DNA copy number variation: Main characteristics, evolutionary significance, and pathological aspects

Abstract

Copy number variants (CNVs) were the subject of extensive research in the past years. They are common features of the human genome that play an important role in evolution, contribute to population diversity, development of certain diseases, and influence host-microbiome interactions. CNVs have found application in the molecular diagnosis of many diseases and in non-invasive prenatal care, but their full potential is only emerging. CNVs are expected to have a tremendous impact on screening, diagnosis, prognosis, and monitoring of several disorders, including cancer and cardiovascular disease. Here, we comprehensively review basic definitions of the term CNV, outline mechanisms and factors involved in CNV formation, and discuss their evolutionary and pathological aspects. We suggest a need for better defined distinguishing criteria and boundaries between known types of CNVs.

Keywords: CNV formation; Copy number variants; Evolution; Genetic diseases; Human genome; Structural variation.

Fig. 1

Publication records. PubMed search for the term “copy number variation” as of July 24, 2020. Limiting results to the year 2004 reduced the number of entries considerably. Excluded entries are highlighted in grey; (A) no filter applied; (B) applying a built-in species-specific filter for “humans”.

Fig. 2

Timeline of CNV research. It includes research milestones (orange) in the context of evolving methods for the assessment of CNVs (green) and the minimal length of variants to be considered as CNVs at a given time (blue). Main trends of CNV research are visible, e.g., the relatively wide time-frame following the first descriptions of large CNVs around the beginning of the 20th century. This nearly century-long phase was mainly about the development of methods, which finally allowed genome-wide, high-resolution CNV detection around the beginning of the 21st century, leading to the recognition of common features of CNVs and a subsequent shift in their definition, allowing shorter and shorter variants to be considered CNVs.

Fig. 3

Recurrent vs. non-recurrent rearrangements. Recurrent CNVs have the same size and common breakpoints enriched in low-copy repeats (LCRs). Non-recurrent CNVs with different sizes may share the smallest region of overlap (SRO). CNVs may occur as inherited or de novo events. Inherited CNVs are not recurrent events but always share the same breakpoints, resulting in a similar phenotypic effect. De novo CNVs are independently arising events that may have recurrent or distinct (non-recurrent) breakpoints. Even CNVs with non-recurrent breakpoints may show overlapping effects, as they disrupt the same SRO.