Genes are very small structures inside almost
every cell of the body. Genes are the instructions, or blueprints, that tell our
body how to grow and develop, build necessary proteins, and thus determine an
individual's characteristics, such as eye color and blood type. It is estimated
that there are about 100,000 genes, each of which is an instruction that the cells
of the body need to grow and survive. Genes come in pairs and are made of strands
of genetic material called deoxyribonucleic acid, or DNA. They line up similar
to beads on a string to form larger structures called chromosomes. Genetic disorders
are caused when the instruction coded by a particular gene is changed and the
gene can no longer perform its proper function.
diagram, called a karyotype, shows the chromosomes of a male (XY). A karyotype
arranges the chromosomes into their 23 pairs. Just as genes come in pairs, chromosomes
also come in pairs. Each cell in our body has 23 pairs of chromosomes (for a total
of 46); one member of each pair is inherited from the mother and the other from
the father. The first 22 pairs (numbered 1 through 22) are called autosomes and
they determine most of our features. The last pair is called the sex chromosomes
and they determine if we are male or female. Females have two X chromosomes and
males have one X chromosome and one Y chromosome.
two patterns of inheritance that involve genes on the autosomes. Genetic disorders
that follow this pattern are said to have autosomal dominant or autosomal recessive
inheritance. One characteristic of autosomal dominant disorders is that males
are affected equally as frequently as females. There are also some disorders that
are caused by genes on the sex chromosomes. The genes for these disorders are
located on the X chromosome and, therefore, are said to have X-linked inheritance.
X-linked disorders can also be dominant or recessive.
Autosomal dominant means that a person only needs
one copy of the changed gene in order to have the disorder. Usually, the changed
gene is inherited from a parent who also has the disorder and every generation
in the family may have members with the disorder. There are some instances in
which a person has the gene that causes the disorder and does not show symptoms
of the disorder, but can still pass the gene to his or her children. A person
who carriers a gene for an autosomal dominant disorder has a 50% chance of passing
the gene to each child.
Autosomal recessive means that it is necessary
to have two copies of the changed gene to have the disorder. Each parent contributes
one changed copy of the gene to the child who has the disorder. The parents are
called carriers of the disorder because they have one normal copy of the gene
and one changed copy of the gene, but they do not show symptoms of the disorder.
When both parents are carriers of the changed gene, each of their children has
a 25% chance of having the disorder, a 50% chance of being a carrier of the disorder
(like their parents), and a 25% chance of neither being a carrier nor having the
disorder. These risks are the same for each pregnancy. When there is more than
one person in a family who has the disease, these people are often in the same
X-linked dominant inheritance follows a pattern
similar to autosomal dominant inheritance except that more females are affected
than males. However, X-linked dominant disorders are very rare.
X-linked recessive disorders are usually
only seen in males and they are much more common than X-linked dominant disorders.
People with an X-linked recessive disorder do not have any normal copies of the
gene. Males only have one X chromosome, so if a male inherits a changed gene on
his X chromosome (which is always inherited from his mother), then he does not
have another copy of the working gene to compensate. Females with one copy of
a changed gene on one X chromosome are called carriers of X-linked recessive disorder.
It is rare for a female to have the changed gene on both her X chromosomes. In
most cases, females who are carriers do not show symptoms because the working
copy of the gene compensates for the non-working copy of the gene. Carrier females
have a 25% of having a son with the disorder, a 25% chance of having a son without
the disorder, a 25% chance of having a carrier daughter and a 25% chance of having
a daughter who is not a carrier. Males with an X-linked recessive disorder cannot
pass the disorder to their sons, but 100% of their daughters will be carriers.
Some disorders, however,
are determined by changes in more than one gene. These disorders, known as complex
disorders, do not follow the same predicted pattern of inheritance seen in autosomal
or X-linked dominant and recessive disorders. Sometimes changes in these genes
must be in combination with certain environmental factors, such as exposure to
certain chemicals or medications or maybe even diet. This type of inheritance
is often referred to as multifactorial because many different factors, genetic
and/or environmental, are involved. A person will have a complex disorder if he
or she has the right combination of changed genes and environmental exposures.
