Fine mapping NIDDM QTL 1 using heterogeneous stock rats

描述（由申请人提供）： 非胰岛素依赖型糖尿病（NIDDM）是一个日益严重的健康问题，预计到2030年全球将有超过3.6亿人受到影响。虽然遗传背景沿着环境在NIDDM的发展和进展中起作用，但对基因组在这种疾病中的作用知之甚少。虽然已经在糖尿病动物模型中鉴定了大量的数量性状基因座（QTL），但是由于缺乏足够的重组和等位基因表示，致病基因的鉴定仍然难以捉摸。高度的重组和增加的等位基因代表性异质性股票（HS）大鼠允许在相对较短的时间内（不到两年）的QTL的精细定位。大鼠NIDDM QTL 1（NIDDM 1）是位于大鼠1号染色体上的一个36 centiMorgan区域，在多个F2互交中鉴定为葡萄糖耐受不良。到目前为止，尚未在该地区发现致病基因。我们建议使用异质性股票（HS）大鼠精细地图大鼠NIDDM1在努力确定一个致病的变异体（S）或基因（S）在这一地区。具体而言，我们计划使用葡萄糖耐量试验对500只HS动物进行表型分析。我们将使用NIDDM 1区域内每250至500千碱基间隔的微卫星和SNP标记对这些动物进行基因分型。将使用软件程序HAPPY分析数据，该软件程序在QTL分析之前构建概率祖先单倍型。我们预期在该区域内将鉴定出一个以上的基因座，并且每个基因座将包含一到两个兆碱基区域。我们将测序最强的QTL在8个创始近交系的HS和确定致病变异的基础上，在创始菌株的表型和基因型比较。通过与我的导师和合作导师的工作，我将获得知识和技能，在糖尿病的遗传学和复杂性状的统计分析。培训将通过个性化辅导、指定短期课程和参加会议来完成。这项培训将是成为糖尿病分子遗传学领域独立研究人员的重要一步。随着当今糖尿病发病率的增加，我们有必要增加对这种疾病潜在机制的理解。确定NIDDM的易感基因不仅可以更好地理解在这种疾病中发挥作用的机制，而且还可以更好地诊断和治疗。

DESCRIPTION (provided by applicant): Non-insulin dependent diabetes mellitus (NIDDM) is a growing health problem with over 360 million people worldwide projected to be affected by 2030. While genetic background along with the environment play a role in the development and progression of NIDDM, little is known about the role of the genome in this disease. While a large number of quantitative trait loci (QTL) have been identified in animal models for diabetes, identification of causative genes has remained elusive due to lack of sufficient recombination and allelic representation. The high degree of recombination and increased allele representation in heterogeneous stock (HS) rats allow for fine-mapping of QTL in a relatively short time-period (less than two years). Rat NIDDM QTL 1 (NIDDM1) is a 36 centiMorgan region on rat chromosome one identified in multiple F2 intercrosses for glucose intolerance. To date, no causative genes have been identified in this region. We propose to use heterogeneous stock (HS) rats to fine-map rat NIDDM1 in an effort to identify a causative variant(s) or gene(s) in this region. Specifically, we plan to phenotype 500 HS animals using a glucose tolerance test. We will genotype these animals using microsatellite and SNP markers spaced every 250 to 500 Kilobases within the NIDDM1 region. The data will be analyzed using a software program, HAPPY, that constructs probabalistic ancestral haplotypes prior to QTL analysis. We expect that more than one locus will be identified within this region and that each locus will encompass a one to two Megabase region. We will sequence the strongest QTL in the eight founding inbred strains of the HS and identify causative variants based on phenotype and genotype comparisons in the founder strains. By working with my mentor and co-mentors I will gain knowledge and skills in the genetics of diabetes and statistical analysis of complext traits. Training will be accomplished via personalized mentoring, specified short courses and conference participation. This training will be an important step toward becoming an independent researcher in the field of the molecular genetics of diabetes. With the increasing rate of diabetes today, it is pertinent to increase our understanding of the mechanisms underlying this disorder. Identifying susceptibility genes for NIDDM will not only provide a better understanding of the mechanisms that play a role in this disorder but will also lead to better diagnosis and treatment.