Genetics and Evolution of Fetal Human Fat Accretion During Development

描述（由申请人提供）：出生时体脂高或低的新生儿在儿童期和成年期易患代谢和/或心血管健康不良。与几乎所有哺乳动物都存在的成年肥胖不同，在灵长类动物和哺乳动物中，出生时显著的脂肪量是人类独有的，这表明一种最近进化的遗传成分。发育过程中的脂肪增加是由母体代谢因素（如葡萄糖和甘油三酯）调节的，但我们现在已经确定遗传因素也有助于新生儿出生时的肥胖。在一项多种族新生儿的全基因组关联研究中，这些新生儿的母亲在妊娠期间接受了葡萄糖检测，我们在染色体33q25 .31上发现了一个位点，该位点在多种族群体中显示出与新生儿肥胖的关联。相关区域是基因间的，我们建议鉴定基因座内的遗传变异，以解决3q25.31内的遗传变异影响基因座中存在的长链非编码rna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。目标1：使用靶向基因组捕获和下一代测序，在800名北欧、非洲-加勒比、墨西哥-美国和泰国血统的新生儿中，在皮肤褶皱总数的上、下10百分位数中，识别3q25.31内额外的常见、低频和罕见变异，皮肤褶皱总数是衡量新生儿肥胖的一个指标。目的2：利用高通量方法确定变异对3号染色体位点内基因表达和lncRNAs表达的影响。目的3：使用比较基因组学方法来定义人类与其他非人类灵长类动物相比，3号染色体位点的潜在遗传结构和功能。目的4：通过对来自四个种族群体的10900名HAPO新生儿进行基因分型，证明具有功能影响的变异与新生儿肥胖有关。完成这些目标将为调节新生儿人体测量特征的遗传因素提供基本的新见解。这将对胎儿结局、新生儿的长期健康以及支持新生儿大脑发育的独特人类特征的进化产生重要影响。

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.