Detecting Deletions by Analysis of Genetic Markers in Pedigrees

Sammanfattning: A deletion is defined as a missing piece of a chromosome, ranging in size from as small as a single base pair to as much as an entire arm of a chromosome. Deletions can cause diseases, but may also have a neutral effect in the genome. In this thesis, I describe how inherited deletions can be detected by analysis of the segregation pattern of genetic markers in pedigrees. These methods are based on the fact that a deletion encompassing a genetic marker constitutes a null allele for that marker. Thus, a heterozygote for a null allele will appear to be homozygous for the other allele. The methods I present for detecting deletions for a single marker also apply for detecting null alleles. The thesis consists of both theoretical work on the probabilities to detect deletions in different pedigree structures and applications of the methods to identify deletions in families with Protein S deficiency and von Willebrand disease type 1. In the first paper, deletions in the PROS1 gene are indicated during a linkage study on eight families with Protein S deficiency, a dominant coagulation disorder. The second paper describes how the probabilities to detect a deletion causing a dominant disease using genetic markers depend on the allele frequencies of the marker and the size of the pedigree. The formulae are general and can be applied to a pedigree of any size. The method is shown to be efficient in pedigrees of the size that were used in paper I. In the third paper, large deletions in the PROS1 gene are identified in three of the eight families with Protein S deficiency. In the fourth paper, the probabilities to detect a neutral deletion for various pedigree structures given a fixed total sample size are calculated. It is shown that for biallelic markers it is more efficient to add children than to add grandparents to a parent-offspring trio.