| 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:
- 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.
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
Chapter 67, Movement Disorders), which causes severe deterioration in brain 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-Chromosome Inactivation
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.
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.
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. |
X-Linked Genes continued
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 mito-chondria 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 tumor
genes) (see page 789 in Chapter 162, Causes and Risks of Cancer). Sometimes 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 poly-merase 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.
The Merck Manual of Medical Information--Home Edition Section 1. Fundamentals
Chapter 2 |
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