Inimese DNA koopiaarvu variatsioonid: nende tekkemehhanismid ja ...

Human copy number variations: mechanisms of formation and methods of
detection.
Olga Tšuiko
Summary
During the recent years our knowledge regarding to human copy number variants has greatly
increased due to completion of Human Genome Sequencing project and establishing of
HapMap project. Nowadays, numerous databases for describing CNV-s have been created,
according to which, it is now clear that CNV distribution among human genome is rather
wide and a major part of CNV-s might be involved in the development of an abnormal
phenotype. CNV-s were shown to cause sporadic diseases and mendelian or complex traits,
by affecting gene dosage, disruption of the gene or by causing the positional effect. The use of
microarrays has made it possible to establish that in about of 10-20% of clinical cases, the
reason for developmental delay lies in the submicroscopic DNA aberrations. Despite the fact,
that SNP-s are considered to be the main factor in the determination of human variability, it
was proposed that CNV-s are responsible for most of genetic and phenotypic variation.
Thanks to accelerated development of methods for studying copy number changes, three main
mechanisms were proposed for the formation of CNV-s: recombination-based Non-Allelic
Homologous Recombination and Non-Homologous End Joining, and a relatively new
replication-based mechanism – Fork Stalling and Template Switching/Microhomology
Mediated Break Induced Replication. Detailed CNV maps offer a great deal of interest for
researches involved in the study of evolution as well. It is thought that CNV may be a leading
force in the human evolution via gene duplication and exon shuffling. However, a lot of CNV
regions are yet to be discovered, especially those that cover only a couple of dozens of base
pairs. Thus, further studies in the improving of methods of CNV detection and increasing
resolution may give an opportunity to examine CNV mechanisms of formation in greater
detail and to give the picture of how genomic rearrangements affect genes and their regulatory
elements. Understanding of the molecular basis for CNV formation will provide the
opportunity to find more regions, susceptible to genomic rearrangements, thus being a very
promising tool in clinical molecular diagnostic development and proper assessment of
medical methods.
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