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Guilt by association, nailing culprit genes
A relatively unused technique for
finding common disease-predispos­
ing genes should ultimately surpass
the approaches currently in vogue,
according to a statistical study by
Neil Risch, professor o f genetics at
Stanford University School o f Medi­
cine
This method
called associa­
tion analysis — will be especially
useful in understanding the genetic
basis o f complex disorders, if a par­
ticular gene increases disease risk
only moderately or else m utiple ge­
netic factors are involved.
"Using this technique, it should
be feasible in the next decade to test
each o f the estimated 100,000 hu­
man genes for possible links with
every disease," Risch said.
Risch will present his findings on
Friday, Feb. 14. at the morning ses­
sion (8:30 to 11:30a in ), “Complex
Traits: Where Are the G enes?” at
the annual meeting o f the American
Association for the Advancement o f
Science, held in Seattle.
In the study, he created math-
ematical models to compare asso­
ciation analysis with linkage analy­
sis — the method used to map most
genes until now. Risch compared
the num ber o f people who would
have to be studied by each method in
order to identify disease genes with
varying propert ies. "The data showed
that linkage analysis requires sam ­
pling far more people to generate the
same amount o f information," he
said.Scientists have used linkage
analysis to find genes for many dis­
orders, including H untington's dis­
ease and A lzheim er's disease.
This approach, which is part o f a
process called "positional cloning,”
identifies disease genes by theirchro-
mosomal location, gradually zero­
ing in on them among their neigh­
bors in the genome.
Researchers compare the co-in­
heritance o f known landmarks, or
genetic markers, in the genome with
the disease state o f family members.
They locate the disease gene by find­
ing the markers closest to it
those
most highly correlated with inherit­
ance o f the disease
“ The nice thing about linkage
analysis is that you can find genes
involved in disease by using only a
limited number o f genetic markers
along the various chrom osom es.”
said Risch. “ Even if you’re some
distance away, you still detect a sig­
nal that’s strong enough to see where
the gene resides. With association
studies, you could be at the gene next
door and still have no signal.”
But the problem with linkage
analysis is that it depends on having
that strong signal, which occurs only
if the gene is the predominant cause
o f disease, Risch explained. "If the
gene is one o f many factors that lead
to the disease, the signal w on’t be
loud enough to detect, even if you' re
very close,” he said.
Association tests are more pow­
erful in such cases because they give
clear-cut answers to specific ques­
tions, Risch explained. Scientists ask
directly whether affected individu­
als have a certain characteristic, and
get a yes or no answer. They find out
FDA calls “party drug” deadly
A m ericans should avoid a popu­
lar party drug called GHB because
the concoction, often prom oted to
teen-agers over the Internet as an
aphrodisiac or an easy high, can
be deadly, the governm ent warned
Tuesday.
Crim inal investigators from the
Food and Drug A dm inistration are
track in g dow n laboratories that
illeg ally produce the ch em ical,
which was banned in 1991 but is
experiencing a resurgence
par­
ticu larly as a “ date rape" drug
that, w hen slipped into a w o m an ’s
drink, can render her helpless.
GHB is blamed for dozens o f
hospitalizations and at least three
deaths. A Texas high school stu­
dent died in August after som eone
slipped the chem ical into her soft
drink at a dance club. A W inches­
ter, Va., woman in her 20s was
thought to have been in a drunken-
d riv in g crash until an au to p sy
show ed she had taken G H B in­
stead o f alcohol.
Just a week ago, three M assa­
chusetts college students were hos­
pitalized after trying GHB. Two
fell into a com a, but alUeventually
recovered. The drug, know n by
the street names “cherry m eth,”
“ liquid X" and “ liquid ecstasy ," is
believed one o f several that sick­
ened dozens o f youths at a New
Y ear’s Eve concert in I.os Ange-
les.
C alifornia doctors last fall
reported having to resuscitate H ol­
lyw ood n ig h tclu b p atro n s who
stopped breathing after ingesting
the drug.
“ I he in d iv id u a l c o n s u m e r
should not even be thinking about
taking this d rug,” said Jim Dahl,
assistant director o f the FD A ’s
crim inal investigations office. “ It
is very bad for you, and it can
certainly cause d eath .”
