HIGH THROUGHPUT GENOTYPING AND DNA SEQUENCING FOR STUDYING THE GENETIC CONTRIBUTIONS TO HUMAN HEALTH AND DISEASE: Whole Genome Sequencing of Bilateral Cleft Lip and Palate families from Africa

口面部裂(OFCs)是人类最常见的出生缺陷之一，全世界每700名新生儿中就有一名受到影响。对OFC的遗传学和分子病因学的调查是预防的必要前提，并将对与OFCS相关的金融、教育、医疗、心理和文化问题产生巨大影响--从而带来显著的公共健康利益。我们已经在人类OFC遗传学方面取得了合理的进展，通过七项针对CL/P的基因组广泛关联研究(GWAS)，三项针对CL/P的Meta分析，三项仅针对腭裂(CPO)的GWAS研究，以及两项确定了60多个危险基因和几个从头变异的全基因组测序(WGS)研究。拟议的特定目标将使我们能够识别和测试增加CL/P风险的常见和罕见的遗传变异，并在积累了人类最大遗传变异的人群中识别与特定OFC表型相关的遗传变异。使用全基因组测序来识别罕见的功能变异有望极大地扩大已进行的少数OFC外显子研究的结果。我们假设，双侧完全性唇腭裂(BCLP)是临床上最严重的OFC类型，与不太严重的类型相比，突变负荷更高，关注BCLP将有助于发现新的风险变异。这种方法是可靠的，因为我们使用临床同质队列，以最大限度地减少遗传异质性，并增加发现BCLP遗传因素的可能性。这项申请将由布塔利博士作为首席调查员领导。他将与约翰·霍普金斯大学的陶布博士和NHGRI的阿迪耶莫博士合作。总体而言，实验设计和方法、PI和CO-IS以及本提案中概述的环境为改善口腔和颅面健康提供了催化剂。

Orofacial clefts (OFCs) affects one out of every 700 infants born worldwide and are some of the most common birth defects in humans. Investigations into the genetic and molecular etiology of OFC is an essential pre- requisite for prevention and will have a huge impact on financial, educational, medical, psychological, and cultural problems associated with OFCs—leading to significant public health benefits. We have made reasonable progress in human OFC genetics through seven Genome Wide Association Studies (GWAS) for CL/P, three meta-analyses for CL/P, three GWAS for cleft palate only (CPO), and two Whole Genome Sequencing (WGS) study identifying over 60 risk loci and several de novo variants. The proposed specific aims will allow us to identify and test both common and rare genetic variants that elevate risk for CL/P, and to identify genetic variants associated with specific OFC phenotypes in the population that has accumulated the greatest genetic variation in the human race. The use of whole-genome sequencing to identify rare functional variants is expected to substantially expand the findings from the few exome studies of OFC that have been conducted. We hypothesize that bilateral complete cleft lip and palate(BCLP), the most clinically severe form of OFC, is associated with a higher mutation load than less severe forms and focusing on BCLP will facilitate the discovery of novel risk variants. This approach is robust in that we are using a clinically homogeneous cohort in order to minimize genetic heterogeneity and increases the likelihood of discovering genetic factors for BCLP. This application will be led by Dr Butali as Principal Investigator. He will collaborate with Dr. Taub at John Hopkins University and Dr. Adeyemo at the NHGRI. Collectively, the experimental design and approach, the PI and co-Is, and the environment outlined in this proposal provide the catalyst to improve oral and craniofacial health.