Heterozygosity mapping for human dominant trait variants
Heterozygosity mapping for human dominant trait variants
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DOI：
10.1002/humu.23765
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发表时间：
2019-07-01
期刊：
影响因子：
3.9
通讯作者：
Ott, Jurg
中科院分区：
文献类型：
--
作者：
Imai-Okazaki, Atsuko;Li, Yi;Ott, Jurg
纯合性作图是一种众所周知的技术，用于识别可能含有导致常染色体隐性遗传疾病的基因的纯合变异，但一直缺乏用于常染色体显性性状的类似方法。我们开发了一种基于显性性状附近序列变异的杂合频率来绘制显性疾病基因图谱的方法。我们通过理论分析证明，与基因组其他地方的变异相比，围绕遗传性显性疾病变异的 DNA 变异往往具有更高的杂合性。我们在家庭成员和无关群体对照中获得的已知显性致病变异的序列数据中证实了这种现象的存在。与我们的测试统计数据相关的基于计算机的经验显着性水平估计方法显示，对于许多（但不是全部）携带致病性变异的个体，全基因组 p 值小于 0.05。
Homozygosity mapping is a well-known technique to identify runs of homozygous variants that are likely to harbor genes responsible for autosomal recessive disease, but a comparable method for autosomal dominant traits has been lacking. We developed an approach to map dominant disease genes based on heterozygosity frequencies of sequence variants in the immediate vicinity of a dominant trait. We demonstrate through theoretical analysis that DNA variants surrounding an inherited dominant disease variant tend to have increased heterozygosity compared with variants elsewhere in the genome. We confirm existence of this phenomenon in sequence data with known dominant pathogenic variants obtained on family members and in unrelated population controls. A computer-based approach to estimating empirical significance levels associated with our test statistics shows genome-wide p-values smaller than 0.05 for many but not all of the individuals carrying a pathogenic variant.