Lecture 22 - Linkage and Recombination

Question 1

Purpose of indirect testing with markers

Answer 1

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.

Question 2

Disadvantages of indirect testing?

Answer 2

Need correct diagnosis

DNA from family members needed

Question 3

What are the two ways of flagging chromosomes?

Answer 3

Single nucleotide polymorphisms (SNPs)

Microsatellites (variable # of tandem repeats)

Question 4

Mutation

Answer 4

Permanent heritable change in genomic DNA sequence, often used incorrectly to indicate a “bad” change

Question 5

Polymorphism

Answer 5

Sequence variant found at a frequency of at least 1% (at least 2% of people are heterozygotes), often incorrectly used to mean benign

Question 6

Rare genetic varient

Answer 6

Mutation w/ frequency less than 1%

Question 7

Recombination

Answer 7

formation of new combinations of linked genes by crossing over between loci (avg of 3 crossovers per chromosome per generation)

Question 8

Linkage

Answer 8

Genes close enough together on same chromosome have tendency to be transmitted together without crossovers

Question 9

Haplotypes

Answer 9

group of alleles from closely linked loci - usually inherited as a unit

Question 10

Crossing over

Answer 10

reciprocal exchange of the segments between chromatids of homologous chromosomes (mechanism of recombination)

Question 11

Linkage disequilibrium

Answer 11

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)

Question 12

What are the 3 classes of mutations?

Answer 12

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)

Question 13

What is the gene that’s the exception for intragenic markers, and why?

Answer 13

For Duchenne Muscular Dystrophy, the dystrophin gene is so big that intragenic markers still have significant recombination rate with disease-causing mutation

Question 14

Which are more useful… flanking markers or markers on the same side?

Answer 14

Flanking markers - since it would take a double cross over (rather than a single) to cause an error

Question 15

Coupling

Answer 15

Alleles at different loci are said to be coupled when they are on the same chromosome (cis)

Question 16

Repulsion

Answer 16

Alleles at different loci are said to be in repulsion when on opposite chromosomes (in trans)

Question 17

Phase

Answer 17

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)

Question 18

Lod Score (Z)

Answer 18

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