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Seemingly small but big: How do microstructural variations affect our genes?
In the field of genetic research, microstructural variation (SV) is an important factor affecting genome stability and function. Although these structural variations can be considered "minor" to a certain extent, their potential impact on the human genome and disease cannot be underestimated. The scope of structural variation not only covers different forms such as gene deletion, duplication, copy number variation (CNV), insertion, inversion and translocation, but is also closely related to a series of genetic diseases. As research deepens, scientists have begun to realize that these seemingly small variations can actually significantly affect our health and genetic risks.
About 13% of the human genome is identified as structurally variant in normal populations, and no fewer than 240 genes exist in the form of homotypic deletions in different populations, which means that these genes are not essential in the human body.
Types and effects of microstructural variations
Microstructural variations can be divided into microscopic variations and submicroscopic variations. Microscopic variations refer to structural variations that can be detected by light microscopy, including aneuploidy, marker chromosomes, and large-scale rearrangements. Although the frequency of these variants appears to be low in the general population, about one in every 375 live births, research shows that the actual incidence may be underestimated because impactful structural variants are not easy to identify.
In contrast, submicroscopic structural variations are more subtle and difficult to detect. Research exploring these tiny variations began in 2004, and with advances in whole-genome sequencing technology, by 2015, scientists were able to detect structural variations as small as 100 base pairs. These variants often include deletions, duplications, and insertions, and their mutation rates are much higher than microscopic variants, which may cause further single nucleotide variations or indels within a specific range of the genome.
Spontaneous structural variations (de novo) disrupt genes almost four times more frequently in autism, research suggests, which may explain their impact on some genetic disorders.
The broad impact of copy number variation
Copy number variations (CNVs) are an important category of structural variations involving insertions, deletions, and duplications in the genome. The latest research found that about 28% of suspected regions actually contain CNVs in individuals without genetic diseases, and these variations not only affect the number of copies, but also involve many non-coding regions. Since copy number variation is often caused by unbalanced recombination, similar sequences such as LINE and SINE may be a common mechanism causing CNV.
Reversal and its correlation
There are several known inversions associated with human disease. For example, a 400-kb inversion in the factor VIII gene is often the primary cause of hemophilia A, while smaller inversions can also cause Hunter syndrome. However, new research suggests that each person may have as many as 56 hypothetical reversals, making the number of non-disease-related reversals far higher than expected. In addition, the study points out that inversion breakpoints are often closely associated with segmental duplications, suggesting that certain inversions with selective advantages may be increasingly common in European populations.
Correlation between structural variation and phenotype
Although some genetic diseases are suspected to be caused by structural variations, the relationship is not clear. Some studies have shown that specific structural variants can lead to different phenotypic outcomes in different individuals, which means that it is unrealistic to simply classify these variants into "normal" or "disease" categories. Indeed, some variants may be subject to positive selection. Specifically, spontaneous CNVs disrupt genes four times more frequently in autism than in controls, making structural variation an important role in studying human inheritance.
These genetic markers derived from structural variations can be used to infer the relationship between populations in different regions and further reveal the future evolutionary trends of humans.
Progress in detection technology
With the development of new technologies, the detection of structural variations in human genes has reached high resolution. Current detection methods can be divided into two categories: structurally specific tests and whole-genome scans. Commonly used technologies for whole-genome scanning include array comparative genomic hybridization, which can effectively identify CNVs by detecting copy number differences by hybridizing DNA fragments from a specific genome and a reference genome. In addition, with the development of next-generation sequencing technology, a variety of methods for detecting structural variations have emerged, which is critical to revealing the diversity and complexity of structural variations.
Although microstructural variations are numerous and widespread, their impact on our genetic characteristics and health remains a huge and incompletely solved puzzle. With the advancement of science and technology, how can we understand the profound impact of these small variations on the human genome and its descendants?