Sometimes these disorders are caused by changes in one or more genes that make
a person susceptible to developing the disorder after exposure to specific environmental
factors. The close relatives of someone with a complex disorder have a higher
chance of later developing the disorder than the close relatives of someone who
does not have the disorder. Diabetes, heart disease, neural tube defects, autism,
Alzheimer disease, and many cancer syndromes are examples of disorders that can
be caused by multifactorial, or complex, inheritance.
Scientists use maps of the chromosomes (similar to a road map)
in order to look for genes. However, these maps are still somewhat incomplete.
Thus, looking for a gene is a difficult task and often takes years to accomplish.
Searching for genes that cause a specific disorder is somewhat like trying to
find a street on a city map that lists the city's major landmarks, but not the
as gas stations or restaurants can be used as landmarks when locating a friend's
house, scientists use markers to find a gene. The instructions encoded in genes
are written in a special genetic alphabet consisting of four letters A,
T, C, and G (called nucleotide bases). These bases are the critical chemicals
from which DNA is made. Markers are areas of DNA along the chromosomes which have
differences in the string of genetic letters so that the "message" on each member
of a chromosome pair is slightly different. These differences (called polymorphisms)
do not usually affect a person's health; they act as "flags" that can be tested
in individuals. Scientists can track which marker came from a person's mother
and which came from a person's father.
Scientists have maps
of the markers on each chromosome, just like people have maps that tell them where
streets are. These maps have been developed by scientists all over the world.
One of the major goals of the Human Genome Project, which is funded, in part,
by the U.S. Department of Energy and the National Institutes of Health, is to
develop a detailed map of markers evenly spread throughout the entire human genome,
or the whole human DNA (like a landmark found on every other street block). Each
year this map becomes more dense, providing researchers with more markers to test
when looking for genes that cause disorders. In fact, there are so many markers
on the genetic map that the scientists' ability to find genes responsible for
disorders has progressed rapidly.
Scientists test many
different markers on all the chromosomes, trying to find markers that are consistently
found in family members who have a particular disorder, but not in family members
without the disorder. These markers are landmarks that identify which chromosome
a disorder gene is located on (like which street a house is on). Certain statistical
methods can tell a scientist how close these landmarks are to a gene. Testing
more markers will narrow the search area of the gene (like which block a friend's
house is on). Markers that are very close to a gene are said to be linked because
the marker is rarely inherited without that gene also being inherited (the marker
and gene "travel together"). Once scientists find a set of markers that are linked
to a gene, then scientists say that they have found linkage.
Linkage tells us approximately where
on a chromosome a gene is located. Scientists still need to determine the exact
location of the gene (like which house on the street). One common method uses
"candidate" genes, which are genes known to be localized to the region. A gene
is called a "candidate" if the function of it relates in some way to the effect
the disorder has on the individuals who have the disorder. This laboratory technique
is like knocking on the door of every house on a block until you find the one
your friend lives in. Similarly, scientists test the candidate genes for changes
that might cause the disorder. If there are not any changes in the gene of a person
who has the disorder, then that candidate gene could not have caused the disorder.
If after all the candidate genes are tested and none are found to be responsible
for the disorder, then the researcher studies genes whose functions are not yet
known. Many genes may be tested until the right gene is found. Then comes the
long process of understanding how the gene works and why it causes the problems
that it does.
Abstracted in part from publications
distributed by the NCHGR Office of Communications.
We usually start
with a family history. We also need a small amount of blood (for DNA), and a brief
clinical evaluation specific for the disorder being studied. Most of the time
this is done outside of the medical center at a place and time convenient to the
family. Today many families are spread across the country or world. These members
can still participate as we can often obtain samples by mail or through the cooperation
of fellow researchers who are near the family members.
information provided to the researchers at the Center for Human Genetics is considered
medical information, including family histories. Therefore, all information on
individuals, as well as on the family, is kept confidential.
The Center for
Human Genetics is a research organization. The Center for Human Genetic's policy
is one of long-term commitment to families participating in research studies.
To this end, we remain in contact with members through update letters or newsletters.
If requested by family members or an attending physician, recommendations for
formal referral for genetic counseling or for clinical and laboratory evaluation
man be made. While information on inherited disorders and suggestions for further
evaluation may be provided, routine medical care must remain with the primary