Anecdotal , Historical and Critical Commentaries on Genetics Edited by James F . Crow and William F . Dove Haldane , Bailey , Taylor and Recombinant - Inbred Lines

THAT mouse Mecca, the Jackson Laboratory, has repeatedly pioneered in bringing mouse genetics to its present state. There was George Snell’s NobelPrize-winning work on histocompatibility, Roy Stevens’ work on embryonal carcinoma, Tibby Russell’s on hematopoiesis, and many others (reviewed by Paigen 2003a,b). It has also been the site of several important methodological innovations. First and most important, C. C. Little had the foresight to establish inbred lines (Crow 2002). His first line was started in 1909; by 1980, there were .300 (Paigen 2003a). Another innovation was the development of congenic strains—inbred lines with a small foreign chromosomal region introgressed by repeated backcrossing into the line (Snell 1948). A third was chromosome substitution (consomic) strains. These have a single chromosome introgressed into an inbred line (Singer et al. 2004). The fourth innovation, in many ways the cleverest, was recombinant inbred (RI) lines. These innovations each required many years of advance work before they could be utilized effectively. Such projects certainly would not fare well as grant applications today. Only in an organization with a long-time commitment, such as the Jackson Laboratory, could such projects be carried through. The idea of RI lines arose sometime in the 1950s or 1960s in the fertile mind of Donald Bailey. Don is a quiet, low-key scientist who has not made a big splash in the genetic world at large. But within the Jackson Laboratory and with others who know his work, he has long been revered. He is knowledgeable and creative—the person to go to for help with a technical problem or to search for a new idea. The principle of RI lines is simple (Bailey 1971). In retrospect it has a ‘‘why didn’t I think of it’’ quality: Two inbred lines are crossed and the hybrids are intercrossed to produce F2 progeny. Pairs of the F2 mice are then mated to establish inbred lines through repeated sibmating. The genomes of each of these lines are a homozygous mosaic of chromosomal regions from the two founding inbreds. These RI lines are then typed for the genotypes and phenotypes that differed between the two founders. Sets of RI lines have a number of advantages. Since each RI line is nearly homozygous, its genotype is reproducible and individual genetic variation is minimized. Replications average out the effects of environmental influences and measurement errors. Furthermore, once a line has been genotyped, this information can be used over and over. Unlinked loci largely randomize during the process, even though inbred lines can show ‘‘linkage disequilibrium’’ for loci on different chromosomes (Graber et al. 2006), but linked genes retain some of the linkage disequilibrium that characterized the two founding inbred strains. Furthermore, there are several meioses in the F2 and during the inbreeding stage, with the result that the amount of recombination is increased fourfold; this is now called map expansion and is very advantageous for mapping closely linked loci. For the history of linkage studies in the mouse, see Lyon (1990). Bailey started with 12 RI lines from a cross of BALB/ cBy and C57BL/6By (designated C 3 B6). Of these, 7 survived for 30 generations of sib-mating. Bailey identified 11 loci and classified them as to the strain of origin. Three were coat-color genes and 8 were histocompatibility factors. The power of the method was shown by the immediate discovery that some phenotypically similar histocompatibility factors mapped to different locations. Despite the small number of RI lines, Bailey and his associates were able to discover some 20 linkages in the next 5 years (Taylor 1978). The next person to enter the RI story was Ben Taylor. Ben joined the Jackson Laboratory in 1969 and immediately started generating RI lines and developing the theory. He, like Don, is soft spoken and reticent, with a manner that belies his sharp mind. Author e-mail: [email protected]