Download What is a gene mutation and how do mutations occur

5th lesson
Medical students
Medical Biology
Mutations
Gene mutation
A gene mutation is a permanent alteration in the DNA sequence that makes up
a gene, such that the sequence differs from what is found in most people. Mutations
range in size; they can affect anywhere from a single DNA building block (base pair)
to a large segment of a chromosome that includes multiple genes. Mutations can lead
to changes in the structure of an encoded protein or to a decrease or complete loss in
its expression. Because a change in the DNA sequence affects all copies of the
encoded protein, mutations can be particularly damaging to a cell or organism. In
contrast, any alterations in the sequences of RNA or protein molecules that occur
during their synthesis are less serious because many copies of each RNA and protein
are synthesized.
Gene mutations can be classified in two major ways:
Hereditary mutations : are inherited from a parent and are present throughout a
person’s life in virtually every cell in the body. These mutations are also called germ
line mutations because they are present in the parent’s egg or sperm cells, which are
also called germ cells. When an egg and a sperm cell unite, the resulting fertilized egg
cell receives DNA from both parents. If this DNA has a mutation, the child that grows
from the fertilized egg will have the mutation in each of his or her cells.
Acquired (or somatic) mutations: occur at some time during a person’s life and are
present only in certain cells, not in every cell in the body. These changes can be
caused by environmental factors such as ultraviolet radiation from the sun, or can
occur if a mistake is made as DNA copies itself during cell division. Acquired
mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on
to the next generation.
Genetic changes that are described as de novo (new) mutations in some cases,
the mutation occurs in a person’s egg or sperm cell but is not present in any of the
person’s other cells. In other cases, the mutation occurs in the fertilized egg shortly
after the egg and sperm cells unite. (It is often impossible to tell exactly when a de
novo mutation happened.) As the fertilized egg divides, each resulting cell in the
1
growing embryo will have the mutation. De novo mutations may explain genetic
disorders in which an affected child has a mutation in every cell in the body but the
parents do not.
As all the cells divide during growth and development, cells that arise from the
cell with the altered gene will have the mutation, while other cells will not. Most
disease-causing gene mutations are uncommon in the general population. However,
other genetic changes occur more frequently. Genetic alterations that occur in more
than 1 percent of the population are called polymorphisms. They are common enough
to be considered a normal variation in the DNA. Polymorphisms are responsible for
many of the normal differences between people such as eye color, hair color, and
blood type. Although many polymorphisms have no negative effects on a person’s
health, some of these variations may influence the risk of developing certain
disorders.
Top 11 Most Common Human Mutations
1. Baldness is more common in men, as testosterone sensitive form is the most
common. Baldness is due to mutations in several genes from one or both parents.
2. Chinese lack, enables others to drink and eat milk and dairy products.
3. Pimples, are linked to a family history. If your parents experienced bad pimples,
you are more likely to suffer of severe acne too.
4. High fertility in women: Identical twins are random events, but fraternal twins
emerge in families again and again. A gene is involved in multiple eggs released
during ovulation (hyperovulation).
5. Heart disease, diabetes, stroke or high blood pressure come in family.
6. Obesity :genes were beneficial to our ancestors, as they could store "reserves"
during scarcity periods. But today, there are no shortage periods. Also, many of today's
obesity cases are linked to eating too much "unhealthy" food.
7. The male "aggressive behaviors" are more likely to be encoded in genes than nonaggressive antisocial behaviors like stealing.
2
8. Color blind : mutation is located on the X-chromosome. Men only have one Xchromosome, so that one is enough to induce the condition, but women have two X
chromosomes, and they require the mutation in double set to experience the condition.
9. Increasing evidence links breast cancers to particular genes. Those with mutation
tend to develop cancer earlier and in both breasts. The same mutations increase the risk
of developing prostate, breast, pancreas and other cancers in men.
10.Half of the alcoholism risk seems to be hereditary. There are several genes
involved, working differently from one individual to another.
11.The chin dimple is caused by an incomplete fusion of the right and left sides of the
jaw when encountering on the chin area.
A fundamental genetic difference between organisms is whether their cells
carry a single set of chromosomes or two copies of each chromosome. The former are
referred to as haploid; the latter, as diploid. Many simple unicellular organisms are
haploid, whereas complex multicellular organisms (e.g., fruit flies, mice, humans)
are diploid.
Mutations are Recessive or Dominant
Different forms of a gene (e.g., normal and mutant) are referred to as alleles.
Since diploid organisms carry two copies of each gene, they may carry identical
alleles, that is, be homozygous for a gene, or carry different alleles, that is, be
heterozygous for a gene. A recessive mutation is one in which both alleles must be
mutant in order for the mutant phenotype to be observed; that is, the individual must
be homozygous for the mutant allele to show the mutant phenotype.
