MAPPING GENES FOR BODY WEIGHT AND FATNESS IN MICE

老鼠和人类体重和脂肪的遗传变异可以用多基因遗传来最好地解释。由于缺乏环境和实验控制，很难确定基因参与人类肥胖症的发展。老鼠模型已被证明是发现影响体型的基因的有用工具，因为实验控制可以保持对繁殖和环境的控制。该项目的目标是通过跟踪F2杂交中这些表型与基因的共分离，在小鼠中识别导致体重、体长和脂肪库重变化的基因及其等位基因。特定目的L：在129/)(129)(129)和C57BL/6ByJ(B6)小鼠品系的F2杂交后代中筛选与体重、体长和脂肪库重共分离的标记：将利用多态基因座对129和B6品系杂交小鼠的体重、体长和脂肪库重进行基因分型，并进行连锁分析以寻找影响这些表型变异的区域。之所以选择这些菌株进行分析，是因为129菌株比B6菌株更轻、更瘦，而且F2代存在较大的表型差异。小鼠4号染色体的初步结果显示，体重的瘦素受体基因(Lepr)附近的LOD得分为8.8，约占基因变异的15%。具体目标2：对提供初步连锁证据的区域进行饱和基因分型。当确定连锁区时，将对侧翼区域进行密集的基因分型，以确定最有可能包含目标基因的1-5 cM区域。具体目标3：候选基因的评估：序列变异的鉴定和等位基因特征：将对129和B6菌株的候选基因进行测序，以识别影响体重、长度和脂肪储存重量的等位基因变异。对4号染色体的定位表明，可能存在以前未识别的Lepr等位基因，这些等位基因可能会导致小鼠体重、体长和脂肪储存重量的变化，因此将使用B6和129小鼠的DNA对Lepr进行测序。2号染色体似乎还包含一个或多个基因，证明与体重(LOD=4.8)和体长(LOD=3.6)有关联，该区域包含几个候选基因。该项目的目标是了解等位基因变异性如何影响小鼠的体重、体长和脂肪库体重。这些基因的同源基因可能与人类肥胖有关，并可能对人类健康产生重大影响。

Genetic variation in body weight and fatness in mice and humans is best explained by multigenic inheritance. Characterizing genetic involvement in the development of human obesity has been difficult due to lack of environmental and experimental control. Mouse models have proved to be a useful tool in the discovery of genes that influence body size because experimental control can be maintained over breeding and environment. The goal of this project is to identify genes and their alleles in mice that lead to variability in body weight, body length, and adipose depot weight, by tracking the co-segregation of genotypes with these phenotypes in an F2 intercross. Specific Aim l: Genome screen for markers that co-segregate with body weight, body length and adipose depot weight in an F2 intercross derived from the 129/) (129) and C57BL/6ByJ (B6) mouse strains: Hybrid mice from the 129 and B6 strains, phenotyped for body weight, body length and adipose depot weight, will be genotyped using polymorphic loci, and linkage analysis will be conducted to find regions influencing variation in these phenotypes. These strains were chosen for analysis because the 129 strain is lighter and leaner than the B6 strain, and large phenotypic variation exists within the F2 generation. Preliminary results from mouse chromosome 4 gave a LOD score of 8.8 near the leptin receptor gene (Lepr) for body weight, which accounts for approximately 15 percent of the genotypic variance. Specific Aim 2: Saturation genotyping of areas that give preliminary evidence for linkage. When areas of linkage are identified, the flanking regions will be densely genotyped to identify the 1-5 cM region most likely to contain the gene of interest. Specific Aim 3: Evaluation of candidate genes: identification of sequence variation and allele characterization: Candidate genes from the 129 and B6 strain will be sequenced to identify allelic variation that affects body weight, length and adipose depot weight. Mapping of chromosome 4 suggests previously unidentified alleles of Lepr may exist that lead to variation in body weight, body length and adipose depot weight in mice and therefore Lepr will be sequenced using DNA from B6 and 129 mice. Chromosome 2 also appears to contain a gene or genes that give evidence for linkage to body weight (LOD=4.8) and body length (LOD=3.6), and this region contains several candidate genes. The goal of this project is to understand how allelic variability affects body weight, body length, and adipose depot weight in the mouse. Orthologs of these genes may be involved in human obesity, and may have a significant impact on human health.