Haplotypes And Linkage Disequilibrium

When several genes or genetic markers are closely spaced on a chromosome, they tend to be inherited together as a group, and such a group of genetic markers on a chromosome is known as a haplo-type. For example, the HLA loci encode highly polymorphic genes that are located in a region of approx 3.6 million bp on the short arm of chromosome 6. This region of the genome is known as the major histocompatibility complex (MHC); the MHC includes class I and class II HLA genes, several genes that encode components of the complement system, and several other genes such as tumor necrosis factor and steroid 21-hydroxylase (Fig. 6). An MHC haplotype includes several million base pairs of DNA, as exemplified by the frequent Caucasian haplotype HLA-A3, -B8, -DRB1*0301, which spans over 2 million bp (13). Identification of MHC haplotypes is of importance when searching for a potential donor for organ or bone marrow transplantation. Siblings have a 1-in-4 probability of having inherited the same MHC haplotypes from their parents and are therefore the most likely potential donors of an MHC-identical match.

When several alleles exist at independent polymorphic loci, the frequencies of expected combinations of alleles in the population is given by the product of the allele frequencies. For example, if locus A has two alleles, Ai and A2, with frequencies of 0.3 and 0.7, and locus B also has two alleles, B1 and B2, with frequencies of 0.6 and 0.4, then the expected frequencies of combinations of alleles are Ai/Bi 0.18 (i.e., 0.3 x 0.6); A1/B2 0.12; A2/B1 0.42; and A2/B2 0.28. If these findings were observed in a population, then the markers would be referred to as being in linkage equilibrium. When markers on a chromosome are not randomly associated with each other, they are said to be in linkage disequilibrium. For example, a deletion that includes both the steroid 21-hydroxylase gene (CYP21) and the adjacent complement 4B gene is frequently seen on a haplotype that includes the HLA markers A3, B47, and DR7 (14). This haplotype is associated with congenital adrenal hyperplasia because of deficiency of steroid 21-hydroxylase, an autosomal recessive inborn error of metabolism. Similarly, hereditary hemochromatosis resulting from a mutation, C282Y, in the HFE gene, is in linkage disequilibrium with the HLA-A3 gene.

Linkage disequilibrium may indicate a founder effect. For example, the C282Y mutation in HFE arose in a chromosome that also contained the HLA-A3 allele, and this combination of alleles at these two loci has been transmitted to the descendents of the individual in whom this mutation occurred. Because the HFE locus and the HLA-A locus are in relatively close proximity, the HFE mutation is still in linkage disequilibrium with the HLA-A3 allele. Over many generations, recombinations between HFE and HLA-A would be expected to bring the HFE mutation into chromosomes with different HLA-A alleles. The extent of linkage disequilibrium between a founder mutation and other closely spaced genetic markers is therefore a function of the age of the mutation as well as the distance between the loci in question. For example, based on haplotype analysis, it has been estimated that the C282Y mutation in HFE arose approximately 60-70 generations ago (15).

Several examples of linkage disequilibrium involving disease-causing genes provide insight into the structure of human populations. The C282Y mutation in HFE is found in 10% of the Caucasian population of northern European (Celtic) ancestry, which means that 1 in 10 people of this group are descendents of a single founder individual. In the United States alone, these number approx 20 million people. Similarly, 5-8% of the Caucasian population have the factor V Leiden mutation, which predisposes to thrombophilia. Haplotype analysis of markers in and around the factor V gene in these people demonstrates that these are also descendents of a single founder individual (16).

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