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Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability

Nature Reviews Genetics volume 8, pages 639–646 (2007)Cite this article

Abstract

A considerable and unanticipated plasticity of the human genome, manifested as inter-individual copy number variation, has been discovered. These structural changes constitute a major source of inter-individual genetic variation that could explain variable penetrance of inherited (Mendelian and polygenic) diseases and variation in the phenotypic expression of aneuploidies and sporadic traits, and might represent a major factor in the aetiology of complex, multifactorial traits. For these reasons, an effort should be made to discover all common and rare copy number variants (CNVs) in the human population. This will also enable systematic exploration of both SNPs and CNVs in association studies to identify the genomic contributors to the common disorders and complex traits.

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Figure 1: Influence of copy number variations (CNVs) on penetrance and variation in severity of the phenotype.
Figure 2: Possible haplotype configurations in a copy number variation (CNV)-prone chromosomal region.
Figure 3: The genetic and environmental risks combined confer the total risk for a complex phenotype.

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Acknowledgements

We thank all the past and present members of our laboratories and clinics for ideas, debates and discussions. We thank J. Lupski for critical reading of the manuscript. Work in J.S.B.'s laboratory is funded by grants from the SNF (Swiss National Science Foundation) and the University of Lausanne, Switzerland. The laboratory of X.E. is supported by: the Departament d'Educació i Universitats and the Departament de Salut of the Catalan Autonomous Government (Generalitat de Catalunya); the Ministry of Health and the Ministry of Education and Science of the Spanish Government; the European Union Sixth Framework Programme; and Genoma España. S.E.A.'s laboratory is supported by the SNF, European Union, US National Institutes of Health and the Lejeune and ChildCare Foundations (France).

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Authors and Affiliations

  1. Jacques S. Beckmann is at the Department of Medical Genetics, University of Lausanne and Centre Hospitalier Universitaire Vaudois, 2 Avenue Pierre Decker, 1011 Lausanne, Switzerland.,

    Jacques S. Beckmann

  2. Xavier Estivill is at the Genes and Disease Program, Center for Genomic Regulation (CRG), National Genotyping Center (CeGen), CIBERESP and Pompeu Fabra University (UPF), Charles Darwin s/n, PRBB building, E-08003 Barcelona, Catalonia, Spain.,

    Xavier Estivill

  3. Stylianos E. Antonarakis is at the Department of Genetic Medicine and Development, University of Geneva Medical School, and University Hospital of Geneva, 1 rue Michel-Servet, 1211 Geneva, Switzerland.,

    Stylianos E. Antonarakis

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DATABASES

OMIM

Alzheimer disease

atypical haemolytic–uraemic syndrome

BRCA1

BRCA2

hereditary neuropathy with liability to pressure palsies

neurofibromatosis type 1

Parkinson disease

tuberous sclerosis

FURTHER INFORMATION

Centre for Genomic Regulation

Database of Genomic Variants

DECIPHER

International HapMap Project

NCBI Single Nucleotide Polymorphism

OMIM Morbid Map

UCSC Genome Bioinformatics

Glossary

Aneuploidy

Having more or less than the typical chromosome number (46 for humans).

Array comparative genomic hybridization

A technology in which sampled and reference DNA are differentially labelled and hybridized on BAC or oligonucleotide microarrays to show copy number differences between the sampled genomes.

Association study

A population-based genetic study that examines whether a marker allele segregates with a phenotype (such as disease occurrence or a quantitative trait) at a significantly higher rate than would be predicted by chance alone. This is ascertained by genotyping variants in both affected and unaffected or control individuals.

BAC

A DNA construct, derived from a fertility plasmid (or F-plasmid), which usually carries an insert of 100–300 kb. Complete genomic libraries cloned in BACs (or PACs, which are produced from P1-plasmids) have been useful in constructing arrays for array comparative genomic hybridization experiments.

Copy number variant or polymorphism

A structural genomic variant that results in confined copy number changes in a specific chromosomal region. If its population allele frequency is less than 1%, it is referred to as a variant; if its frequency exceeds 1%, the term polymorphism is used.