GHB,
or
gam m a
hydroxybutyrate, is an odorless,
nearly tasteless drug that produces
a high But it also can cause vom ­
iting, trem ors and seizures, side
effects strong enough to send some
people into comas.
The drug com m only is distrib­
uted as a w hite pow der or clear
liquid that can be mixed into a
drink It sells for about $10 a vial.
GHB was originally developed as
a surgical anesthetic but had so many
side effects that it was abandoned. In
1990, the FDA began investigating
reports that body builders were abus­
ing GHB as an alternative to ste­
roids The following year, the FDA
declared it illegal to manufacture or
sell GHB for any purpose.
But after an initial lull, the FDA
says, GHB is on the rise again. Since
1995, I DA prosecutors have begun
45 investigations o f underground
GHB manufacturing or distribution,
12 o f which have resulted in convic­
tions so far.
Its inherent danger aside, doctors
say GHB is made so haphazardly
that people might think the dose that
gave them a m i Id buzz once is safe to
try again —-only to have the same
amount send them into a coma be­
cause the new batch is more potent.
“ It's a very narrow margin of
error," said Dr. Rossanne Philen of
the Centers for Disease Control and
Prevention, which is preparing to
publish a study o f GHB injuries in
Texas and New York. “There’s no
easy way for an individual who is
going to consume this substance to
tell the purity o f it.”
GHB proponents actually declare
it legal to possess because the Drug
Enforcement Administration has not
yet listed the chemical as a con­
trolled substance like cocaine or
marijuana. But two states, Georgia
and Rhode Island, have separately
declared GHB a controlled sub­
stance, and other states are consid­
ering the move.
Meanwhile, the FDA is urging
police officers, emergency rooms and
coroners to begin aggressively test­
ing for GHB when young people
wind up in emergency rooms w ith
the chem ical’s symptoms, so the
government can get a better sense of
how widely it is abused
Glaucoma diagnosis key found
whether there are relative differ­
ences in the frequency o f a particular
genetic variant, or allele, in people
with and without disease
“This approach gives a loud sig­
nal,” said Risch “ It’s much more
powerful You get more information
than by try ing to find some attribute
that is shared by affected individu­
als A limitation o f association stud­
ies, however, is that you need to be
on top o f or very close to the impli­
cated gene to have a signal.”
Association studies have already
been done when researchers have
had an idea o f what causes a particu­
lar condition. For instance, earlier
this year scientists in New York
used this approach to find a muta­
tion that decreases a person's risk o f
HIV infection. They knew that a
certain protein interacts with the
cellular molecule that allows HI V to
enter the I cells o f the immune
system So they looked at the gene
for this cofactor in different people
and found something startling.
“ What they saw was that a piece
!
t
I
“The key to this method is that
you need a candidate gene,”
Risch said “ Instead o f gradually
getting closer to the disease gene,
you ask, ‘Is this it?” ’
Although linkage analysis has
succeeded in identifying genes with
a strong influence on disease, “there
are a lot more genes with small
effects on disease, and those are
what we re turning to now,” he ex­
plained
The genetic variations that cause
complex diseases are widespread
“These variations are very common,
and they’ve been in the human popu­
lation fo ra long time," said Richard
Myers, professor o f genetics and di­
rector of the Stanford Human G e­
nome Center. " They probably con­
tribute to common diseases like au­
toimmune disease, psychiatric dis­
ease and cancer, which often are not
thought o f as being genetic. Getting
these diseases probably requires the
inheritance o f multiple genes and
some interactions with the environ­
ment as well.”
Researchers who discover
maleness gene win prize
The Amory Prize for Reproduc­
tive Biology was awarded today by
the American Academy o f Arts
and Sciences to an American and
two Britishers for discovering the
single gene men carry that deter­
mines whether a w om an’s fertil­
ized egg develops into a male.
According to their studies, in­
structions from the SR Y gene cause
a fem ale's fertilized egg to develop
testes and become a male. Without
th e se g e n e tic in s tru c tio n s , a
woman’s (and every mammal’s)
fertilized egg develops ovaries and
blossoms into a female.
