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Advances in the field known as molecular genetics, and a National
Multiple Sclerosis Society research project headed by Dr. Stephen Hauser
at
the University of California, San Francisco, give hope that doctors
will
someday be able to answer the crucial question, "What makes people
susceptible to multiple sclerosis?"
Despite many years of research, the cause of multiple sclerosis remains
elusive. However, most scientists and physicians who have studied
the puzzle
of why certain people get the disease while others don't are convinced
that
heredity_the genes we inherit from our ancestors_is a very important
factor.
There are two types of evidence that make scientists think susceptibility
to
multiple sclerosis depends on the genes a person inherits. The
first comes
from studies of populations: people from different ethnic groups have
different tendencies to develop multiple sclerosis.
MS is typically a disease of Caucasians. Many groups of
people_Eskimos, African blacks, and Asians_rarely develop MS.
The second type of evidence comes from studies of families in which
MS occurs
more frequently than chance would dictate. The average person
in the United
States has about one chance in 1,000 of developing MS.
Close relatives, such as children, siblings or non-identical twins,
of people
with MS, have a higher chance of developing MS_about one in 100 to
one in 50.
Moreover, the identical twin of someone with MS, who shares all the
same
genes, has a one in three, or even higher, chance of developing the
disease.
These facts tell us genes are important for determining who may get
MS, but
they are not the whole story: the identical twins of people with MS
would
always get MS if genes were the only factors involved. So other_perhaps
environmental factors_are involved in causing MS, in addition to genes.
MS is not directly inherited, but genetic factors determine who
is
susceptible to the unknown environmental trigger.
In the past few years scientists have developed a set of tools that
gives
them the ability to pinpoint the genetic factors that make a person
susceptible to MS. These tools are the methods of molecular
genetics_techniques for isolating and determining the chemical structure
of
genes.
In the 1980s scientists began to apply the tools of molecular genetics
to
human diseases caused by defects in single genes. This work led
to major
advances in our understanding of such diseases as Duchenne muscular
dystrophy
and cystic fibrosis and are leading to attempts to use the basic genetic
information to treat these diseases.
News stories appear almost daily about advances in knowledge of human
genes
and genetic diseases.
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Genes
Are the Recipes of Life
Genes, the units of heredity discovered by Gregor Mendel more than a
century
ago, contain the recipes, or instructions, to make the proteins of
which all
living things, from bacteria to humans, are built, and that all organisms
use to carry out their functions.
Genes are pieces of a long molecule known as deoxyribonucleic acid,
or DNA,
and are located along structures called chromosomes in the nuclei_or
control
centers_of cells in our bodies.
The information carried in genes is coded in the sequence of the chemical
units_called bases_strung together to make DNA, similar to the way
information on this page is coded in the sequence of letters on it:
each
individual letter carries little information, but strung together in
the
proper sequence they make up words, sentences, and entire books.
The genetic "alphabet" has only four "letters" (or bases), and they
are
arranged in a particular sequence in each gene. The sequence
of bases in a
gene tells a cell how to make a particular type of protein, just as
the
sequence of letters form the words in a recipe that tell a cook how
to make a
particular dish.
Most of the trillions of cells in a person's body have two complete
sets of
genes_one inherited from the mother, one from the father. Each
set contains
all the instructions needed to build all human proteins.
The collection of all the genes for all human proteins is known as the
"human
genome"_and numbers about 100,000 genes.
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Errors
in Genes Can Cause Diseases
In order for genes to be passed from one generation to another_to be
inherited_they must be copied from the parents' genes. The detailed
structure of DNA molecules helps insure that accurate copies are made,
and
the cells that do the copying have "proofreading" mechanisms that correct
most copying errors.
Like human proofreaders, however, these cellular devices sometimes make
mistakes. Because the genome is copied many times for each generation,
there
are many slightly different versions of all human genes among the population.
Some of this variation is quite harmless, and, indeed, is partly what
gives
each of us our unique characteristics. Except for identical twins,
no two
people have the same sequence of DNA bases in their genes. Differences
in
the DNA sequence are so unique to an individual that DNA analysis can
be used
for identification in much the way that fingerprints are.
While variation in genes is normal, sometimes a difference in the code
of a
gene can be responsible for a disease that is inherited. Many
human diseases
are caused by errors in single genes: cystic fibrosis, sickle cell
anemia,
Duchenne muscular dystrophy, and Huntington's disease are by now familiar
examples.
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MS
Genetics Is More Complex
The situation for diseases such as multiple sclerosis is more complicated,
unfortunately. In contrast to single-gene diseases where inheritance
patterns are relatively simple, the pattern in MS is much more complex.
