Deletion Mutations

The chromosomal mutations leading to the loss of a part of a chromosome are known as deletion mutations. A segment of a chromosome is missing. Chromosomal breaks instigate deletions. Physical, chemical or biological agents lead to chromosomal breaks. Other factors such as transposable elements, recombination, and replication also lead to chromosomal breaks. Deletion pertains to a particular segment in the chromosome, or a Centromeric region, a telomeric region or complete chromosomal deletion. Hence, the effect of deletion is different in all the above cases. The severe condition arises due to recessive genes with deleterious effects. However, a heterozygote individual may not express the phenotype. Loss of a centromere leads to an acentric chromosome. Another condition involving the complete loss of a chromosome from the genome leads to more serious effects. Detection of deletions is possible with the karyotype analysis.

Deletions also occur due to erroneous crossing over during meiosis. Other causes of deletions include loss occurring from the translocation events, unequal crossing over, and breakage without re-joining. There are three types of deletions such as terminal, intercalary, and microdeletions. The terminal deletion occurs at the end of the chromosome. Chromosomal interior regions also get affected by the deletion mutations. Such mutations are known as intercalary deletions. Minute deletions involving a small number of base pairs are known as microdeletions.

Image: Deletion mutation

Role of chromosomal breakage in causing deletion mutations:

Breaks occur in the chromosomes to remove or excise out a particular segment or a region in a chromosome. Most of the chromosomal deletions arise due to double-stranded breaks. There are several reasons for the chromosomal breaks. Mutagenic agents such as UV radiations, chemical exposure or any biological agent may induce breaks in the chromosomes. Lesions occur due to DNA damage. Failure of the repair mechanisms and erroneous DNA replication also contribute to the unrepaired breaks in the chromosomes. Intercalary deletions arise due to two breaks in a chromosomal segment. If the two ends join bearing a Centromeric region, a short chromosome forms. The deleted fragment gets degraded or lost. It is known as an acentric fragment since it does not contain a centromere. Terminal deletion arises due to a single break at the end of the chromosome. A small segment of the chromosome gets deleted or lost due to single breaks. The terminal deletions delete the telomeres situated at the ends of the chromosomes. The size of the deletion determines the gene functionality. A small segment of chromosome gets deleted or involves an irreversible single nucleotide deletion. Small deletions (intragenic deletions) inactivate few genes. These genes lose their function. Multiple gene deletions (multigenic) target a large segment of a chromosome. These deletions involving many genes lead to lethality. Heterozygote survival is also at risk in case of multigenic deletions. The deletion loops commonly arise due to heterozygous deletions. Deleted genes do not encode any protein products.

The role of ectopic recombination in deletion:

The repeated DNA sequences at different sites undergo homologous recombination. The configuration of these sequences having same orientation is known as direct repeat configuration. Homologous recombination in these sequences results in loss of the genetic material (deletion). It leads to a loss of an acentric fragment. Another concept of inverted repeats involves an opposite orientation of repeated sequences. Example of deletion due to ectopic recombination includes the loss of fertility genes on the Y chromosome. 

Deletion syndromes:

The deletion syndrome	The region of the chromosome involved in the deletion	Type of deletion	Clinical features
Cri-du-chat syndrome	The p arm of the 5th chromosome gets deleted.	Microdeletion or partial deletion	Microcephaly, cat-like cry, physical and mental retardation.
Prader-Willi syndrome	A small segment of paternal 15th chromosome gets deleted.	Microdeletion	Intellectual and behavioral problems.
Jacobson’s syndrome	The q arm of the 11th  chromosome gets deleted	Terminal deletion	Congenital heart disease, developmental delay, and thrombocytopenia.
Di-George syndrome	The q arm of the 22nd chromosome gets deleted	Interstitial deletion	Congenital heart defects, cleft lip or palate, and T-cell deficiency.

                      Table: Deletion mutations and conditions associated with the same. 

Karyotyping, FISH, and other cytogenetic techniques help in detecting deletion mutations. In lower organisms such as Drosophila and bacteriophages, deletion mapping is possible. It is easy to determine the physical location of the gene on a chromosome using deletions. The phenomenon of pseudo-dominance involves an unexpected expression of the recessive alleles in the absence of the dominant allele. The Drosophila strain for the study involved a heterozygous fly with an X-linked recessive mutation. Notch gene deletions in Drosophila also cover up the nearby wild-type expressive genes. Such Drosophila strains exhibit a wild-type recessive allele. These strains have white eyes since there is no wild-type allele. The polytene chromosomes present in the salivary gland show a banded pattern. Notch deletions lead to missed bands in this chromosome. Deletion mapping helps to study them.

References:

[1] Genetics, Daniel Hartl, Maryellen Ruvolo

[2] Human Chromosomes, Orlando J. Miller, Eeva Therman

[3] Biology of Disease, Nessar Ahmed, Maureen Dawson, Chris Smith, Ed Wood
[4] Emery's Elements of Medical Genetics, Peter D Turnpenny, Sian Ellard

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