REVIEW URRENT C OPINION
Copy number variations and human genetic disease Fady M. Mikhail
Purpose of review Recent studies clearly demonstrate that copy number variations (CNVs) are widespread in our genome and play an important role in human genetic variation, accounting for both human population diversity and human genetic disease. This review will discuss the most current knowledge regarding our understanding of the biology of CNVs in relation to human genetic disease. Recent findings CNVs associated with human genetic disease can be either recurrent, with a common size and breakpoint clustering, or nonrecurrent, with different sizes and variable breakpoints. Two types of recurrent CNVs have been distinguished, including the syndromic forms in which the phenotypic features are relatively consistent, and those in which the same recurrent CNV can be associated with a diverse set of diagnoses. Recently, the ‘Two-hit model’ was used to explain the phenotypic variability associated with the latter group of recurrent CNVs. Nonrecurrent CNVs, on the contrary, occur at a relatively lower frequency at the individual locus level but collectively they are as common as recurrent CNVs. Finally, the study of CNV burden in different diseases demonstrated a clear trend of an increasing CNV burden in diseases with more severe phenotypes. Summary In spite of the advances in the study of the CNV landscape associated with human genetic disease, there still remain many unexplored questions especially regarding the role of CNVs in the pathogenesis of complex human genetic diseases. Keywords array comparative genomic hybridization, chromosomal microarray, copy number variation, microdeletion, microduplication, segmental duplications
INTRODUCTION Over the past decade, genomic research has explored a recently appreciated variation in the human genome. These studies revealed that our genome contains multiple regions of genomic DNA copy number gains and losses, now formally termed copy number variations (CNVs). These are regions of the genome ranging in size from kilobases (kb) to megabases (Mb) that are present in variable copy numbers. Recent studies clearly demonstrate that CNVs are widespread in our genome and play an important role in human genetic variation, accounting for both human population diversity as well as human genetic disease. This review will discuss the most current knowledge regarding our understanding of the biology of CNVs in relation to human genetic disease.
ARRAY TECHNOLOGIES USED TO DETECT COPY NUMBER VARIATIONS Advances in chromosomal microarray (CMA) technologies, including array comparative genomic www.co-pediatrics.com
hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays, have enabled the characterization of CNVs in human control populations and human diseases with a strong genetic component. Studies in the control population have shown that between any two individuals, the number of base pair (bp) difference due to CNVs is more than 100-fold higher than SNPs [1,2 ]. These CMA technologies have been widely used in both research and clinical settings over the last few years. aCGH involves hybridizing a test sample of interest and a control reference sample, each differentially labelled with different coloured fluorescent dyes, &
Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA Correspondence to Fady M. Mikhail, MD, PhD, Department of Genetics, University of Alabama at Birmingham, 720 20th Street South, Kaul Human Genetics Building, Room #314A, Birmingham, AL 35294, USA. e-mail: [email protected] Curr Opin Pediatr 2014, 26:646–652 DOI:10.1097/MOP.0000000000000142 Volume 26 Number 6 December 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Copy number variations and human genetic disease Mikhail
KEY POINTS
(a) Recurrent CNVs
CNVs are widespread in our genome and play an important role in human genetic variation accounting for both human population diversity and human genetic disease.
(b) Non-recurrent CNVs
The ‘Two-hit’ model can explain the phenotypic variability observed for some pathogenic CNVs. Some CNVs can potentially be risk factors for complex human genetic diseases; however, there still remain many unexplored questions regarding their role in these diseases.
to a microarray slide containing thousands of DNA probes covering the entire human genome, or only certain regions of interest. Differences in hybridization between the two samples, as measured by the ratio of fluorescence of the two fluorescent dyes, are used to detect the presence of copy number differences between the two samples [3]. Highdensity SNP arrays can also be used to detect CNVs. In these experiments, the deviation from the expected fluorescent intensities of the two alleles of an SNP and spanning several adjacent SNPs are used to detect CNVs in a specific sample [4,5]. High-resolution CMAs can detect CNVs bigger that 50 kb across the euchromatic portion of human genome. Also, clinically relevant haploinsufficient genes have been targeted at a higher resolution on many CMA platforms allowing the detection of CNVs as small as 5–10 kb in these targeted regions.
