Other Free Encyclopedias » Medicine Encyclopedia » Genetics in Medicine - Part 3 » Linkage and Recombination - Basic Concepts, Calculating Linkage And Map Distance, Statistical Approaches

Linkage and Recombination - Statistical Approaches

chromosome differences genetic disease marker genetic humans

In experimental organisms, genetic mapping of loci involves counting the number of recombinant and nonrecombinant offspring of selected matings. Genetic mapping in humans is usually more complicated than in experimental organisms for many reasons, including researchers' inability to design specific matings of individuals, which limits the unequivocal assignment of recombinants and nonrecombinants. Therefore, maps of markers in humans are developed by means of one of several statistical algorithms used in computer programs.

Genetic maps can assume equal recombination between males and females, or they can allow for sex-specific differences in recombination, since it has been well established that there are substantial differences in recombination frequencies between men and women. Chromosomes recombine more often in females. On average, the female map is two times as long as the male map.

The complexity of the underlying statistical methods used to generate them renders genetic maps sensitive to marker genotyping errors, particularly in small intervals, and these maps are less useful in regions of less than about 2 centimorgans. While marker order is usually correct, genotyping errors can result in falsely inflated estimates of map distances.

Disease gene mapping is greatly facilitated by the availability of dense genetic maps. Linkage analysis for the mapping of disease genes boils down to the simple idea of counting recombinants and nonrecombinants, but in humans this process is complicated for a variety of reasons. The generation time is long in humans, so large, multigenerational pedigrees in which a disease or trait is segregating are rare. Scientists cannot dictate matings or exposures. They also cannot require that specific individuals participate in a study. Thus the process of linkage analysis in humans requires a statistical framework in which various hypotheses about the linkage of a trait locus and marker locus can be considered. How far apart are the disease and marker, and how certain is the conclusion of linkage?

When the inheritance pattern for a disease is clearly known (e.g., auto-somal dominant, sex-linked, etc.), the genetic data can be treated with a statistical approach that determines the likelihood that the gene is linked to a particular marker, at a particular position on a specific chromosome. This approach is often termed the "lod score approach," where "lod" is short for logarithm of the odds.

Lod score linkage analysis is used most frequently to consider diseases that follow a Mendelian pattern of transmission within families. Positive lod scores, especially those greater then 3.0, suggest evidence for linkage between a disease gene and a marker locus. Negative lod scores suggest that the disease gene and marker locus are unlinked to one another.

Marcy C. Speer

Bibliography

Strachan, Tom, and Andrew P. Read. Human Molecular Genetics. New York: Wiley-Liss Publishers, 1999.

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