Mini Review Quantitative trait loci define genes and pathways underlying genetic variation in longevity Robert J. Shmookler Reis a,b,c,d, * , Ping Kang a,b , Srinivas Ayyadevara a,b a Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA b Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA c Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA d Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA Received 15 April 2006; received in revised form 8 June 2006; accepted 13 June 2006 Available online 17 August 2006 Abstract Quantitative trait locus (QTL) mapping provides a means to discover and roughly position regions of the genome that harbor genes responsible for natural variation in a complex trait. QTL mapping has been utilized extensively in the pursuit of genes contributing to longevity, chiefly in two animal models, the nematode Caenorhabditis elegans and the dipteran insect Drosophila melanogaster. Research on both species has demonstrated that a relatively small set of loci accounts for most of their genetic variance in lifespan. QTL mapping complements the discovery of longevity genes by mutagenesis screens, because the two procedures are predicted to unveil overlapping but distinct types of genes. We argue that information gained from animal models, even invertebrates, can greatly facilitate the process of gene identification and testing of homologous genes in humans. Published by Elsevier Inc. Keywords: QTL; Quantitative trait locus; Genetic mapping; Genetics of longevity; Caenorhabditis elegans; Drosophila melanogaster; Stress response genes; Longevity; Aging; Lifespan; Oxidative stress 1. Introduction The study of aging was launched into prominence, and its scientific credibility enhanced, in large measure due to studies showing that the lifespans of invertebrates can be greatly extended by chemically induced mutations to single genes (Riddle et al., 1981; Klass, 1983; Duhon et al., 1996; Yang and Wilson, 1999). The first such genes to be discov- ered belong to a pathway in Caenorhabditis elegans, closely corresponding to the mammalian insulin-response and IGF-1 (insulin-like growth factor 1) response pathways, from which it is roughly equally diverged. In addition to this pathway, many dozens of other gene mutations have been reported to extend life in nematodes and insects (see Science SAGE KE, http://sageke.sciencemag.org/). Many of these genes encode proteins that might alter metabolic rate, which could either signify the pivotal role of metabo- lism in the etiology of aging, or may simply reflect the rel- ative complexity of such pathways and the relative ease of their disruption. At present, no longevity-affecting pathway is fully understood, nor do we know what other genes and pathways might also impact lifespan. Mutagenesis has one rather serious drawback, as detailed below – it reveals only genes for which disabling mutations actually extend life. Why such genes should exist at all is a bit of a puzzle, but clearly there may be many longevity-modifying genes not discoverable in this way. A number of laboratories have undertaken a second, rather more difficult approach to identifying genes and pathways that affect lifespan in model organisms: the genetic mapping of quantitative trait loci (QTLs). This strategy in many respects complements the mutagenesis approach, because QTL mapping deals almost exclusively with nondeleterious genetic changes – variants that have 0531-5565/$ - see front matter Published by Elsevier Inc. doi:10.1016/j.exger.2006.06.047 * Corresponding author. Tel.: +1 501 257 5560; fax: +1 501 257 5578. E-mail address: rjsr@uams.edu (R.J. Shmookler Reis). www.elsevier.com/locate/expgero Experimental Gerontology 41 (2006) 1046–1054