Population-scale variability of the human UDP-glycosyltransferase +gene family
+This repository was created to maintain version control of this +pharmacogenomics project at Karolinska Institutet (KI) under the +supervision of Volker M. Lauschke and Yitian Zhou.
+Abstract
+Human UDP-glycosyltransferases (UGTs) are responsible for the +glycosylation of a wide variety of endogenous substrates and commonly +prescribed drugs. Different genetic polymorphisms in UGT genes are +implicated in interindividual differences in drug response and cancer +risk. However, the genetic complexity beyond these variants has not been +comprehensively assessed. We here leveraged whole-exome and whole-genome +sequencing data from 141,456 unrelated individuals across 7 major human +populations to provide a comprehensive profile of genetic variability +across the human UGT gene family. Overall, 9666 exonic variants were +observed of which 98.9% were rare. To interpret the functional impact of +UGT missense variants, we developed a gene family-specific variant +effect predictor. This algorithm identified a total of 1208 deleterious +variants, most of which were found in African and South Asian +populations. Structural analysis corroborated the predicted effects for +multiple variations in substrate binding sites. Combined, our analyses +provide a systematic overview of UGT variability, which can yield +insights into interindividual differences in phase 2 metabolism and +facilitate the translation of sequencing data into personalized +predictions of UGT substrate disposition.
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Global landscape of human UGT variability. A: +Schematic representation of the canonical transcripts of the UGT1A and +UGT2A loci, including gene-specific and shared exons. +B: The total number of variants across the four human +UGT gene families is shown. C: The distribution of +variant types is shown for all exonic variants. D: Of +all exonic UGT variants, 98.9% and 97.4% were rare or very rare with +global MAF <1% and <0.1%, respectively. Furthermore, 59.8% were +singletons found only in one individual. E: Observed +against expected missense-to-synonymous variant ratio indicates the +mutational constraints of all human UGT genes. Abbreviations: MAF: minor +allele frequency.
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Ethnogeographic variability within the human UGT gene family. +A: Frequency distribution of the UGT1A1 promoter polymorphism +across seven human populations. B: MAFs of putatively +deleterious variants across all UGT genes. Only the variants that map to +gene-specific exons are shown for each gene. Variants localized in +shared exons of the UGT1A or UGT2A loci are shown as UGT1A[1−10] and +UGT2A[1−2], respectively. C: The average number of +deleterious UGT variants per individual is shown for different +populations. The eight variants responsible for the largest +contributions to overall functional variability are shown +individually.
+Data access
+No raw data were generated in this project. All used data can be +directly downloaded from the corresponding cited sources (gnomAD, +Ensembl, ClinVar, AlphaMissense, and COSMIC).
+Code availability
+All code run in R/Bash required to perform the analyses and produce +the figures and results can be found in the code +section where they are carefully described.
+Article citation
+++González-Padilla, D., Camara, M. D., Lauschke, V. M., & Zhou, Y. +(2024). Population-scale variability of the human +UDP-glycosyltransferase gene family. Journal of Genetics and Genomics. +doi: https://doi.org/10.1016/j.jgg.2024.06.018
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