Targeted capture and massively parallel sequencing of 12 human exomes
Open accessAbstract
Genome-wide association studies suggest that common genetic variants explain only a modest fraction of heritable risk for common diseases, raising the question of whether rare variants account for a significant fraction of unexplained heritability. Although DNA sequencing costs have fallen markedly, they remain far from what is necessary for rare and novel variants to be routinely identified at a genome-wide scale in large cohorts. We have therefore sought to develop second-generation methods for targeted sequencing of all protein-coding regions ('exomes'), to reduce costs while enriching for discovery of highly penetrant variants. Here we report on the targeted capture and massively parallel sequencing of the exomes of 12 humans. These include eight HapMap individuals representing three populations, and four unrelated individuals with a rare dominantly inherited disorder, Freeman-Sheldon syndrome (FSS). We demonstrate the sensitive and specific identification of rare and common variants in over 300 megabases of coding sequence. Using FSS as a proof-of-concept, we show that candidate genes for Mendelian disorders can be identified by exome sequencing of a small number of unrelated, affected individuals. This strategy may be extendable to diseases with more complex genetics through larger sample sizes and appropriate weighting of non-synonymous variants by predicted functional impact.
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In genome research, an average sequence coverage depth of 30-fold has been accepted as sufficient for detecting single-nucleotide polymorphisms and nucleotide insertions or deletions.
“In genome research, an average depth of sequence coverage of 30-fold has been accepted as sufficient for single-nucleotide polymorphism (SNP) and nucleotide insertion or deletion (indel) detection (15–22).”
From Carrier testing for severe childhood recessive diseases by next-generation sequencing (2011) · cites this paper as [17]
The paper reports SNP and indel detection in exomes with average coverage of 51× (Abstract; page unavailable). Its Methods specify at least 8× coverage for variant calling, but our copy does not say that an average depth of 30× is an accepted sufficient threshold for detecting both SNPs and indels. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTarget capture and next-generation sequencing have shown efficacy and, recently, scalability for resequencing human genomes and exomes.
“Target capture and next-generation sequencing (NGS) have shown efficacy and, recently, scalability for resequencing human genomes and exomes, providing an alternative potential paradigm for comprehensive carrier testing (15–22).”
From Carrier testing for severe childhood recessive diseases by next-generation sequencing (2011) · cites this paper as [17]
The paper’s Abstract reports targeted capture and massively parallel sequencing of 12 human exomes, with sensitive variant detection across more than 300 Mb of coding sequence. Its discussion describes the approach as reproducible and able to extend a given amount of sequencing across more samples, supporting efficacy and scalability for exomes. It does not demonstrate resequencing whole human genomes. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMicroarray-based detection of structural variation and exome- and genome-wide sequencing have been pivotal for rare disease gene discovery, supported by in silico analysis and variant prioritization.
“Microarray-based detection of structural variation10 and exome-and genome-wide sequencing11,12 have been pivotal, bolstered by in silico analysis and prioritization of the discovered genetic variants.”
From A brief history of human disease genetics (2020) · cites this paper as [11]
Two recent papers suggest that leveraging functional annotations and computational methods for predicting the consequences of specific rare variants can be used to great advantage in identifying disease-predisposing variants, at least for rare monogenic conditions.
“In fact, two recent papers23, 36 suggest that leveraging functional annotations and computational methods for predicting the consequences of specific rare variants can be used to great advantage in the identification of disease-predisposing variants, at least for rare monogenic conditions.”
From Statistical analysis strategies for association studies involving rare variants (2010) · cites this paper as [36]
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- Authors
- Ng, S. B., Turner, E. H., Robertson, P. D., Flygare, S. D., Bigham, A. W., Lee, C., Shaffer, T., Wong, M., Bhattacharjee, A., Eichler, E. E., Bamshad, M., Nickerson, D. A., & Shendure, J.
- Affiliations
- University of Washington (US)
- Agilent Technologies (United States) (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Ng, Sarah B.
- Shendure, Jay
- ORCID
- Venue
- Nature
- Published
- 2009-08-16
- Volume
- 461
- Issue
- 7261
- Pages
- 272-276
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2844771
- OpenAlex
- W1973878786
- Cited by
- 2,030
- References
- 33
- Citations by year
- 2026: 25 · 2025: 37 · 2024: 58 · 2023: 41 · 2022: 64 · 2021: 85 · 2020: 81 · 2019: 96 · 2018: 100 · 2017: 114 · 2016: 126 · 2015: 172 · 2014: 179 · 2013: 217 · 2012: 214
- FWCI
- 123.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (R01HL094976)
- National Human Genome Research Institute (R21HG004749)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- targeted capture, exome sequencing, Freeman-Sheldon syndrome, rare variants, novel variants, monogenic disorders, candidate gene identification, sequencing cost reduction, HapMap, non-synonymous variants, protein-coding regions
- MeSH terms
- Exons, Gene Frequency, Genes, Dominant, Genetic Testing, Haplotypes, Humans, Sensitivity and Specificity, Syndrome, Genetic Variation, Gene Library, Genome, Human, Sequence Analysis, DNA, Sample Size, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, RNA Splice Sites, INDEL Mutation
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