A duplication mutation is a genetic alteration where a segment of DNA is copied and inserted into the genome, resulting in extra copies of the genetic instructions. This alteration is a significant source of variation, potentially causing human disease while also serving as a primary engine for long-term evolutionary change.
The Physical Mechanism of Gene Duplication
The most frequent way a duplication mutation arises is through unequal crossing over during meiosis, the specialized cell division that creates sperm and egg cells. Homologous chromosomes exchange genetic material, and while recombination is normally precise, the chromosomes sometimes misalign due to repetitive DNA sequences.
When misaligned, the exchange leads to one chromatid receiving an extra segment of DNA (duplication), while the reciprocal chromatid loses that segment (deletion). Repetitive DNA elements near duplication breakpoints confuse the cellular machinery, making the region prone to unequal exchange. This mechanism causes the majority of large-scale duplication events.
Smaller duplications can occur due to replication slippage, an error in DNA replication. This happens when the DNA polymerase enzyme temporarily detaches from the template strand during synthesis, especially in areas with short, repeating sequences. When the enzyme reattaches incorrectly, the newly synthesized strand contains extra copies of the repeat unit.
Immediate Effects on Gene Function
The immediate consequence of a duplication mutation is an increase in gene copies, leading to an altered level of the gene’s product. This is the gene dosage effect, where protein production is proportional to the number of functional gene copies. If a duplication results in three copies instead of two, the cell typically produces about 150% of the normal protein amount.
This overproduction can severely disrupt cellular function, especially if the protein is sensitive to concentration changes. Biological systems rely on a precise balance of interacting proteins, and excess protein can throw the entire pathway into disarray. This imbalance may result in a toxic effect or interfere with complex structure formation, such as preventing the proper assembly of a multi-protein complex.
The cellular response is not always linear, as some genes have regulatory feedback loops that partially compensate for the extra copies. For genes lacking this buffering capacity, the increase in protein product translates the physical duplication into a biological consequence. Susceptibility is determined by the specific function of the duplicated gene.
Specific Disorders Caused by Duplications
The health consequences of duplication mutations depend on the size of the duplicated segment and the specific genes it contains. Charcot-Marie-Tooth Disease Type 1A (CMT1A), a common inherited neurological disorder, is caused by a duplication of a 1.5-million-base-pair region on chromosome 17 that includes the PMP22 gene.
Individuals with CMT1A have three copies of the PMP22 gene, leading to an overabundance of the Peripheral Myelin Protein 22. This excess protein damages the Schwann cells, which produce the myelin sheath insulating peripheral nerves. The resulting poor formation or thinning of the myelin sheath impairs nerve conduction, causing muscle weakness and numbness.
Duplications involving larger segments result in microduplication syndromes, which typically involve multiple contiguous genes. These chromosomal changes often lead to a wide spectrum of neurodevelopmental and cognitive issues. For instance, the reciprocal microduplication of the region linked to CMT1A causes Potocki-Lupski syndrome.
Potocki-Lupski syndrome is characterized by low muscle tone, developmental delay, and features of autism spectrum disorder. The severity of these syndromes can vary greatly among affected individuals (variable expressivity). The gain of genetic material disrupts the balance of many genes simultaneously, leading to complex effects on development and organ function.
Duplication as a Driver of Evolution
While duplications can be detrimental to health, they are a powerful source of novelty and adaptation over evolutionary timescales. A redundant gene copy provides a buffer against harmful mutations, as the original gene copy maintains its necessary function. The spare copy is free from the pressure of natural selection, allowing it to accumulate mutations without negatively affecting the organism’s survival.
This freedom often leads to neofunctionalization, where the duplicated gene evolves a completely new function different from the ancestral gene. The evolution of the globin gene family, including hemoglobin and myoglobin, is a prime example. An ancient duplication event separated the ancestor of myoglobin (stores oxygen in muscle tissue) from the ancestor of hemoglobin (transports oxygen in the blood).
Further duplications and divergence created the distinct alpha and beta globin chains, which assemble into the specialized, four-subunit hemoglobin protein found in red blood cells. This complex structure was made possible by gene duplication, allowing for the sophisticated regulation of oxygen binding and release necessary for complex animal life.