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Position effect variegation (PEV) is a phenomenon wherein the expression level of a gene strongly depends on its genomic position. PEV can be observed when a gene is moved via a chromosome rearrangement or identical genetic constructs are inserted into different regions of the genome. The eukaryotic genome has a domain organization, and gene activity within a domain depends not only on the nucleotide sequence of a gene, but also on the state of surrounding chromatin, thus being regulated epigenetically. Chromatin is a complex of DNA, RNA, and associated structural and regulatory proteins. The epigenetic status of chromatin depends on the replication time of a given genomic region, particular regulatory DNA motifs, and contacts with the inner nuclear envelope (lamina) and other chromosome regions (topologically associated domains). PEV results from the changes in the epigenetic state of a gene and provides a unique tool to study the molecular and biochemical processes that underlie the establishment and switching of epigenetic states. Understanding the molecular mechanisms of PEV in human is of clinical importance, in particular, for the detection and treatment of retroviral infections because the local chromatin state may determine the latent/active state transition of an infection, such as HIV. In addition, a large number of human neurodegenerative diseases are caused by epigenetic gene inactivation due to expansion of short repeats. Finally, to apply gene therapy methods, it is important to develop approaches that ensure a necessary level of transgene expression with sufficient accuracy.