ATP-binding cassette (ABC) transporters constitute a superfamily of 48 structurally similar membrane transporters that mediate the ATP-dependent cellular export of a plethora of endogenous and xenobiotic substances. Importantly, genetic variants in ABC genes that affect gene function have clinically important effects on drug disposition and can be predictors of the risk of adverse drug reactions and efficacy of chemotherapeutics, calcium channel blockers, and protease inhibitors. Furthermore, loss-of-function of ABC transporters is associated with a variety of congenital disorders. Despite their clinical importance, information about the frequencies and global distribution of functionally relevant ABC variants is limited and little is known about the overall genetic complexity of this important gene family. Here, we systematically mapped the genetic landscape of the entire human ABC superfamily using Next-Generation Sequencing data from 138,632 individuals across seven major populations. Overall, we identified 62,793 exonic variants, 98.5% of which were rare. By integrating five computational prediction algorithms with structural mapping approaches using experimentally determined crystal structures, we found that the functional ABC variability is extensive and highly population-specific. Every individual harbored between 9.3 and 13.9 deleterious ABC variants, 76% of which were found only in a single population. Carrier rates of pathogenic variants in ABC transporter genes associated with autosomal recessive congenital diseases, such as cystic fibrosis or pseudoxanthoma elasticum, closely mirrored the corresponding population-specific disease prevalence, thus providing a novel resource for rare disease epidemiology. Combined, we provide the most comprehensive, systematic, and consolidated overview of ethnogeographic ABC transporter variability with important implications for personalized medicine, clinical genetics, and precision public health.

中文翻译：

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人类ABC转运蛋白的人种地理和个体间变异性。

ATP结合盒（ABC）转运蛋白构成48个结构相似的膜转运蛋白的超家族，这些膜转运蛋白介导大量内源性和异源性物质的ATP依赖性细胞输出。重要的是，影响基因功能的ABC基因中的遗传变异对药物的处置具有重要的临床意义，并且可以预测药物不良反应的风险以及化学疗法，钙通道阻滞剂和蛋白酶抑制剂的功效。此外，ABC转运蛋白的功能丧失与多种先天性疾病有关。尽管它们具有临床重要性，但有关功能相关的ABC变体的频率和全局分布的信息仍然有限，并且对该重要基因家族的整体遗传复杂性知之甚少。这里，我们使用来自七个主要人群的138,632个人的下一代测序数据，系统地绘制了整个人类ABC超家族的遗传景观。总体而言，我们鉴定出62,793个外显子变体，其中98.5％是罕见的。通过使用实验确定的晶体结构将五种计算预测算法与结构映射方法集成在一起，我们发现功能性ABC变异性广泛且具有高度的群体特异性。每个人都携带着9.3至13.9种有害的ABC变种，其中76％仅在单个人群中发现。与常染色体隐性先天性疾病（如囊性纤维化或弹性假黄瘤）相关的ABC转运蛋白基因的致病变异的携带率密切反映了相应的人群特异性疾病患病率，从而为罕见病流行病学提供了新的资源。综合起来，我们提供了民族地理ABC转运蛋白变异性的最全面，系统和综合的概述，对个性化医学，临床遗传学和精确的公共卫生具有重要意义。