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Sauteraud R, Stahl JM, James J, et al. Inferring genes that escape X-Chromosome inactivation reveals important contribution of variable escape genes to sex-biased diseases. Genome Res. 2021;31(9):1629-1637doi: 10.1101/gr.275677.121.
Sauteraud, R., Stahl, J. M., James, J., Englebright, M., Chen, F., Zhan, X., Carrel, L., & Liu, D. J. (2021). Inferring genes that escape X-Chromosome inactivation reveals important contribution of variable escape genes to sex-biased diseases. Genome research, 31(9), 1629-1637. https://doi.org/10.1101/gr.275677.121
Sauteraud, Renan, et al. "Inferring genes that escape X-Chromosome inactivation reveals important contribution of variable escape genes to sex-biased diseases." Genome research vol. 31,9 (2021): 1629-1637. doi: https://doi.org/10.1101/gr.275677.121
Sauteraud R, Stahl JM, James J, Englebright M, Chen F, Zhan X, Carrel L, Liu DJ. Inferring genes that escape X-Chromosome inactivation reveals important contribution of variable escape genes to sex-biased diseases. Genome Res. 2021 Sep;31(9):1629-1637. doi: 10.1101/gr.275677.121. Epub 2021 Aug 23. PMID: 34426515; PMCID: PMC8415373.
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Genome Res. 2021 Sep;31(9):1629-1637. doi: 10.1101/gr.275677.121. Epub 2021 Aug 23.

Inferring genes that escape X-Chromosome inactivation reveals important contribution of variable escape genes to sex-biased diseases.

Genome research

Renan Sauteraud, Jill M Stahl, Jesica James, Marisa Englebright, Fang Chen, Xiaowei Zhan, Laura Carrel, Dajiang J Liu

Affiliations

  1. Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania 17033, USA.
  2. Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, Pennsylvania 17033, USA.
  3. Institute for Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania 17033, USA.
  4. Department of Clinical Science, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8821, USA.

PMID: 34426515 PMCID: PMC8415373 DOI: 10.1101/gr.275677.121

Abstract

The X Chromosome plays an important role in human development and disease. However, functional genomic and disease association studies of X genes greatly lag behind autosomal gene studies, in part owing to the unique biology of X-Chromosome inactivation (XCI). Because of XCI, most genes are only expressed from one allele. Yet, ∼30% of X genes "escape" XCI and are transcribed from both alleles, many only in a proportion of the population. Such interindividual differences are likely to be disease relevant, particularly for sex-biased disorders. To understand the functional biology for X-linked genes, we developed X-Chromosome inactivation for RNA-seq (XCIR), a novel approach to identify escape genes using bulk RNA-seq data. Our method, available as an R package, is more powerful than alternative approaches and is computationally efficient to handle large population-scale data sets. Using annotated XCI states, we examined the contribution of X-linked genes to the disease heritability in the United Kingdom Biobank data set. We show that escape and variable escape genes explain the largest proportion of X heritability, which is in large part attributable to X genes with Y homology. Finally, we investigated the role of each XCI state in sex-biased diseases and found that although XY homologous gene pairs have a larger overall effect size, enrichment for variable escape genes is significantly increased in female-biased diseases. Our results, for the first time, quantitate the importance of variable escape genes for the etiology of sex-biased disease, and our pipeline allows analysis of larger data sets for a broad range of phenotypes.

© 2021 Sauteraud et al.; Published by Cold Spring Harbor Laboratory Press.

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