[15]  Wei Zhang,et al.  Gene Set Enrichment Analyses Revealed Differences in Gene Expression Patterns between Males and Females , 2009, Silico Biol..

[16]  N. Chen,et al.  Chemokine-like factor 1, a novel cytokine, induces nerve cell migration through the non-extracellular Ca2+-dependent tyrosine kinases pathway , 2010, Brain Research.

[17]  Nathalie Delorme,et al.  Prosaposin down-modulation decreases metastatic prostate cancer cell adhesion, migration, and invasion , 2010, Molecular Cancer.

[18]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

[19]  A. Arnold,et al.  Tissue-specific expression and regulation of sexually dimorphic genes in mice. , 2006, Genome research.

[20]  R. Guigó,et al.  Transcriptome genetics using second generation sequencing in a Caucasian population , 2010, Nature.

[21]  Wei Zhang,et al.  Gender-specific differences in expression in human lymphoblastoid cell lines , 2007, Pharmacogenetics and genomics.

[22]  E. Birney,et al.  Heritable Individual-Specific and Allele-Specific Chromatin Signatures in Humans , 2010, Science.

[23]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[24]  Thomas Meitinger,et al.  Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution , 2010, Nature Genetics.

[25]  K. Dewar,et al.  Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. , 2009, American journal of human genetics.

[26]  T. Mackay,et al.  Sex-specific quantitative trait loci affecting longevity in Drosophila melanogaster. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[27]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[28]  S. Carroll,et al.  Genetic and molecular insights into the development and evolution of sexual dimorphism , 2009, Nature Reviews Genetics.

[29]  M. Olivier.  A haplotype map of the human genome. , 2003, Nature.

[30]  P. Deloukas,et al.  Common Regulatory Variation Impacts Gene Expression in a Cell Type–Dependent Manner , 2009, Science.

[31]  R. Daniel Camerini-Otero,et al.  The Expression Profile of the Major Mouse SPO11 Isoforms Indicates that SPO11β Introduces Double Strand Breaks and Suggests that SPO11α Has an Additional Role in Prophase in both Spermatocytes and Oocytes , 2010, Molecular and Cellular Biology.

[32]  Yoav Gilad,et al.  Sex-specific genetic architecture of human disease , 2008, Nature Reviews Genetics.

[33]  Joseph T. Glessner,et al.  Common variants at 5q22 associate with pediatric eosinophilic esophagitis , 2010, Nature Genetics.

[34]  Simon C. Potter,et al.  The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study , 2011, PLoS genetics.

[35]  R. Redon,et al.  Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes , 2007, Science.

[36]  F. Collins,et al.  Potential etiologic and functional implications of genome-wide association loci for human diseases and traits , 2009, Proceedings of the National Academy of Sciences.

[37]  Jing Cui,et al.  Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci , 2010, Nature Genetics.