5th lesson Medical students Medical Biology
Mutations
Gene mutationA 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 HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7752/" proteinor to a decrease or complete loss in its HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7493/" expression.
a- Because a change in the HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7455/" DNA sequence affects all copies of the encoded protein, mutations can be particularly damaging to a cell or organism.
b- In contrast, any alterations in the sequences of HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7786/" RNAor 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 persons life in virtually every cell in the body.
These mutations are also called germ line mutations because they are present in the parents 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 persons 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 persons egg or sperm cell but is not present in any of the persons 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 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 persons health, some of these variations may influence the risk of developing certain disorders.
Top 11 Most Common Human Mutations
Top of Form
Bottom of Form
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.
Chinese lack, enables others to drink and eat milk and dairy products.
Pimples, are linked to a family history. If your parents experienced bad pimples, you are more likely to suffer of severe acne too.
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).
Heart disease, diabetes, stroke or high blood pressure come in family.
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.
The male "aggressive behaviors" are more likely to be encoded in genes than non-aggressive antisocial behaviors like stealing.
Color blind : mutation is located on the X-chromosome. Men only have one X-chromosome, 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.
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.
Half of the alcoholism risk seems to be hereditary. There are several genes involved, working differently from one individual to another.
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 HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7404/" chromosome. The former are referred to as HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7548/" haploid; the latter, as HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7451/" diploid. Many simple unicellular organisms are haploid, whereas complex multicellular organisms (e.g., fruit flies, mice, humans) are HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7451/" diploid.
Mutations are Recessive or Dominant
Different forms of a HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7519/" gene(e.g., normal and mutant) are referred to as HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7328/" alleles. Since HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7451/" diploidorganisms carry two copies of each gene, they may carry identical alleles, that is, be HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7568/" homozygousfor a gene, or carry different alleles, that is, be HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7556/" heterozygousfor a gene.A HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7767/" recessive HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7669/" mutation
is one in which both alleles must be mutant in order for the mutant HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7715/" phenotypeto be observed; that is, the individual must be HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7568/" homozygousfor the mutant HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7328/" alleleto show the mutant phenotype.
Recessive mutations inactivate the affected HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7519/" geneand lead to aloss of function.For instance,
HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7767/" recessivemutations may remove part of or all the gene from the HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7404/" chromosome,
disrupt HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7493/" expressionof the gene
or alter the structure of the encoded HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7752/" protein, thereby altering its function.
Conversely, HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7460/" dominantmutations
often lead to again 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 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 HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7715/" phenotype.I
n other cases, mutations in one HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7328/" allelemay 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 asdominant negative mutations.
Mutations involve large or small DNA alterations
Different types of mutations.
Point mutations, which involve alteration in a single base pair, and small deletions generally directly affect the function of only one gene.
Missense HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7669/" mutation,which results in a HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7752/" proteinin which one HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7331/" amino acidis substituted for another.
Nonsense HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7669/" mutation,in which a stop HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7413/" codonreplaces an HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7331/" amino acidcodon, leading to premature termination of HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7845/" translation.
Frame shift HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7669/" mutation,which causes a change in the HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7764/" reading frame, leading to introduction of unrelated amino acids into the HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7752/" protein, generally followed by a stop HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7413/" codon.
The second major type of HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7669/" mutationinvolves large-scale changes in HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7404/" chromosomestructure and can affect the functioning of numerous genes, resulting in major phenotypic consequences. Suchchromosomal mutationscan involve
deletion or insertion of several contiguous genes
inversion of genes on a chromosome
or the exchange of large segments of HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7455/" DNAbetween 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 HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7455/" DNAreplication.
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 HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7455/" DNAdouble helix. Subsequent replication leads to a mutant daughter cell in which a TAbase pairreplaces the wild-type CG base pair.
Another 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 HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7669/" mutationat HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7413/" HYPER14codonHYPER156 of the β-globingene
as a result of this mutation, the glutamicacidat position 6 in the normal HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7752/" proteinis 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 β-globin subunits. The erythrocytes of affected individuals become rigid and their transit through capillaries is blocked, causing severe pain and tissue damage.
( Because the erythrocytes ofHYPER13 HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7556/" heterozygousindividuals are resistant to the parasite causing malaria, which is endemic in Africa, the mutant HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7328/" allelehas 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 HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7669/" mutationin somatic cells (i.e., non-germ line body cells) also is an important mechanism in certain human diseases, includingretinoblastoma,which is associated with retinal tumors in children.
Chromosome mutations:
HYPERLINK "https://en.wikipedia.org/wiki/Chromosomal_translocation" \o "Chromosomal translocation" 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 HYPERLINK "https://en.wikipedia.org/wiki/Astrocytoma" \o "Astrocytoma" astrocytoma, a type of brain tumor.
HYPERLINK "https://en.wikipedia.org/wiki/Chromosomal_inversion" \o "Chromosomal inversion" Chromosomal inversions: reversing the orientation of a chromosomal segment.
HYPERLINK "https://en.wikipedia.org/wiki/Loss_of_heterozygosity" \o "Loss of heterozygosity" Loss of heterozygosity: loss of one HYPERLINK "https://en.wikipedia.org/wiki/Allele" \o "Allele" allele, either by a deletion or a HYPERLINK "https://en.wikipedia.org/wiki/Genetic_recombination" \o "Genetic recombination" recombinationevent, in an organism that previously had two different alleles.
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 :
Abnormal cell growth and division ( cell proliferation )
Propensity to spread and invade other parts of the body (metastasis).
Difference between cancer and other genetic diseases :
cancer is caused by mutations that occur predominantly in somatic cells. Only about (5 - 10% ) percent of cancers have a hereditary component.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.
Practical lesson:
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 ).
Turner syndrome : Abnormal female with 45 chromosomes , the sex chromosome is X chromosome only .
Klinefelter syndrome :
Abnormal male with 47 chromosome, the sex chromosomes are XXY .
Abnormality in Chromosome Structure :
Structural abnormalities results from chromosomal breakage and abnormal reunion .
- Deletion :
Cri Du Chat Syndrome : The syndrome associated with deletion of part of short arm of chromosome 5 .
Bladder carcinoma showing ring chromosome in addition to other chromosomal abnormalities .