The accuracy of statistical methods for estimation of haplotype frequencies: An example from the CD4 locus

Haplotype analysis has become increasingly important for the study of human disease as well as for reconstruction of human population histories. Compu ter programs have been developed to estimate haplotype frequencies statisti cally from marker phenotypes in unrelated individuals. However, there curre ntly are few empirical reports on the accuracy of statistical estimates tha t must infer linkage phase. We have analyzed haplotypes at the CD4 locus on chromosome 12 that consist of a short tandem-repeat polymorphism and an Al u insertion/deletion polymorphism located 9.8 kb apart, in 398 individuals from 10 geographically diverse sub-Saharan African populations. Haplotype f requency estimates obtained using gene counting based on molecularly haplot yped (phase-known) data were compared with haplotype frequency estimates ob tained using the expectation-maximization algorithm. We show that the estim ated frequencies of common haplotypes do not differ significantly with the use of phase-known versus phase-unknown data. However, rare haplotypes are occasionally miscalled when their presence/absence must be inferred. Thus, for those research questions for which the common haplotypes are most impor tant, frequency estimates based on the phase-unknown marker-typing results from unrelated individuals will be sufficient. However, in cases where know ledge of rare haplotypes is critical, molecular haplotyping will be necessa ry to determine linkage phase unambiguously.