The technique of conversion provides several advantages for gene mapping projects of complex diseases such as cancer. The approach takes advantage of selective retention of a subset of human chromosomes within somatic cell hybrids, isolating single copies of all desired human chromosome pairs. This strategy functions both to simplify mutation detection, as well as allow unambiguous phase information to be determined. Constructing haplotypes on the basis of conventional genotype and pedigree data is challenging, particularly for late age of onset diseases such as cancer.

Identification of which homolog is retained in a particular hybrid is determined by conventional genotyping of a few markers per chromosome. These 'haploid' hybrids can then be used to increase the sensitivity of traditional mutation analysis as the disease causing chromosome will not be accompanied by the normal wild-type allele. Additionally, haplotypes maybe determined simply by genotyping each haploid hybrid. We have typed DNA from 100 hybrids to examine chromosomal retention patterns, test the feasibility of conversion for whole genome analysis, and evaluate assumptions regarding appropriate experimental design.

We have investigated the theoretical efficiency of using haplotypes compared to conventional genotypes in linkage and linkage disequilibrium studies. In the linkage disequilibrium setting, we determined the Fisher information (with respect to haplotype frequency) provided by unrelated individuals. For two-SNP haplotypes, conversion provides 5–45% more information per subject than standard genotyping, depending on true haplotype frequencies; for five-SNP haplotypes, improvement ranges 20–92%. As Fisher information is inversely related to sample size, conversion requires up to 12.5 times fewer subjects than standard genotyping to obtain the same information. We currently are completing similar calculations in the linkage analysis setting. The extra cost associated with conversion includes hybrid construction and characterization, and duplicate genotyping. However, the increased information per subject reduces overall recruitment and phenotyping costs, which tend to dominate those for genotyping. The efficiency of using conversion to construct haplotypes is likely to increase even further as automated methods of genotyping continue to improve.