Morgan: ‘linked’ genes; chromosomal theory of inheretance
Þ
the closer two genes are on a chromasome, the lower the probability they will be separated by recombination
q
= genetic distance or recombination value (cM = centamorgans); 1 cM = 1% recombination
linked loci; < 50 cM (50 cM will happen by random chance)
Determining Distance between Homologous Chromosomes
genetic distance between two loci can be empirically determined
phenotypic traits can be used for linkage analysis
other genetically determined differences can also be used to identify and follow alleles
immunologically
electrophoretically
microscopically
molecular genetically
polymorphism
: mutations that are present in more than 2% of the population
heteromorphism
: mutations present in less than 2% of the population
disease loci which segregate in families can be studied for linkage
Þ gene mapping of hereditary traits (diseases)
Statistical Measures of Linkage
p value < 0.0005 is required (more stringent than the normal 0.05)
lod score is more commonly used (Log10 of the Odds Ratio)
odds ratio = (odds result is due to linkage)/(odds result is not due to linkage)
lod score > 3 is significant for linkage (odds ratio greater than 1/1000)
need at least 11 affected of unaffected members of a family to reach this score
Other Approaches for Determining Pathogenesis
(disease mapping compliments these)
classical genetics
: disease is traced back through causative protein
Þ RNA Þ gene Þ map position
reverse genetics
: linkage analysis is used to locate the map position of the gene causing the disease Þ various methods are then used to identify the responsible gene (Duchene Muscular Dystrophy; CF; Huntington’s; BRCA1)
(1) Positional-Candidate Analysis: look at existing genetic maps (Human Genome Project, various other maps) and test genes that have already been mapped to the area in question to find a candidate for the disease-causing gene
limited by the fact that only 10% of human genes have been mapped
(2) Positional Cloning: used in absence of a co-localizing candidate gene; map the disease and then scour the area looking for new genes that could be disease-causing