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。虽然遗传背景和环境在NIDDM的发生和发展中起着一定的作用，但对基因组在这种疾病中的作用知之甚少。虽然在糖尿病动物模型中已经发现了大量的数量性状基因座(QTL)，但由于缺乏足够的重组和等位基因表达，致病基因的识别仍然很难。异种系(HS)大鼠的高度重组和增加的等位基因表达允许在相对较短的时间段(不到两年)内对QTL进行精细定位。大鼠NIDDM QTL 1(NIDDM1)是大鼠第一染色体上一个36 centiMorgan的区域，在多个F2代杂交中被鉴定为糖耐量异常。到目前为止，还没有在这个区域发现致病基因。我们建议使用异种系(HS)大鼠来精细定位大鼠NIDDM1，以努力确定该区域的致病变异(S)或基因(S)。具体地说，我们计划使用葡萄糖耐量试验对500只HS动物进行表型。我们将使用NIDDM1区域内每250到500个碱基间隔的微卫星和SNP标记对这些动物进行基因分型。这些数据将使用软件程序Happy进行分析，该程序在QTL分析之前构建可能的祖先单倍型。我们预计，在该区域内将发现一个以上的基因座，每个基因座将包含一到两个百万碱基的区域。我们将对HS的8个创始自交系中最强的QTL进行测序，并根据创始品系的表型和基因型比较来确定致病变异。通过与我的导师和合作导师的合作，我将获得糖尿病遗传学和复杂性状统计分析方面的知识和技能。培训将通过个性化指导、指定的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的独立研究人员的重要一步。随着当今糖尿病发病率的增加，有必要增加我们对这种疾病背后的机制的了解。识别NIDDM的易感基因不仅有助于更好地了解在这种疾病中发挥作用的机制，而且还将导致更好的诊断和治疗。

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.