Introduction to gene mapping: linkage at a crossroads

Linkage mapping has been quite successful in establishing marker maps of human chromosomes and in localizing genes for many human disorders. These successes have, in turn, enabled positional cloning of many of the disease genes first localized through linkage mapping. Disorders for which linkage mapping has been successful have a relatively simple relationship between disease phenotype and risk genotypes. In contrast, reliable localization of susceptibility genes for complex disorders has been remarkably elusive. Recent advances in technology will enable very dense maps of single-nucleotide polymorphisms (SNPs) to be genotyped for modest cost in large number of individuals. Thus, we stand at a crossroads with respect to gene mapping. One newer road leads away from linkage mapping to large-scale association studies, many of which will be conducted in unrelated individuals. The historically familiar road, with linkage mapping of families segregating for a disease or disease-related phenotype(s), is suspected by some of becoming a road less traveled. We focus here on advances in gene mapping methodologies included in this section and speculate on future directions of gene mapping in human genetics.

Keywords: linkage analysis; mapping; positional cloning; association; complex disorders