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二代测序技术的涌现推动了基因组学研究,特别是在疾病相关的遗传变异研究中发挥了重要作用.虽然大多数遗传变异类型都可以借助于各种二代测序分析工具进行检测,但是仍然存在局限性,比如短串联重复序列的长度变异.许多遗传疾病是由短串联重复序列的长度扩张导致的,尤其是亨廷顿病等多种神经系统疾病.然而,现在几乎没有工具能够利用二代测序检测长度大于测序读长的短串联重复序列变异.为了突破这一限制,我们开发了一个全新的方法,该方法基于双末端二代测序辨识短串联重复序列长度变异,并可估计其扩张长度,将其应用于一项基于全外显子组测序的运动神经元疾病临床研究中,成功地鉴定出致病的短串联重复序列长度扩张.该方法首次原创性地利用测序读长覆盖深度特征来解决短串联重复序列变异检测问题,在人类遗传疾病研究中具有广泛的应用价值,并且对于其他二代测序分析方法的开发具有启发性意义.
The advent of second-generation sequencing technologies has spurred genomics research, particularly in disease-related genetic variation studies, and while most types of genetic variation can be detected with the help of various second-generation sequencing analysis tools, they still exist Limitations such as length variation of short tandem repeats.Many genetic diseases are caused by the length expansion of short tandem repeats, especially various neurological diseases such as Huntington’s disease.However, few tools are now available to test with second-generation sequencing To overcome this limitation, we have developed a brand new method based on double-terminal sequencing to identify the length variation of short tandem repeats and to estimate the length of the expansion It was successfully used in a clinical study of motor neuron disease based on whole exome sequencing to successfully identify pathogenic short tandem repeats. This method, for the first time, uses in situ sequencing of the reads to cover depth features Detection of short tandem repeat variation in human genetic disease research has a wide range of Use value, and is instructive for the development of other second-generation sequencing methods.