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7 Identification and Mapping of Genes Determining Longevity
Pages 108-126

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From page 108...
... Indeed, DNA sequence homology is used as a metric to determine evolutionary relationships among species. Second, molecular genetic manipulation changes both the genotype and the phenotype of an organism.
From page 109...
... Their subsequent extension to humans andlor the identification of gerontogenes directly in humans is the subject of another author. Finally, we will review work from our laboratory on the genetic determination of mortality rates.
From page 110...
... The former approach involves the identification of genetic diseases of potential relevance to aging, while the latter has most often involved the study of candidate genes for association between allelic variants in that candidate and life expectancy. In mice, a few studies have attempted to go beyond the use of candidate genes by using genetic markers spanning the whole genome (German et al., 1988; Fuel et
From page 111...
... We will then describe our work on QTL mapping of life-history traits in the nematode Caenorhabditis elegans and some early work on mapping QTLs involved in specifying adult demographic characters. Finally, we will speculate as to how these studies may be extended to other demographic parameters not yet assessed in C
From page 112...
... and is determined by the segregation of many genes or QTLs QTL Quantitative trait locus; one of a suite of genes specifying any particular phenotype QTL mapping The process of determining probable sites and probable effect sizes of a QTL or QTLs RI Recombinant inbred; an inbred strain generated by 20 generations of sibling mating from the F2 of two inbred strains or by 10 generations of self-fertilization (hermaphroditic species) SDP Strain distribution pattern; the pattern of alleles at a locus across a series of RI strains derived from crosses between the same initial inbred parents be genetically linked.
From page 113...
... This problem can be partially alleviated by using allelic information from markers on both sides of the QTL; this results in the determination of linkage using an "interval-mapping approach." Interval mapping is more mathematically sophisticated and more biologically precise because algorithms have been developed that can account for recombination events in the interval. Interval mapping uses these detected recombination events to suggest most probable locations and effect sizes for the QTL within the interval.
From page 114...
... selected on the basis of extended vegetative survival under nongrowing conditions also had increased replicative life spans argues for considerable coordinate control. One gene was studied in detail and shown to be a mutation in SIR4, a gene involved in transcriptional silencing.
From page 115...
... The extended life span of these mutants was detected in a search for extended life expectancy in some cases and serendipitously in others. Mapping Induced Mutants The fact that genes located close together on the chromosome remain together during crosses allows the construction of genetic maps and ultimately even the identification of genes by "positional cloning." There is only one example of "mapping" a gerontogene using assessment of life expectancy as the character that is being mapped, and that is the mapping of age-1 (Friedman and Johnson, 1988; Johnson et al., 1993~.
From page 116...
... in Mapping QTLs for Longevity and Other Life-History Traits C elegans, a nematode worm, is a prime candidate for QTL mapping and the study of coadapted gene complexes, since it is normally inbreeding but can also
From page 117...
... RI-based QTL mapping allows an analysis of the effects of individual genes on different traits and of interactions among genes in specifying individual traits not possible in F2 populations. We found several instances where genes do not act independently and instead interact to determine mean life span and mean fertility.
From page 118...
... The genes, their location, and the amount of genetic variation explained by each can be determined by QTL mapping. Most importantly, it is possible to gain some insight into the interactions between and among these QTLs in specifying their respective phenotypes.
From page 119...
... Subsequent cloning of the genes involved in life expectancy and drug sensitivity, respectively, are still under way.
From page 120...
... Mortality of Pure Strains Because increased mean life expectancy could result from lower initial mortality rate, or from a slower rate of increase in mortality (or to alterations in both)
From page 121...
... The differences among quartiles was modeled using a Gompertz model and was due almost entirely to differences in the rate of increase of the exponent with essentially no significant difference in initial mortality rate. There still was evidence of a linear period late in life when mortality rates stopped increasing exponentially with increasing age, as demonstrated by a model-comparison approach (Brooks et al., 1994~.
From page 122...
... QTL mapping offers a useful alternative to localizing genes, but cloning of the genes underlying these QTLs will be problematic. Mortality alterations that result from changes in these genes can be studied, and results from the Johnson laboratory suggest that much of the flattening of mortality rates at later ages in humans could result from genetic heterogeneity among individuals.
From page 123...
... Lithgow, and T.E. Johnson 1994 Mortality rates in a genetically heterogeneous population of Caenorhabditis elegans.
From page 124...
... Lander, E.S., and D Botstein 1989 Mapping Mendelian factors underlying quantitative traits using RFLP linkage maps.
From page 125...
... Inoue, and J.H. Thomas 1996 Analysis of the roles of daf-28 and age-1 in regulating Caenorhabditis elegans dauer formation.
From page 126...
... Johnson 1996 Mapping quantitative trait loci specifying hermaphrodite survival or self fertility in the nematode Caenorhabditis elegans. Genetics 142:801-817.


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