MAPPING BY ADMIXTURE LINKAGE DISEQUILIBRIUM IN HUMAN-POPULATIONS - LIMITS AND GUIDELINES

Certain human hereditary conditions, notably those with low penetrance and those which require an environmental event such as infectious dis ease exposure, are difficult to localize in pedigree analysis, because of uncertainty in the phenotype of an affected patient's relatives. A n approach to locating these genes in human cohort studies would be to use association analysis, which depends on linkage disequilibrium of flanking polymorphic DNA markers. In theory, a high degree of linkage disequilibrium between genes separated by 10-20 cM will be generated a nd persist in populations that have a history of recent (3-20 generati ons ago) admixture between genetically differentiated racial groups, s uch as has occurred in African Americans and Hispanic populations. We have conducted analytic and computer simulations to quantify the effec t of genetic, genomic, and population parameters that affect the amoun t and ascertainment of linkage disequilibrium in populations with a hi story of genetic admixture. Our goal is to thoroughly explore the rang es of all relevant parameters or factors (e.g., sample size and degree of genetic differentiation between populations) that may be involved in gene localization studies, in hopes of prescribing guidelines for a n efficient mapping strategy. The results provide reasonable limits on sample size (200-300 patients), marker number (200-300 in 20-cM inter vals), and allele differentiation (loci with allele frequency differen ce of greater than or equal to .3 between admired parent populations) to produce an efficient approach (>95% ascertainment) for locating gen es not easily tracked in human pedigrees.