Structural variation in the human genome is operationally defined as genomic alterations, varying between individuals, that involve DNA segments larger than 1 kilo base (kb), and could be either microscopic or submicroscopic. This definition distinguishes them from smaller variants that are less than 1 kb in size such as short deletions, insertions, and single nucleotide variants. Humans have an incredibly complex and intricate genome that has been shaped and modified over time by evolution. About 99.9% of the DNA-sequence in the human genome is conserved between individuals from all over the world, but some variation does exist. Single nucleotide polymorphisms (SNPs) are considered to be the largest contributor to genetic variation in humans since they are so abundant and easily detectable. It is estimated that there are at least 10 million SNPs within the human population but there are also many other types of genetic variants and they occur at dramatically different scales. The variation between genomes in the human population range from single nucleotide polymorphisms to dramatic alterations in the human karyotype. Human genetic variation is responsible for the phenotypic differences between individuals in the human population. There are different types of genetic variation and it is studied extensively in order to better understand its significance. These studies lead to discoveries associating genetic variants to certain phenotypes as well as their implications in disease. At first, before DNA sequencing technologies, variation was studied and observed exclusively at a microscopic scale. At this scale, the only observations made were differences in chromosome number and chromosome structure. These variants that are about 3 Mb or larger in size are considered microscopic structural variants. This scale is large enough to be visualized using a microscope and include aneuploidies, heteromorphisms, and chromosomal rearrangements. When DNA sequencing was introduced, it opened the door to finding smaller and incredibly more sequence variations including SNPs and minisatellites. This also includes small inversions, duplications, insertions, and deletions that are under 1 kb in size. In the human genome project the human genome was successfully sequenced, which provided a reference human genome for comparison of genetic variation. With improving sequencing technologies and the reference genome, more and more variations were found of several different sizes that were larger than 1 kb but smaller than microscopic variants. These variants ranging from about 1 Kb to 3 Mb in size are considered submicroscopic structural variants. These recently discovered structural variants are thought to play a very significant role in phenotypic diversity and disease susceptibility.
Types of structural variants Structural variation is an important type of human genetic variation that contributes to phenotypic diversity. There are microscopic and submicroscopic structural variants which include deletions, duplications, and large copy number variants as well as insertions, inversions, and translocations. These are several different types of structural variants in the human genome and they are quite distinctive from each other. A translocation is a chromosomal rearrangement, at the inter- or intra-chromosomal level, where a section of a chromosome changes position but with no change in the whole DNA content. A section of DNA that is larger than 1 kb and occurs in two or more copies per haploid genome, in which the different copies share greater than 90% of the same sequence, are considered to be segmental duplications or low-copy repeats. These are only a few of the several different types of structural variants that have been known to exist in the human genome. A table visualizing these different forms of structural variants, as well as others, is shown in Figure 1. An inversion is a section of DNA on a chromosome that is reversed in its orientation in comparison to the reference genome. There have been many studies identifying inversions because they have been found to have a big role in many diseases. A study found that forty percent of haemophilia A patients had a factor 8 gene inversion of a certain region that was four hundred kb in size. The inversion breakpoint was found to be around a segmental duplication which is observed in many other inversion events. It is difficult to completely understand how each structural variant is created. It was previously known that repeated sequences on a chromosome increases the probability of non allelic homologous recombination. These repeated sequences could cause deletions, duplications, inversions, and inverted duplication chromosomes. The products of this mechanism from the sequence repeats is depicted in Figure 2. A study was done on the olfactory receptor gene clusters where they questioned if there was an association between normal rearrangement of 8p and the repeated inverted sequences. The researchers observed that the rearrangement of chromosomes was actually caused by the homologous recombination in the 8p-reps. Therefore, they concluded that the substrate used in order to make rearrangements at the intrachromosomal level are the genes for olfactory receptors. This discovery revealed the role that inverted duplicates have in affecting the development of structural variants. The mechanisms and ways in which structural variants are produced are important to better understand the development of these types of genetic variants.
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