Linkage mapping and LOD scores - AndersenLab/Genetic-Analysis GitHub Wiki
Lecture 13
Phase:
The phase of an individual is the chromosomal arrangement of two loci of interest. For example, alleles at a disease locus and a marker locus. If you know the phase of an individual, you know which marker allele is on the same chromosome as the disease-causing allele.
Example of phase shown on slide 2:
You know that individual I1 is heterozygous for the disease allele (Dd) and has marker allele 1 and 2. You do not know if the D allele is on the same chromosome as marker allele 1 or marker allele 2 (D1/d2 or D2/d1). Therefore you do not know the phase of individual I1.
Individual II1 is affected and therefore carries the D allele. His father (I1) was also affected and must have given him this disease allele. II1 has two marker alleles: 1 and 4. Because his father (I1) only had marker alleles 1 and 2, II1 must have inherited marker allele 1 from his father. Therefore, the disease allele (D) must be on the same chromosome as the marker allele 1 in individual II1. Therefore you do know the phase of individual II1 (D1/d4).
Now that you know the phase of II1, you might be able to determine the phase of his progeny.
III1 inherited the disease allele and markers 1 and 3. We know he inherited the disease allele from his father, but he could have inherited marker allele 1 from either his mother or his father. However, 3 must have come from his mother, so his phase is (D1/d3). These chromosomes are both parental, so we label individual III1 as a P for parental.
III7 inherited the disease allele from her father. She also inherited marker alleles 1 and 4. Marker allele 4 must have been inherited from her father, because her mother did not have this allele. Therefore, she inherited D and 4 from her father even though those alleles are not found on the same chromosome in her father. Therefore, her (D4) chromosome was only possible if recombination occurred.
Sometimes we do not know the phase of the parents, like in slide 3. In this case, we don't know if individual I1 is (D1/d4) or (D4/d1). We would assign the progeny to parental (P) or recombinant (R) groups given each phase possibility for I1.
Just because you know the genotypes of the parents does not mean you can tell the phase of progeny. Examples on slide 4 show how you could still have an uninformative individual even if you know that individual's parent's genotypes at the disease locus and marker locus.
The recombination frequency tells you how close a marker is to the disease locus. You can calculate this by (number of recombinants/total progeny). We call this value "theta". If theta is 0, that means the two loci are very close to each other -- they are in perfect linkage. If the theta is 0.5, that means the two loci are maximally distant from each other -- they are unlinked. Remember that the maximum recombination frequency between two markers is 0.5.
Pop Quiz: What is the advantage of finding a marker locus nearby the disease locus?
We can report the association of the disease phenotype in this case (D allele) with a certain marker allele as the log of the odds score (LOD). This is the same as the log10(probability of the given pedigree given the calculated recombination frequency/probability of the given pedigree given no linkage, where theta is 0.5)
If we know the phase:
The probability of the pedigree given the calculated theta is: (1-theta)#non-recombinants x (theta)#recombinants and the probability of the pedigree with no recombination is (0.5)(total #progeny)
If we don't know the phase:
The equation is on slide 21
Further resources: