The genetic information encoded in DNA serves as the instruction manual for life, guiding the development and function of every organism. Although the cellular machinery for copying and maintaining this blueprint is highly precise, errors can occur. A deletion represents one of the most fundamental types of these errors, involving the permanent loss of a piece of the genetic code. This loss can range from a single molecular unit to a large segment of a chromosome, and the consequences depend on where this missing information was located.
Defining Genetic Deletion
A deletion in genetics is a mutation where one or more nucleotide base pairs are lost from a DNA sequence, or a segment is missing from a chromosome. Nucleotides are the basic building blocks of DNA, and their sequence dictates the formation of proteins. The severity of a deletion is connected to how it impacts the protein-coding sequence of a gene.
If the number of deleted bases is not a multiple of three, the deletion causes a frameshift mutation, which alters the entire reading frame downstream of the mistake. Imagine a sentence of three-letter words where one letter is removed; all subsequent words become nonsensical, leading to a completely altered or prematurely terminated protein product. Even a deletion that is a multiple of three bases preserves the reading frame but results in the loss of one or more amino acids, potentially impairing protein function.
Classifying Deletions by Scale
Deletions are classified based on the physical size of the lost material, which provides insight into the potential scope of the functional disruption. The smallest scale is the point deletion, involving the loss of just one or two base pairs within a gene’s sequence. These deletions are typically responsible for frameshift mutations and often lead to severe, single-gene disorders.
Microdeletions involve the loss of small segments of DNA, often ranging from tens of thousands up to a few million base pairs (Mb). These deletions frequently encompass several functional genes and are too small to be observed using traditional microscopy techniques. Specialized methods like fluorescent in situ hybridization (FISH) or chromosomal microarray analysis are required to identify these losses.
The largest scale is the chromosomal deletion, where a large, visible portion of a chromosome arm is missing, typically involving more than 5 Mb of genetic material. These large-scale losses can be detected through a standard karyotype, which is a visual assessment of the chromosomes. A chromosomal deletion results in the loss of hundreds of genes, almost always leading to significant developmental and medical syndromes.
Biological Mechanisms Leading to Deletion
Errors that create deletions often occur during the cellular processes that maintain and copy DNA. One common mechanism is replication slippage or slipped-strand mispairing, which occurs during DNA replication. This error frequently happens in regions containing repetitive DNA sequences.
During replication, the DNA polymerase enzyme can temporarily detach from the template strand, causing the newly synthesized strand to misalign. If the new strand re-anneals further back on the template, a small loop forms on the template strand. When replication resumes, this looped-out section is skipped, resulting in a small deletion in the new DNA molecule. This type of error is a common cause of point deletions and small frameshift mutations.
Larger deletions, especially microdeletions and chromosomal deletions, are often a consequence of errors during DNA repair or recombination. Non-Allelic Homologous Recombination (NAHR) is a significant source of these larger structural variants. NAHR occurs when highly similar DNA sequences, known as low-copy repeats (LCRs), mistakenly align during meiosis instead of the correct pairing partners.
This misalignment during meiosis leads to an unequal exchange of genetic material between homologous chromosomes. The chromosome receiving less material ends up with a deletion, while the other receives a duplication. The presence of LCRs creates “hotspots” that make certain chromosomal regions highly susceptible to recurrent NAHR-mediated deletions, resulting in specific genomic disorders.
Another mechanism is the faulty repair of double-strand DNA breaks, primarily involving Non-Homologous End Joining (NHEJ). NHEJ is an emergency pathway that attempts to ligate broken DNA ends back together without a homologous template, making it error-prone. The repair enzymes often trim the broken ends before joining them, which can result in the loss of a few nucleotides at the repair junction. This process can lead to small deletions at the break site, contributing to point deletions or small insertions/deletions (indels) that cause frameshift mutations.
Health Consequences of Genomic Deletions
The clinical outcome of a genomic deletion depends on the size of the lost segment and the specific genes removed. Deletions that remove a single gene can cause conditions like Duchenne muscular dystrophy, while larger deletions typically result in complex syndromes affecting multiple body systems. The loss of a gene often results in a loss-of-function phenotype, meaning the body cannot produce the necessary protein.
Cri-du-chat syndrome is an example of a large chromosomal deletion, caused by the loss of a segment from the short arm of chromosome 5 (5p). Individuals with this syndrome exhibit severe intellectual disability, microcephaly, and a characteristic high-pitched, cat-like cry in infancy. This condition demonstrates the profound impact of losing a large number of genes simultaneously.
Microdeletions are responsible for contiguous gene syndromes, where the loss of several adjacent genes causes a distinct set of symptoms. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are classic examples, both resulting from a microdeletion in the same region of chromosome 15 (15q11-q13). The different outcomes occur because the deleted region contains imprinted genes; expression depends on whether the chromosome was inherited from the mother or the father. A paternal deletion causes PWS, leading to insatiable hunger and intellectual impairment, while a maternal deletion causes AS, characterized by severe developmental delay and balance issues.