Technical Report MSC-2011-16

Title: Genetic Linkage Analysis in the Presence of Germline Mosaicism
Authors: Omer Weissbrod
Supervisors: Dan Geiger
Abstract: Genetic linkage analysis is a widely used statistical method for associating disease genes with their location on the chromosome. This method has proved to be very successful in mapping genes involved in simple Mendelian diseases. However, it is less powerful in mapping genes that do not follow Mendelian inheritance patterns. With the growing availability of genomic data, it becomes increasingly clear that some human genetic traits do not follow such patterns, and thus their associated genes may elude detection. This finding motivates the development of new statistical tests that are more suitable to genetic mapping of such non-standard genetic traits.

In this work we consider a genetic condition called germline mosaicism that does not follow standard Mendelian inheritance patterns. Germline mosaicism violates some of the assumptions that underlie standard genetic linkage analysis. The standard method of genetic linkage analysis is therefore not suitable for analysis of traits caused by this condition. We develop a statistical model that is suitable for analysis of traits caused by this condition, and develop a statistical test to determine whether a genetic trait has been introduced by germline mosaicism. We also extend the method of genetic linkage analysis to incorporate germline mosaicism. Finally, we use our extended statistical model to provide solid statistical evidence for the location of the gene responsible for a syndrome recently discovered in Israel, called the MDN syndrome. This finding may prompt further genetic research to help identify exactly the causative gene of this syndrome.

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