Cystic Fibrosis (CF) is caused most often by removal of amino acid 508 (Phe508del, deltaF508) within CFTR, yet dozens of additional CFTR variants are known to give rise to CF and many variants in the genome are known to contribute to CF pathology. To address CFTR coding variants, we developed a sequence-to-structure-to-dynamic matrix for all amino acids of CFTR using 233 vertebrate species, CFTR structure within a lipid membrane, and 20 ns of molecular dynamic simulation to assess known variants from the CFTR1, CFTR2, ClinVar, TOPmed, gnomAD, and COSMIC databases. Surprisingly, we identify 18 variants of uncertain significance within CFTR from diverse populations that are heritable and a likely cause of CF that have been understudied due to nonexistence in Caucasian populations. In addition, 15 sites within the genome are known to modulate CF pathology, where we have identified one genome region (chr11:34754985-34836401) that contributes to CF through modulation of expression of a noncoding RNA in epithelial cells. These 15 sites are just the beginning of understanding comodifiers of CF, where utilization of eQTLs suggests many additional genomics of CFTR expressing cells that can be influenced by genomic background of CFTR variants. This work highlights that many additional insights of CF genetics are needed, particularly as pharmaceutical interventions increase in the coming years.

囊性纤维化 (CF) 最常见的原因是去除 CFTR 中的 508 号氨基酸（Phe508del、deltaF508），但已知还有数十种其他 CFTR 变异会导致 CF，并且已知基因组中的许多变异会导致 CF 病理学。为了解决 CFTR 编码变异问题，我们使用 233 种脊椎动物物种、脂膜内的 CFTR 结构以及 20 ns 的分子动态模拟，为 CFTR 的所有氨基酸开发了一个从序列到结构到动态的矩阵，以评估来自CFTR1、CFTR2、ClinVar、TOPmed、gnomAD 和 COSMIC 数据库。令人惊讶的是，我们从不同人群中发现了 CFTR 中具有不确定意义的 18 种变异，这些变异是可遗传的，并且可能是 CF 的原因，但由于在高加索人群中不存在，因此尚未得到充分研究。此外，已知基因组内的 15 个位点可调节 CF 病理学，我们在其中鉴定了一个基因组区域 (chr11:34754985-34836401)，该区域通过调节上皮细胞中非编码 RNA 的表达而有助于 CF。这 15 个位点只是了解 CF 共修饰符的开始，其中 eQTL 的利用表明 CFTR 表达细胞的许多其他基因组可能受到 CFTR 变体基因组背景的影响。这项工作强调，需要对 CF 遗传学进行许多额外的了解，特别是随着未来几年药物干预措施的增加。