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.