Linkage and Association

Question 1

Penetrance

Answer 1

• Link b/n genotype frequency and phenotype frequency
• Penetrance coefficient (f)
• Probability that someone w/ give genotype is actually affected by disease phenotype

Question 2

Phenocopies

Answer 2

• When someone has the disease w/o any corresponding gene so disease due to spontaneous mutation not inherited
• AKA disease phenotype w/o disease genotype

Question 3

P(affected) - Phenotype Frequency

Answer 3

penetrance x genotype frequency for ea possible genotype

FAA(p^2) + FAB (2pq) + FBB (q^2)

Question 4

2 Methods to Gene Mapping

Answer 4

1- Linkage (study large families- used for rare Mendelian diseases)

2- Association (study population - used for more complex diseases w/ possible genetic and environmental components)

Question 5

Linkage

Answer 5

• Violates Mendel’s Second Law (independent assortment)
• Linked genes are ones that are close together enough on chromosome to be inherited together (linked genes will be split by recombination <50% of the time)

Depends on distance b/n alleles (greater distance = more chance of recombination)

Question 6

Coupling, Repulsion and Phase

Answer 6

• 2 alleles are cis (same side/chromo) …coupling
• 2 alleles are trans (diff sides/chromo)…repulsion

-Phase just refers to whether 2 alleles are cis or trans so knowing phase means you know the relationship b/n 2 alleles

Question 7

Genetic Marker

Answer 7

Any polymorphic DNA sequence w/ known location in genome (acts as a tag for that particular region so you can track how that region is inherited in family)

-SNPs RFLPs DIPs or microsatellite markers (repetitive DNA)

Question 8

Why must a genetic marker by polymorphic?

Answer 8

-If a family is homozygous for the genetic marker then all will inherit that gene so you will not be able to track which chromosome is being given to which offspring (ALL THE SAME)

Question 9

Haplotype

Answer 9

-Compound allele OR block of alleles formed by specific genetic markers on same chromosome (coupled) that are usually transmitted altogether as a unit

Question 10

Recombination Fraction

Answer 10

=R/(R + NR) OR # recomb/(TOTAL)

The greater the fraction - more likely to recombine- further apart on chromosome

For random meiosis crossover you expect recombination factor to be .5 so if less than .5 genes possibly linked

Question 11

What is genetic linkage measured in?

Answer 11

centimorgans (cM)

Loci that are 1 cM apart means …crossover occurs b/n these genes in 1 of 100 meiosis

**Genetic distance is different than physical distance meas in bps

Question 12

What is the approximate relationship b/n genetic distance and physical distance?

Answer 12

1 cM is about 1 million base pairs long

Question 13

Lod scores (z)

Answer 13

-Used to determine whether a recombination factor < .5 is actually significant evidence of linkage

• if Lod > or = 3 then say sig odds of linkage
• if Lod < or = -2 then say sig odds against linkage
• Logarithm of odds ratios log(odd of link/odds of not link)
• If mult recomb fractions for given family, calc all lod scores and use recomb fraction with best Lod score as the most likely set of alleles that are linked

Question 14

Why do we use multipoint linkage analysis?

Answer 14

-Using multiple genetic markers allows you to find more precise location of disease gene because you can see that it is somewhere b/n the 2 markers w/ lowest recombination

Question 15

Parametric v non-parametric linkage analysis

Answer 15

Parametric- must specify a disease model (AKA must know the diseased sequence you are looking for); more powerful
**Often the model is incorrect (limitation)

Non-parametric- do not need to specify a disease model; just operate on basis that people w/ same disease phenotype should also have more similarities in genotype than stranger
**less powerful

Question 16

Association Testing

Answer 16

• Family based or case-control
• Look for differences in allele frequency b/n cases and controls
• DOES NOT PROVE CAUSATION

-Results in an odds ratio
OR = 1 …no association
OR>1 …association w/ disease (inc odds of having had the allele if you have the disease)
OR<1 …allele protects you from disease (dec odds of having had the allele if you have the disease)