While it had been more or less
conventional wisdom that sex de­
termination occurs when chromo­
somes o f men and women get to­
gether. the nature o f the gene or
genes involved and the mechanism
by which this information is trans­
ferred was unknown.
For solving “one o f the central
problems in biology, namely how
the two sexes form,” the Academy
bestowed its Amory Prize for the
first time in five years. The award
ceremony took place at the 1795th
Stated Meeting o f the Academy at
Academy House here.
Presiding at the ceremony were
Jaroslav Pelikan, President o f the
Academy and Sterling Professor ol
History at Yale University, and Paul
R Schim m el, C hairm an o f the
Academy’s Amory Prize Commit­
tee and Joan D. & Catherine T.
Macarthur Professor o f Biochemis­
try and Biophysics at Massachusetts
Institute o f Technology.
The three prize-winners are David
C. Page o f MIT, the Whitehead In­
stitute and the Howard Hughes Medi­
cal Institute; Peter Goodfellow of
SmithKline Beecham; and Robin H.
Lovell-Badge o f the MRC National
Institute for Medical Research.
The scientists operated on the
assum ption that w hatever gene
causes maleness is missing in men
with female(XX)chromosomes, and
present in women with male (XY)
chromosomes They found that mu­
tations o f the SR Y gene causes its
instructions to the fertilized egg to
go awry so that male development is
prevented or incomplete. The inci­
dence of human intersex is estimated
at between 2 to 4 per 10,000 births.
Dr. Page was recognized for devel­
oping the first map o f the Y chromo­
some that identified the approximate
location of the SR Y gene. This map
was ultimately expanded into the first
detailed map o f a human chromo­
some. In subsequent work, Page’s
team has also characterized thé re­
gion o f the Y chromosome that ex-
changes with the X chromosome,
and has identified regions of the Y
chromosome that contain genes for
stature and for development o f tes­
ticular tumors and characterized a
gene on the long arm o f the Y chro­
mosome responsible for one o f the
most common forms o f male infer
tility Page has also begun to charac­
terize genes on the X chromosome
essential for female development.
In 1990, using the gene map de
veloped by Page, British teams led
by Robin Lovell-Badge and Peter
Goodfellow, then at the Imperial
Cancer Research Fund (ICRF), used
special cloning techniques to isolate
what they suspected was the male­
determining gene in both mice and
men and then proved that it was
responsible for testicular develop­
ment When they introduced the
gene, which they named SRY, into
newly fertilized mouse eggs, it caused
the genetic female mice to develop
into males.
How the SRY gene causes the
sexually indifferent gonad o f the
embryo to develop into a testis is
not entirely clear, but the subse­
quent work o f Goodfellow and
Lovell-Badge indicates that the
product o f SRY is a protein that
binds to DNA and appears to bend
DNA sharply.
Advertise In
(Tin'
U CSFeye researchers say a study
ophthalmology. UCSF has filed a
The University has exclusively
published in the journal Science is
series o f patent applications begin­
licensed these patent rights for the
J.iovtkiiiii
“proof in principle” o f their theory
ning in 1994 covering the TIGR
development ofdiagnostic products
(Obscvbrr
from several years ago that a par­
gene for diagnosis ofglaucom a and
to InSite Vision Inc. o f Alameda,
( all 503-288-0033
ticular gene — known as the TIGR
other uses.
California.
gene
w illb eo n e ofthe
keys to glaucom a diag­
nosis and that defects in
the gene could account
The flu virus is spread by close contact and usually needs help to infect a person.
for more than 20 percent
GROUND ZERO
FIGHTING THE INFECTION
o f adult glaucoma.
The mouth, nose and eyes contain a type of cell the flu
The body gets wise to the invader and
The Science article re­
virus prefers. The body uses natural defenses such as
creates a hostile environment to kill the
ports that m utations o f
nose hairs, mucus and cilia to try to i keep
I
the virus
virus. Here is how the body reacts:
from reaching the cells.
the TIGR gene play a
Sore throat: Inflamed respiratory tract.
