How does the Chromosomal Mutation occurs?

Mutations are heritable changes in genetic materials producing alternate forms of any gene (alleles). Of two broad types of mutation, one affect gene, called gene mutation; other affect whole chromosome or chromosomal segment called chromosomal aberrations.

Gene mutations at nucleotide level are generally known as point mutation. Chromosomal mutation may be due to changes in chromosome structure (deletion, duplication, inversion, and translocation) or number (euploidy, aneuploidy).

Chromosomal mutation:

In eukaryotic organisms, DNA molecules in nucleus combine with proteins, mainly histones, to make chromosomes. Each chromosome represents a single DNA molecule. Chromosomes are usually only clearly visible and identifiable, when cells arc dividing, at which time the chromosomes have already divided into daughter chromatids.

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However, daughter chromatids retain connection to each other at a position called centromere. Number of chromosomes, their lengths and positions of their centromeres are unique to each species. These characters are used as descriptors for species karyotype. Chromosomes themselves mutate and evolve (Beaumont and Hoare, 2003).

Inversion:

When a region of a chromosome breaks off and rotates 180° before rejoining the chromosome, then the phenomenon is called inversion. When the centromere is not included in inversion, it is called paracentric inversion.

When inversion includes centromere it is called pericentric inversion. Crossing over in a heterozygous pericentric inversion results in deletions and duplication and also produces rod, shaped acrocentric chromosomes. A crossing over in inverted region of a heterozygous paracentric inversion produces a dysenteric chromosome.

Translocation:

Breakage of a chromosomal region and rejoining either at other end of the same chromosome or another non-homologous chromosome is termed translocation. This may be simple -, shift- and reciprocal translocation. In simple translocation, a single break in a chromosome occurs and broken piece gets attached to one end of a non-homologous chromosome.

In shift translocation, broken segment of one chromosome gets inserted intestinally in a non­homologous chromosome. In reciprocal translocation, a segment from one chromosome is exchanged with a segment from another non- homologous one. In Oenothera, a rare series of reciprocal translocation is reported involving all of its 7 chromosome pairs.

If each chromosome end is labeled with different numbers, normal set of 7 chromosomes would be represented as 1-2, 3-4, 5-6, 7-8, 9-10, 11-12 and 13-14. Likewise a translocation set would be represented as 2-3, 4-5, 6-7, 8-9, 10-11, 12-13 and 14-1. Such a multiple translocation heterozygote would form a ring of 14 chromosomes during meiosis.

Various lethals in each of two haploid sets of 7 chromosomes administer structural heterozygosis. Since, only alternate disjunction from the ring can form viable gametes, each group of 7 chromosomes behaves as a single large linkage group with recombination confined to pairing ends of each chromosome. Each set of chromosome inherited as a single unit is called a “Renner complex”.

Deletion:

Deletion involves loss of a chromosomal region. A terminal portion of a chromosome is lost due to oniy one break in terminal deletion. An intermediate portion of a chromosome is lost due to two breaks in intercalary deletion.

Here, chromosome is broken into three pieces, middle one of which is lost and remaining two pieces get joined again. Notch- wing mutation is an example of deletion. Notch- wing is a recessive allele and when this allele behaves like a dominant allele and is phenotypic ally expressed, and then this phenomenon is called pseudo dominance. Pseudo dominance (deletion) is found in criduchat syndrome where human individuals loss a portion of short arm of chromosome 5.

Duplication:

Presence of a chromosomal part in excess of normal chromosomal complement is called duplication. This may be tandem-, reverse tandem-, displaced and transposed duplication. In tandem duplication, duplicated region is situated by the side of normal corresponding chromosome section. Here, gene sequences are essentially similar in both normal and duplicated region of chromosome.

In reverse tandem duplication, sequence of genes in duplicated chromosomal region is reverse to that of normal chromosome. In displaced duplication, duplicated region is not located adjacent to normal chromosome.

