The variome concept: focus on CNVariome

Abstract

Background: Variome 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.

Conclusion: Variome (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.

Keywords: Copy number variations; Genome variations; Pathways; Somatic mosaicism; Variome.

Fig. 1

Schematic representation of the variome (CNVariome) concept; a set of genomic variations (e.g. CNV) may contribute to functional variability of molecular/cellular pathways or create several V_ps symbolically depicted as colored laboratory tubes; when the number of genomic variations achieves a critical level (i.e. saturation in genomic variations), an alteration to the pathway occurs (e.g. left-most and right-most tubes). A screenshot of CNV analysis by Chromosome Analysis Suite (ChAS) 3.10.15© 2015 Affymetrix Inc. was used to depict individual variome (CNVariome)

Fig. 2

Interplay between V_i and V_s; CNVariome and sequence variome forming V_i may alter pathways critical for maintaining genome stability, cell cycle, and/or programmed cell death; the result of such alterations is likely to be a susceptibility for specific V_s, which encompass somatic mosacism as well as chromosome and genome instability