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Allelic heterogeneitiy
Means that a genetic disease can be caused by various mutations in the same
gene.
--> Almost all genetic diseases show some form of allelic heterogeneity
Clinical heterogeneity
Means that different mutations in one gene can cause different diseases.
--> e.g. sodium channel gene
Recombination Hot Spots
206 kb region on Chr. 1. 95% of all recombination events take place at a few loci
only, the so called Hot Spots. The average recombination frequency there is up to
70 cM/Mb. Outside of these hot spots the recombination frequency is about 0.04
cM/Mb.
it is clear that chromosomes have local recombination hotspots where crossing over is much more likely to occur than in other places on the chromosome. Recombination hotspots are local regions of chromosomes, on the order of one or two thousand base pairs of DNA (or less—their length is difficult to measure), in which recombination events tend to be concentrated. Often they are flanked by “coldspots,” regions of lower than average frequency of recombination (Lichten and Goldman 1995).
Dimensions of the human
genome
• Whole genome haploid =3 billion base pairs
• Average chromosome=150 megabases
• Human genetic map=3000 centimorgans
• 1 megabase ~= 1 centimorgan
• Average human gene~= ~10 ,000 base pairs
Genetic Linkage Can Be Used
to Exclude Candidate Genes
• Test genetic markers which are very
close to each candidate gene for
cosegregation with the disease
phenotype in a family
• Exclude candidate genes which show
independent assortment with disease
phenotype
Using Genetic Linkage to Find the Location of a Gene Causing a Clinical Phenotype
What Is a LOD Score?
• A LOD score is an odds ratio expressed in alogarithmic form
• Logarithmic form was used because when LOD scores were first developed calculators were not readily available
• LOD scores are used to evaluate the likelihood of linkage between two loci when a series of tests for linkage across the genome are carried out
-->Logarithm of the Odds (LOD)
Maximum recombination frequency is θ = 0.5 (no linkage).
When there is linkage, the recombination frequency is θ < 0.5.
The probability that a meisose is recombinant, is equal to the
recombination frequency θ. The probability that a meisose is
non-recombinant, is equal to 1 – θ
LOD Score is a Test for the
Likelihood of Genetic Linkage
• A LOD score is a specific case of an odds
ratio designed to test for linkage between two
genes A and B
Multipoint Mapping
Multipoint mapping has the added advantage of using information from many markers simultaneously. This is helpful both in identifying individuals at risk to develop disease and in locating a gene with sufficient precision to determine the gene product.
Why multipoint mapping?
1) Ideally, it is possible that using one linkage analysis, the whole
genome can be investigated, and with the results it is possible to
calculate the order of the genes on the chromosomes (position
within genome). This is more efficient than many independent 2-
point mappings.
2) The problem of certain non-informative markers can be
circumvented. (e.g. marker B compensates the weak information
content of marker A).
From Phenotype to Genotype
•Advances in the field of genetics, genomics and proteomics have made it possible to decipher changes that can cause disease.
•It still remains a challenge to establish a link between specific alleles and a phenotype in the case of polygenic traits (e.g. asthma, multiple sclerosis, type I diabetes, some cancers, autism,
schizophrenia, depression, hypertension, peptic ulcers, obesity etc.).
•Polygenetic traits depend on simultaneous presence of several genes, therefore they are inherited in complex Mendelian patterns.
•However, there is a large variety of monogenic traits, where clear links have been established
to single disease causing alleles (OMIM ® - Online Mendelian Inheritance in Man ®).
•Monogenic traits are often classified as “orphan diseases” with very small patient populations (EU: < 5 per 10’000; US < 7.5 per 10’000).
•Treatment of orphan diseases is economically only of limited interest. Study of such diseases often leads to the identification of novel potential drug targets and clinic development of drugs is often cheaper due to small and better defined patient populations.
•Once on the market, it is possible to seek approval for other indications.
Allelic heterogeneitiy
Means that a genetic disease can be caused by various mutations in the same
gene.
--> Almost all genetic diseases show some form of allelic heterogeneity
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