Question

What is copy number variation? What is the immediate consequence at the molecular level of an increase in copy number of a gene? Under what circumstances might this have a deleterious effect?

Answer 1

Copy number is defined as total number of a gene present in the genotype of an individual. Copy number variation (CNV) is studied in terms of a population. Polymorphism in the number of copies of a gene in a population corresponds to the copy number variation. It varies both evolutionarily and physiologically creating changes in the phenotype. Somatic CNV can be generated through Non homologous end joining, non homologous recombination, defects in DNA replication and repair. Soamtic CNs can be found in human skin and hepatocytes. CNVs can have a large impact on the transcriptome. Concentrations of RNA of enzymes involved in nutrient uptale in humans has been significantly affected due to CNV. Human genome has around 6 billion nucleotides which is packed into double set of 23 chromosomes, one set inherited by each parent. It was earlier thought that gene can be present only in 2 copies but now it has been established that segments of DNA of 1 kb or more can vary in their number, which is called copy number variation and it can lead to gene dosage imbalance offers changes in gene expression and ultimately genetic disease. Indels are insertions or deletions of a fragment of genome with respect of one another and these can cause frameshift mutations. Deletion can be homo or heterozygous. Insertion can be dispersed or tandem in the genome. Deletions can lead to lower expression of genes than normal and also it can unmask a recessive allele which was previously not expressed. Variations if found in the gene regulatory region then it would again lower the expression of a gene, if it a deletion and gene expression would be increased if duplicated. CNVs comprises of atleast three times the number of Single Nucleotide Polymorphism (SNPs) hence it is important to undertake the study of CNV and its mechanism of formation. It can help us hunting the genes down for various genetic diseases. It can be helpful tool to identify the genetic familial condition. It can let us know the target region which is involved in causing chromosomal aberrations leading to developmental defects. A study showed that around 12% of human genome is copy number variable in sample of 270 DNAs (Redon et al., 2006). Till date there around 2000 CNVs. Most of the CNVs are found to be benign having no effect but some of them have srious effectson the developmental genes hence causing disease. Diseases like Alzheimer's and Parkinson's, Prader-Willi, Velocardiofacial and Smith-Magenis syndromes are known to be due to CNV. Also, in breat cancer, there is overexpression of ERBB2 gene. According to scientists genes involved in developmental stage and brain activity and function are found to have CNV. CNV includes structural variations where a region of DNA can either be deleted or duplicated. So genetic makeup of the parents are required in order to assert whether the variation is inherited or is de novo. Errors during mitosis or meiosis can kead to deletion or duplication, which was earlier studied through microscope and now through sequencing. Most common type of CNV is trinucleotide repeats (TNRs). CNV can make a network switch change its gene expression equilibrium and lead to diseases. CNV is not deleterious always, as overexpression of CCL3L1, a chemokine suppresses HIV.