Identifying genes and genetic variation underlying human diseases and complex phenotypes via recombination mapping

Abstract

Understanding the mechanisms by which DNA and DNA variation influence diseases, naturally occurring phenotypic variation, and complex biological systems, has been one of the major tasks associated with contemporary human genetics research. The identification and characterization of specific genetic variations that influence particular human diseases and phenotypes is complicated by the fact that most diseases and phenotypes are influenced by many genetic and environmental factors. Thus, the identification of any particular phenotypically relevant factor might be hampered as other relevant factors may obscure its individual effect. Over the years numerous methods and study designs have been described to identify disease causing genes and mutations. One in particular - meiotic or recombination mapping - has received considerable attention over the last 50 years, and has been used widely with varying degrees of success. This review describes the motivation behind, and problems associated with, recombination mapping, in terms of both linkage mapping and linkage disequilibrium mapping.

Figure 1. Graphical representation of the inheritance of patterns of alleles at neighbouring loci associated with an individual chromosome segment (i.e. ‘haplotypes’)

The locus with alleles ‘–’ and ‘*’ represents a locus harbouring a disease allel/disease mutation (‘*’)and a non-disease allele (‘–’). The slightly shaded chromosome harbours the disease causing mutation. The two offspring in the first generation both inherited the mutation and, because no recombination event occurred to shuffle alleles on the parental chromosome harbouring the mutation, they also received all the alleles possessed by the parent with the mutation at loci in the vicinity of the site of the mutation (i.e. the offspring were transmitted the ‘haplotype’ TGC*TAC). The dotted lines represent generations passing. The two families in the most recent generations both have parents who have inherited the mutation. However, because of recombinations event occurring in the line of descent from their common ancestor possessing the mutation, they received different alleles at the two outermost loci away from the mutation, but still were transmitted, intact, a ‘core’ ancestral haplotype encompassing the mutation (i.e. GC*TA). Note that within each of these families, the offspring who were transmitted the mutation inherited longer haplotypes (i.e. AGC*TAC for the ‘left’ family and TGC*TAG for the ‘right’ family).