POLYMORPHIC GENES MODULATING LIFESPAN IN C ELEGANS

高分辨率染色体作图将用于识别和 描述线虫中通常控制成虫寿命的基因 秀丽隐杆线虫 通过研究衰老模型的遗传学 生物体如C.我们希望能更好地了解 人类衰老的遗传决定因素，以及预防或 改善衰老相关疾病。 认识到基因 研究衰老是否受到劳动强度的极大阻碍， 存活测定的可变性提出了一种新的测定系统， 部分自动化的监测许多存活的文化并行。 在C. elegans 遗传作图：多态性的数量增加了12到15倍， 可用于染色体定位的标记，以及一种用于 在一次操作中确定高密度基因型。 超过1000 重组-近交（RI）系将从菌株间产生， “一切皆有因，一切皆有果，一切皆有果。 寿命最短的10%的品系将被基因分型， 重新评估。 这种“选择性基因分型”大大增加了 作图程序，每种评价的基因型。 作为一个更极端的 应用选择性基因分型，高密度作图分析， 按比例缩小以应用于单个蠕虫。 因此，样本 最长寿的0.5-2%的个体将从大的， 包含几千个不同RI系的异源培养物， 作为一个同步老化的群体生长（Ebert等人，遗传学135：1003， 1993年）。 发现对寿命有显著影响的基因座也将被 测试与其他网站的互动。 为了进一步明确 基因区域，将为每个基因创建同源系。 重要的基因座，在一个否则同质（和对比）的遗传 背景;因此，涉及的基因将定位于 多个同类系之间的重叠。 将寻找候选基因 并将检查菌株间 多态性--正如对株间杂交中涉及的基因所预期的那样。 为多基因定位开发的新程序可能具有更广泛的 应用，包括人类基因组计划中的实用程序。

High-resolution chromosome mapping will be used to identify and characterize genes which normally govern adult longevity in the nematode Caenorhabditis elegans. By studying the genetics of aging model organisms such as C. elegans, we hope to gain a better understanding of the genetic determinants of human aging, and the ability to prevent or ameliorate senescence-associated diseases. Recognizing that the genetic study if aging has been greatly impeded by the labor-intensity and variability of survival assays a new assay system is proposed to partially automate the monitoring of many survival cultures in parallel. Progress has also been made on several improvements in C. elegans genetic mapping : a 12 to 15-fold increase in the number of polymorphic markers available for chromosomal mapping, and a novel procedure for determining high-density genotypes in a single operation. Over 1000 recombinant-inbred (RI) lines will be generated from inter-strain crosses; al lines will then be assessed for lifespan, and the longest- and shortest-lived 10% of lines will be genotyped and their survivals reassessed. Such "selective genotyping" greatly increases the power of mapping procedures, per genotype evaluated. As an even more extreme application of selective genotyping, the high-density mapping assay is being scaled down for application to individual worms. Thus, a sample of the longest-lived 0.5-2% of individuals will be analyzed from large, heterogenous cultures comprising several thousand different RI lines, grown as a synchronously-aging cohort (Ebert et al., Genetics 135: 1003, 1993). Loci found to have significant effects on lifespan will also be tested for interaction with other sites. In order to further define the gene regions identified, congenic lines will be created for each significant locus, in an otherwise-homogenous ( and contrasting) genetic background; the implicated genes will thus be localized to the areas of overlap between multiple congenic lines. Candidate genes will be sought in the indicated regions, and will be examined for inter-strain polymorphism-as expected for genes implicated in inter-strain crosses. The novel procedures developed for polygene mapping may have broader applications, including utility in the Human Genome Project.