FounderTracker

FounderTracker identifies significantly recurrent identity by descent (IBD) haplotypes in dense single nucleotide polymorphism (SNP) array data to detect founder mutations in cancer cohorts.

Key Features:

• Genome-wide detection: Operates genome-wide on dense genotype and tumor SNP profile data to detect chromosome fragments inherited from a common ancestor among seemingly unrelated individuals.
• Haplotype signature identification: Searches for common haplotype signatures within a sample population that may indicate disease-causing mutations inherited from a shared founder.
• Assumptions and approach: Assumes the wild-type allele often undergoes loss of heterozygosity (LOH) in tumors of germline mutation carriers and defines a minimal conserved haplotype as the overlap between ancestral chromosome fragments.
• IBD sharing detection: Detects haplotypes with significant IBD sharing within recurrent regions of LOH to highlight genomic loci likely to harbor founder mutations.
• Validation and performance: Validated on two real cancer datasets identifying founder mutations in well-characterized tumor suppressor genes and evaluated on simulated data to assess detection of IBD tracts by size and frequency, demonstrating high power and specificity, especially for low-prevalence haplotypes.
• Advantages over existing methods: Outperforms existing methods in detecting founder mutations, facilitating discovery of unknown founder mutations that contribute to missing heritability in cancer.

Scientific Applications:

• Cancer founder mutation discovery: Identification of recurrent founder mutations and conserved haplotypes in cancer cohorts.
• Localization of germline mutations: Use of recurrent LOH and significant IBD sharing to localize loci harboring germline tumor suppressor mutations.
• Missing heritability analysis: Detection of low-prevalence founder haplotypes that may account for portions of missing heritability in cancer.

Methodology:

Detects IBD haplotypes from dense SNP array genotype and tumor SNP profile data, searches for common haplotype signatures, identifies recurrent LOH regions and haplotypes with significant IBD sharing to pinpoint candidate founder loci, and was validated using two real cancer datasets plus simulations evaluating IBD tract detection by size and frequency.