Such duplication may be homobranchial or heterobranchial. In transposed duplication, duplicated chromosomal portion becomes attached to a non­homologous chromosome. In extra-chromosomal duplication, duplicated chromosomal part acts as an independent chromosome in presence of centromere.

Changes in chromosome morphology:

Morphological changes in chromosome are observed in case of isochromosoine, ring chromosome and Robertsonian translocation. In is chromosome, both chromosome arms are identical due to division of a centromere in wrong plane, producing two daughter chromosomes, each of which carries information of one arms only but present twice. In case of ring chromosome, breakage at each end of chromosome occurs and broken ends are joined.

Robertsonian translocation is believed to play a role in evolution of human beings. Humans and great apes have 46 and 48 chromosomes respectively. Humans would have evolved from ape ancestor due to centric fusion of two acrocentric chromosomes to produce a single large one. Actuatlly, such translocation results in reduction of chromosome number due to whole arm fusion in the non­homologous chromosome.

Changes in chromosome number:

Gametic chromosome number constitutes a basic set of chromosomes called genome. Chromosomal aberrations may include whole genomes and entire single chromosome. Changes in chromosome number are called heteroploidy. Heteroploidy may be either aneuploidy or euploidy.

Aneuploidy:

Monosomy:

A 2n-l complement due to loss of one chromosome is called monosome Monosomy for X chromosome is found in humans 45, X Turner syndrome.

Trisomy:

A 2n+l complement due to addition of an extrachromosome is called trisomy. In primary trisomic, extra chromosome is identical to its homology. In secondary trisomic, extra chromosome is an isochromosome. In tertiary trisomic, extra chromosome is the product of translocation. In human, trisomy is found in Down’s syndrome, Edward’s syndrome and Patau syndrome.

Tetrasomy:

Organisms with two extra chromosomes are known as tetrasomics (2n + 2). Tetrasomics is found in wheat.

Euploidy:

When the genomes contain chromosome in multiplies of some basic numbers. Euploids are organisms with balanced set or sets of chromosomes in any number. A basic set of chromosome number is called monoploid.

When more than two sets of chromosomes are present, the term polyploid applies. Only even-number polyploids are fertile. Odd number of chromosomes cannot be divided in two at reductional meiotic division. Addition of one or more extra sets of chromosomes, identical to normal haploid complement of same species results in autopolyploid.

Combination of chromosome sets from different species as a consequence of interspecific mating results in allopolyploid. When a diploid gamete is fertilized by a haploid gamete or two sperm fertilize an ovum, then triploids are produced.

Polyploids with equivalent of four haploid genomes derived from two separate species are called allotetraploid. Endopolyploidy is the condition in which, only certain cells of diploid organisms are polyploids. In Gerris, 1024 to 2048 copies of each chromosome are found in salivary gland cells.

Chromosome variations are no longer used as markers in population genetic studies. However, they play an important role in evolution. Chromosome duplications provide an extra copy of a block of DNA that may contain complete gene sequences. As might be expected, duplications are less harmful than deletions.

When duplications contain complete gene sequences, natural selection can operate independently on both the new and old sequences to produce divergent roles for genes. This is the principal process for evolution of new genes (Beaumont and Hoare, 2003).

Gene mutation:

A gene is a unit of information held as a code in a discreet sequence of DNA. Discovery by Watson and Crick of structure of DNA in 1953 was a landmark in our understanding of how genetic information passes from generation to generation.

DNA is a polymeric molecule consisting of chains of nucleotide monomers. Complete DNA molecule actually consists of two polynucleotide chains, wrapped around each other in the form of a double helix. Sugar phosphate backbones are at the outside of the molecule, while bases point towards middle of the structure.

Two strands of the molecule run in opposite direction. Fundamental beauty of DNA molecule is a result of complementary base pairing where G can only bond with C, and A can only bond with T, at middle of the molecule.

