Linkage Analysis

Linkage analysis is used to pinpoint the location of disease genes within the genome. Given genetic data from a family with a strong history of a disease, it is possible to trace the inheritance of the disease through the family, and thereby localize the genetic region (or locus) responsible for disease in that family. In practice, linkage analysis combines the biological rules of inheritance with statistical inference to identify a linked locus.

Linkage analysis is based on research conducted by Gregor Mendel in the 1860s. Mendel's second law of inheritance states that genetic loci are inherited independently of one another. This independent assortment occurs because genes are located on individual chromosomes, which are redistributed randomly every time an egg or sperm cell is produced. This is why siblings have similar, but not identical, traits; each sibling arose from a unique assortment of parental chromosomes. When two loci are located on separate chromosomes, they will be inherited independently, meaning that the loci will be distributed to the same offspring about 50% of the time. However, loci on the same chromosome are inherited together more frequently. Because portions of each chromosome are rearranged during meiosis, two loci that are near each other are inherited together more frequently than loci distant from each other on the same chromosome. Thus, it is possible to determine the relative position of loci by examining inheritance patterns in a family.

Linkage analysis traces inheritance patterns, and therefore must use genetic and phenotypic data collected from groups of related individuals, some of which have the trait of interest. In most linkage studies, genetic data are collected by genotyping family members for several hundred genetic markers distributed at known locations throughout the genome. Commonly used markers are microsatellite markers and single nucleotide polymorphisms. Researchers then use statistical software to determine which markers are likely to be near the trait locus, based on marker inheritance patterns in affected and unaffected family members.

Linkage analysis requires making several assumptions. First, it is assumed that the trait of interest is genetic. This is usually established by performing a familial aggregation analysis, which can determine if relatives of an affected individual are more likely to have a trait than individuals in the general population. However, familial aggregation of a trait can also be caused by nongenetic factors, including shared environmental exposures and shared behaviors. Second, linkage analysis assumes that the trait follows Mendelian rules of inheritance and that the mode of inheritance is known. This assumption can be tested via segregation analysis that uses statistical tests to identify the most likely mode of inheritance for a trait.

Several phenomena can complicate linkage analyses. Genetic heterogeneity, a situation in which several distinct genes cause the same phenotype via different pathways, can make it nearly impossible to establish linkage. Epistasis, a state in which two or more genes interact to cause a phenotype, will also obscure linkage. While linkage analysis can provide clues about the location of a gene associated with a phenotype, it does not identify a causal allele or mutation. Linkage analyses in several families may identify the same locus linked to the same disease, but each family's disease may be caused by a unique genetic variant. For this reason, linkage analyses are often followed by a genetic association study, which can identify causal alleles in the candidate gene identified by linkage analysis.

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