Box 4 | Haplotype mapping 

Haplotype mapping is often carried out as part of a genome scan. In a population isolate, the appearance of a rare Mendelian disease is almost always attributable to a single founder gene or mutation. The disease allele can be identified by searching for a common haplotype signature shared among patients. As the ancestral haplotype signature is passed from generation to generation, it is disrupted by recombination. Partial conservation of the haplotype signature in a patient strongly suggests that the disease locus resides in the conserved region of the haplotype.

As an example of haplotype mapping, the figure shows a chromosome segment that bears a disease locus (designated d) and six marker loci (designated a, b, c, e, f and g). Each of the four haplotypes shown is a sequence of numbered alleles at these six markers. The disease allele enters the population on the background of the ancestral haplotype signature. The three patient haplotypes allow us to reconstruct the signature and map the disease locus d. Patient haplotype 1 has experienced recombination between markers a and b, patient haplotype 2 has experienced recombination between markers e and f, and patient haplotype 3 has experienced recombination between markers b and c. The smallest region of overlap lies between markers b and f and consequently contains the disease locus d.

The smallest region of overlap inferred from multiple, partially conserved haplotypes is often much smaller than the smallest region of overlap inferred from linkage mapping of contemporary pedigrees. In population isolates, haplotype signatures can extend over several centiMorgans¹⁴. For some rare diseases, haplotype mapping has been successful using only four or five patients and a sparse genome scan of only 200–300 markers^{16, 17}.

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