Homozygosity mapping using Whole Genome SNP chips to identify a region of linkage disequilibrium
Genes involved in rare recessive disorders are hard to identify. While it is possible to find linkage with one or just a few pedigrees, fine mapping followed by gene identification is difficult due to the small number of informative meioses available.
We have previously identified a family of Slovenian descent in which 5 out of 14 siblings are affected by a syndrome of late onset ataxia with saccadic intrusions, SCASI (Swartz et al. Ann Neurol 54(6):824-8, 2003). We have mapped this gene (LOD score 3.28) to a 20 cM interval of 1p36 (Burmeister et al., unpubl.).
Although the family is not consanguinous, the rarity of the disorder, and origin of paternal and maternal grand parents from an isolated area, suggests that a single founder mutation is likely the cause of SCASI. We therefore hypothesized that the mutation might be located in a region of homozygosity within the 20 cM linkage interval. To test this idea, DNA from two affecteds, an unaffected, noncarrier sibling as well as an unrelated control sample was hybridized to the “early access” version of the Affymetrix 500 K chips, which contain SNPs about every 6 kb. Several regions of homozygosity > 400 kb in size in the 20 cM/10 Mbp interval were identified. A two stage Hidden Markov model was built to assess the probability of a region being homozygous due to LD with the causative mutation rather than by chance. Genotypes, allele frequencies and background LD among markers are all taken into account in this model. LD based genetic distance rather than physical distance was used to measure the significance of all observed homozygous regions.
Work is in progress to test candidate genes in the region of highest likelihood of homozygosity and linkage disequilibrium.
We thank Affymetrix for hybridization and early access to data.