The Genom of Homo sapiens.pdf

366 DRAYNA ET AL.Figure 1. Distribution of PTC taste thresholds in the Utah CEPH population. Individuals classified as tasters by the method of Kalmus(1958) are indicated by light gray bars; those classified as non-tasters are indicated by dark gray bars.performed using GENEHUNTER with variance components,and subsequently using SOLAR, again combiningall families. The results of these analyses were highlyconsistent; linkage to markers on chromosome 7q wasobserved in both analyses, with a maximum LOD scoreof 8.85 (Drayna et al. 2003). When families were analyzedone at a time, none of the families was large enoughto provide a significant LOD score for linkage individually.However, a large fraction of families (about 50%)showed highest scores genome-wide on chromosome 7q.Another fraction of families displayed highest scores onboth 7q and another locus elsewhere in the genome, anda third small fraction displayed negative scores across thelength of 7q. A second linkage analysis performed conditioningon the chromosome 7q linkage resulted in highestscores observed on the distal portion of the short arm ofchromosome 16.Linkage analysis in the Utah CEPH families was thusconsistent with the view that a single major locus, actingas a largely Mendelian recessive allele and residing onchromosome 7q, is responsible for PTC taste blindness. Inaddition, a significant fraction of the phenotype is due toadditional factors, one of which may reside on chromosome16. This finding is in contrast to previous conflictinglinkage results, which were performed on numerous familiesthat were generally much smaller than the Utah familieswe have studied, and thus provided much less resolvingpower for linkage studies. These early studiesnevertheless were successful in directing attention to thelong arm of chromosome 7, at the same time that theydemonstrated aspects of complex inheritance for this trait.FINDING THE CHROMOSOME 7 GENEWe initially focused our efforts on identifying the generesiding on chromosome 7q. We performed additionalgenotyping for high-resolution linkage and haplotypestudies in all of the CEPH families that showed linkageonly on chromosome 7q and nowhere else in the genome.An example of the results of this genotyping is shown inFigure 2. The assumption for this work was that in thesefamilies, PTC taste blindness behaved as a simpleMendelian recessive trait, and recombination breakpointslocalized the causative gene to an interval of ~4 cM,bounded by D7S684 on the proximal side and D7S498 onthe distal side. This region contains over 5 Mb of genomicDNA, and ~156 known and predicted genes. Among theseis the gene encoding the KEL blood group antigen, thusconfirming previous linkage results between PTC and theKEL blood group locus (Chautard-Freire-Maia 1974;Conneally et al. 1976). To further refine the location of thisgene, we performed additional genotyping with SNPsacross this region and further refined the recombinationbreakpoints in these families to a 2.6-Mb interval, from139.2 Mb to 141.8 Mb on the chromosome 7 genomic sequence.Despite this reduction in size of the interval, manygenes remained as candidates. Of particular interest were anumber of candidate genes involved in chemosensory perception.These included 7 members of the TAS2R bittertaste receptor gene family (Adler et al. 2000), and 9 genesannotated as Odorant Receptor (OR)-like, indicating theywere candidate odorant receptors (Buck and Axel 1991).Because both of these gene families encode 7 transmem-