Genetics and Evolution of Fetal Human Fat Accretion During Development

描述（由申请人提供）：出生时具有高或低体脂的新生儿在儿童期和成年期对不良代谢和/或心血管健康的易感性增加。与几乎所有哺乳动物都存在的成年肥胖症不同，出生时大量的脂肪是灵长类动物和哺乳动物中人类所独有的，这表明最近进化的遗传成分。 发育期间的脂肪积累受母体代谢因素（例如，葡萄糖和甘油三酯），但我们现在已经确定遗传因素也有助于出生时的新生儿肥胖。在一项对多种族新生儿队列进行的全基因组关联研究中，我们发现了3号染色体3q25.31上的一个基因座，该基因座在多个种族群体中与新生儿肥胖的测量值相关。相关区域是基因间的，我们建议确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非编码RNA表达的假设。我们将通过使用作为高血压和不良妊娠结局（HAPO）研究的一部分收集的DNA和表型数据执行以下特定目标来解决这一假设。目标1：使用靶向基因组捕获和下一代测序，在皮肤褶皱总和（新生儿肥胖指标）的上下第10位数中，在总共800名北方欧洲人、非洲-加勒比人、墨西哥-美国人和泰国血统的新生儿中，识别3q25.31内的其他常见、低频和罕见变异。目的2：使用高通量方法来确定变异体对3号染色体基因座内基因表达和lncRNA表达的影响。目标3：使用比较基因组学方法来确定与其他非人灵长类动物相比，人类3号染色体基因座的潜在遗传结构和功能。目标4：通过对来自四个种族组的多达10，900名额外的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的测量相关。实现这些目标将提供基本的新的洞察力的遗传因素调节新生儿人体测量特征。 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生长至关重要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.