Copy number alterations (CNAs) are genetic variations where sections of DNA in a cell’s genome are present in an abnormal number of copies. These changes involve gains or losses of DNA segments, which can be small or encompass large chromosomal regions. Understanding CNAs provides insight into how our genetic makeup can vary, impacting both normal biological functions and the development of diseases.
The Basics of Copy Number Alterations
A “copy number” refers to how many times a particular segment of DNA is present within a cell’s genome. In most human cells, each gene and DNA segment typically exists in two copies, one inherited from each parent. Copy number alterations disrupt this usual two-copy state, leading to an abnormal number of copies for a specific DNA region.
The two primary types of CNAs are deletions and duplications. Deletions involve the loss of a DNA segment, where a cell might have only one or zero copies of a particular gene or region. Conversely, duplications occur when an extra copy of a DNA segment is gained, leading to three or more copies of that region. These alterations range in size from thousands of base pairs to millions, or even entire chromosome arms.
CNAs differ from other genetic variations, such as single nucleotide polymorphisms (SNPs) or point mutations. While SNPs involve a change in a single DNA building block (nucleotide), CNAs affect much larger segments of DNA, typically greater than 1,000 base pairs. CNAs are considered a type of structural variation, as they involve larger-scale rearrangements of the genome rather than just single-base changes.
How Copy Number Alterations Arise
Copy number alterations primarily arise from errors during DNA replication and repair within cells. One common mechanism is unequal crossing over, which happens during meiosis (cell division producing sperm and egg cells) or mitosis (cell division for growth and repair). This process involves the misalignment of homologous chromosomes, or segments within the same chromosome, during recombination. When these misaligned segments exchange genetic material, one chromosome gains an extra copy of a DNA segment (duplication) while the other loses that segment (deletion).
Faulty DNA repair processes also contribute to the formation of CNAs. When double-stranded breaks occur in DNA, the cell attempts to repair them. Errors in these repair pathways can lead to the gain or loss of DNA segments.
CNAs can be inherited from parents if they are present in the germline cells (sperm or egg). However, many CNAs are acquired during an individual’s lifetime, occurring in somatic cells (non-reproductive cells). These somatic CNAs are not inherited and can accumulate in specific tissues, such as in cancer cells.
Copy Number Alterations and Human Health
Copy number alterations play a role in various human health conditions, influencing both disease susceptibility and development. Their impact often stems from altering gene dosage, which changes how much protein is produced from a gene.
In cancer, CNAs are a common feature and contribute to tumor formation and progression. For instance, duplications can lead to the overexpression of oncogenes, which are genes that promote cell growth and division. An example is the HER2 gene amplification in breast cancer, where extra copies of HER2 lead to excessive protein production, driving tumor growth.
Conversely, deletions can result in the loss of tumor suppressor genes that regulate cell division and prevent uncontrolled growth. The loss of tumor suppressor genes like TP53 or RB1 is frequently observed in various cancers, removing a brake on cell proliferation. Identifying these CNAs can offer insights into cancer biology and potential therapeutic strategies.
Beyond cancer, CNAs are associated with a range of developmental disorders and other genetic conditions. For example, Down syndrome (Trisomy 21) is caused by an extra copy of chromosome 21, a large-scale duplication. Microdeletions and microduplications are linked to conditions like DiGeorge syndrome (a deletion on chromosome 22q11.2) and Williams syndrome (a deletion on chromosome 7q11.23). These smaller CNAs can lead to developmental delays, intellectual disabilities, and specific physical features. CNVs have also been linked to neuropsychiatric disorders such as autism and schizophrenia.
Identifying Copy Number Alterations
Scientists and clinicians employ several methods to detect and characterize copy number alterations in DNA samples. These technologies identify regions of the genome where the copy number deviates from the expected two copies.
Array comparative genomic hybridization (aCGH) is one established technique. This method involves labeling a patient’s DNA with a fluorescent dye and normal DNA with a different colored dye. Both labeled DNA samples are then mixed and hybridized to a microarray, which contains thousands to millions of DNA probes. By measuring the ratio of the two fluorescent signals at each probe, researchers can identify regions where the patient’s DNA has more (duplication) or less (deletion) DNA compared to the reference.
Next-generation sequencing (NGS) methods have become powerful for CNA detection. NGS technologies sequence millions of DNA fragments simultaneously to provide high-resolution data on the entire genome. By analyzing the number of sequenced reads mapping to specific genomic regions, bioinformatics algorithms can infer copy number gains or losses. NGS can identify CNAs with high sensitivity, even detecting those present in a small percentage of cells within a sample, which is particularly useful in cancer research. These sequencing techniques comprehensively map and quantify DNA segments, aiding in both research and clinical diagnostics.