Duplicon

A duplication, or portion thereof, of genomic sequence that shows a high level of sequence identity (over 90%) to another region of a reference genome. Also sometimes referred to as a low copy repeat or segmental duplication.

Genomic disorder

A disorder that results from the gain, loss or re-orientation of a genomic region that often contains dosage-sensitive gene(s). The result is a genomic rearrangement (such as duplication, deletion and inversion). Segmental duplications are often involved in the rearrangement event through non-allelic homologous recombination.

Haplotype Block

A chromosomal region in which groups of alleles at different genetic loci are inherited together more often than would be expected by chance. Adjacent blocks are separated by recombination hotspots (short regions with high recombination rates).

Hardy–Weinberg equilibrium

The binomial distribution of genotypes in a population, such that frequencies of genotypes AA, Aa and aa will be p2, 2pq and q2, respectively, where p is the frequency of allele A, and q is the frequency of allele a.

High-resolution tiling path CGH arrays

Arrays for comparative genomic hybridization (CGH) that offer a resolution in the order of bases to kilobases. The arrays currently use BACs or long oligonucleotides.

Hypomorphic

Describes an allele that carries a mutation that causes a partial loss of gene function.

Linkage disequilibrium

A measure of whether alleles at two loci coexist within gametes in a population in a nonrandom fashion. Alleles that are in linkage disequilibrium are found together on the same haplotype more often than would be expected by chance.

Microsatellite

A class of repetitive DNA sequences, scattered throughout the genome, that are made up of tandemly organized repeats of 2–8 nucleotides in length. They can be highly polymorphic and are frequently used as molecular markers in population genetics studies.

Minisatellites

Regions of DNA in which repeat units of 7–100 bp are arranged in tandem arrays of 0.5–30 kb long.

Multiplex amplification and probe hybridization

A technique in which, following hybridization to immobilized samples of nucleic acid sequences, amplification of each oligonucleotide probe yields a product of unique size. The copy number of target sequences is reflected in the relative intensities of the amplification products.

Multiplex ligation-dependent probe amplification

A technique involving the ligation of two adjacent annealing oligonucleotides followed by quantitative PCR amplification of the ligated products, allowing the detection of deletions, duplications and trisomies, and characterization of chromosomal aberrations in copy number or sequence and SNP or mutation detection.

Non-allelic homologous recombination

Recombination between non-allelic paralogous segmental duplications (also known as low copy repeats); a major mechanism leading to deletions, duplications and inversions, as well as complex structural polymorphism and rearrangements in the human genome.

Paralogous sequence variants

Genetic changes that are not due to polymorphism but to nucleotide mismatches from paralogous copies of duplicated sequences of the genome. About 20% of the SNPs deposited in databases are not true SNPs but paralogous sequence variants.

Penetrance

The extent to which a given genotype manifests itself in a given phenotype. The penetrance of some genotypes for some diseases is age-related, complicating the determination of true penetrance.

Quantitative multiplex PCR of short fluorescent fragments

Semi-quantitative, high-throughput analysis of targeted genomic alterations using locus-specific primers.

Restriction fragment length polymorphism

A fragment length variant of a DNA sequence that is generated through the gain or loss of a site for a restriction enzyme.

Tagging SNPs

SNPs that are correlated with and therefore can serve as proxies for a set of variants with which they are in linkage disequilibrium.

Ultra high-throughput sequencing

A compendium of new sequencing technologies with a common aim to accelerate (from years to days or hours) and reduce the cost (from millions to thousands or hundreds of dollars) of sequencing.

Uniparental disomy

A state wherein both homologues (alleles) at a locus derive from the same parent. Uniparental disomy of some chromosomal segments generates characteristic syndromes.

Variable number of tandem repeat locus

A locus that contains a variable number of short tandemly repeated DNA sequences that vary in length and are highly polymorphic.

Whole-genome tiling array

A high-density oligonucleotide array that represents the majority of DNA sequences of an organism's genome.

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Beckmann, J., Estivill, X. & Antonarakis, S. Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nat Rev Genet 8, 639–646 (2007). https://doi.org/10.1038/nrg2149

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