WFECTOH
ro le in p rim ary open
F e v e r A body's reaction to infection.
S hiver Another heat-creating effort.
angle glaucoma (POAG)
Flu virus attacks and
Headaches, m uscle aches ana fatigue:
infects a cell.
the most common form
Caused by cells releasing interleukin -
a substance that fights infection and
ofglaucom a, affecting an
Cell stops normal
activates other parts of the immune
e stim a te d 3 m illio n
function and begins
system.
CEU
producing the flu virus.
Americans, and the sec­
New viruses are
ond lead in g cau se o f
DANGER:
released and spread to
blindness in the United
other cells.
Kills or damages
States The study was
cells in respiratory
tract that defend
conducted by University
against bacteria.
o f Iowa researchers, w ho
ATTACKMG THE B 00Y
More susceptible
had been studying a rare
The virus incubates in the body for a day or two,
to bronchitis and
form o f glaucoma called
multiplying in the epithelial cells lining the respiratory tract.
pneumonia.
juvenile glaucoma, and
PASSING T « BUG
w as c o -a u th o re d by
UCSF researchers.
Here is an example of how the flu virus can be transmitted:
The TIGR gene was
Kids: Biggest
Acquaintance:
At th e office:
Parents:
Crowded places:
transmitter of virus
Pick up
Handshake
originally cloned at the
Again, sneeze,
Sneeze, cough Using phone
because of more
kids and
passes on v t j s . or touch
cough or touch
U CSF D ep artm en t o f
after
infected
physical contact j
virus.
transmits virus.
passes virus to person can
Ophthalmology by mo­
and less likelihood
nearby
co-
transmit
virus.
to wash hands, /
lecular biologist Thai D.
Nguyen, Ph D., using a
human cell culture sys­
tem developed by Jon R
Polansky, M D , UCSF
associate p ro fesso r o f
SO U R CE- UnWersity ot Calitomi«, Irvine; research by SUSAN KELLEHER "
Battling the flu
was missing from this particular
gene in some people,” Risch said.
“ Individuals who have tw ocopiesof
tliis defective gene
and as a result
lack the cellular protein it encodes
are resistant to HIV infection ”
In this case, the mutation is ben­
eficial But the same approach can
be used to detect genes that cause
disease: Researchers can ask whether
there is an association between a
particular genetic variant and dis­
ease.
“The HIV story is a case in which
one gene predisposes people to re­
sistance,” said Dr David Cox, pro­
fessor o f genetics and co-director of
the Stanford Human Genome Cen­
ter. “ But the same approach can be
used for conditions with multifacto­
rial causes. In these cases, certain
combinations o f genes predispose
people to disease The question is
which genes differ between normal
and diseased populations. T hat’s
how you figure out which alleles and
patterns ofalleles are associated with
disease.”
ANNOUNCING THE
Northeast
Eye Center
A Clinical Care and Teaching Affiliate
o f the Pacific University College o f Optometry
The Pacific University College o f Optometry is pleased to announce the
opening o f its Northeast Eye Center, conveniently located in Northeast Portland
at the Multnomah County Health Center—corner o f MLK Jr. Blvd. and
Killingsworth Pacific University faculty and staff offer a full range o f affordable
state-of-the-art vision services provided in a caring and compassionate manner
EYE CARE SERVICES INCLUDE:
■ Examinations for eyeglasses and contact lenses
■ Care for those with diabetes and high blood pressure
■ Treatment o f eye injuries and diseases such as glaucoma
■ Excellent selection o f frames and sunglasses
■ Free vision screenings for children and adults
BI Examination o f children with reading problems
Some sight-threatening conditions— such as diabetes and high blood pressure-
are common in African Americans, Hispanics and other minority populations.
Therefore early detection and continued monitoring are important to insure
good vision and eye health.
To schedule an appointment or free screening and for more information about
vision care services, please call 248-3821.
Northeast Eye Center, Multnomah County Northeast Health Center
5329 N.E. MLK Jr. B lvd, Portland
(Comer o f N.E. MLK and Killingsworth)
2 4 8 -3 8 2 1