Chapter 22, Problem 19P

Canavan disease, caused by homozygosity for a recessive allele, is a severe neurodegenerative syndrome usually resulting in death by the age of 18 months. The frequency of Canavan disease is particularly high in Jewish populations. In an effort to map the gene causing this condition, researchers looked at 10 SNPs (1–10) spaced at roughly 100 kb distances along chromosome 17 in five affected Jewish patients (Cases) and four unaffected Jewish individuals (Controls). In the accompanying table, each row depicts a single haplotype. (Every individual is diploid and therefore has two haplotypes, although only one is shown in the table.) G, C, A, and T represent the actual nucleotide at the indicated SNP location.

Case	SNP1	SNP2	SNP3	SNP4	SNP5	SNP6	SNP7	SNP8	SNP9	SNP10
1	G	T	G	T	T	T	C	A	G	T
2	A	T	G	T	T	T	C	A	G	T
3	G	T	G	T	T	T	C	A	G	C
4	A	A	G	T	T	T	C	T	C	C
5	G	A	G	C	C	T	G	A	C	C
Control
6	A	A	G	T	T	T	C	A	G	T
7	G	T	G	G	C	T	G	A	G	T
8	A	T	C	T	C	G	C	T	C	C
9	G	T	C	G	T	G	G	A	C	T

a.	Does the disease-causing mutation appear to be in linkage disequilibrium with any of the SNP alleles? If so, which ones?
b.	Where is the most likely location for the Canavan disease gene? About how long is the region to which you can ascribe the gene?
c.	How many independent mutations of the Canavan gene are suggested by these data?
d.	Suppose that individuals 2–9 are Ashkenazic (whose ancestors lived in the Rhine river basin of Germany and France after the Jews were expelled from Judea in 70 A.D.) while individual 1 is Sephardic (a non-Ashkenazic Jew). Would these facts provide any information about the history of the mutations causing Canavan disease?
e.	For mapping genes by haplotype association, why is it often helpful to focus on certain subpopulations? Does this strategy have any disadvantages?
f.	Human chromosome 17 is an autosome, so each person has two copies of each region along the chromosome. With this in mind, explain the practical difficulty in determining haplotypes. (Hint: Consider heterozygosity.) In light of this difficulty, how could the researchers determine any individual haplotype, such as any of those shown in the table?