NATURAL VARIATION IN NEURON NUMBER IN MICE IS LINKED TO A MAJOR QUANTITATIVE TRAIT LOCUS ON CHR-11

Common genetic polymorphisms-as opposed to rare mutations-generate alm ost all heritable differences in the size and structure of the CNS. Su rprisingly, these normal variants have not previously been mapped or c loned in any vertebrate species. In a recent paper (Williams et al., 1 996a), we suggested that much of the variation in retinal ganglion cel l number in mice, and the striking bimodality of strain averages, are caused by one or two quantitative trait loci (QTLs). To test this idea , and to map genes linked to this variable and highly heritable quanti tative trait, we have counted ganglion cells in 38 recombinant inbred strains (BXD and BXH) derived from parental strains that have high and low cell numbers. A genome-wide search using simple and composite int erval-mapping techniques revealed a major QTL on chromosome (Chr) 11 i n a 3 cM interval between Herb and Krt1 (LOD = 6.8; genome-wide p = 0. 001) and possible subsidiary QTLs on Chr 2 and Chr 8. The Chr 11 locus , neuron number control I (Nnc1), accounts for one third of the geneti c variance among BXH strains and more than half of that among BXD stra ins, but Nnc1 has no known effects on brain weight, eye weight, or tot al retinal cell number. Three strong candidate genes have been mapped previously to the same region as Nnc1. These genes-Rara, Thra, and Erb b2-encode receptors for retinoic acid, thyroxine, and neuregulin, resp ectively. Each receptor is expressed in the retina during development, and their ligands affect the proliferation or survival of retinal cel ls.