Determining linkage

Question 1

What are CEPH families?

Answer 1

Uncharacteristically large human families used in several studies to map polymorphisms in the human genome

Question 2

What are the 4 criteria that had to be met for a family to be a CEPH family?

Answer 2

1. 3 generations
2. Both sets of grandparents had to be alive
3. Both parents had to be alive
4. Mean sibship of 8.3

Question 3

How do we determine linkage in humans?

Answer 3

Count number of recombinants in offspring from parents with informative meiosis

Question 4

Why is determining linkage so hard in humans?

Answer 4

Can’t control crosses and families are so small, so resolution is low. Need to run statistics to determine if the number of parental and recombinant offspring is different from the expected 50:50 ratio if the loci were unlinked

Question 5

What do we calculate to determine if two loci are linked or not in humans?

Answer 5

Lod scores

Question 6

What do Lod scores calculate?

Answer 6

Theta - the recombination frequency

Question 7

What Lod score is statistically significant and indicates linkage?

Answer 7

3

Question 8

What is the formula for Lod scores when we know phase? What does each symbol mean?

Answer 8

Lod theta = log of (1-theta)^P x (theta)^R/(0.5)^R+P

Theta = probability of a gamete being recombinant 
1-theta = probability of a gamete being parental 
P = number of parental offspring 
R = number of recombinant offspring

Question 9

Do we usually calculate Lod scores for a single value of theta?

Answer 9

No, will calculate for multiple values. Computer programs will run hundreds

Question 10

What would the Lod score for unlinked loci be?

Answer 10

-2 or less

Question 11

What is the maximum likelihood score?

Answer 11

The value of theta with the highest LOD score. The most likely value for RF

Question 12

What do we do when we have multiple LOD scores >3?

Answer 12

The highest one is considered the true theta. Any others less than 1 away from the highest are support intervals

Question 13

Even though we can calculate the LOD scores when we don’t know phase, why is it less powerful?

Answer 13

Have to account for both possible phases, so we’re less certain of the theta values

Question 14

What does a LOD score of negative infinity mean?

Answer 14

Excludes that possibility of theta entirely

Question 15

What do we do with maximum likelihood scores that are less than 3?

Answer 15

Not complete garbage. Since each meiosis event in a family and between families is independent, we can add LOD scores from different kindreds together to increase confidence

Question 16

Why do we need to be careful when adding up LOD scores from different kindreds?

Answer 16

Locus heterogeneity is a thing and we can’t add scores up if its not the same disease with the same cause between the kindreds

Question 17

Why can’t the narrowed critical region for the disease gene only include markers with significant LOD scores?

Answer 17

We don’t know exactly where linkage drops off, so we need to include the flanking markers so we don’t miss anything