Everyone has a photographic memory, some just don't have film!
--- Steven Wright

Eichler Lab

Department of Genome Sciences,
University of Washington

Research Program

Human Variation and Disease:

The combined incidence of detected de novo rearrangements that are mediated by segmental duplications is estimated at 1/1000 livebirths. This includes 3% of all birth defects where mental retardation is the primary diagnosis.  Based on our research, we have identified 130 regions of the human genome that we believe show a predilection to segmental aneusomy.  Our paralogy map of the human genome therefore provides a road-map to investigate regions with an increased probability of rearrangement.  Children with undiagnosed mental retardation provide a sensitized background in order to study copy number variation. One goal of our future research is to assess the frequency of duplication-mediated segmental aneusomy within (a) the normal human population and (b) a population of patients with idiopathic mental retardation.  The aim of this research is to address two fundamental questions: What is the nature and frequency of duplication-mediated structural polymorphisms within the human genome?  Are there an excess of de novo events among children with mental retardation and congenital birth defects?  As our primary method for detection of variation in copy number, we will employ an array comparative genomic hybridization (array CGH) procedure using a well-characterized set of probes flanked by low-copy repeat sequences. Preliminary surveys of copy number variation in the normal population show an expected enrichment near regions of segmental duplication. A targeted analysis of these regions is therefore warranted. As a second method to identify finer scale variation (10-30 kb), we have developed a computational approach based on the assessment of fosmid paired end-sequence against the reference genome.  The latter has led to the subcloning of hundreds of sites of potential structural polymorphism of which eighty-two encompass genes.  We plan to sequence these sites to determine the precise structure of these microrearrangements. We hypothesize that structural variation (deletion, duplication and inversions) is an underestimated mutational force in contributing to genetic disease---particularly disease susceptibility loci.  The characterization of this variation will provide the basis for developing the necessary assays to perform association studies with human genetic disease.

Segmental Duplication Databases