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

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Presentation transcript:

Computational Molecular Biology Biochem 218 – BioMedical Informatics Doug Brutlag Professor Emeritus Biochemistry & Medicine (by courtesy) The Human Genome Project

Maeve’s Office Hours Monday and Friday 3:30 to 5:00 PM Beckman Center B403A Please Maeve to set up an appointment if you want to meet with her. 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.

Current Topics in Genome Analysis

Hierarchical Sequencing vs. Whole Genome Shotgun Sequencing © Gibson & Muse A Primer of Genome Science from Gibson & Muse, A Primer of Genome Science

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), Weber, J. L., & Myers, E. W. (1997). Human whole-genome shotgun sequencing. Genome Res, 7(5), – list_uids= http:// list_uids= –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), Green, P. (1997). Against a whole-genome shotgun. Genome Res, 7(5), – list_uids= http:// list_uids= –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

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

Public Human Genome Project Strategy

Contig Formation as Mapping Progresses Lander & Waterman

Public Genome Assembly Process

BAC and PAC Libraries in Public Human Genome Project uids= uids=

Total Genome Sequence Information

Comparing Chromosome 2 Sequence Versus Genetic Maps

Synteny Between Human and Mouse =PubMed&dopt=Citation&list_uids= =PubMed&dopt=Citation&list_uids=

Celera Sequencing

Celera Scaffolds

Celera Assembler

Chromosome 21: Public vs Celera Assemblies

Chromosome 8: Public vs. Celera

Finishing Strategy for the Public Genome Project opt=Citation&list_uids=

Finished Sequence in 2004 (Build 35)

Chromosome 7: Draft versus Finished Sequence ds= ds=

Substitutions in BAC Overlaps with BACs from Same or Different Libraries

Gaps in BAC Overlaps with BACs from Same or Different Libraries

Duplications and Deletions in the Human Genome

Percentage of Chromosomes Duplicated n&list_uids= n&list_uids=

Available Next Generation Sequencing Technologies Illumina – Solexa – Illumina Technology – 454 Life Sciences – 454 Life Sciences Technology – Applied Biosystems Inc. (ABI) SOLID Sequencing – ABI SOLID Sequencing Technology – SOLiDSystemSequencing/OverviewofSOLiDSequencingChemistry/index. htmhttp://www3.appliedbiosystems.com/AB_Home/applicationstechnologies/ SOLiDSystemSequencing/OverviewofSOLiDSequencingChemistry/index. htm

Next Generation Sequencing Technologies in Development Pacific BioSciences – Pacific BioSciences Technology – Helicos – Helicos Technology – bid/64/Default.aspxhttp:// bid/64/Default.aspx Complete Genomics – Complete Genomics Technology – /technicalDetails.aspxhttp:// /technicalDetails.aspx