The human body is built from instructions encoded in deoxyribonucleic acid (DNA), which is organized into the genome. This instruction manual dictates everything from eye color to complex organ functions. For any given segment of DNA, the number of copies present in a cell is not always the standard two, one inherited from each parent. The count of these specific DNA segments can vary widely among individuals and even between different cells within the same person. Understanding this variability in DNA copy number is fundamental to grasping human genetics and its impact on health.
Defining DNA Copy Number
DNA copy number refers to the number of times a specific, measurable segment of DNA is present within the cell nucleus. For most of the human genome, the expected baseline is two copies of every gene and chromosomal region, a state known as diploidy. This two-copy state is established when a sperm and an egg, each carrying a single set of chromosomes, combine during fertilization.
The copy number can deviate significantly from this standard two. A DNA segment may have a copy number of zero, indicating a complete deletion, or one, which is called a heterozygous deletion. Conversely, a segment may be duplicated, resulting in three, four, or even dozens of copies of the same gene or region.
The size of the affected segment can range dramatically, spanning from a handful of DNA base pairs to millions of base pairs that encompass multiple entire genes. The measurement itself is merely a physical count of the DNA sequence in question. The downstream effects, which relate to how much protein is produced from the gene, ultimately determine the biological outcome.
Natural Variation in the Human Genome
Deviations from the two-copy norm are known as Copy Number Variations (CNVs). CNVs are widespread and represent a major source of genetic difference between people. These structural changes are not inherently detrimental; a vast number of CNVs are considered benign, contributing to the normal spectrum of human phenotypic diversity. They are a significant component of genetic polymorphism, often defining individual traits rather than causing disease.
A well-studied example of a CNV that contributes to adaptation is found in the gene for salivary amylase, \(AMY1\). This enzyme is responsible for breaking down starch in the mouth. Populations with a traditional diet high in starch tend to have a higher number of \(AMY1\) gene copies than populations with low-starch consumption. This increased copy number allows for the production of more amylase enzyme, providing a digestive advantage in metabolizing starches.
CNVs also influence individual differences in how the body processes medications. The \(CYP2D6\) gene codes for a liver enzyme involved in metabolizing many common drugs and frequently shows copy number variation. An individual with multiple copies of \(CYP2D6\) may metabolize certain medications much faster than a person with the standard two copies. This genetic difference can lead to variations in drug response, requiring clinicians to adjust dosages to achieve the intended therapeutic effect.
Copy Number Changes and Disease
While many CNVs are harmless or adaptive, others can be disruptive, leading to serious medical conditions. When copy number changes affect genes sensitive to dosage, the resulting imbalance in protein production can initiate or contribute to disease. These implications manifest across a wide range of disorders, from congenital syndromes to acquired diseases like cancer.
In cancer, copy number changes are a hallmark of genomic instability and a primary driver of tumor growth. This process often involves the amplification, or gaining of many copies, of genes that promote cell division, known as oncogenes. For instance, in some breast and gastric cancers, the \(ERBB2\) gene (\(HER2\)) can be amplified many times over. This high copy number leads to an overproduction of the HER2 protein, which constantly signals the cell to grow and divide uncontrollably.
The opposite scenario, the deletion or loss of a DNA segment, is equally damaging when it affects tumor suppressor genes. These genes normally act as the cell’s brake pedal, slowing down cell division or initiating cell death when damage occurs. The loss of a tumor suppressor gene, such as \(TP53\), removes this regulatory mechanism, allowing mutated cells to proliferate without restraint. These localized gains and losses provide the cancer cell with a selective advantage.
Large-scale copy number changes, often involving entire chromosomes or large segments, are responsible for many genetic syndromes. A classic example is aneuploidy, the presence of an abnormal number of chromosomes, such as Trisomy 21, which causes Down syndrome. This condition results from having three copies of chromosome 21 instead of the usual two. Similarly, smaller microdeletions and microduplications are associated with various developmental disorders, including specific forms of intellectual disability and autism spectrum disorders.
How Scientists Analyze Copy Number
Detecting and quantifying DNA copy number relies on technologies capable of measuring the relative amount of a DNA segment. These methods allow researchers and clinicians to compare the DNA from a patient’s cells to a normal reference genome to identify regions of gain or loss. The output of these analyses is a precise count of the number of DNA segments present, revealing deviations from the expected two copies.
Array Comparative Genomic Hybridization (aCGH)
aCGH involves labeling a patient’s DNA with one fluorescent color and a control DNA sample with a different color. Both samples are mixed and hybridized to a slide containing thousands of known DNA probes. By measuring the ratio of the two colors at each probe location, scientists can pinpoint regions where the patient’s DNA is either overrepresented (a gain) or underrepresented (a loss).
Quantitative Polymerase Chain Reaction (qPCR)
qPCR is often used to confirm or focus on a specific, known copy number change. This method uses fluorescent chemistry to measure the amount of a target DNA sequence in real-time as it is copied in a laboratory reaction. By comparing the amplification rate of the target sequence to a known reference sequence, the number of copies can be accurately calculated.
Next-Generation Sequencing (NGS)
NGS has emerged as a high-throughput method for copy number analysis across the entire genome. NGS involves sequencing millions of small DNA fragments and then mapping them back to the reference genome. A region with a higher copy number will produce a greater number of sequenced fragments, while a region with a deletion will yield fewer fragments. By simply counting the number of sequence reads that align to a specific area, NGS provides a comprehensive and highly detailed map of a person’s DNA copy number landscape.