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By
Sylvia Wrobel |
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BASED
ON TWIN AND FAMILY STUDIES,autism
is one of the most highly heritable of all neuropsychiatric disorders.
Its complex genetics likely involve the interaction of multiple
susceptibility genes, acting in concert with one or more unknown
environmental factors. Although few of these susceptibility genes
have been identified, Emory human geneticist Michael Zwick believes
he knows where more are hiding.
Zwick focuses on a narrow region of
the X chromosome for two reasons. First, because boys have only
one X chromosome, they are a least four times more likely than girls
(who have two X chromosomes) to be affected by autism. Second, the
X chromosome neighborhood already is known to be home to a large
number of genes that cause problems with brain development when
severely mutated. That neighborhood includes the fMR1 gene responsible
for fragile X syndrome, the most common cause of inherited mental
retardation. One of five children with fragile X also meets the
criteria for autism, making fMR1 the most common known cause of
autism, even though it accounts for only 2% to 5% of cases.
However, Zwick believes the relatively
small number of cases may be only the beginning of the fMR1/autism
story. Fragile X is caused by a triple repeat in the fMR1 gene,
an error that inactivates the gene. Zwick's boss, Stephen
Warren, chair of Emory's Department of Human Genetics and
discoverer of the fragile X gene, previously found another mutation,
unrelated to the classic triplet repeat, in the fMR1 coding sequence.
Numerous such variations may occur in fMR1 and in the nearby fMR2
gene, also known to cause mental retardation. But until Zwick's
efforts, no one had looked at the nucleotide makeup of the fMR1
gene where disease-causing variations could be spotted. There was
a good reason. Only recently, thanks to work by Zwick and a handful
of other pioneers, has the technology existed to search efficiently
for such subtle variations. |
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Dime-sized
technology
The project to sequence the human genome was necessarily enormous,
deliberately anonymous and generic, and prohibitively expensive,
restricted to large "industrial-strength" facilities.
Zwick envisions a more practical alternative to genome sequencing
that is focused, individualized, fast, and cheap. That is why he
is developing technology and software that enable smaller laboratories
to rapidly and inexpensively generate large quantities of genetic
data for individuals.
One surprise in sequencing the human
genome was how few gene differences are found among individuals.
On average, any two human genomes have only eight differences for
every 10,000 base pairs (the order of A-T-G-C nucleotides that determines
which protein a specific gene will produce).
Resequencing compares the genome of
individuals or groups (such as patients with a specific disease)
to the entire human genome to identify where those differences occur
and to find out if a larger than expected number of people with
the same condition have the same differences.
In his search for autism susceptibility
genes, Zwick takes this process one step further by looking at how
the genes of boys affected by autism and their healthy fathers differ
from both the human genome and from each other. His research, conducted
in a pantry-sized area and using equipment that would easily fit
in the trunk of a car, is a good example of the emerging technology's
power and efficiency.
While Zwick often speaks to families
touched by autism, he does not know the autistic sons and their
fathers whose DNA fills his dime-sized resequencing chips. The patient
samples and information come from the Autism Genetic Resource Exchange,
a gene bank with pedigrees, genomic scans, and/or DNA samples of
almost 830 families with more than one member diagnosed with some
form of autism.
From this wealth of data, Zwick first
selected 314 families with two affected sons, both of whom share
the same portion of the X chromosome from their mother. He then
chose one of each pair of brothers at random and sequenced the region
of his chromosome containing the fMR1 and fMR2 genes, as well as
all the unique noncoding sequences outside these genes. He next
sequenced the same region of the X chromosome for each father of
the boys with autism. |
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The
project to sequence the human genome was necessarily enormous,
deliberately anonymous, and prohibitively expensive, restricted
to large ‘‘industrial-strength" facilities.
Zwick envisions a more practical alternative to genome
sequencing that is focused, individualized, fast, and cheap. |
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Illuminating
father-son variants
Before this genetic information is resequenced, first against the
human genome, next against each father-son pair, each male's
genetic material is hybridized—a process of mixing and separating
the DNA in liquid form to yield paired DNA fragments—on a
computer chip three-quarters of an inch square, no thicker than
a microscope slide. A laser scans the chip to visualize the male's
DNA and determine its sequence.
The chip with genetic material from
the son with autism and the chip with genetic material from his
father then are entered onto a computer loaded with software previously
developed by Zwick and his colleagues at Johns Hopkins. The screen
fills with an array of colored dots, and the bright lights mark
the genetic differences between the son and father.
Variants from the human genome found
in both individuals probably do not cause disease—or at least
are not related to autism. Variants from the human genome found
only in the son, and not in his father, are candidates for autism
susceptibility gene mutations. Statistical analysis of all 314 father/son
sets will determine how common, how rare, and how meaningful such
differences are in relation to autism. The cost of using the new
technology? Less than .001 cent per base pair.
Identifying variations contributing
to autism would help scientists develop new early diagnostic tests,
leading to earlier intervention. Understanding which genes—or
more precisely which specific mutation or mutations of specific
genes—are involved in susceptibility to autism would guide
development of treatment, perhaps even lead to the first drug therapy.
Knowing which genes are involved would also elucidate environmental
influences that may contribute to autism.
Even if he finds the variations he
is searching for, Zwick knows they will be only part of the complex
autism puzzle. But his new technology stands ready to be used to
look for more answers throughout the genome, and its implications
go beyond any one disorder. Next-generation genomics technologies
like Zwick's will help deliver a genome-sequencing center
on every laboratory bench. |
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