Purpose of indirect testing with markers
Whenever it is not possible to test for disease causing mutations (either bc too many mutations or disease causing gene not mapped), can use linked markers to perform carrier testing and pre-natal diagnoses.
Disadvantages of indirect testing?
Need correct diagnosis
DNA from family members needed
What are the two ways of flagging chromosomes?
Single nucleotide polymorphisms (SNPs)
Microsatellites (variable # of tandem repeats)
Permanent heritable change in genomic DNA sequence, often used incorrectly to indicate a "bad" change
Sequence variant found at a frequency of at least 1% (at least 2% of people are heterozygotes), often incorrectly used to mean benign
Rare genetic varient
Mutation w/ frequency less than 1%
formation of new combinations of linked genes by crossing over between loci (avg of 3 crossovers per chromosome per generation)
Genes close enough together on same chromosome have tendency to be transmitted together without crossovers
group of alleles from closely linked loci - usually inherited as a unit
reciprocal exchange of the segments between chromatids of homologous chromosomes (mechanism of recombination)
Recombination is less likely to occur between tightly linked loci so they tend to go toegether in tandem from parent to offspring.
(ex. markers for cystic fibrosis have been close to CF gene for a long time)
What are the 3 classes of mutations?
1. Linked extragenic markers (label attached to suitcase by a length of string - longer string, increased risk it will get cut off)
2. Intragenic markers (label on suitcase - far less likely to become separated)
3. Disease-causing mutations (bomb inside suitcase)
What is the gene that's the exception for intragenic markers, and why?
For Duchenne Muscular Dystrophy, the dystrophin gene is so big that intragenic markers still have significant recombination rate with disease-causing mutation
Which are more useful... flanking markers or markers on the same side?
Flanking markers - since it would take a double cross over (rather than a single) to cause an error
Alleles at different loci are said to be coupled when they are on the same chromosome (cis)
Alleles at different loci are said to be in repulsion when on opposite chromosomes (in trans)
when mutations are known to be on the same or different chromosome (known to be in coupling or repulsion - phase is known)
When it is not known which mutation is on which homologous chromosome (ie whether the alleles at different loci are in coupling or repulsion - phase not known)
Lod Score (Z)
Statistical method that tests genetic marker data in families to determine whether two loci are linked
Lod score is on log scale
Lod of 3 in an autosome and of 2 in an X-linked is taken as proof of linkage
Lod of -2 = unlinked
^^^ lod = ^^^ likelihood genes are linked