The human genome is incredibly diverse and each individual’s genome includes a number of repetitive elements. A specific type of repetitive sequence is copy number variation (CNV). CNV was defined in 2006 by Redon et al. in the journal Nature as the presence of variable numbers of repetitions of a portion of DNA larger than 1 kb (i.e. 1000 nucleotide bases) compared to a reference genome, but the common definition encompasses even larger swaths of DNA. The Wellcome Trust Sanger Institute, which heads up the Copy Number Variation Project, defines CNV as variable numbers of repetitions of 10 kb (10,000 base pairs) to 5000 kb (5 million base pairs) sequences. These longer genomic changes are sometimes referred to as microduplications.
These large portions of DNA likely harbor genes. Genes normally exist in two copies, one on each chromosome, but the number of gene copies present can actually vary due to CNV. The addition or removal of a copy of a gene can result in altered protein expression or missing protein expression. Most often, though, these repetitive sequences have no influence on the phenotype. Approximately 12 percent of the human genome is copy number variable based on the CNV Map, but only 2000 CNVs have been identified. Each genome in the CNV mapping project had approximately 100 copy number variations. They are cataloged in the Database of Genomic Variants.
De novo copy number variation is a form of this repetitive element that is not inherited from one’s parents. The variation in DNA elements occurs during meiosis or early embryogenesis. Various processes involved in replicating and splitting chromosomes during gamete formation (meiosis) result in creating genetic diversity, such as crossing over, and can cause portions of the chromosome to be deleted or copied. Similar changes can occur during mitosis of the early cells of the zygote and blastocyst after fertilization. Such changes in the DNA have been associated with human disease, including schizophrenia and autism. They can occur on any of the chromosomes, including the sex chromosomes. Angelman Syndrome has been associated with a number of de novo CNVs on the X chromosome. However, many healthy individuals carry copy number variants in their chromosomes and don’t even know it because they cause no signs, symptoms or abnormalities.
Non-inherited genetic diseases like the changes in phenotype caused by some de novo CNVs are also referred to as sporadic. The rate of de novo CNV has been estimated as 0.5 to 3 percent, a lower rate than point mutations (also known as single nucleotide polymorphisms, or SNPs). However, CNV affects larger areas of the chromosome and can potentially cause more problems despite their low numbers, including neuropsychiatric diseases as noted above. De novo CNV can be passed to offspring, becoming inherited copy number variants.
CNV is turning out to be more common than once thought and often goes unnoticed, but it may be part of the underlying causes of some diseases. Though de novo copy number variation arises new in the organism who’s genome it affects, CNV has been speculated to play a role in evolution as the de novo sequences eventually get passed on to offspring. This natural process of creating repetitive genetic elements originates from the genetic machinery and is still not quite understood.