Copy number analysis is a scientific technique used to examine variations in the amount of specific DNA segments within an individual’s genome. This analysis detects instances where DNA is not always present in the typical two copies, one inherited from each parent. It provides insights into how certain parts of our genetic instruction manual might be duplicated or missing.
Understanding Copy Number Variations
Copy number variations (CNVs) are segments of DNA that differ in their number of copies among individuals, involving either duplications (more than two copies) or deletions (fewer than two copies). CNVs can range considerably in size, from thousands to millions of DNA base pairs.
To illustrate, imagine a book that normally has two copies of every page. A CNV would be like finding a version of the book with an extra copy of a particular chapter, or perhaps a missing page or section. While CNVs are a natural component of human genetic diversity, accounting for up to 10% of an individual’s genome, some can be associated with various health conditions.
The Significance of Copy Number Changes
Changes in DNA copy number affect gene function. When there are too many copies of a gene, it can lead to an overexpression of the gene’s product, such as a protein. Conversely, having too few copies or a deletion of a gene can result in insufficient protein production or even a complete loss of function. These gene dosage effects can disrupt normal biological processes.
Specific CNVs have been linked to a range of human health conditions, including developmental disorders like autism spectrum disorder, intellectual disability, and various congenital anomalies. CNVs are also observed in certain cancers, where gene amplifications or deletions can drive tumor growth or affect treatment response. However, many CNVs are benign and contribute to the normal genetic differences observed among people. For instance, variations in the amylase gene copy number are seen across different populations, correlating with historical dietary starch intake.
Methods for Detecting Copy Number Variations
Detecting copy number variations involves technologies that scan an entire genome for missing or extra DNA segments. Chromosomal microarray analysis (CMA) is one such method, utilizing microarrays: glass slides or silicon chips spotted with millions of known DNA sequences (probes). CMA compares a patient’s DNA to a reference DNA sample, identifying regions where the copy number differs. This technique can detect changes as small as 5-10 kilobases, offering a resolution higher than traditional methods like karyotyping.
Another method for detecting CNVs is Next-generation sequencing (NGS), which offers a base-by-base view of the genome. NGS can identify smaller or novel copy number variants that microarrays might miss, and it can precisely map their genomic locations. Common NGS-based methods include read-pair, split-read, read-depth, and assembly, with read-depth often used for its ability to detect CNV dosage.
Real-World Applications of Copy Number Analysis
Copy number analysis has many applications, particularly in clinical diagnostics. It is used to diagnose genetic syndromes, identify genetic causes of developmental delays, and perform prenatal testing for certain conditions. For example, it can aid in diagnosing unexplained intellectual disability, providing a diagnosis in approximately 15 to 20 percent of such cases. In prenatal settings, CNV analysis can be performed on cell-free fetal DNA from maternal blood, offering a less invasive method to detect chromosomal changes.
Beyond diagnostics, copy number analysis is used in cancer research and diagnostics. It helps identify gene amplifications or deletions in tumors, influencing cancer cell growth, drug sensitivity, and treatment resistance. For instance, amplification of the HER2 gene in breast cancer can guide targeted therapy with drugs like trastuzumab. Furthermore, studying CNVs helps understand human population diversity and evolutionary patterns.