Linkage+Analysis

=**Objectives**=


 * 1. Be able to describe the genetic consequences of chromosomal crossing-over with regard to genetic recombination and the preparation of genetic linkage maps.** (p.629,632)

If two genes are linked on a chromosome and crossing-over never ever occurs, then gamates produced will always have parental chromosomes. Chromosomal crossing-over can result in genetic recombination, resulting in gamates of the same genotype as parental chromosomes, but also some that are different (recombinant). Crossing-over results in the physical exchange of genetic material between chromatids of the paired homologous chromosomes through the formation of chiasmata. Only 2 of the four chromatids are involved in any single crossing-over event because crossing-over prevents interactionf of nearby elements; however, multiple crossing-over events can occur on a chromosome.

The physical distance between two loci on the same chromosome is roughly proportional to the probability of a cross-over occuring between the two loci. Therefore, the frequency of observed recombinants can be used to measure the distance between two loci on the same chromosome. The recombinant frequency (RF) of 0.01 or 1%is defined as 1 map unit or 1 cM. If two loci are greater than 50cM (RF=0.5) will behave as if they are on different chromsomes; 50% RF is the highest recombination you can get.


 * 2. Be able to apply knowledge of recombination, linkage, and genetic markers to probelsm involving both animal genetic models and human pedigrees.** (p.637)

Linkage between a gene and a particular trait begins with studying the segregation of the disease in large families using polymorphic markers. For some disease, the presence of an aberrant phenotype is very closely associated with a particular locus or set of loci (haplotype), and are said to be in __linkage disequilibrium__.

Basically with genetic marker linkage analysis, look for common haplotypes between affected individuals and try to determine the unique genotype that results in the disease phenotype. However, be aware that chromosomal crossing-over can produce individuals with recombinate chromosomes and may indicate the specific haplotype rather than genotype that is linked to disease.


 * 3. Be able to define the term lod score. Students will be expected to be able to use and interpret lod scores to answer linkage analysis problems.** (p.641)

Lod score stands for the logarithm of odds ratio score. The basic idea is that you take the log for each individual in a generation of the likelihood of linkage (RF value) divided by the likelihood of no linkage (RF=0.5).

(1) So for each individual in the generation of interest, determine the number of individuals exhibiting inheritance of parental meiotic products and the number of individuals exhibiting inheritance of recombinant meiotic products. (2) Multiply the RF value for each person who got a recombinant chromosome and 1-RF for each individual who got a parental chromosome to get the precent chance of getting that particular distribution of parental and recombinant offspring at a give RF value. (3) Take that number and divide by 0.5^n where 0.5 is the RF value for no linkage and n is the number of individuals in the generation of interest. (4) Take the Log of that quotient to get the Lod Score.

A Lod Score of greater than 3 indicates that there is a need to infer linkage. A Lod score of less than -2 means there is need to infer no linkage. Any Lod score in between means you don't have enough information.

The idea of Lod Analysis is for the generation of a Lod score for a range of possible RF values and determine if there is a likelihood for linkage (most RF values yield Lod score greater than 3) and also the most likely distance between the link genes (the RF corresponding to the highest Lod score).