瑞典卡洛琳斯卡研究所Yitian Zhou等研究人员合作揭示人类UDP-糖基转移酶基因家族的种群规模变异性。相关论文于2024年7月4日在线发表在《遗传学报》上。

研究人员利用来自七大主要人群的141456名无关个体的全外显子组和全基因组测序数据，提供了人类UDP-糖基转移酶（UGT）基因家族遗传变异的全面概况。总体上，观察到9666种外显子变异，其中98.9%为罕见变异。为了解释UGT错义变异的功能影响，研究人员开发了一个基因家族特定的变异效应预测器。该算法共识别出1208种有害变异，其中大多数在非洲和南亚人群中发现。

结构分析证实了多种底物结合位点变异的预测效果。综合分析提供了UGT变异的系统概览，可以深入了解个体间二相代谢的差异，并有助于将测序数据转化为个性化的UGT底物处置预测。

研究人员表示，人类UGT负责对多种内源性底物和多种常用药物进行葡萄糖醛酸化。UGT基因中的不同遗传多态性与个体间药物反应和癌症风险的差异有关。然而，这些变异之外的遗传复杂性尚未得到全面评估。

附：英文原文

Title: Population-scale variability of the human UDP-glycosyltransferase gene family

Author: Volker M. Lauschke a b c d, Yitian Zhou a b

Issue&Volume: 2024/07/04

Abstract: Human UDP-glycosyltransferases (UGTs) are responsible for the glucuronidation of a wide variety of endogenous substrates and multiple 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 seven 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 inter-individual differences in phase 2 metabolism and facilitate the translation of sequencing data into personalized predictions of UGT substrate disposition.

DOI: 10.1016/j.jgg.2024.06.018

Source: https://www.sciencedirect.com/science/article/pii/S1673852724001619