Chromosomal mutations
Chromosomal mutations are fundamental changes in the normal structure or number of an organism's chromosomes. These changes represent a variation from the standard, healthy genetic makeup, often referred to as the wild-type condition. The study of these chromosomes, both normal and mutated, is a specialized field called cytogenetics. These mutations can occur spontaneously, simply due to errors in cell processes, or they can be intentionally caused (induced) in a lab by exposing cells to agents like specific chemicals or radiation.
I. Variations in Structure
The most common types of chromosomal mutations involve alterations to the structure of a chromosome, and all of these structural changes typically begin with one or more breaks in the chromosome. Once a chromosome breaks, the ends become unstable and are prone to adhering to other broken pieces. Four main types of structural mutations are recognized. Deletions involve the loss of a chromosomal segment, which reduces the amount of DNA and, critically, this type of mutation can never revert to the wild-type state because the material is gone. In contrast, a duplication is the addition of genetic material, where a segment of the chromosome is repeated. The other two types involve the rearrangement of existing material: an inversion occurs when a segment breaks, flips around, and re-attaches, changing the orientation of genes; and a translocation occurs when a segment breaks off and attaches to a completely different chromosome, changing the location of the genetic material within the genome.
Deletion
A deletion is a chromosomal mutation characterized by the loss of a segment of a chromosome, resulting in a reduction in the total amount of DNA. Breaks that initiate a deletion can be induced by various agents, including heat, ionizing radiation, viruses, chemicals, or errors during recombination. A key consequence is that, because the segment is physically missing, a deletion mutation can never revert to the wild-type state.
Human Disorders Associated with Deletions:
Cri-du-chat syndrome: Caused by a heterozygous deletion of part of the short arm of human chromosome 5. Phenotypes include severe intellectual disability, physical abnormalities, and a characteristic high-pitched cry resembling a cat's mew.
Prader-Willi syndrome: Results from heterozygosity for a deletion of part of the long arm of chromosome 15. This syndrome is characterised by poor sucking reflex in infancy, followed by the onset of compulsive eating (hyperphagia) in early childhood, leading to severe obesity and related health issues, along with behavioural problems and intellectual disability.
Duplication
A duplication is a structural mutation that leads to the doubling of a chromosomal segment, thus increasing the amount of DNA on a chromosome. The size and arrangement of the duplicated segment can vary widely:
Tandem Duplication: The duplicated segment is adjacent to the original segment, and the gene order is the same in both.
Reverse Tandem Duplication: The duplicated segment is adjacent to the original, but the gene order is the opposite.
Terminal Tandem Duplication: The duplicated segment is arranged in tandem at the end of the chromosome.
Inversion
An inversion is a mutation where a chromosomal segment is excised (cut out) and then reintegrated at an orientation 180 degrees from its original position. This change alters the order of genes but does not change the amount of genetic material.
Inversions are categorized based on their relationship to the centromere:
Paracentric Inversion: An inversion that does not include the centromere.
Pericentric Inversion: An inversion that does include the centromere.
Translocation
A translocation involves a change in the position of chromosome segments and the genes they contain to a different location in the genome, with no net gain or loss of genetic material.
Translocations are classified based on where the segment moves:
Nonreciprocal Intrachromosomal Translocation: A chromosome segment changes position within the same chromosome (intra-).
Nonreciprocal Interchromosomal Translocation: A chromosome segment is transferred from one chromosome to another (inter-), but the transfer is one-way.
Reciprocal Interchromosomal Translocation: Segments are exchanged between two different, non-homologous chromosomes.
Chromosomal Mutations and Human Tumors
Most human malignant tumors have chromosomal mutations, especially translocation. Two examples are Chronic Myelogenous Leukaemia and Burkitt Lymphoma.
Chronic Myelogenous Leukemia (CML) and the Philadelphia Chromosome
CML is a cancer characterized by the uncontrolled replication of white blood cell stem cells (myeloblasts) and is frequently fatal if untreated. Ninety percent of CML patients have the Philadelphia chromosome in their cancerous cells. The Philadelphia chromosome results from a reciprocal translocation involving chromosome 9 and chromosome 22.
This exchange creates a fusion gene on chromosome 22 where the ABL proto-oncogene is positioned next to the BCR gene (breakpoint cluster region). The resulting BCR-ABL gene acts as an oncogene. It produces a protein called a tyrosine kinase that stimulates the cell to grow and divide excessively, leading to the overproduction of white blood cells.
