Haplotype mapping

20/3/03. By Richard Twyman

Haplotypes, groups of closely linked alleles that tend to be inherited together, can be used to map human disease genes very accurately.

All our chromosomes come in pairs, one in each pair inherited from each parent. While each chromosome of a pair contains the same genes in the same order, the sequences are not identical. For example, there are single nucleotide polymorphisms (SNPs) approximately every 1000 nucleotides. It is therefore possible to distinguish sequence variants that come from our mother and our father. These are termed maternal and paternal alleles.

The ability to distinguish between maternal and paternal alleles allows human disease genes to be mapped by linkage analysis . In germ cells, which produce eggs or sperm, the maternal and paternal chromosomes pair up and exchange segments of DNA, a process called recombination. After recombination, the chromosomes contain a mixture of alleles from each parent. Recombination will occur frequently between DNA sequences that are a long way apart but only rarely between sequences that are close together. Therefore, by measuring the frequency of recombination between the disease gene and other DNA sequences whose location is already known, the position of the disease gene can be established.

Haplotype mapping: A new mutation (X) arises in the proximity of six single nucleotide polymorphisms, with the ancestral haplotype signature TATCAT. Over several generations, the haplotype signature may be eroded by recombination. For example, contemporary haplotype 1 was produced by recombination between the first and second SNPs. The new alleles are shown in pink. However, the smallest conserved haplotype signature in all patients carrying the disease allele places the disease between SNPs 3 and 4. This technique provides a candidate region of about 10 000 bp, which is smaller than most human genes.

Another consequence of recombination is that blocks of sequences on the same chromosome tend to be inherited together, a phenomenon known as linkage disequilibrium. Such groups of alleles, which are rarely separated by recombination, are known as haplotypes. In the human genome, haplotypes tend to be approximately 60 000 bp in size and therefore contain up to 60 SNPs that travel as a group.

Haplotypes can be exploited for the fine mapping of disease genes. The principle of haplotype mapping is shown in the Figure. A new mutation responsible for a genetic disease always enters the population within an existing haplotype, which is termed the ancestral haplotype.

Over several generations, recombination events may occur within the haplotype but the disease allele and the closest SNPs still tend to be inherited as a group. If this haplotype can be identified in a group of patients with the disease, typing the alleles within the haplotype allows a conserved region to be identified, which pinpoints the mutation responsible for the disease. Due to the abundance of SNPs, this technique has the potential to map genes very accurately. There is therefore much interest in developing a haplotype map of the entire human genome.