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Computational Molecular Biology Biochem 218 – BioMedical Informatics 231 Doug Brutlag Professor.

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Presentation on theme: "Computational Molecular Biology Biochem 218 – BioMedical Informatics 231 Doug Brutlag Professor."— Presentation transcript:

1 Computational Molecular Biology Biochem 218 – BioMedical Informatics 231 http://biochem218.stanford.edu/ http://biochem218.stanford.edu/ Doug Brutlag Professor Emeritus Biochemistry & Medicine (by courtesy) The Human Genome Project

2 Maeve’s Office Hours Monday and Friday 3:30 to 5:00 PM Beckman Center B403A Please Email Maeve to set up an appointment if you want to meet with her. –maeveo@stanford.edumaeveo@stanford.edu Take the elevator to the fourth floor of Beckman and turn left. The hallway leads directly to the lab B403 and my office is inside the lab at B403A.

3 Current Topics in Genome Analysis 2010 http://www.genome.gov/12514288 http://www.genome.gov/12514288

4 Hierarchical Sequencing vs. Whole Genome Shotgun Sequencing © Gibson & Muse A Primer of Genome Science from Gibson & Muse, A Primer of Genome Science http://www.sinauer.com/genomics/

5 The Human Genome Project: How should we do it? Weber, J. L., & Myers, E. W. (1997). Human whole-genome shotgun sequencing. Genome Res, 7(5), 401-409.Weber, J. L., & Myers, E. W. (1997). Human whole-genome shotgun sequencing. Genome Res, 7(5), 401-409. –http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation& list_uids= 9149936http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation& list_uids= 9149936 –Use multiple length clones 2 kb, 10 kb and 50 kb –Use clone end sequencing generating mate-pairs –Able to use long clones to leap over repeated regions –Clone length permits one to measure length of repeated regions. –Will find more polymorphisms (SNPs) –Costs less –BAC clone artifacts Differential amplification BACs not stable in bacteria will be lost. Repeated regions will recombine and be lost Green, P. (1997). Against a whole-genome shotgun. Genome Res, 7(5), 410-417.Green, P. (1997). Against a whole-genome shotgun. Genome Res, 7(5), 410-417. –http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation& list_uids=9149937http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation& list_uids=9149937 –Preferred clone-by-clone BAC sequencing –Distributed versus monolithic organization –BACs linked to genetic maps –Costs less (sequence 4x human genome) –Finishing simplified and fewer gaps –Haplotyping automatic –Longer repeat regions lengths measured

6 Gene Myers Let’s sequence the human genome with the shotgun strategy That is impossible, and a bad idea anyway Phil Green 1997 History of Whole Genome Assembly Thanks to Serafim Batzoglou

7 Public Human Genome Project Strategy http://www.genome.gov/ http://www.genome.gov/

8 Contig Formation as Mapping Progresses Lander & Waterman 1988 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3294162 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3294162

9 Public Genome Assembly Process

10 BAC and PAC Libraries in Public Human Genome Project http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_ uids=11237011 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_ uids=11237011

11 Total Genome Sequence Information 2001 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11237011 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11237011

12 Comparing Chromosome 2 Sequence Versus Genetic Maps http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11237011 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11237011

13 Synteny Between Human and Mouse http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db =PubMed&dopt=Citation&list_uids=11237011 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db =PubMed&dopt=Citation&list_uids=11237011

14 Celera Sequencing http://www.celera.com/ http://www.celera.com/

15 Celera Scaffolds http://www.sciencemag.org/cgi/content/full/291/5507/1304 http://www.sciencemag.org/cgi/content/full/291/5507/1304

16 Celera Assembler

17 Chromosome 21: Public vs Celera Assemblies http://www.sciencemag.org/cgi/content/full/291/5507/1304 http://www.sciencemag.org/cgi/content/full/291/5507/1304

18 Chromosome 8: Public vs. Celera http://www.sciencemag.org/cgi/content/full/291/5507/1304 http://www.sciencemag.org/cgi/content/full/291/5507/1304

19 Finishing Strategy for the Public Genome Project http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&d opt=Citation&list_uids=15496913

20 Finished Sequence in 2004 (Build 35) http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15496913 http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15496913

21 Chromosome 7: Draft versus Finished Sequence http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&dopt=Citation&list_ui ds=15496913 http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&dopt=Citation&list_ui ds=15496913

22 Substitutions in BAC Overlaps with BACs from Same or Different Libraries

23 Gaps in BAC Overlaps with BACs from Same or Different Libraries

24 Duplications and Deletions in the Human Genome

25 Percentage of Chromosomes Duplicated http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&dopt=Citatio n&list_uids=15496913 http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&dopt=Citatio n&list_uids=15496913

26 Available Next Generation Sequencing Technologies Illumina – Solexa –http://www.illumina.com/http://www.illumina.com/ Illumina Technology –http://www.illumina.com/technology/sequencing_technology.ilmnhttp://www.illumina.com/technology/sequencing_technology.ilmn 454 Life Sciences –http://www.454.com/http://www.454.com/ 454 Life Sciences Technology –http://www.454.com/products-solutions/how-it-works/index.asphttp://www.454.com/products-solutions/how-it-works/index.asp Applied Biosystems Inc. (ABI) SOLID Sequencing –http://solid.appliedbiosystems.com/http://solid.appliedbiosystems.com ABI SOLID Sequencing Technology –http://www3.appliedbiosystems.com/AB_Home/applicationstechnologies/ SOLiDSystemSequencing/OverviewofSOLiDSequencingChemistry/index. htmhttp://www3.appliedbiosystems.com/AB_Home/applicationstechnologies/ SOLiDSystemSequencing/OverviewofSOLiDSequencingChemistry/index. htm

27 Next Generation Sequencing Technologies in Development Pacific BioSciences –http://www.pacificbiosciences.com/http://www.pacificbiosciences.com/ Pacific BioSciences Technology –http://www.pacificbiosciences.com/index.php?q=technology-introductionhttp://www.pacificbiosciences.com/index.php?q=technology-introduction Helicos –http://www.helicosbio.com/http://www.helicosbio.com/ Helicos Technology –http://www.helicosbio.com/Technology/TrueSingleMoleculeSequencing/ta bid/64/Default.aspxhttp://www.helicosbio.com/Technology/TrueSingleMoleculeSequencing/ta bid/64/Default.aspx Complete Genomics –http://www.completegenomics.com/http://www.completegenomics.com Complete Genomics Technology –http://www.completegenomics.com/technology /technicalDetails.aspxhttp://www.completegenomics.com/technology /technicalDetails.aspx

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