The variome concept: focus on CNVariome

Abstract

BackgroundVariome may be used for designating complex system of interplay between genomic variations specific for an individual or a disease. Despite the recognized complexity of genomic basis for phenotypic traits and diseases, studies of genetic causes of a disease are usually dedicated to the identification of single causative genomic changes (mutations). When such an artificially simplified model is employed, genomic basis of phenotypic outcomes remains elusive in the overwhelming majority of human diseases. Moreover, it is repeatedly demonstrated that multiple genomic changes within an individual genome are likely to underlie the phenome. Probably the best example of cumulative effect of variome on the phenotype is CNV (copy number variation) burden. Accordingly, we have proposed a variome concept based on CNV studies providing the evidence for the existence of a CNVariome (the set of CNV affecting an individual genome), a target for genomic analyses useful for unraveling genetic mechanisms of diseases and phenotypic traits.ConclusionVariome (CNVariome) concept suggests that a genomic milieu is determined by the whole set of genomic variations (CNV) within an individual genome. The genomic milieu is likely to result from interplay between these variations. Furthermore, such kind of variome may be either individual or disease-specific. Additionally, such variome may be pathway-specific. The latter is able to affect molecular/cellular pathways of genome stability maintenance leading to occurrence of genomic/chromosome instability and/or somatic mosaicism resulting in somatic variome. This variome type seems to be important for unraveling disease mechanisms, as well. Finally, it appears that bioinformatic analysis of both individual and somatic variomes in the context of diseases- and pathway-specific variomes is the most promising way to determine genomic basis of the phenome and to unravel disease mechanisms for the management and treatment of currently incurable diseases.

A map of copy number variations in the Tunisian population: a valuable tool for medical genomics in North Africa

“…All these findings emphasize the importance of decoding this type of variation to decipher the required part of the genome for normal human development due to the gene function loss [83][84][85][86] . Our study is the first step in building a Tunisian-specific structural variation database, thus paving the way to assess the burden of rare and common CNV of the Tunisian "CNVariome" in a much larger cohort 87 .…”

The Cytogenomic “Theory of Everything”: Chromohelkosis May Underlie Chromosomal Instability and Mosaicism in Disease and Aging

“…As described previously, such kind of susceptibility may be a result of alterations to molecular and cellular pathways safeguarding genome stability [12,23,24]. Recently, a model for pathway-based classification of genomic burden (CNV burden) resulting in CIN/GIN and SCM was proposed [25]. Using this model and a novel bioinformatic method for pathway-based CNV/gene prioritization [26], we evaluated CNV burden effect on pathways required for genome stability maintenance (e.g.…”

“…Pathway analysis was performed using CNVariome concept and data laundering protocol, which were recently described in details [25,26]. The enrichment by genome stability maintenance pathways was additionally analyzed using statistical Z-test.…”

Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome

“…These underlying genetic alterations may be of different types, and the better known are those associated to dominant point mutations. However, the genetic heterogeneity of complex neurological diseases such as cerebral palsy [4], epilepsy [5], and autism [6,7] has already been associated to a combination of several different pathogenic gene variants, and to several CNVs in affected individuals, and the combination of CNV changes contributes to the individual variome [8,9].…”