Genomic Structural Variation: Methods & Protocols

The draft human genome sequence, completed more than a decade ago, was an important starting point for understanding genetic variation in humans. Intensive efforts to characterize single-nucleotide polymoprhisms (SNPs), and later the discovery of extensive copy number variation (CNV) and structural variation, have highlighted the complex and dynamic nature of the our genome.

Genomic Structural Variants Earlier this month, Springer Press published  Genomic Structural Variants, an outstanding new volume edited by Lars Feuk of Uppsala University in Sweden. This book provides an in-depth description of key developments in our understanding of structural variation and its implications for human disease.

Most, if not all of these advances have been driven by technological innovation. The editor writes, “Over the past decade, the introduction of array-based technologies has revolutionized genomics and genetic diagnostics… Now, we are on the brink of a paradigm shift in genetics with the advent of massively parallel sequencing in research and diagnostics.”

The contributors include James Lupski, Stephen Scherer, Ira Hall, Aaron Quinlan, Deanna Church, Bauke Ylstra, Richard K. Wilson, and a number of other distinguished scientists. Here are the topics covered, with my own brief summary and a link to each article.

Genome Architecture
What Genomic Disorders Have Taught Us
SV in Subtelomeres
Complex Regions of the Genome

Nature of Structural Variation
SV Effect on Gene Expression
CNV Population Genetics
SV and Somatic Mosaicism

Detection of SV
Interpreting SVs in Personal Genome Sequencing
Massively Parallel Sequencing Approaches for SVs
Array-based Prenatal Diagnosis
GSV in Mammals

SV and CNV in Human Disease
Microdeletion and Microduplication Syndromes
SV in Intellectual Disability
CNV in Autism Spectrum Disorder
CNV and Psychiatric Disease Risk

Methods and Resources
Online SV Resources
SNP Array Algorithms for CNV
Targeted Screening of CNVs
Array-CGH of FFPE Tissues

What Have Studies of Genomic Disorders Taught Us About Our Genome?

Alexandra D. Simmons, Claudia M. B. Carvalho and James R. Lupski
An overview of high-resolution analysis methods and what they’ve taught us about the architectural features, structure, and rearrangement mechanisms of the genome.   Article | PDF

Microdeletion and Microduplication Syndromes

Lisenka E. L. M. Vissers and Paweł Stankiewicz
An overview of how microdeletions and microduplications form in the genome and the wide variety of phenotypes — including Mendelian and complex diseases — that they can cause.   Article | PDF

Structural Genomic Variation in Intellectual Disability

Rolph Pfundt and Joris A. Veltman
A review of detection and interpretation of copy number variations in mental retardation, with a focus on diagnostic application and interpretation.   Article | PDF

Copy Number Variation and Psychiatric Disease Risk

Rebecca J. Levy, Bin Xu, Joseph A. Gogos and Maria Karayiorgou
An update on the substantial progress toward understanding the role of rare CNVs in the etiology of complex psychiatric diseases, such as schizophrenia.   Article | PDF

Detection and Characterization of Copy Number Variation in Autism Spectrum Disorder

Christian R. Marshall and Stephen W. Scherer
A description of the history of genomic structural variation in ASD and how CNV discovery has been used to pinpoint novel ASD-susceptibility loci.   Article | PDF

Structural Variation in Subtelomeres

M. Katharine Rudd
A guide to the composition and structural variation of subtelomeres, and how FISH and array technologies have been applied to characterize them.   Article | PDF

Array-Based Approaches in Prenatal Diagnosis

Paul D. Brady, Koenraad Devriendt, Jan Deprest and Joris R. Vermeesch
An overview of the recent developments on the use of array CGH in the prenatal setting and a discussion of how to best implement it.   Article | PDF

Structural Variation and Its Effect on Expression

Louise Harewood, Evelyne Chaignat and Alexandre Reymond
A discussion of the profound and dramatic effect that SVs can have on the expression of genes mapping within them, nearby, and elsewhere in the genome.   Article | PDF

The Challenges of Studying Complex and Dynamic Regions of the Human Genome

Edward J. Hollox
A review of key advances in the understanding of the variable structure of our genome, and a discussion of methods that may allow us to analyse this structure in fine detail.   Article | PDF

Population Genetic Nature of Copy Number Variation

Per Sjödin and Mattias Jakobsson
An update on recent progress on understanding CNVs, and discussion of population genetics, recombination, mutation, selection, and demography of these variants.   Article | PDF

Detection and Interpretation of Genomic Structural Variation in Mammals

Ira M. Hall and Aaron R. Quinlan
A summary of the current state of knowledge of SV in mammals, and an exploration of the key biological insights that can be gained by applying NGS methods to model organisms.   Article | PDF

Structural Genetic Variation in the Context of Somatic Mosaicism

Jan P. Dumanski and Arkadiusz Piotrowski
A review combining evidence of structural variation in the context of somatic cells, highlighting the methodoligcal aspects of detection, challenges, and opportunities related to this field.   Article | PDF

Online Resources for Genomic Structural Variation

Tam P. Sneddon and Deanna M. Church
A description of current structural variation online resources highlighting how major databases have addressed the challenges in capturing, storing, and displaying SV data.   Article | PDF

Algorithm Implementation for CNV Discovery Using Affymetrix and Illumina SNP Array Data

Laura Winchester and Jiannis Ragoussis
A review of approaches to detect SVs by SNP array intensities, the importance of the quality control, and some guidelines for implementation.   Article | PDF

Targeted Screening and Validation of Copy Number Variations

Shana Ceulemans, Karlijn van der Ven and Jurgen Del-Favero
A description of methods used for SV screening and validation, including FISH, qPCR, paralogue ratio test, molecular copy-number counting, multiplex PCR, and others.   Article | PDF

High-Resolution Copy Number Profiling by Array CGH Using DNA Isolated from Formalin-Fixed, Paraffin-Embedded Tissues

Hendrik F. van Essen and Bauke Ylstra
A series of protocols tailored to array CGH of FFPE solid malignancies: from sectioning FFPE blocks to specific cynosures for pathological revision, DNA isolation, quality testing, and amplification.   Article | PDF

Characterizing and Interpreting Genetic Variation from Personal Genome Sequencing

Anna C. V. Johansson and Lars Feuk
An overview of whole-genome sequences completed to date and the challenge of interpreting the whole-genome sequence data both from a technical and clinical perspective.   Article | PDF

Massively Parallel Sequencing Approaches for Characterization of Structural Variation

Daniel C. Koboldt, David E. Larson, Ken Chen, Li Ding and Richard K. Wilson
Our own contribution to this volume is a review of methods and software applications for detecting, assembling, and characterizing SVs by next-generation sequencing.
Article | PDF

Levy RJ, Xu B, Gogos JA, & Karayiorgou M (2012). Copy number variation and psychiatric disease risk. Methods in molecular biology (Clifton, N.J.), 838, 97-113 PMID: 22228008

Johansson AC, & Feuk L (2012). Characterizing and interpreting genetic variation from personal genome sequencing. Methods in molecular biology (Clifton, N.J.), 838, 343-67 PMID: 22228021

Koboldt DC, Larson DE, Chen K, Ding L, & Wilson RK (2012). Massively parallel sequencing approaches for characterization of structural variation. Methods in molecular biology (Clifton, N.J.), 838, 369-84 PMID: 22228022

Marshall CR, & Scherer SW (2012). Detection and characterization of copy number variation in autism spectrum disorder. Methods in molecular biology (Clifton, N.J.), 838, 115-35 PMID: 22228009

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