Replication process produces daughter DNA molecules, each of which has one parental strand and one copied strand. This is called semi-conservative replication.

During replication process, various proofreading activities take place and almost all errors are corrected by removing the incorrect base and inserting the correct one. In spite of proofreading, a few errors are inevitable and it is estimated that about one in every 3 billion bases is incorrectly inserted. Such errors are called point mutations.

Without such errors, no genetic change at DNA level would take place, but with too many errors, daughter cells would too often be non-viable and organisms carrying that DNA would soon become extinct. Gene mutations may be Point mutation and Gross mutation.

Point mutation:

Point mutations results from base substitution in a gene that codes for a polypeptide. This may be missence, nonsence or samesense mutation. Missence mutations results in replacement of one sense codon for another.

Sickle-cell anemia is a good example of such mutation. A nonsense mutation creates one of the three terminating codons (UGA, UAA, and UAG). Such mutation produces polypeptides that are shorter than normal ones and are unable to function properly and therefore represent a loss of biological characteristic.

Frameshift mutations result due to insertion or deletion of one or more bases causing reading frame of gene to be altered and a different set of codons to be read downstream (3′) of the mutation. Several examples have been observed in individuals with haemophilia A.

These include a deletion of four bases that results in a change of reading frame after codon 50 and an insertion of 10 bases which alters reading frame beyond codon 38. Splice site mutations alter signal sequences for splicing that occur at 5′ and 3′ ends of intones leading to a failure of RNA transcribed from mutated gene to be spliced properly.

Mutations also in introns result in creation of splice sites, again causing splicing to occur abnormally. Promoter mutations affect the way through which gene transcription is regulated. Such mutation is associated with hemophilia B.

Gross mutations cause substantial alterations to DNA, often involving long stretches of sequence. Such mutations may be categorized into deletions, insertions, rearrangements and trinucleotide repeat mutations.

Deletion mutations involve loss of a portion of DNA sequence. Insertion mutation occurs as a result of insertion of extra bases, usually from another part of a chromosome. Rearrangement mutations involve segments of DNA sequence within or outside a gene exchanging portion with each other. An unusual form of gene mutation, trinucleotide repeat mutations has been described that involves unstable trinucleotide repeat sequences.

During meiosis, a dramatic increase in mutineer of copies of trinucleotide repeat occurs, which leads to development of disease in subsequent offspring’s. Gross mutations involve major alterations to gene sequences and invariably have a serious effect on encoded protein and are frequently associated with a mutant phenotype.

Molecular basis of gene mutation:

Sequence of nucleotides determines structure of rRNA, mRNA and tRNA as well as proteins that are required by living cells. Genetic information should be accurately replicated and passed on to future generations for survival of species.

Insertion, deletion or substitution of one or more bases in mutation results from error(s) in replication of a gene within DNA molecule. One spontaneous mistake generally occurs in 10⁴ to 10⁷ replication. Such mistake leads to a heritable change in sequence of a DNA molecule.

Many mutations are due to instability of nucleotide bases in DNA. Nucleotide bases upon absorbing sufficient energy from bombarding water molecules undergo structural changes, called tautomeric shifts. A tautomeric shifts causes redistribution of electrons and protons in bases, so that they no longer pair normally.

Actually, spontaneous movement of a hydrogen atom from one position to another within a base converts it to an alternative isomeric from one called a tautomer. The process itself involves a tautomeric shift.

All purines and pyrimidincs can exist as tautomers. When a tautomeric shift occurs, altered base tends to pair with wrong complementary base, thus creating a mutation that would give rise to a different phenotype. Some genes contain regions that are more likely to mutate than others. These sites are called hotspots.

Benzer first demonstrated hotspots during his landmark study of topology of r” locus of bacteriophage T₄. Benzer mapped a total of 1612 spontaneous mutations in r¹¹ locus and found 60 sites within locus those exhibited a larger than expected number of mutations.