Inbred Mice Strains: Untapped Resource For Genome-Wide Quantitative Association Study For Craniofacial Shape

项目摘要/摘要 全基因组关联研究(GWAS)涉及扫描基因组中的密集基因标记以 找出与特定表型相关的遗传变异。虽然它们更常用于 病例/对照设计寻找与疾病相关的变异，表型可以是定量的，也可以是 用来理解遗传基础的表型变异。现在有五个GWA试图发现基因 导致多个不同人群的正常面部变异。对于一个复杂的特征，比如 脸型，这些研究的结果有些平淡无奇。每项研究似乎都确定了 一组独特的基因，在多项研究中只复制了PAX3。一些不同之处可能是 由于表型的量化方式和使用的统计分析的不同。潜在的更多 令人担忧的是，这些研究中所测量的东西缺乏组织特异性。传统套装 人类面部的解剖标志聚集在眼睛、鼻子和嘴巴周围。虽然这些地标是 由于它们的可重复性和易于捕获而被选中，本质上它们位于将受到 肌肉张力和神经、脂肪量、年龄和面部表情，所有这些都有实质性的 与之相关的环境噪音。毫无疑问，脸型在很大程度上是由人决定的 在遗传学上，该信号可能在目前测量到的人类面部GWA型中丢失。在这里我们 建议评估一种潜在的未开发资源，即各种近交系小鼠，以进行 颅面形态定量分析。近交系菌株的表型是稳定的和可复制的，它们是 基因上是一致的，因此他们的基因类型是公开可用的，不需要昂贵的 单独进行基因分型。年龄和其他环境因素对表型的影响也是 在近亲交配模型中被最小化。我们的飞行员用32个近交系和10个F1杂交组合显示了多个基因座(14) 超过标准单变量映射的显著阈值。根据试点的结果，我们 申请资金，使用所有商业上可获得的近交系进行更广泛的关联研究 通过密集的基因分型和多变量关联图谱。在模型生物体上进行GWA仍然是 与人体研究相关，其中大多数转向老鼠模型以进一步评估其参与的 表型中的候选基因。老鼠和人类GWA之间的任何重叠发现都将证实 该基因座对人类表型的贡献。识别新的基因变种也有可能 影响未来人类研究的方向。

PROJECT SUMMARY/ABSTRACT Genome-wide association studies (GWAS) involves scanning dense genotype markers across the genomes to find genetic variations associated with a particular phenotype. While they are more commonly used in case/control designs to find variants associated with a disease, the phenotypes can be quantitative, and can be used to understand genetic basis phenotypic variation. There are now five GWAS that tried to find genes responsible for the normal facial variation in multiple different human populations. For a complex trait like a facial shape, findings of these studies have been somewhat underwhelming. Each study appears to identify unique sets of genes, and only PAX3 has been replicated in multiple studies. Some of the differences might be due to differences in how phenotypes were quantified and the statistical analysis employed. Potentially more concerning is the lack of tissue specificity of what is exactly being measured in these studies. Traditional sets of anatomical landmarks on human face cluster around eyes, nose, and mouth. While these landmarks are selected for their repeatability and ease of capture, by nature they are on regions that will be impacted by muscle tone and innervation, amount of fat, age, and facial expression, all of which has substantial environmental noise associated with them. While there is no question facial shape is largely determined genetically, the signal may be lost in the current measured phenotype in human facial GWAS. Here we propose to evaluate a potentially untapped resource, diverse set of inbred strains of mice, to conduct quantitative GWAS for craniofacial shape. Phenotypes in inbred strains are stable and reproducible, they are genetically uniform and as such their genotypes are publicly available, negating the need for expensive genotyping individually. The impact of age and other environmental factors on the phenotype are also minimized in inbred models. Our pilot with 32 inbred strains and 10 F1 crosses showed multiple loci (14) exceeding the significance threshold with standard univariate mapping. Based on the results of the pilot we request funds to conduct a more extensive association study using all commercially available inbred strains with dense genotyping and multivariate association mapping. Doing a GWAS on a model organism is still relevant to the human studies, most of which turn to mouse models to further evaluate the involvement of their candidate genes in the phenotype. Any overlapping finding between mouse and human GWA will confirm the contribution of that locus to the phenotype in humans. Identification of novel gene variants can also potentially influence the direction of the future studies in humans.