Homo sapiens Raw sequence reads

For autosomal dominant diseases, if an affected child is born to unaffected parents it must be due to a new mutation in one of the parent's germlines. For some diseases, the frequency of such new cases is orders of magnitude greater than expected based on the small number of causal mutations. Examples include Apert syndrome, achondroplasia, MEN2B, Noonan syndrome, and Rett syndrome. These diseases share four characteristics leading to the acronym RAMP: Recurrent mutations, Autosomal dominant, Male biased (new mutation is almost always in the father's germline), and Paternal age effect (older fathers are more likely to have affected children than younger fathers). One possibility is that these disease mutations are mutation hotspots, another is that these mutations are positively selected for in the male germline. The hotspot hypothesis predicts that the mutations will be spatially uniform, while germline selection predicts that they will be clustered. We have studied the spatial distribution of disease mutations in testes from normal donors and found that they were strongly clustered, supporting the germline selection hypothesis. We are continuing our work studying germline selection, in particular, studying the feasibility of using the Safe Sequencing System to measure extremely rare mutation frequencies.

针对常染色体显性遗传病（autosomal dominant diseases），若表型正常的父母生育了患病子女，则致病根源必然为父母一方生殖细胞发生的新发突变。部分此类疾病的新发突变病例数，较基于少量致病突变位点所预期的频率高出数个数量级。相关病例包括阿佩尔综合征（Apert syndrome）、软骨发育不全（achondroplasia）、多发性内分泌腺瘤2B型（MEN2B）、努南综合征（Noonan syndrome）以及雷特综合征（Rett syndrome）。这类疾病具备四大共同特征，据此可缩写为RAMP：复发性突变（Recurrent mutations）、常染色体显性遗传（Autosomal dominant）、男性偏倚（新发突变几乎均源自父亲的生殖细胞）以及父亲年龄效应（年龄较大的父亲相较于年轻父亲，生育患病子女的概率更高）。针对该现象存在两种主流假说：其一为突变热点假说，即此类疾病相关突变为突变热点区域；其二为生殖细胞正向选择假说，即此类突变在男性生殖细胞中受到正向选择。突变热点假说预测突变位点在空间上呈均匀分布，而生殖细胞选择假说则预测突变位点会呈现聚集特征。我们针对正常供体的睾丸组织中疾病突变的空间分布开展了研究，结果显示突变位点呈现显著聚集，这一发现支持了生殖细胞选择假说。目前我们仍在持续推进生殖细胞选择相关研究，其中重点探究利用安全测序系统（Safe Sequencing System）测量极罕见突变频率的可行性。