POPULATION AND EVOLUTIONARY GENETICS OF NIDDMI

描述（研究者摘要）：2型糖尿病是最常见的糖尿病之一。 人类常见的代谢紊乱，具有复杂的病因， 环境和遗传因素。最近，位置候选区域， NIDDM 1已被提出含有导致糖尿病的变异 风险根据节俭基因型假说，糖尿病易感性 基因型在古代的盛宴时期赋予了选择优势 饥荒。在这项申请中，我们建议详细研究 遗传候选区域的群体和进化遗传学 易患2型糖尿病。我们研究的最终目标是 提供变异的单倍型结构的信息， 设计和解释重复研究，了解塑造 原住民人群中该基因座的序列变异和LD，以及 在这一地区使用自然选择的标志来验证映射 证据 为了推进这些目标，我们建议： 调查序列变异的小随机样本（10个人），从每个 四个主要民族（非洲人，亚洲人，欧洲人和美洲原住民）， 在NIDDM1候选易感区域发现的两个基因。数据 将对本次调查中产生的数据进行分析， 积极的自然选择。这些区域除了包含 候选糖尿病易感性变异将在特定的 目标二。 对25个样本中的序列变异和LD进行详细分析 每个个体来自三个主要种族群体的大量远交种群 （非洲、亚洲和欧洲）。我们将利用这些数据提供关键的 疾病地图的信息，并寻找自然选择的标志 基于“节俭”基因型假说。 对NIDDM 1候选者进行广泛的等位基因频率调查 在20个人群样本中的易感性变异， 2型糖尿病的发病率与种族和地理来源有关。的 调查结果将进行分析，以询问是否有风险的基因型频率 与不同人群的糖尿病患病率相关。此外，本发明还提供了一种方法， 我们将能够确定种群间的 分化是显着不同的观察到的大量 中性进化的核基因座的地理分布， 等位基因频率与环境特征相关，如纬度 或者气候。

DESCRIPTION (Investigator's Abstract): Type 2 diabetes is one of the most common metabolic disorders in humans and has a complex etiology due to environmental and genetic factors. Recently, a positional candidate region, NIDDM1, has been proposed to contain variation which contributes to diabetes risk. According to the thrifty genotype hypothesis, diabetes susceptibility genotypes conferred a selective advantage in the ancient past in times of feast a famines. In this application, we propose to conduct a detailed study on the population and evolutionary genetics of the candidate region for the genetic susceptibility to type 2 diabetes. The ultimate goals of our study are to provide information on the haplotype structure of variation that can be used to design and interpret replication studies, understand the forces that shape sequence variation and LD at this locus in aboriginal human populations, and use the signature of natural selection on this region to validate the mapping evidence. To advance these goals, we propose to: Survey sequence variation in small random samples (10 individuals) from each of four major ethnic groups (Africans, Asians, Europeans, and Native Americans) in the two genes found in the NIDDM1 candidate susceptibility region. The data generated in this survey will be analyzed to identify sub-regions with evidence for positive natural selection. These regions in addition to those containing candidate diabetes susceptibility variants will be further studied in Specific Aim 2. Conduct a detailed analysis of sequence variation and LD in a sample of 25 individuals each from large outbred populations from three major ethnic groups (Africa, Asia, and Europe). We will use these data to provide critical information for disease mapping and look for the signature of natural selection based on the "thrifty" genotype hypothesis. Carry out an extensive survey of allele frequencies at NIDDM1 candidate susceptibility variants in 20 human population samples with a broad range of ethnic and geographic origins and rates of type 2 diabetes prevalence. The survey results will be analyzed to ask if the at-risk genotype frequencies correlate with diabetes prevalence rates In different populations. In addition, we will be able to determine whether the degree of inter-population differentiation is significantly different from that observed at a large number of neutrally evolving nuclear loci and whether the geographic distribution of allele frequencies is correlated with environmental features, such as latitude or climate.