Transcriptomic signatures of rare variant impacts across sex and the X chromosome
Summary: The human X chromosome contains hundreds of genes and has well-established impacts on sex differences and traits. However, the X chromosome is often excluded from many genetic analyses, limiting broader understanding of variant effects. In particular, the functional impact of rare variants...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-07-01
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| Series: | HGG Advances |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247725000661 |
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| author | Rachel A. Ungar Taibo Li Nikolai G. Vetr Nicole Ersaro Alexis Battle Stephen B. Montgomery |
| author_facet | Rachel A. Ungar Taibo Li Nikolai G. Vetr Nicole Ersaro Alexis Battle Stephen B. Montgomery |
| author_sort | Rachel A. Ungar |
| collection | DOAJ |
| description | Summary: The human X chromosome contains hundreds of genes and has well-established impacts on sex differences and traits. However, the X chromosome is often excluded from many genetic analyses, limiting broader understanding of variant effects. In particular, the functional impact of rare variants on the X chromosome is understudied. To investigate functional rare variants on the X chromosome, we use observations of outlier gene expression from Genotype Tissue Expression consortium data. We show that outlier genes are enriched for having nearby rare variants on the X chromosome, and this enrichment is stronger for males. Using the RIVER model, we identified 733 rare variants in 450 genes predicted to have functional differences between males and females. We examined the pharmacogenetic implications of these variants and observed that 25% of drugs with a known sex difference in adverse drug reactions were connected to genes that contained a sex-biased rare variant. We further identify that sex-biased rare variants preferentially impact transcription factors with predicted sex-differential binding, such as the XIST-modulated SIX1. Overall, we observed more within-sex variation than between-sex variation. Combined, our study investigates functional rare variants on the X chromosome, and further details how sex stratification of variant effect prediction improves identification of rare variants with predicted sex-biased effects, transcription factor biology, and pharmacogenomic impacts. |
| format | Article |
| id | doaj-art-07b9d9dbdc9546809bb84802a09210a6 |
| institution | OA Journals |
| issn | 2666-2477 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj-art-07b9d9dbdc9546809bb84802a09210a62025-08-20T02:10:03ZengElsevierHGG Advances2666-24772025-07-016310046310.1016/j.xhgg.2025.100463Transcriptomic signatures of rare variant impacts across sex and the X chromosomeRachel A. Ungar0Taibo Li1Nikolai G. Vetr2Nicole Ersaro3Alexis Battle4Stephen B. Montgomery5Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA; Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USADepartment of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USADepartment of Pathology, School of Medicine, Stanford University, Stanford, CA, USADepartment of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, USADepartment of Computer Science, Johns Hopkins University, Baltimore, MD, USADepartment of Genetics, School of Medicine, Stanford University, Stanford, CA, USA; Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA; Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, USA; Corresponding authorSummary: The human X chromosome contains hundreds of genes and has well-established impacts on sex differences and traits. However, the X chromosome is often excluded from many genetic analyses, limiting broader understanding of variant effects. In particular, the functional impact of rare variants on the X chromosome is understudied. To investigate functional rare variants on the X chromosome, we use observations of outlier gene expression from Genotype Tissue Expression consortium data. We show that outlier genes are enriched for having nearby rare variants on the X chromosome, and this enrichment is stronger for males. Using the RIVER model, we identified 733 rare variants in 450 genes predicted to have functional differences between males and females. We examined the pharmacogenetic implications of these variants and observed that 25% of drugs with a known sex difference in adverse drug reactions were connected to genes that contained a sex-biased rare variant. We further identify that sex-biased rare variants preferentially impact transcription factors with predicted sex-differential binding, such as the XIST-modulated SIX1. Overall, we observed more within-sex variation than between-sex variation. Combined, our study investigates functional rare variants on the X chromosome, and further details how sex stratification of variant effect prediction improves identification of rare variants with predicted sex-biased effects, transcription factor biology, and pharmacogenomic impacts.http://www.sciencedirect.com/science/article/pii/S2666247725000661rare variantX chromosomemachine learningsex differences |
| spellingShingle | Rachel A. Ungar Taibo Li Nikolai G. Vetr Nicole Ersaro Alexis Battle Stephen B. Montgomery Transcriptomic signatures of rare variant impacts across sex and the X chromosome HGG Advances rare variant X chromosome machine learning sex differences |
| title | Transcriptomic signatures of rare variant impacts across sex and the X chromosome |
| title_full | Transcriptomic signatures of rare variant impacts across sex and the X chromosome |
| title_fullStr | Transcriptomic signatures of rare variant impacts across sex and the X chromosome |
| title_full_unstemmed | Transcriptomic signatures of rare variant impacts across sex and the X chromosome |
| title_short | Transcriptomic signatures of rare variant impacts across sex and the X chromosome |
| title_sort | transcriptomic signatures of rare variant impacts across sex and the x chromosome |
| topic | rare variant X chromosome machine learning sex differences |
| url | http://www.sciencedirect.com/science/article/pii/S2666247725000661 |
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