Recessive mutations inactivate the affected gene and lead to a loss of
function. For instance, recessive mutations may remove part of or all the gene from
the chromosome, disrupt expression of the gene, or alter the structure of the encoded
protein, thereby altering its function. Conversely, dominant mutations often lead to
a gain of function. For example, dominant mutations may increase the activity of a
given gene product, confer a new activity on the gene product, or lead to its
inappropriate spatial and temporal expression. Dominant mutations, however, may be
3
associated with a loss of function. In some cases, two copies of a gene are required for
normal function, so that removing a single copy leads to mutant phenotype. In other
cases, mutations in one allele may lead to a structural change in the protein that
interferes with the function of the wild-type protein encoded by the other allele. These
are referred to as dominant negative mutations.
Mutations involve large or small DNA alterations
Different types of mutations. (a) Point mutations, which involve alteration in a single
base pair, and small deletions generally directly affect the function of only one gene.
Missense mutation, which results in a protein in which one amino acid is substituted
for another.
Nonsense mutation, in which a stop codon replaces an amino acid codon, leading to
premature termination of translation.
Frame shift mutation, which causes a change in the reading frame, leading to
introduction of unrelated amino acids into the protein, generally followed by a
stop codon.
(b)
The
second
major
type
of mutation involves
large-scale
changes
in chromosome structure and can affect the functioning of numerous genes, resulting
in major phenotypic consequences. Such chromosomal mutations can involve deletion
or insertion of several contiguous genes, inversion of genes on a chromosome, or the
exchange of large segments of DNA between non homologous chromosomes .
Mutations occur Spontaneously and can be Induced
Mutations arise spontaneously at low frequency owing to the chemical
instability of purine and pyrimidine bases and to errors during DNA replication.
Natural exposure of an organism to certain environmental factors, such as ultraviolet
light and chemical carcinogens (e.g., aflatoxin B1 toxin), also can cause mutations.
A common cause of spontaneous point mutations is the deamination of
cytosine to uracil in the DNA double helix. Subsequent replication leads to a mutant
daughter cell in which a T·A base pair replaces the wild-type C·G base pair. Another
4
cause of spontaneous mutations is copying errors during DNA replication. Although
replication generally is carried out with high fidelity, errors occasionally occur.
Some Human Diseases Are Caused by Spontaneous Mutations
Genetic diseases arise by spontaneous mutations in germ cells (egg and
sperm), which are transmitted to future generations. For example, sickle-cell anemia, ,
is caused by a single missense mutation at codon 6 of the β-globin gene; as a result of
this mutation, the glutamic acid at position 6 in the normal protein is changed to a
valine in the mutant protein. This alteration has a profound effect on hemoglobin, the
oxygen-carrier protein of erythrocytes, which consists of two α-globin and two βglobin subunits. The erythrocytes of affected individuals become rigid and their
transit through capillaries is blocked, causing severe pain and tissue damage. Because
the erythrocytes of heterozygous individuals are resistant to the parasite causing
malaria, which is endemic in Africa, the mutant allele has been maintained. It is not
that individuals of African descent are more likely than others to acquire a mutation
causing the sickle-cell defect, but rather the mutation has been maintained in this
population by interbreeding.
Spontaneous mutation in somatic cells (i.e., non-germ line body cells) also is
an important mechanism in certain human diseases, including retinoblastoma, which
is associated with retinal tumors in children.
Chromosome mutations:
Chromosomal translocations: interchange of genetic parts from non homologous
chromosomes.
Interstitial deletions: an intra-chromosomal deletion that removes a segment of DNA
from a single chromosome, thereby apposing previously distant genes. For example,
cells isolated from a human astrocytoma, a type of brain tumor.
Chromosomal inversions: reversing the orientation of a chromosomal segment.
Loss
of
heterozygosity:
loss
of
one allele,
either
by
a
deletion
a recombination event, in an organism that previously had two different alleles.
5
or
Down syndrome ( Mongolism ) : A child with Down syndrome has 47 chromosomes
instead of 46 chromosomes because Trisomy for chromosome 21 (three copies of
chromosome 21 autosome ).
6
2- Turner syndrome : Abnormal female with 45 chromosomes , the sex
chromosome is X chromosome only .
3-Klinefelter syndrome :
Abnormal male with 47 chromosome, the sex chromosomes are XXY .
Somatic mutation or cancer :
Cancer is a genetic disease that arises from mutations in genes controlling many
aspects of cellular function .
All cancer cells share 2 fundamental properties :
1- Abnormal cell growth and division ( cell proliferation )
2- Propensity to spread and invade other parts of the body (metastasis).
7
Difference between cancer and other genetic diseases :
1- cancer is caused by mutations that occur predominantly in somatic cells. Only
about (5 - 10% ) percent of cancers have a hereditary component.
2- cancers rarely arises from a single mutation, but from the accumulation of many
mutations , as many as six to twelve .
The mutations that lead to cancer affect multiple cellular functions, including
repair of DNA damages, cell division, apoptosis, cellular differentiation, majority
behavior, and cell to cell contact.
8