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Burkitt Lymphoma is a virus-induced tumour that affects immune cells called B cells, particularly common in Africa. Ninety percent of BL tumours are associated with a reciprocal translocation involving chromosome 8 and chromosome 14. The distal end of chromosome 8, including the MYC proto-oncogene, exchanges places with the distal end of chromosome 14. The translocation positions the MYC gene next to a highly active gene that codes for immunoglobulin. This placement causes the MYC gene to be overexpressed, causing uncontrolled cell growth and division that defines Burkitt lymphoma.
II. Variations in Chromosome Number
When an organism or a cell has one complete set of chromosomes or an exact multiple of complete sets, that organism or cell is euploid. Thus, eukaryotic organisms that are normally diploid (such as humans and fruit flies) and that are normally haploid (such as yeast) are euploids. Chromosome mutations resulting in variations in the number of individual chromosomes are examples of aneuploidy. An aneuploid organism or cell has a chromosome number that is not an exact multiple of the haploid set of chromosomes.
Changes in One or a Few Chromosomes
Generation of Aneuploidy. Changes in chromosome number can occur in both diploid and haploid organisms. The nondisjunction of one or more chromosomes during meiosis I or meiosis II typically is responsible for generating gametes with abnormal numbers of chromosomes.
Nondisjunction is the failure of chromosomes to separate during meiosis, which can occur in the first or second meiotic division.
If it happens in meiosis I, homologous chromosomes fail to separate, resulting in all four daughter cells being aneuploid (having an abnormal number of chromosomes); two cells will have (n+1) chromosomes and two will have (n-1).
If it happens in meiosis II, sister chromatids fail to separate in one of the two cells, leading to two normal cells with (n) chromosomes and two aneuploid cells (one with (n+1) and one with (n-1)).
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Types of Aneuploidy. In aneuploidy, one or more chromosomes are lost from or added to the normal set of chromosomes. Aneuploidy can occur due to the loss of individual chromosomes in meiosis or rarely in mitosis by nondisjunction. In animals, autosomal aneuploidy is almost always lethal, so in mammals it is detected only in aborted fetuses.
Aneuploidy is tolerated by plants, in species that are polyploid (having more sets of chromosomes than two). In diploid organisms, there are four main types of aneuploidy
1. Nullisomy (a nullisomic cell) involves a loss of one homologous chromosome pair. Nullisomy arises if nondisjunction occurs for the same chromosome in meiosis in both parents, producing gametes with no copies of that chromosome and one copy of all other chromosomes in the set.
2. Monosomy (a monosomic cell) involves a loss of a single chromosome. Monosomy can arise if nondisjunction in meiosis in a parent produces a gamete with no copies of a particular chromosome and one copy of all other chromosomes in the set.
3. Trisomy (a trisomic cell) involves a single extra chromosome, the cell has three copies of particular chromosome and two copies of all other chromosomes. Trisomy can arise if nondisjunction in meiosis in a parent produces a gamete with two copies of a particular chromosome and one copy of all other chromosomes in the set.
4. Tetrasomy (a tetrasomic cell) involves an extra chromosome pair. There are four copies of one particular chromosome and two copies of all other chromosomes. Tetrasomy can arise if nondisjunction occurs for the same chromosome in meiosis in both parents, producing gametes with two copies of that chromosome and one copy of all other chromosomes in the set.)
A double monosomic has two separate chromosomes present in only one copy each. A double tetrasomic has two chromosomes present in four copies each. In both cases, meiotic nondisjunction involved two different chromosomes in one parent’s gamete production.
In humans, autosomal monosomy is rare. Autosomal trisomy accounts for about one-half of chromosomal abnormalities producing fetal deaths. Only a few autosomal trisomies are seen in live births. Most of these (trisomy-8, -13, and -18) result in early death. Only trisomy-21 (Down syndrome) survive to adulthood.
Trisomy-21 occurs when there are three copies of chromosome 21. Individuals with trisomy-21 have Down syndrome, characterized by such abnormalities as low IQ, epicanthal folds (in which the skin of the upper eyelid forms a layer that covers the inner corner of the eye), short and broad hands, and below-average height. Down syndrome is named for the late-nineteenth-century English physician John Langdon Down, who, in 1866, gave an accurate description of a person with the condition.
