POLYMORPHIC GENES MODULATING LIFESPAN IN C ELEGANS

提出了一种新的策略来识别和初步表征基因 以及决定成年人寿命的基因组之间的相互作用 线虫C.优雅 用C.线虫株 (e.g., N2 xBO或N2 xDH 424）具有与亲本菌株相似的寿命， 然而F2和衍生的近交系在以下方面显示出增加的变化： 寿命，范围从父母水平的70-160%。 这意味着 多个基因在这些菌株之间具有多态性，决定了C. elegans 寿命 我们建议通过鉴定等位基因来描述这些基因 一致存在于最长寿的重组近交后代的 株间杂交 位于Tc 1转座子侧翼的独特探针， 在BO和DH 424菌株的基因组DNA中存在，但在N2菌株中不存在 和C12 a，将用于确定纯合子的源菌株 （N2或C12 a）x（BO或DH 424）杂合基因组的区域。 等位基因比率（- Tc 1：+Tc 1）在F1杂合子中必须为1：1， F1代幼蠕虫和后代之间的差异归因于 有利于一个等位基因的生殖选择。 然而，如果一个给定的等位基因 在年轻人和最长寿的5%的人之间， 蠕虫，都在同一代（Fn大于或等于12），这 表明多态性标记和寿命之间的联系 决定基因--两个等位基因中的一个赋予更大的 寿命比另一个。 多重引物聚合酶链反应 组，特异于BO中定位的Tc 1元件侧翼的序列，和/或 DH 424 DNA，将用于分析> 100个存活时间最长的 在这样的群体中的个体蠕虫，以确定基因的组合， 在长寿蠕虫中经常共分离的等位基因。 比较 这些基因组与那些在高氧或晚期缺氧条件下选择的基因组相比， 繁殖力等等，将指示底层 这些特征的遗传决定因素。 寿命鉴定- 调节基因，以及对长寿有不同贡献的等位基因， 将有助于我们理解 衰老 从长远来看，同源基因的比较研究， 包括人类在内的其他物种， 衰老的机制，并可能牵连遗传相互作用， 年龄相关疾病的病因学。

A novel strategy is proposed to identify and initially characterize genes and interacting groups of genes which determine adult lifespan in the nematode C. elegans. The F1 progeny of crosses between C. elegans strains (e.g., N2xBO or N2xDH424) have lifespans similar to the parental strains, and yet F2's and derived inbred clones show increased variation in lifespans, which range from 70-160% of parental levels. This implies that multiple genes, polymorphic between these strains, determine C. elegans lifespan. We propose to characterize such genes by identifying alleles consistently present in the longest-lived recombinant inbred progeny of inter-strain crosses. Unique probes flanking those Tc1 transposons which are present in genomic DNA of the BO and DH424 strains, but absent from N2 and C12a, will be used to determine the source strain for homozygous regions of (N2 or C12a)x(BO or DH424) hybrid genomes. The allele ratio (- Tc1:+Tc1) must be 1:1 in the F1 heterozygotes, and any consistent shift between young worms at F1 and later generations would be attributed to reproductive selection favoring one allele. However, if a given allele ratio changes consistently between young adults and the longest-lived 5% of worms, both at the same generation (Fn greater than or equal to 12), this would indicate linkage between that polymorphic marker and a lifespan determining gene -- for which one of the two alleles conferred greater lifespan than the other. Polymerase chain reaction with multiplex primer sets, specific for sequences flanking mapped Tc1 elements in BO and/or DH424 DNA, will be used to analyze > 100 of the longest-surviving individual worms in such populations, to identify combinations of gene alleles which frequently co-segregate in long-lived worms. Comparison of these gene sets with those selected under conditions of hyperoxia or late fecundity, etc., will indicate the extent of overlap between the underlying genetic determinants for these traits. Identification of lifespan- modulating genes, and of alleles with differing contributions to longevity, will aid our understanding of the molecular mechanisms underlying senescence. In the long term, comparative studies of cognate genes in other species, including man, should reveal whether they share a common mechanism of senescence, and may implicate genetic interactions in the etiology of age-associated diseases.