Genetics and Evolution of Fetal Human Fat Accretion During Development

描述(由申请人提供)：出生时体内脂肪含量高或低的新生儿在儿童和成年后更容易受到代谢和/或心血管健康不良的影响。与基本上存在于所有哺乳动物中的成年肥胖症不同，出生时显著的脂肪量是人类在灵长类动物和哺乳动物中所独有的，这表明最近进化出的基因成分。发育过程中脂肪的积累受到母体代谢因素(如葡萄糖和甘油三酯)的调节，但我们现在已经确定，遗传因素也会导致新生儿出生时的肥胖。在对母亲在怀孕期间接受血糖测试的多民族新生儿进行的全基因组关联研究中，我们确定了3号染色体上的一个基因座，3q25.31，该基因座显示出在多个种族群体中与新生儿肥胖指标的关联。相关区域是基因间的，我们建议识别该基因座内的遗传变异，以解决3q25.31内的遗传变异影响该基因座中存在的长非编码RNA的表达的假设。我们将通过使用作为高血糖和不良妊娠结局(HAPO)研究的一部分收集的DNA和表型数据来解决这一假设。目的1：利用有针对性的基因组捕获和下一代测序，在北欧、非洲加勒比、墨西哥裔美国人和泰国裔总共800名新生儿中，识别3q25.31内其他常见、低频和罕见的变异，计算皮褶总和，以衡量新生儿肥胖程度。目的2：用高通量方法确定变异对基因表达和3号染色体内lncRNAs表达的影响。目的3：利用比较基因组学方法确定人类与其他非人类灵长类动物相比的3号染色体基因座的潜在遗传结构和功能。目的4：通过对来自四个种族的10,900名额外的HAPO新生儿进行SNPs基因分型，证明具有功能影响的变异与新生儿肥胖的衡量标准有关。实现这些目标将为调节新生儿人体测量特征的遗传因素提供根本的新见解。这将对胎儿结局、新生儿的长期健康以及对支持新生儿大脑发育至关重要的独特人类特征的演变具有重要影响。

DESCRIPTION (provided by applicant): Newborns with high or low body fat at birth have an increased susceptibility to poor metabolic and/or cardiovascular health in childhood and adulthood. Unlike adult adiposity which is present in essentially all mammals, significant fat mass at birth is unique to humans among primates and mammals more generally, suggesting a recently evolved genetic component. Fat accretion during development is modulated by maternal metabolic factors (e.g., glucose and triglycerides), but we have now determined that genetic factors also contribute to newborn human adiposity at birth. In a genome wide association study performed in a multi-ethnic cohort of newborns whose mothers underwent glucose testing during gestation we identified a locus on chromosome 3, 3q25.31, which exhibits association in multiple race groups with measures of newborn adiposity. The associated region is intergenic, and we are proposing to identify genetic variation within the locus to address the hypothesis that genetic variants within 3q25.31 affect the expression of long noncoding RNAs present in the locus. We will address this hypothesis by performing the following specific aims using DNA and phenotype data collected as part of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study. Aim 1: To use targeted genomic capture and next generation sequencing to identify additional common, low frequency and rare variants within 3q25.31 in a total of 800 newborns of Northern European, Afro-Caribbean, Mexican-American and Thai ancestry in the upper and lower 10th percentiles for sum of skinfolds, a measure newborn adiposity. Aim 2: To use high throughput approaches to define the impact of variants on gene expression and expression of lncRNAs within the chromosome 3 locus. Aim 3: To use comparative genomic approaches to define the underlying genetic architecture and function of the chromosome 3 locus in humans compared to other non-human primates. Aim 4: To demonstrate that variants which have a functional impact are associated with measures of newborn adiposity by genotyping the identified SNPs in up to 10,900 additional HAPO newborns from the four race groups. Accomplishing these aims will provide fundamental new insight into genetic factors regulating newborn anthropometric traits. This will have important implications for fetal outcomes, long-term health of the newborn, and evolution of unique human traits important for the support of neonatal brain growth.