This has led scientists to believe that a person is susceptible to multiple
sclerosis only if he or she inherits an unlucky combination of several
genes.
Until a few years ago, the problem of identifying those genes seemed
hopelessly complex. However, advances in molecular genetics,
and the
identification of large families in which several members have multiple
sclerosis_"multiplex" MS families_changed the outlook, and research
to
uncover MS susceptibility genes has begun.
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Research
in Progress
In 1991, the National Multiple Sclerosis Society, through its peer-review
committee, selected one project, "Genomic search for susceptibility
genes in
multiple sclerosis," as having the most promising combination of factors
needed for success: the scientific
expertise necessary to find and identify the genes, and access to a
large
number of families in which several members have accurately diagnosed,
well-documented multiple sclerosis.
Dr. Stephen Hauser and Dr. Donald Goodkin are collaborating with Drs.
Allen
Roses and Margaret Pericak-Vance at Duke University in Durham, N.C.,
and Dr.
Jonathan Haines at the Massachusetts General Hospital on this project.
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Hunting
for Needles in the Haystack
Dr. Hauser and his colleagues have the challenging task of finding
an unknown
number of genes that confer susceptibility to MS among the 3.5 billion
DNA
bases that code the 100,000 or so genes in the human genome.
To do this they are probing the DNA of white blood cells from families
where
more than one member has multiple sclerosis, looking for identifiable
patterns in the DNA code that are inherited in common by the individuals
with
the disease, but are absent from their healthy relatives.
The investigators have located some 80 multiplex families who have agreed
to
participate in this study. Because the genes are unknown,
the investigators
are searching for patterns of DNA genetic material that are consistently
inherited by people with MS. These Recognizable patterns are
called "DNA
markers".
Through advances in research on human genetics, scientists now have
hundreds
of these markers to choose from, located throughout the human genome.
As one
of these markers is identified as being consistently inherited by people
with
MS, the scientists focus on that area, seeking markers closer to the
gene.
Eventually the absolute location of a gene can be identified.
This process
of moving closer to the gene until it is identified has to be repeated
for
each of the marker regions found in the DNA from the multiplex MS families.
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After
the Genes Are Located
After the location of each susceptibility gene is identified, the role
that
the gene plays in the immunological and neurological aspects of multiple
sclerosis will have to be determined. In some cases the role
may be
relatively easy to determine.
Because the immune system is so involved in producing the damage in
multiple
sclerosis, many scientists think that at least some of the susceptibility
genes are related to the immune system.
Indeed, there have already been reports linking some immune system genes,
such as T cell receptor, the MHC complex and immunoglobulin genes,
to
multiple sclerosis. However, so far none of these candidate genes
of the
immune system has been linked absolutely to MS.
Because Dr. Hauser and his colleagues are looking at all of the human
genome,
they will be able to pinpoint not only the immune system genes that
may be
involved in multiple sclerosis susceptibility, but also other genes.
They
will likely find that previously unidentified genes contribute to multiple
sclerosis in ways we cannot currently predict.
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What It
May Mean To People With MS
The most important reason for finding the genes that confer susceptibility
to
multiple sclerosis is that their discovery may lead to the development
of new
therapeutic approaches and more effective treatments for the disease.
The prospect that we will at last be able to get at a basic cause of
the
disease_an unthinkable possibility only a few years ago_is very exciting.
Knowledge of the genetics of multiple sclerosis will provide other benefits.
For example, it may help predict the clinical course of the disease
in some
individuals, making it easier for doctors to tailor therapies and provide
information people need for life decisions.
Another possible benefit may lie in early diagnosis of people belonging
to
families in which one or more member already has multiple sclerosis.
Early
diagnosis could be valuable since many physicians believe that the
earlier MS
is treated, the better the outcome will be.
PUB DATE: JAN 1995
SOURCE: NMSS Information Resource Center and Library. Education
Department, "FACTS & ISSUES", National Multiple Sclerosis
Society, New York,
c1995.
DISCLAIMER: The National Multiple Sclerosis Society is proud to
be a source
of information about multiple sclerosis. Our comments are based
on
professional advice, published experience and expert opinion, but do
not
represent therapeutic recommendation or prescription.
For specific information and advice, consult your personal physician.
To
contact either the Information Resource Center and Library of the NMSS,
or
your Local Chapter, call 1-800-FIGHT MS (1-800-344-4867).
Transmitted: 95-08-24 16:20:03 EDT