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A.
John Iafrate, MD, PhD
Instructor in Pathology,
Harvard Medical School
Assistant Pathologist, Massachusetts General Hospital
Diagnostic
Molecular Pathology Laboratory
Massachusetts General Hospital
55 Fruit Street - WRN 508
Boston, MA 02114
Phone: 617-726-0166
Fax: 617-726-2365
Email: aiafrate@partners.org |
Research
Interests:
We have recently identified a new source
of significant genetic polymorphism, large-scale copy
number variants (LCVs). These polymorphisms involve
copy number gains or losses of large genomic regions
(kilobases up to several megabases), and were identified
using high-resolution genomic microarrays to compare
the genomes of phenotypically normal individuals.
LCVs are common, and we identified in 55 normal individuals
over 200 LCVs distributed throughout the genome. Because
of their large size and because they largely involve
euchromatin, LCVs are distinct from other previously
described sources of human genetic variations such
as single nucleotide polymorphisms, insertion-deletion
polymorphisms and polymorphism in the quantities of
repetitive DNA (e.g. alpha-satellites and mini- and
microsatellites. Based on our studies, and recent
publications, we estimate that LCVs will result in
10-20 megabases of sequence difference between individuals
on average, a number equal to or likely greater than
the total number of predicted single nucleotide polymorphisms
between given individuals (5-10,000,000). We speculate
that we have identified merely the tip of the iceberg
of copy number polymorphisms, and once larger populations
of ethnically diverse individuals are screened the
total number of LCVs will be much higher.
The functional consequence of large-scale copy number
polymorphisms is largely unknown, but potentially
of major impact on disease susceptibility. An impact
on human variation is likely as we found that 56%
of LCVs overlapped with known gene coding regions,
and 25% encompassed one or more entire genes. LCVs
could impact genetic disease pathogenesis by two mechanisms,
(1) gene dosage gains or losses could lead to a disease-associated
gain or loss in expression of a critical developmental
gene, or (2) complex genomic repeat structures typical
of LCV loci could predispose to chromosomal rearrangements
that give rise to disease via non-allelic homologous
recombination.
Our continuing work is focused on the detailed structural
analysis of LCVs using high-resolution fluorescence
microscopy imaging techniques, quantitative PCR and
BAC sequencing. This analysis will answer questions
about the mechanisms by which LCVs arise, and will
yield information to be used in population genetic
studies. In addition, we have initiated studies to
test the association of large-scale copy number polymorphisms
with specific genetic diseases.
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