Integrating genome structure information and statistical analysis of co-segregation of rare genetic variants with phenotypes in families

在家族遗传学研究中，具有感兴趣表型的亲属共享稀有遗传变异(RV)是推断RV参与表型的关键信息。我带头开发了在远亲对象之间分享房车的概率，作为将房车与一种表型联系起来的基础。将这种方法应用于全基因组测序研究面临着一些挑战：1)目前还没有一种有效的方法来分组基因间变异，预计这些变异对基因调控有类似的影响；2)RV的丰富意味着在需要精确描绘的小基因组区域内，多个RV出现在同一单倍型上；以及3)由于表面上不相关的家庭成员之间的未知关系，RV共享的概率可能被低估。我建议在我的研究计划中通过以下具体目标来应对这些挑战：

In familial genetic studies, sharing of rare genetic variants (RVs) by relatives with a phenotype of interest is a key piece of information to infer the involvement of the RVs in the phenotype. I have spearheaded the development of RV sharing probabilities among distantly related subjects as basis to link RVs to a phenotype. The application of this approach to whole genome sequencing studies presents a number of challenges: 1) there is currently no validated approach to group intergenic variants expected to have a similar impact on gene regulation; 2) the abundance of RVs implies that multiple RVs occur on the same haplotype within small genomic regions which need to be precisely delineated and 3) RV sharing probabilities may be underestimated due to unknown relationships among apparently unrelated family members. I propose to address these challenges in my research program through the following specific objectives: