Philadelphia, PA (3/1/98)- A new gene-mapping technique
promises to speed the process of identifying the genetic roots of numerous
diseases.
The new method, called direct identical by descent (IBD) mapping, was
developed by scientists at the Children's Hospital of Philadelphia. Direct
IBD mapping combines a technique called genomic mismatch scanning (GMS)
with DNA microarray technology.
Neurologist Vivian G. Cheung, M.D., and colleagues have already used
the new method to map the segment of DNA known to be responsible for a
rare disease called congenital hyperinsulinism. Congenital hyperinsulinism
is an autosomal recessive disease that occurs at relatively high frequency
among Ashkenazi Jews. The genetic mutation responsible for the disease
was discovered in 1995 using positional cloning. Positional cloning is
labor intensive because hundreds to many thousands of markers have to be
typed, one at a time. Then one needs to determine how frequently a particular
marker is inherited with the disease, and approximately how close that
marker is to the disease gene. Since linkage to each marker must be assessed
individually, the method is extremely time consuming. The current study
indicates that direct IBD mapping is an alternative method, capable of
accomplishing the same result much more rapidly and efficiently.
"What we wanted to be able to do was to get rid of the one-step-at-a-time
procedures," said Cheung. With direct IBD, "we pull out all of the interesting
areas in one step instead of doing it through, say, a thousand steps."
Maps of DNA can have several
levels of detail; from the banding patterns of the chromosomes, to clones
of overlapping segments of DNA, and ultimately to the base-by-base sequence
of DNA.
The genomic mismatch scanning (GMS) component of IBD mapping facilitates
rapid mapping of a gene by locating areas of genomic identity between two
affected individuals. One such area of identity should include the disease-causing
gene. The DNA microarray component of the technique is then utilized to
map the genomic location of the identity region.
In order to identify regions of identity, the DNA from two affected
subjects is split into single strands and then mixed together again. The
strands from one subject that do not match with strands from the second
subject are discarded and the ones with matching segments of DNA are labeled
and placed on a microarray, a glass slide that contains mapped DNA segments.
The microarray developed for this study included segments that make up
chromosome 11. The GMS-selected DNA samples were found to hybridize to
only a few segments on the microarray, thus localizing the gene for hyperinsulinism
to a relatively small region of chromosome 11.
One of the advantages of this method, according to Cheung, is that the
technology for producing the microarray need not be disease specific. "Our
hope is that in two years we'll be able to put the entire genome down on
one microarray, so people can scan any part of the genome on that one microarray,"
she said. While in this case the method was used to map a single-gene disease,
the technology should also be useful for mapping complex traits. "Our ultimate
goal is to be able to find really common disease genes, such as the genes
for diabetes," she said.
The research appears in the March 1998 issue of "Nature Genetics"
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