Exome Project
The Exome Project
The National Heart, Lung, and Blood Institute (NHLBI) and National Human Genome Research Institute (NHGRI) have funded a new program known as the Exome Project. The goal of this project is to develop cost-effective, high-throughput sequencing of the protein coding regions of the human genome for application in well-phenotyped populations. Three groups are currently funded to test and implement approaches in four key areas — sample preparation, target capture, sequencing, and data management and analysis — to generate an integrated resequencing pipeline with the potential to reduce the cost of exome analysis.[1]
Contents
Background
The exome is the part of the genome formed by exons, the coding portions of genes that are expressed. Providing the genetic blueprint used in the synthesis of proteins and other functional gene products, the exome is the most functionally relevant part of the genome, and, therefore, the most likely to contribute to the phenotype of an organism. The exome of the human genome consists of roughly 180,000 exons constituting about 1% of the total genome or about 30 megabases of DNA.[2] Though comprising a very small fraction of the genome, mutations in the exome are thought to harbor 85% of disease-causing mutations.[3] Exome sequencing has proved to be an efficient strategy to determine the genetic basis of more than a two dozen Mendelian or single gene disorders.[4]
Examples of research projects using exome sequencing include the nonprofit Personal Genome Project (PGP), the NIH-funded Exome Project, the NHGRI-funded Mendelian Exome Project, the NHLBI Grand Opportunity Exome Sequencing Project and the microarray-based Nimblegen SeqCap EZ Exome from Roche Applied Science.
Current Exome Project Participants
- Broad Institute
- Stacey Gabriel
- Chad Nusbaum
- Harvard Medical School
- George Church
- Jonathan Seidman
- Kun Zhang
- University of Washington
- Deborah Nickerson
- Jay Shendure
- Phil Green
- Evan Eichler
- NHLBI
- Weiniu Gan
- Alan Michelson
- Deborah Applebaum-Bowden
- NHGRI
- Lu Wang
Glossary
- sequence depth
- for a given genome, each base has on average been sequenced n number of times:
- Coverage = (Nb of Reads)*(Read Length) / (Genome Size)
- Sequencing depth represents the (often average) number of nucleotides contributing to a portion of an assembly. On a genome basis, it means that, on average, each base has been sequenced a certain number of times (10X, 20X...). For a specific nucleotide, it represents the number of sequences that added information about that nucleotide. Such depth varies quite a lot depending on the genomic region. In consequence, an average sequencing depth of 30X leaves a lot of small portions of a genome un-sequenced while other receive a lot more sequences.
- coverage
- appears to have 3 meanings:
- the theoretical "fold-coverage" of a shotgun sequencing experiment: number of reads * read length / target size
- the theoretical or empirical "breadth-of-coverage" of an assembly: assembly size / target size
- the empirical average "depth-of-coverage" of an assembly: number of reads * read length / assembly size
- (1) and (3) are not the same because of sequencing error and un-clonable/un-mappable regions of the genome. Lander-Waterman theory deals with the relationship between (1) and (2).
- see: here for more info.
See also
- List of Collaborative Genome Projects
- seqinR — package for the R environment is a library of utilities to retrieve and analyse biological sequences.
- wikipedia:Exome sequencing
- wikipedia:Copy-number variation
- wikipedia:Indel
References
- ↑ The Exome Project — from the Genome Sciences Dept. at the University of Washington.
- ↑ Ng, SB; Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, Shaffer T, Wong M, Bhattacharjee A, Eichler EE, Bamshad M, Nickerson DA, Shendure J. (9/10/2009). "Targeted capture and massively parallel sequencing of 12 human exomes". Nature, 7261(461): 272-276. DOI:10.1038/nature08250 .
- ↑ Choia, M; Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, Nayir A, Bakkaloğlu A, Ozen S, Sanjad S, Nelson-Williams C, Farhi A, Mane S, Lifton RP (10 November 2009). "Genetic diagnosis by whole exome capture and massively parallel DNA sequencing". PNAS, 45(106): 19096-19101. DOI:10.1073/pnas.0910672106 .
- ↑ Bamshad, MJ; Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J (27 September 2011). "Exome sequencing as a tool for Mendelian disease gene discovery". Nature Reviews Genetics. 11(12): 745-755. DOI:10.1038/nrg3031 .
Further reading
- Chakravarti A (2011). "Genomic contributions to Mendelian disease". Genome Res. 21: 643-644. DOI:10.1101/gr.123554.111 .
External links
- The Exome Project — from the Genome Sciences Dept. at the University of Washington.
- Exome Variant Server — part of NHLBI Exome Sequencing Project (ESP) @UW
- Mendelian Exome Sequencing Project (Mendelian Exome)
- Online Mendelian Inheritance in Man (OMIM) — @NCBI
- wikipedia:exome
