33 - LOD Scores

LOD Scores

© SPMM Course other locus will also be transmitted to the daughter cell. But linked loci are close enough together so that the chance of a recombination is less than 50%. Thus, their inheritance is not independent. The distance between two loci can be inferred by estimating the frequency with which cross-overs occur among them. The lesser the cross-over, the closer the loci. Because this is done by looking at recombination in families, this is called as recombination frequency. The recombination frequency provides a measure of the genetic distance between any pair of linked loci. Genetic distances are often expressed in centiMorgans (cM). One centiMorgan is equal to a 1% recombination frequency between two loci. 1 cM is approximately equal to 1 million base pairs of DNA (1 Mb). But crossovers occur more commonly at telomeres and less common near centromeres. LOD Scores To estimate the likelihood that two loci are truly linked with a specific recombination frequency, an LOD score is used. The LOD ("log of the odds") is estimated using the following expression LOD = log 10 (probability that recombination frequency is the observed value Ø) (probability that the recombination frequency is 50% i.e. chance) A logarithm is used because it allows LOD scores from different individual families studied to be added together later to obtain an overall LOD score. An LOD score greater than 3 is usually interpreted as statistical evidence of linkage (i.e., the numerator is 1,000 times greater than the denominator, indicating that linkage is 1,000 times more likely than nonlinkage). Conventionally an LOD score of -2 or less is taken as evidence that two loci are not linked (i.e., nonlinkage is 100 times more likely than linkage). Two loci are said to be in linkage disequilibrium if specific combinations of alleles at the loci are seen together on chromosomes more often than expected by chance. Because recombination is rare for very closely linked loci, such loci are more likely to exhibit linkage disequilibrium. Such linkage disequilibrium can be analysed in association studies too. Two different approaches can be adopted in linkage studies:

1. Candidate gene approach: A protein is suspected to be involved, then the gene is traced from this pathogenetic knowledge.
2. Positional cloning approach: Genes are identified through their positions in the genome rather than functions. Supported by human genome project. A prerequisite for successful linkage analysis (see below) is the availability of a large number of highly polymorphic markers dispersed throughout the genome. Sib pair analysis In this method several hundred DNA markers roughly evenly spaced along the 23 pairs of human chromosomes are taken and genotyping is carried out in a series of concordant sibling pairs. ‘The probability that siblings share 0, 1, or 2 alleles at any marker locus is respectively, 0.25, 0.5, and 0.25. However, if a marker locus is close to (and therefore linked with) a locus conferring susceptibility to