text: Copy number variation was initially thought to occupy an extremely small and negligible portion of the genome through cytogenetic observations. Copy number variations were generally associated only with small tandem repeats or specific genetic disorders, therefore, copy number variations were initially only examined in terms of specific loci. However, technological developments led to an increasing number of highly accurate ways of identifying and studying copy number variations. Copy number variations were originally studied by cytogenetic techniques, which are techniques that allow one to observe the physical structure of the chromosome. One of these techniques is fluorescent in situ hybridization (FISH) which involves inserting fluorescent probes that require a high degree of complementarity in the genome for binding. Comparative genomic hybridization was also commonly used to detect copy number variations by fluorophore visualization and then comparing the length of the chromosomes. One major drawback of these early techniques is that the genomic resolution is relatively low and only large repeats such as whole gene repeats can be detected.
  Recent advances in genomics technologies gave rise to many important methods that are of extremely high genomic resolution and as a result, an increasing number of copy number variations in the genome have been reported. Initially these advances involved using bacterial artificial chromosome (BAC) array with around 1 megabase of intervals throughout the entire gene, BACs can also detect copy number variations in rearrangement hotspots allowing for the detection of 119 novel copy number variations. High throughput genomic sequencing has revolutionized the field of human genomics and in silico studies have been performed to detect copy number variations in the genome. Reference sequences have been compared to other sequences of interest using fosmids by strictly controlling the fosmid clones to be 40kb. Sequencing end reads would provide adequate information to align the reference sequence to the sequence of interest, and any misalignments are easily noticeable thus concluded to be copy number variations within that region of the clone. This type of detection technique offers a high genomic resolution and precise location of the repeat in the genome, and it can also detect other types of structural variation such as inversions.
  In addition, another way of detecting copy number variation is using single nucleotide polymorphisms (SNPs). Due to the abundance of the human SNP data, the direction of detecting copy number variation has changed to utilize these SNPs. Relying on the fact that human recombination is relatively rare and that many recombination events occur in specific regions of the genome known as recombination hotspots, linkage disequilibrium can be used to identify copy number variations. Efforts have been made in associating copy number variations with specific haplotype SNPs by analyzing the linkage disequilibrium, using these associations, one is able to recognize copy number variations in the genome using SNPs as markers. Next-generation sequencing techniques including short and long read sequencing are nowadays increasingly used and have begun to replace array-based techniques to detect copy number variations. In contrast to array-based techniques, sequencing-based detection methods readily identify other classes of structural variation such as inversions and translocations.