Genetics
The body's genetic material is contained within the nucleus
of each of its cells. The genetic material consists of coils of DNA (deoxyribonucleic acid) arranged in a complex way to form
chromosomes. Human cells contain 46 chromosomes in pairs, including one pair of sex chromosomes.
Each DNA molecule is a long double helix that resembles
a spiral staircase. The steps of the staircase, which determine a person's genetic code, consist of pairs of four types of
molecules called bases. In the steps, adenine is paired with thymine, and guanine is paired with cytosine. The genetic code
is written in triplets, so each group of three steps of the staircase codes the production of one of the amino acids, which
are the building blocks of proteins.
When a part of the DNA molecule is actively controlling some function
of the cell, the DNA helix splits open along its length. One strand of the open helix is inactive; the other strand acts as
a template against which a complementary strand of RNA (ribonucleic acid) forms. The RNA bases are arranged in the same sequence
as bases of the inactive strand of the DNA, except that RNA contains uracil and DNA contains thymine. The RNA copy, called
messenger RNA (mRNA), separates from the DNA, leaves the nucleus, and travels into the cytoplasm of the cell. There, it attaches
to ribosomes, the cell's factories for manufacturing proteins.
The messenger RNA instructs the ribosome as to the sequence of amino
acids for
constructing a specific protein. Amino acids are brought to the
ribosome by transfer RNA (tRNA), a much smaller type of RNA. Each molecule of transfer RNA brings one amino acid to be incorporated
into the growing chain of protein. A gene consists of the code required to construct one protein. Genes vary in size, depending
on the size of the protein. Genes are arranged in a precise sequence on the chromosomes; the location of a particular gene
is called its locus.
The two sex chromosomes determine whether a fetus
becomes male or female.
Males have one X and one Y sex chromosome; females have two X chromosomes,
only one of which is active. The Y chromosome carries relatively few genes, one of which determines sex. In males, virtually
all of the genes on the X chromosome, whether dominant or recessive, are expressed. Genes on the X chromosome are referred
to as sex-linked, or X-linked, genes.
X-Chromosome Inactivation
Because a female has two X chromosomes, she has twice as many X-chromosome
genes as does a male. This would seem to result in an overdose
of some genes.
However, one of the two X chromosomes in each cell of the female--except
in the eggs in the ovaries--is thought to be inactivated early in the life of the fetus. The
inactive X chromosome (the
Barr body) is visible under a microscope as a dense
lump in the nucleus of the cell.
The inactivation of the X chromosome explains certain observations.
For example,
extra X chromosomes cause far fewer developmental abnormalities
than extra
nonsex (autosomal) chromosomes, because no matter how many X chromosomes
a person has, all but one seem to be inactivated. Women with three
X chromosomes
(triple X syndrome) are often physically and mentally normal (see
page 1239 in
Chapter 267, Metabolic Disorders). In contrast, an additional autosomal
chromosome
can be fatal during early fetal development. A baby born with an
additional autosomal
chromosome (a trisomy disorder) usually has many severe physical
and mental
abnormalities (see box, page 1239). Similarly, the absence of an
autosomal
chromosome is invariably fatal to the fetus, but the absence of
one X chromosome
usually results in relatively less severe abnormalities (Turner's
syndrome)
(see page 1239 in Chapter 267, Metabolic Disorders).
Gene Abnormalities
Abnormalities of one or more genes, particularly recessive
genes, are fairly common.
Every human being carries six to eight abnormal recessive genes.
However, these
genes don't cause cells to function abnormally unless two similar
recessive genes
are present. In the general population, the chance of a person's
having two similar
recessive genes is very small, but in children of close relatives,
the chances are
higher. Chances are also high among groups that intermarry, such
as the Amish
or Mennonites.
A person's genetic makeup is called a genotype.
The body's response to having
those genes--that is, the expression of the genotype--is called
the phenotype.
All inherited characteristics (traits) are encoded by genes.
Some characteristics,
such as hair color, simply distinguish people from one another;
they aren't considered
abnormal. However, abnormal characteristics expressed by an abnormal
gene may
cause a hereditary disease.
Examples of Genetic Disorders |
| Gene |
Dominant |
Recessive |
| Non-X-linked |
Marfan's syndrome, Huntington's disease |
Cystic fibrosis, sickle cell anemia |
| X-linked |
Familial rickets, hereditary nephritis |
Red-green color blindness, hemophilia |
Single-Gene Abnormalities
The effects of a single-gene abnormality depend on whether the
gene is dominant or recessive and whether it's located on an X chromosome (X-linked). Because each
gene directs the production of a particular protein, an abnormal gene produces an abnormal protein or an abnormal amount of
protein, which may cause an abnormality in cell function and ultimately in physical appearance or bodily function.
Non-X-Linked Genes
The effect (trait) produced by an abnormal dominant gene
on an autosomal
chromosome may be a deformity, a disease, or a tendency to develop certain
diseases.
The following principles generally apply to traits determined
by a dominant gene:
-
When one parent has an abnormal trait and the other does not,
each child has a 50 percent chance of inheriting the abnormal
trait and a 50 percent chance of not inheriting it. However, if
the
parent with the abnormal trait has two copies of the abnormal
gene--a rare occurrence--all of their children will have the
abnormal trait.
-
A person who doesn't have the abnormal trait, even though his
siblings have it, doesn't carry the gene and can't pass the trait
on to his offspring.
The following principles generally apply to traits determined
by a recessive gene:
- People with the trait have at least one parent with the
trait,
unless it's caused by a new mutation.
