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LINKAGE PUZZLES Question 1 Family 1

We assume that all those with the disease phenotype are heterozygous for the disease as it is an autosomal dominant disease. Phase is the relation between alleles at 2 linked loci. When an individual is phase known you know which alleles are inherited from which parent and therefore unambiguously score each meiosis as recombinant or non-recombinant. Informative individuals are all of the individuals which are heterozygous for the disease (Dd) and the co-dominant marker (AB) together with some individuals who are phase known. Informative individuals: II:1 Phase: Z III:1 Z III:2 Z III:3 Z No recombinants are present Non-recombinants are individuals III:1, III:2, III:3 Therefore Family 2 n=3 r:nr = 0:3

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Informative individuals:

II:1

Phase: Z1

No recombinants are present Possible recombinants are individuals II:1 and II:2 Therefore n=2 a:b = 1:1

Family 3

Informative individuals:

II:1 II:2 II:3 II:4

Phase: Z Z Z Z

The recombinant individual is person III:1 Non-recombinants are individuals III:2, III:3, III:4 Therefore n=4 r:nr = 1:3

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Lod Score Analysis across families Theta Family1 Family 2 Family 3 Total 0.00 0.90 0.30 -inf 0.05 0.84 0.26 -0.16 0.94 0.10 0.77 0.21 0.07 1.05 0.15 0.69 0.17 0.17 1.03 0.20 0.61 0.13 0.21 0.95 0.25 0.53 0.10 0.23 0.86 0.30 0.44 0.06 0.22 0.72 0.35 0.34 0.04 0.19 0.57 0.40 0.24 0.02 0.14 0.40 0.45 0.12 0.00 0.08 0.20

The numbers in bold indicate the lod-scores for each individual family When the families are combined to get a combined Z-max of all 3 families we produce a Z-max value of 1.05. This corresponds to a theta value of 0.1. Since theta represents the recombination fraction, the recombination fraction is 0.1. A combined Z-value is the test of linkage. Since we obtained a value of 1.05, which lies between the range of -2<Z<3 we are uncertain that there is linkage present and more families need to be collected to get a more conclusive Z-max value. The theta value indicates that the markers are quite far from each other (0.1cM). Question 2 Microsatellites have a high mutation rate and thus are highly polymorphic (heterozygousity >80%). This results in a higher chance of heterozygotes for the marker being produced than with SNPs. This would be useful in Family 2 since individual II:1 is homozygous and thus noninformative. Using microsatellites may show him to be heterozygous, thus making him informative. We would then be able to work out his phase and determine the phase of individual I:1, which would alter the Z-max value. Furthermore, making individual II:1 heterozygous, would then allow us to include individuals III:1- III:4 in our lod score analysis, making it more representative and hopefully more conclusive Question 3 Knowing the frequency of alleles A and B would influence scoring in family 3 only. If one knew the frequency of alleles A and B, one could then use Hardy-Weinberg analysis to infer the genotype of individual I:1 which is not currently known. We can be sure that individual I:1 is has the genotype AB or BB as he passes on his B allele to all his offspring. If, for example, using Hardy Weinberg analysis, we determine the allele frequency for B is low (0.01 = 1%) we can assume he is heterozygous (AB) and thus informative. If, however, it shows a high allele frequency for B (0.99 = 99%), we can be certain he is homozygous (BB) and thus noninformative. If informative, we are able to include individuals II:1 II:4 in the lod score analysis making it more powerful. Question 4 We would want the additional relative to be the parent of the individual I:1 who has the unaffected phenotype and has the genotype AA. This would allow us to confirm the genotype of

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individual II:1 as being heterozygous, thus making him informative and therefore allowing us to include individuals II:1 II:4 in analysis. Having 8 informative individuals would decrease the ratio of recombinants to non-recombinants since the extra 4 will be shown to be nonrecombinants. This will increase the lod-score for family 3 and thus provide more evidence for linkage. The combined lod-score (Z-max) of the 3 families will also increase as a result.