Articles and Preprints

Impact Of The X Chromosome And Sex On Regulatory Variation

Kukurba, Kimberly R; Parsana, Princy; Smith, Kevin S.; Zappala, Zach; Knowles David A., Fave, Marie-Julie; Zhu, Xiaowei; Weissman, Myrna M.; Potash, James B.; Shi, Jianxin; Kundaje, Anshul; Levinson, Douglas F.; Awadalla, Philip; Mostafavi, Sara; Battle, Alexis; Montgomery, Stephen B

The unique mode of inheritance and regulatory mechanisms of the X chromosome has resulted in distinct patterns of evolution that shape its genetic architecture and the impact of genetic variation between the sexes. Due to these characteristics, however, the X chromosome has often been excluded from genetic analyses. We characterize the impact of the X chromosome and sex on human regulatory variation through analysis of genetic and gene expression data in a cohort of 922 individuals (whole blood RNA-sequencing from 274 males and 648 females). We identify higher variance in gene expression on the X chromosome compared to the autosomes and that differences in variance are more likely to be sex-specific on X due to the hemizygous exposure of cis regulatory variation in males. Furthermore, we identify that cis-expression quantitative trait loci (e@QTL) have weaker effects and influence fewer genes on the X chromosome compared to the autosomes, especially among genes with strong purifying selection. Despite this, we discover a higher proportion of sex-specific eQTLs on the X chromosome compared to autosomes. To subsequently identify the molecular mechanisms underlying discovered sex-specific eQTLs, we generate and connect sex-specific chromatin accessibility (ATAC-seq) to sex-specific expression and eQTL. Furthermore, as sex-specific eQTL can inform sex-specific effects of genetic variation on disease, we integrate eQTL with genome-wide association study data for multiple immune traits to identify sex-specific effect sizes for multiple trait loci. Together, our study provides a genome-wide understanding of how the X chromosome and sex shape human gene regulation and disease.


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February 1, 2022