A direct relationship exists between maternal age and probability of giving birth to an individual with trisomy 21. During the development of a female fetus before birth, the primary oocytes in the ovary undergo meiosis, but stop at prophase I. In a fertile female, each month at ovulation, the nucleus of a secondary oocyte begins the second meiotic division, but progresses only to metaphase, when division again stops. If a sperm penetrates the secondary oocyte, the second meiotic division is completed. The probability of nondisjunction increases with the length of time the primary oocyte is in the ovary. It is important, then, that older mothers-to-be consider testing to determine whether the fetus has a normal set of chromosomes.
Down syndrome can also result from a sort of chromosomal mutation called Robertsonian translocation, which produces three copies of the long arm of chromosome 21. This form of Down syndrome, called familial Down syndrome, is responsible for 2–3% of Down syndrome cases. In Robertsonian translocation, two nonhomologous acrocentric chromosomes (chromosomes with centromeres near their ends, Chromosome 13, 14, 15, 21 or 22) break at their centromeres and then the long arms become attached to a single centromere. The short arms also join, but are lost within a few cell divisions, resulting in 45 total chromosomes but usually no genetic loss or health issues for the carrier. However, carriers have an increased risk of having children with unbalanced chromosomes, potentially leading to conditions like Down syndrome (trisomy 21) or Patau syndrome (trisomy 13) due to abnormal chromosome segregation during reproduction.
Robertsonian translocation
Trisomy-13 produces Patau syndrome. Characteristics of individuals with trisomy- 13 include cleft lip and palate, small eyes, polydactyly (extra fingers and toes), mental and developmental retardation, and cardiac anomalies, among many other abnormalities. Most infants die before the age of 3 months.
Trisomy-18 produces Edwards syndrome. About 80 percent of infants with Edwards syndrome are female. Individuals with trisomy-18 are small at birth and have multiple congenital malformations affecting almost every organ in the body. Clenched fists, an elongated skull, lowset malformed ears, mental and developmental retardation, and many other abnormalities are associated with the syndrome. Ninety percent of infants with trisomy-18 die within 6 months.
Changes in Complete Sets of Chromosomes
Monoploidy and polyploidy involve variations from the normal state in the number of complete sets of chromosomes. Because the number of complete sets of chromosomes is involved in each case, monoploids and polyploids are euploids. Monoploidy and polyploidy are lethal in most animal species, but are less consequential in plants.
Monoploidy. A monoploid individual has only one set of chromosomes instead of the usual two sets. Monoploidy is sometimes called haploidy. Some fungi and males of haploid/diploid species (ants, bees, wasps) are haploid. Monoploidy is seen only rarely among adults in normally diploid organisms. Certain species produce monoploid organisms as a normal part of their life cycle.
Polyploidy. Polyploidy is the chromosomal constitution of a cell or an organism that has more than the normal two sets of homologous chromosomes. Polyploids may arise spontaneously or be induced experimentally. They often result from a breakdown of the spindle apparatus in one or more meiotic divisions or in mitotic divisions. Almost all plants and animals have some polyploid tissues. For example, the endosperm of plants is triploid, the liver of mammals and other vertebrates is polyploid, and the giant abdominal neuron of the sea hare Aplysia has about 75,000 copies of the genome.
Completely polyploid plants include wheat, which is hexaploid (6N), and strawberry, which is octaploid (8N). Some animal species, such as the North American sucker (a freshwater fish), salmon, and some salamanders, are polyploid. In humans, the most common type of polyploidy is triploidy, and it is always lethal.
Two types of polyploidy are encountered in plants. In autopolyploidy, all the sets of chromosomes originate in the same species. The cultivated banana is an example of a triploid autopolyploid plant. In allopolyploidy, the sets of chromosomes involved come from different, though usually related, species. This situation can arise if two different species interbreed to produce an organism.
A example of allopolyploidy is crosses made between cabbages (Brassica oleracea) and radishes (Raphanus sativus). Both parents have a chromosome number of 18, and the hybrids also have 18 chromosomes, 9 from each parent. The hybrids produced are morphologically intermediate between cabbages and radishes. The plants are mostly sterile; however, a few seeds are produced through meiotic errors, and some of those seeds are fertile. The plants produced from those seeds have 36 chromosomes—that is, full diploid sets of chromosomes from both the cabbage and the radish. These plants are fertile and belong to a breeding species named Raphanobrassica.
The cultivated bread wheat, Triticum aestivum, is an allohexaploid with 42 chromosomes. This plant species is descended from three distinct species, each with a diploid set of 14 chromosomes.
