Copy number variations (CNVs) represent a fundamental type of genetic difference found across human genomes. These variations involve alterations in the number of copies of specific DNA segments, meaning some individuals may have more or fewer copies of a particular stretch of DNA compared to others. CNVs are a significant component of the human genome, influencing a wide array of individual characteristics and contributing to both health and disease.
Understanding Copy Number Variations
CNVs encompass two primary types of alterations: deletions, where a segment of DNA is missing, and duplications, where an extra copy of a DNA segment is present. These variations can range considerably in size, from a few thousand DNA base pairs (kilobases) to millions of base pairs (megabases), sometimes even affecting entire genes or large chromosomal regions. While single nucleotide polymorphisms (SNPs) involve a change in a single DNA building block, CNVs represent larger structural changes in the genome, involving segments of 1,000 base pairs or more.
Approximately 4.8% to 9.5% of the human genome can be classified as CNVs. These structural differences can occur throughout the genome, in both gene-coding and non-coding regions. CNVs arise through various genetic mechanisms, including errors during DNA replication, recombination events, and chromosomal rearrangements.
How CNVs Influence Health and Disease
Pathogenic CNVs, those that cause disease, can disrupt normal biological processes by altering the number of gene copies. This concept is known as gene dosage, where having too many or too few copies of a gene can lead to an imbalance in the amount of protein produced, thereby affecting cellular functions. For instance, a deletion might result in a gene’s complete absence or reduced expression, while a duplication could lead to overexpression.
CNVs are associated with a broad spectrum of health conditions, including various developmental disorders. These can include neurodevelopmental conditions such as autism spectrum disorder (ASD) and intellectual disability, where CNVs can disrupt normal brain development and function. Specific CNVs have also been linked to neurological conditions like schizophrenia and bipolar disorder. Additionally, CNVs play a role in the development of certain cancers, where amplifications of specific genomic regions can activate oncogenes or deletions can inactivate tumor suppressor genes, driving tumor progression.
The Role of CNVs in Human Diversity
Not all CNVs result in disease; many are found in healthy individuals and contribute to the normal range of human phenotypic variation. These variations can influence traits such as drug metabolism, immune responses, and even physical characteristics like height. For example, variations in the copy number of the AMY1 gene, which codes for salivary amylase, are associated with differences in starch digestion efficiency among human populations.
CNVs also play a role in human evolution and adaptation to diverse environments. They can provide an adaptive advantage, allowing populations to respond to changing selective pressures. For instance, certain CNVs have been linked to high-altitude adaptation in Tibetan populations. CNVs can create novel genes or diversify existing gene repertoires, shaping human diversity beyond disease susceptibility.
Investigating Copy Number Variations
Scientists and clinicians employ various techniques to identify and study CNVs. One common method is array comparative genomic hybridization (aCGH), which compares an individual’s DNA to a reference DNA to detect gains or losses of genomic material. While aCGH offers insights into CNV presence, its resolution for detecting very small variants can be limited.
Next-generation sequencing (NGS) technologies, such as whole-genome sequencing (WGS) and whole-exome sequencing (WES), have become increasingly prevalent for CNV detection. These methods provide high-resolution data by sequencing DNA fragments and analyzing the depth of coverage or paired-end mapping information to identify regions with altered copy numbers. NGS allows for the detection of CNVs, including those affecting single exons.