UCD School of Biology and Environmental Science & UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin Dublin, Ireland.
Evol Appl. 2013 Apr;6(3):412-22. doi: 10.1111/eva.12047. Epub 2013 Mar 28.
Hereditary deafness affects 0.1% of individuals globally and is considered as one of the most debilitating diseases of man. Despite recent advances, the molecular basis of normal auditory function is not fully understood and little is known about the contribution of single-nucleotide variations to the disease. Using cross-species comparisons of 11 'deafness' genes (Myo15, Ush1 g, Strc, Tecta, Tectb, Otog, Col11a2, Gjb2, Cldn14, Kcnq4, Pou3f4) across 69 evolutionary and ecologically divergent mammals, we elucidated whether there was evidence for: (i) adaptive evolution acting on these genes across mammals with similar hearing capabilities; and, (ii) regions of long-term evolutionary conservation within which we predict disease-associated mutations should occur. We find evidence of adaptive evolution acting on the eutherian mammals in Myo15, Otog and Tecta. Examination of selection pressures in Tecta and Pou3f4 across a taxonomic sample that included a wide representation of auditory specialists, the bats, did not uncover any evidence for a role in echolocation. We generated 'conservation indices' based on selection estimates at nucleotide sites and found that known disease mutations fall within sites of high evolutionary conservation. We suggest that methods such as this, derived from estimates of evolutionary conservation using phylogenetically divergent taxa, will help to differentiate between deleterious and benign mutations.
遗传性耳聋影响全球 0.1%的个体，被认为是人类最致残的疾病之一。尽管最近取得了进展，但正常听觉功能的分子基础仍未完全理解，并且对于单核苷酸变异对疾病的贡献知之甚少。通过对 11 个“耳聋”基因（Myo15、Ush1g、Strc、Tecta、Tectb、Otog、Col11a2、Gjb2、Cldn14、Kcnq4、Pou3f4）在 69 种进化和生态上有差异的哺乳动物中的跨物种比较，我们阐明了是否有证据表明：（i）在具有相似听力能力的哺乳动物中，这些基因是否存在适应性进化；以及，（ii）是否存在长期进化保守的区域，我们预测疾病相关的突变应该发生在这些区域。我们发现，Myo15、Otog 和 Tecta 中的真兽类哺乳动物存在适应性进化的证据。在包括广泛代表听觉专家的蝙蝠在内的分类样本中，对 Tecta 和 Pou3f4 中的选择压力进行检查，并未发现任何与回声定位有关的作用证据。我们根据核苷酸位点的选择估计生成了“保守指数”，并发现已知的疾病突变发生在高度进化保守的位点。我们认为，这种基于从进化上有差异的分类单元推断出的进化保守性估计的方法，将有助于区分有害和良性突变。
