The human genome exhibits remarkable variation among individuals. While much attention often goes to small-scale genetic differences, larger alterations in DNA, known as structural variants, also play a significant role. These extensive changes involve large segments of DNA. Understanding these variations is important for comprehending human health and diversity.
Understanding Structural Variants
Structural variants (SVs) are differences in DNA sequences between individuals that involve large segments of DNA, typically 50 base pairs or larger. These variations are not merely single letter changes but significant rearrangements of DNA chunks, ranging from hundreds of base pairs to over a million.
Structural variants include several main categories of DNA rearrangement:
Deletions occur when a segment of DNA is missing from a chromosome.
Duplications involve the presence of extra copies of a DNA segment.
Inversions happen when a segment of DNA is flipped 180 degrees, reversing its normal orientation within the chromosome.
Translocations involve the movement of a DNA segment from one location to another, either within the same chromosome or between different chromosomes.
Insertions refer to the addition of new genetic material into the genome.
SVs differ from smaller genetic variations like single nucleotide polymorphisms (SNPs) and small insertions or deletions (indels), which involve only one or a few base pairs. Though less common than SNPs, SVs account for a greater amount of nucleotide sequence difference between individuals due to their substantial size, impacting gene function and genomic architecture.
Impact of Structural Variants on Health
Structural variants contribute to a wide range of human health conditions, from developmental disorders to certain cancers. These large-scale genomic changes can disrupt normal biological processes, leading to disease.
One primary mechanism by which SVs cause disease is by altering gene dosage, the number of copies of a particular gene. For example, a deletion might remove a gene entirely, leading to loss of function, while a duplication could result in an excess of gene product. Changes in gene dosage are implicated in developmental disorders and intellectual disabilities.
SVs can also disrupt gene sequences directly or alter their regulation. An insertion or deletion within a gene’s coding region can lead to a non-functional protein or no protein. Similarly, SVs can reposition genes relative to regulatory elements, such as enhancers, leading to inappropriate gene expression—either too much or too little of a particular protein.
In cancer, structural variants often lead to complex genomic rearrangements. A well-known example is the Philadelphia chromosome, a translocation between chromosome 9 and chromosome 22, which creates the BCR-ABL fusion gene. This fusion gene produces an overactive protein that drives uncontrolled cell growth in chronic myeloid leukemia. Other examples include deletions of tumor suppressor genes like TP53 or amplifications of oncogenes such as HER2 in breast cancer. SVs have also been linked to neurological conditions, including autism spectrum disorder, schizophrenia, and intellectual disability, with specific deletions or duplications, such as the 16p11.2 deletion.
Detecting Structural Variants
Identifying structural variants poses unique challenges compared to detecting smaller genetic changes due to their size and complexity. Historically, scientists relied on cytogenetic techniques to visualize large chromosomal rearrangements. Karyotyping involves examining an individual’s complete set of chromosomes under a microscope to detect large-scale changes in chromosome number or structure, typically those 3 megabases or larger. Fluorescence in situ hybridization (FISH) offers higher resolution, using fluorescent probes to bind to specific DNA sequences, allowing researchers to visualize the presence or absence of particular DNA segments or their rearrangements. Chromosomal microarray (CMA) can detect copy number variations, such as deletions or duplications, as small as 20-50 kilobases, by comparing a patient’s DNA to a reference.
High-throughput sequencing technologies have revolutionized SV detection. Next-generation sequencing (NGS) platforms generate millions of short DNA reads, typically tens to hundreds of base pairs long. By aligning these reads to a reference genome, scientists can infer SVs through various signatures, such as abnormal read depth, discordant read pairs (reads mapping unexpectedly far apart or in unusual orientations), or split reads that span a breakpoint. However, short-read sequencing can struggle with highly repetitive genomic regions, where many SVs are located.
Long-read sequencing technologies, such as Pacific Biosciences (PacBio) and Oxford Nanopore Technologies, have improved the ability to detect and resolve complex structural variants. These technologies produce much longer DNA reads, often tens of thousands of base pairs or more, which can span repetitive regions and breakpoints that short reads cannot. This increased read length allows for more comprehensive and accurate mapping of SVs, including inversions that are particularly challenging to detect with shorter reads. Despite these advancements, computational challenges remain due to the sheer volume of data and the inherent complexity of SVs, especially in repetitive areas of the genome.
Structural Variants in Human Diversity
Beyond their role in disease, structural variants contribute to human evolution and genetic diversity across populations. SVs are widespread in the human population and are important substrates for evolution and adaptation.
SVs influence traits and adaptation by altering gene function or regulation, which can provide a selective advantage in specific environments. For instance, some SVs that affect early developmental and neurological traits are older mutations, often fixed within human populations, suggesting their role in the core evolutionary events that distinguish humans from other great apes. These variants might have contributed to the expansion of the human neocortex, a feature unique to humans.
More recent structural variants reflect human migration patterns and adaptation to diverse environments. SVs that shape immune and metabolic traits, for example, are often more recent and may have arisen as human ancestors spread, adapting to different climates, food sources, and pathogens. This genetic adaptation allows populations to thrive in varied habitats.
Studying structural variants provides insights into human origins and the movements of populations. By comparing the SV profiles of different groups, researchers can reconstruct ancestral relationships and track how populations have diversified. Understanding the distribution and types of structural variants across human populations helps explain observed phenotypic differences and sheds light on the genetic underpinnings of human variation and resilience.