TYPES OF COPY NUMBER VARIATIONS Large-scale association studies in human disease revealed two distinct groups of CNVs. The first involves CNVs with a population frequency of more than 1% and can exist in multi-copy number states that can range from 0 to 30 copies per diploid genome [6]. These have been termed common copy number polymorphisms (CNPs). The second type involves larger CNVs (>100 kb) that are individually rare (
Copy number variations and human genetic disease Fady M. Mikhail
Purpose of review Recent studies clearly demonstrate that copy number variations (CNVs) are widespread in our genome and play an important role in human genetic variation, accounting for both human population diversity and human genetic disease. This review will discuss the most current knowledge regarding our understanding of the biology of CNVs in relation to human genetic disease. Recent findings CNVs associated with human genetic disease can be either recurrent, with a common size and breakpoint clustering, or nonrecurrent, with different sizes and variable breakpoints. Two types of recurrent CNVs have been distinguished, including the syndromic forms in which the phenotypic features are relatively consistent, and those in which the same recurrent CNV can be associated with a diverse set of diagnoses. Recently, the ‘Two-hit model’ was used to explain the phenotypic variability associated with the latter group of recurrent CNVs. Nonrecurrent CNVs, on the contrary, occur at a relatively lower frequency at the individual locus level but collectively they are as common as recurrent CNVs. Finally, the study of CNV burden in different diseases demonstrated a clear trend of an increasing CNV burden in diseases with more severe phenotypes. Summary In spite of the advances in the study of the CNV landscape associated with human genetic disease, there still remain many unexplored questions especially regarding the role of CNVs in the pathogenesis of complex human genetic diseases. Keywords array comparative genomic hybridization, chromosomal microarray, copy number variation, microdeletion, microduplication, segmental duplications
INTRODUCTION Over the past decade, genomic research has explored a recently appreciated variation in the human genome. These studies revealed that our genome contains multiple regions of genomic DNA copy number gains and losses, now formally termed copy number variations (CNVs). These are regions of the genome ranging in size from kilobases (kb) to megabases (Mb) that are present in variable copy numbers. Recent studies clearly demonstrate that CNVs are widespread in our genome and play an important role in human genetic variation, accounting for both human population diversity as well as human genetic disease. This review will discuss the most current knowledge regarding our understanding of the biology of CNVs in relation to human genetic disease.
ARRAY TECHNOLOGIES USED TO DETECT COPY NUMBER VARIATIONS Advances in chromosomal microarray (CMA) technologies, including array comparative genomic www.co-pediatrics.com
hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays, have enabled the characterization of CNVs in human control populations and human diseases with a strong genetic component. Studies in the control population have shown that between any two individuals, the number of base pair (bp) difference due to CNVs is more than 100-fold higher than SNPs [1,2 ]. These CMA technologies have been widely used in both research and clinical settings over the last few years. aCGH involves hybridizing a test sample of interest and a control reference sample, each differentially labelled with different coloured fluorescent dyes, &
Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA Correspondence to Fady M. Mikhail, MD, PhD, Department of Genetics, University of Alabama at Birmingham, 720 20th Street South, Kaul Human Genetics Building, Room #314A, Birmingham, AL 35294, USA. e-mail: [email protected] Curr Opin Pediatr 2014, 26:646–652 DOI:10.1097/MOP.0000000000000142 Volume 26 Number 6 December 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Copy number variations and human genetic disease Mikhail
KEY POINTS
(a) Recurrent CNVs
CNVs are widespread in our genome and play an important role in human genetic variation accounting for both human population diversity and human genetic disease.
(b) Non-recurrent CNVs
The ‘Two-hit’ model can explain the phenotypic variability observed for some pathogenic CNVs. Some CNVs can potentially be risk factors for complex human genetic diseases; however, there still remain many unexplored questions regarding their role in these diseases.
to a microarray slide containing thousands of DNA probes covering the entire human genome, or only certain regions of interest. Differences in hybridization between the two samples, as measured by the ratio of fluorescence of the two fluorescent dyes, are used to detect the presence of copy number differences between the two samples [3]. Highdensity SNP arrays can also be used to detect CNVs. In these experiments, the deviation from the expected fluorescent intensities of the two alleles of an SNP and spanning several adjacent SNPs are used to detect CNVs in a specific sample [4,5]. High-resolution CMAs can detect CNVs bigger that 50 kb across the euchromatic portion of human genome. Also, clinically relevant haploinsufficient genes have been targeted at a higher resolution on many CMA platforms allowing the detection of CNVs as small as 5–10 kb in these targeted regions.
TYPES OF COPY NUMBER VARIATIONS Large-scale association studies in human disease revealed two distinct groups of CNVs. The first involves CNVs with a population frequency of more than 1% and can exist in multi-copy number states that can range from 0 to 30 copies per diploid genome [6]. These have been termed common copy number polymorphisms (CNPs). The second type involves larger CNVs (>100 kb) that are individually rare (
