- Structural variants are genetic changes that alter the structure or organization of DNA, usually involving larger genomic segments than typical single-nucleotide variants. They include deletions, duplications, inversions, translocations, insertions, and other rearrangements that can change the amount, orientation, or genomic location of DNA. Structural variants are an important source of genetic variation and can influence gene dosage, gene expression, chromosome organization, development, genetic disorders, cancer, and human evolution.
- The term structural variant (SV) generally refers to a genomic alteration that is larger or structurally more complex than a single-nucleotide change or small insertion or deletion. The precise size thresholds used to distinguish structural variants from smaller variants can vary between research studies and sequencing technologies. Modern genomics increasingly recognizes a continuum between small indels and larger structural changes rather than a completely rigid boundary.
- A deletion occurs when a segment of DNA is lost from the genome. Deletions can range from relatively small sequences to large chromosomal regions containing one or multiple genes. The biological effect depends on the size and location of the deleted region. Loss of an important gene or regulatory element can reduce gene function, while larger deletions can alter the dosage of multiple genes simultaneously.
- A duplication occurs when a DNA segment is present in additional copies. Duplications can increase the dosage of genes located within the duplicated region and may therefore alter the amount of RNA or protein produced. Some duplications involve relatively small DNA segments, whereas larger duplications can affect substantial portions of chromosomes.
- Copy number variations (CNVs) are genomic regions in which individuals differ in the number of copies of a particular DNA segment. Deletions and duplications are major mechanisms responsible for CNVs. Some CNVs are common and contribute to normal genetic diversity, while others can influence susceptibility to disease or directly contribute to genetic disorders.
- An inversion occurs when a segment of DNA is removed, reversed in orientation, and reinserted into the genome. If the inversion does not disrupt an important gene or regulatory region, it may have limited effects. However, an inversion can interrupt a gene, alter regulatory interactions, or affect chromosome pairing and recombination.
- A translocation occurs when a DNA segment becomes associated with a different chromosomal location. In reciprocal translocations, segments of two chromosomes exchange positions. Other rearrangements can involve movement of a DNA segment to a new location without a corresponding reciprocal exchange. Translocations can be harmless in some individuals but can also disrupt genes or alter gene regulation.
- Some structural variants involve insertions, in which DNA is added at a genomic location. The inserted sequence may originate from another region of the same genome or from mobile genetic elements. Depending on where the insertion occurs, it can disrupt a coding sequence, alter regulatory activity, or change chromosome structure.
- Structural variants can also produce more complex rearrangements. These may involve multiple breakpoints, combinations of deletions and duplications, or rearrangement of several genomic segments. Such complex structural changes can be particularly challenging to detect and interpret using conventional sequencing approaches.
- Structural variants can arise through several molecular mechanisms. DNA double-strand breaks followed by inaccurate repair can generate deletions, inversions, and translocations. Errors during DNA replication can also produce duplications or other rearrangements. Recombination between similar or repetitive DNA sequences can cause segments of the genome to be incorrectly exchanged or rearranged.
- Non-allelic homologous recombination (NAHR) is one mechanism that can produce recurrent genomic rearrangements. Similar DNA sequences located at different positions can incorrectly align during recombination, resulting in deletion, duplication, or other structural changes. Repetitive elements throughout the genome can therefore contribute to genomic instability and structural variation.
- Another mechanism is non-homologous end joining (NHEJ), a DNA repair process that joins broken DNA ends without requiring long stretches of sequence similarity. Although NHEJ is an important mechanism for repairing DNA double-strand breaks, inaccurate repair can sometimes generate structural changes. Other repair mechanisms, including microhomology-mediated processes, can also contribute to genomic rearrangements.
- Structural variants may occur in germline cells, allowing them to be inherited, or in somatic cells during an individual’s lifetime. Germline structural variants can contribute to inherited genetic disorders and normal human genetic diversity. Somatic structural variants are particularly important in cancer genetics, where chromosome rearrangements can alter genes involved in cell growth, DNA repair, and cellular signaling.