- Abnormal genetic traits are often caused by new genetic
mutations
rather than by inheritance from the parents.
When one parent has an abnormal trait and the other
does not,
each child has a 50 percent chance of inheriting
the abnormal trait and a 50 percent chance of not inheriting
it.
However, if the parent with the abnormal trait has two
copies of the abnormal gene--a rare occurrence--all of
their
children will have the abnormal trait.
-
A person who doesn't have the abnormal trait, even though
his
siblings have it, doesn't carry the gene and can't pass the
trait on to his offspring.
-
Males and females are equally likely to be affected.
-
The abnormality can, and usually does, appear in every generation.
Dominant genes that cause severe diseases are rare. They tend to
disappear
because the people who have them are often too ill to have children.
However,
there are a few exceptions, such as Huntington's disease
(see page 313 in
function that usually begins after age 35. By the time symptoms
occur, the
person may already have had children.
Recessive genes are expressed only when a person has two such genes.
A person
with one recessive gene doesn't have the trait but is a carrier
of the trait and
can pass the gene on to his children.
X-Linked Genes
Because the Y chromosome in males has very few genes, the genes
on the single X chromosome (X-linked, or sex-linked, genes) are virtually all unpaired and therefore expressed, whether they're
dominant or recessive. But because females have two X chromosomes, the same principles apply to X-linked genes that apply
to genes on autosomal chromosomes: Unless both genes in a pair are recessive, only dominant genes are expressed.
If an abnormal X-linked gene is dominant, affected males transmit
the abnormality
to all of their daughters but none of their sons. The sons of the
affected male
receive his Y chromosome, which doesn't carry the abnormal gene.
Affected females with only one abnormal gene transmit the abnormality to half their children, male or female.
If an abnormal X-linked gene is recessive, nearly everyone with
the trait is male. Men transmit the abnormal gene only to their daughters, all of whom become carriers. Carrier mothers do
not have the trait but transmit the gene to half their sons, who usually have the trait. None of their daughters have the
trait, but half are carriers.
Red-green color blindness, caused by a common X-linked recessive
gene, affects about 10 percent of males but is unusual among females. In males, the gene for color blindness comes from a
mother who is color-blind or who has normal vision but is a carrier of the color-blind gene. It never comes from the father,
who instead supplies the Y chromosome. Daughters of color-blind fathers are rarely color-blind but are always carriers of
the color-blind gene.
Codominant Inheritance
In codominant inheritance, both genes are expressed. An example
is sickle cell
anemia: If a person has one normal gene and one abnormal gene, both
normal
and abnormal red blood cell pigment (hemoglobin) is produced.
Abnormal Mitochondrial Genes
Inside every cell are mitochondria, tiny structures that provide
the cell with energy. Each mitochondrion contains a circular chromosome. Several rare diseases are caused by abnormal genes
carried by the chromosome inside a mitochondrion.
When an egg is fertilized, only mitochondria from the egg become
part of the developing fetus; all mitochondria from the sperm are discarded. Therefore, diseases caused by abnormal mitochondrial
genes are transmitted by the mother. A father with abnormal mitochondrial genes can't transmit any such diseases to his children.
Genes That Cause Cancer
Cancer cells may contain oncogenes, which are genes that cause cancer
(also called
oncogenes are abnormal versions of the genes responsible for growth
and
development before birth, which normally are permanently deactivated
after birth.
These oncogenes may be reactivated later in life and may cause cancer.
How they are reactivated isn't known.
Gene Technology
Rapidly changing technology is improving the detection of genetic
diseases, both before and after birth. Knowledge is expanding especially rapidly in the field of DNA technology.
One effort currently under way, called the Human Genome Project,
is the identification
and mapping of all the genes on human chromosomes. A genome is a
person's entire set of genes. At each locus of every chromosome lies a gene. The function served by that locus, such as eye
color, is the same in everyone. The precise gene at that location, however, varies from person to person, giving each person
his own individual characteristics.
There are several ways to produce enough copies of a gene to
study. Copies of a
human gene can be produced in a laboratory by cloning the gene.
The gene to be
copied is usually spliced into the DNA inside a bacterium. Each
time the bacterium
reproduces, it makes an exact copy of all its DNA, including the
spliced gene. Bacteria
multiply very rapidly, so billions of copies of the original gene
can be produced in
a very short time.
Another technique for copying DNA uses the polymerase chain
reaction (PCR). A
specific segment of DNA, including a specific gene, can be copied
(amplified) more
than 200,000 times in a matter of hours in a laboratory. The DNA
from a single cell is sufficient to start a polymerase chain reaction.
A gene probe can be used to locate a specific gene in a particular
chromosome. A gene that has been cloned or copied becomes a labeled probe when a radioactive atom is added to it. The probe
will seek out its mirror-image segment of DNA and bind to it. The radioactive probe can then be detected by sophisticated
photographic techniques.With gene probes, a number of diseases can be diagnosed before or after birth. In the future, gene
probes will probably be able to test people for many major genetic diseases. However, not everyone who has the gene for a
given disease actually develops that disease.
A technique called the Southern blot test is widely used to
identify DNA. DNA is extracted from the cells of a person being studied and is cut into precise fragments with a type of enzyme
called a restriction endonuclease. The fragments are separated in a gel by a technique called electrophoresis, placed on filter
paper, and covered with a labeled probe. Because the probe binds only to its mirror image, it identifies the DNA fragment.
