11- Drug discovery
- Prediction of adverse effects of drugs
- Prediction of drug effi cacy
Copy Number Variations in the Human Genome
Copy number variation (CNV) refers to variation from one person to another in the
number of copies of a particular gene or DNA sequence (usually exceeding
1,000 bp). CNV is a source of genetic diversity in humans. Numerous CNVs are
being identifi ed with various genome analysis platforms, including array compara-
tive genomic hybridization (aCGH), SNP genotyping platforms, and next- generation
sequencing (NGS). CNV formation occurs by both recombination-based and
replication- based mechanisms and de novo locus-specifi c mutation rates appear
much higher for CNVs than for SNPs. CNVs can cause Mendelian or sporadic
traits, or be associated with complex diseases by various molecular mechanisms,
including gene dosage, gene disruption, gene fusion, position effects, etc. However,
CNV can also represent benign polymorphic variants. CNVs, especially gene dupli-
cation and exon shuffl ing, can be a predominant mechanism driving gene and
genome evolution. CNVs form at a faster rate than other types of mutation, and
seem to do so by similar mechanisms in bacteria, yeast and humans. A review of
some models of the mechanisms that cause CNV reveals that although non-
homologous end-joining mechanisms are well known, the focus is on perturbation
of DNA replication and replication of non-contiguous DNA segments, e.g. cellular
stress might induce repair of broken replication forks to switch from high-fi delity
homologous recombination to non-homologous repair, thus promoting CNV
(Hastings et al. 2009 ).
CNV of DNA sequences is functionally signifi cant but has yet to be fully ascer-
tained. An international team of investigators has published a study showing that
~12 % of human genes vary in the CNV of DNA sequences they contain – a fi nding
that contradicts the statement that the DNA of any two humans is 99.9 % similar
(Redon et al. 2006 ). The discovery indicates that CNV could play a larger role in
genetic disease than previously thought, with broad implications in disease associa-
tion studies, genetic diagnostic testing, and cancer research. The investigators con-
structed a fi rst-generation CNV map of the human genome through the study of 270
individuals from four populations with ancestry in Europe, Africa or Asia (the
HapMap collection). DNA from these individuals was screened for CNV using two
complementary technologies: SNP genotyping arrays, and clone-based comparative
genomic hybridization (CGH). A total of 1,447 copy number variable regions
(CNVRs), which can encompass overlapping or adjacent gains or losses, covering
360 megabases (12 % of the genome) and 6–19 % of any given chromosome were
identifi ed in these populations. These CNVRs contained hundreds of genes, disease
loci, functional elements and segmental duplications. Notably, the CNVRs encom-
passed more nucleotide content per genome than SNPs, underscoring the impor-
tance of CNV in genetic diversity and evolution. The data obtained delineate linkage
Molecular Biological Basis of Personalized Medicine