- Structural variants can affect genes through several mechanisms. A rearrangement may directly disrupt the coding sequence of a gene, remove part of a gene, duplicate it, or change its orientation. Alternatively, the structural change may move a gene away from its normal regulatory environment or place it near a different enhancer or other regulatory element. These effects demonstrate the close relationship between genomic structure and gene regulation.
- Gene dosage is another important mechanism. Deletions can reduce the number of functional copies of a gene, whereas duplications can increase gene dosage. Changes in gene dosage can affect the amount of protein produced and may contribute to disease when precise levels of gene expression are required for normal cellular function.
- Structural variants can also alter three-dimensional genome organization. DNA is arranged within the nucleus into spatial structures that influence interactions between genes and regulatory elements. Large genomic rearrangements may modify these interactions and change gene expression without directly altering the protein-coding sequence of a gene.
- Structural variants play an important role in genetic disorders. Large deletions or duplications can affect multiple genes and produce recognizable clinical syndromes. Other structural changes may disrupt a single gene or alter its regulatory environment. The effects can therefore range from relatively subtle differences to major developmental or physiological abnormalities.
- Structural variants are also common and important in cancer genomes. Somatic deletions, amplifications, inversions, and translocations can alter genes involved in cell proliferation, apoptosis, genome maintenance, and signaling. Some chromosome rearrangements can produce abnormal gene combinations or change regulatory control of genes, contributing to the molecular development of cancer.
- The identification of structural variants is an important component of modern genomic medicine. Traditional cytogenetic methods such as karyotyping can identify relatively large chromosome abnormalities. Chromosomal microarray analysis can detect many copy-number changes but generally does not identify every type of balanced rearrangement. More recently, sequencing technologies have expanded the ability to identify structural variation at increasingly detailed resolution.
- Whole-genome sequencing (WGS) can provide information about many types of structural variants because it examines the entire genomic sequence. Paired-end sequencing, read-depth analysis, split-read analysis, and other computational approaches can provide evidence for deletions, duplications, inversions, and rearrangements. However, some complex structural variants remain difficult to resolve using short-read sequencing.
- Long-read sequencing has become increasingly important for structural-variant analysis. Longer DNA reads can span repetitive regions and complex rearrangements that may be difficult to characterize using short reads. Long-read technologies can therefore improve the detection and resolution of certain structural variants and contribute to more complete characterization of individual genomes.
- Structural-variant interpretation requires consideration of the genomic region affected, the size of the rearrangement, genes and regulatory elements involved, inheritance pattern, population frequency, and available functional or clinical evidence. A structural variant is not automatically pathogenic simply because it changes DNA structure. Many structural variants occur naturally and contribute to normal genetic diversity.
- Structural variants also contribute to human evolution and population genetics. Differences in gene copy number, genomic organization, and repetitive DNA can distinguish populations and individuals. Some structural changes may influence adaptation or biological traits, while many have little observable effect. Studying structural variation therefore provides an important complement to research focused on single-nucleotide variants.
- Structural variants can interact with other forms of genetic variation. A large deletion may contain multiple smaller variants, while a duplication can create additional copies that accumulate further mutations over time. Structural rearrangements can also modify the effects of regulatory variants, splice-site variants, or coding mutations. This illustrates why genomic variation is best understood as an interconnected system rather than as isolated mutation categories.
- Structural variants are increasingly relevant to precision medicine. Identifying a genomic rearrangement can sometimes clarify the molecular cause of a genetic disorder or provide information relevant to cancer classification. Structural-variant analysis may also help researchers identify therapeutic targets and understand why particular tumors or inherited conditions have specific molecular characteristics.
- In summary, structural variants are genomic changes that alter the organization, copy number, orientation, or location of DNA segments. Major categories include deletions, duplications, inversions, translocations, insertions, and complex rearrangements. They can arise through DNA replication errors, recombination, double-strand breaks, and DNA-repair mechanisms. Structural variants may be inherited, occur de novo, or arise somatically, and they can influence gene dosage, gene regulation, chromosome organization, genetic disorders, cancer, evolution, and human genetic diversity.
