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JHU EN.601.749: Computational Genomics: Applied Comparative Genomics

Prof: Michael Schatz (mschatz @
TA: Sam Kovaka (skovaka1 @
Class Hours: Monday + Wednesday @ 1:30p - 2:45p in Hodson 216
Schatz Office Hours: Wednesday @ 3-4p in Malone 323 and by appointment
Kovaka Office Hours: Wednesday @ 4-5p in Malone 216 and by appointment

The primary goal of the course is for students to be grounded in theory and leave the course empowered to conduct independent genomic analyses. We will study the leading computational and quantitative approaches for comparing and analyzing genomes starting from raw sequencing data. The course will focus on human genomics and human medical applications, but the techniques will be broadly applicable across the tree of life. The topics will include genome assembly & comparative genomics, variant identification & analysis, gene expression & regulation, personal genome analysis, and cancer genomics. The grading will be based on assignments, a midterm exam, class presentations, and a significant class project. There are no formal course prerequisites, although the course will require familiarity with UNIX scripting and/or programming to complete the assignments and course project.


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# Date Lecture Readings & Resources Assignment
1. Mo 1/28 Introduction * Biological data sciences in genome research (Schatz, 2015, Genome Research)
* Big Data: Astronomical or Genomical? (Stephens et al, 2015, PLOS Biology)
Sign Up for Piazza
2. We 1/30 Genomic Technologies * Molecular Structure of Nucleic Acid (Watson and Crick, 1953, Nature)
* Coming of age: ten years of next-generation sequencing technologies (Goodwin et al, 2016, Nature Reviews Genetics)
* High‐throughput sequencing for biology and medicine (Soon et al, 2013, Molecular Systems Biology)
Assignment 1
3. Mo 2/4 Whole Genome Assembly * Velvet: Algorithms for de novo short read assembly using de Bruijn graphs (Zerbino and Birney, 2008, Genome Research)
* Quake: quality-aware detection and correction of sequencing errors (Kelley et al, 2010, Genome Biology)
* Allpaths-LG: High-quality draft assemblies of mammalian genomes from massively parallel sequence data (Gnerre et al, 2011, PNAS)
* FALCON-unzip: Phased diploid genome assembly with single-molecule real-time sequencing (Chin et al, 2016, Nature Methods)
4. We 2/6 Whole Genome Assembly and Alignment * Toward simplifying and accurately formulating fragment assembly. (Myers, 1995, J. Comp. Bio.)
* MHAP: Assembling large genomes with single-molecule sequencing and locality-sensitive hashing (Berlin et al, 2015, Nature Biotech)
* Genome assembly forensics: finding the elusive mis-assembly (Phillippy et al, 2008, Genome Biology)
* MUMmer: Alignment of Whole Genomes (Delcher et al, 1999, NAR)
Assignment 2
5. Mo 2/11 Long Read Technologies * Piercing the dark matter: bioinformatics of long- range sequencing and mapping (Sedlazeck et al, 2018, Nature Reviews Genetics)
* Nanopore sequencing and assembly of a human genome with ultra-long reads (Jain et al, 2018, Nature Biotech)
* Characterizing the Major Structural Variant Alleles of the Human Genome (Audano et al, 2019, Cell)
6. We 2/13 Read Mapping * How to map billions of short reads onto genomes (Trapnell and Salzberg, 2009, Nature Biotech)
* Bowtie: Ultrafast and memory-efficient alignment of short DNA sequences to the human genome (Langmead et al, 2009, Genome Biology)
* BWA-MEM: Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM (Li, 2013, arXiv)
* SAM/BAM/Samtools: The Sequence Alignment/Map format and SAMtools (Li et al, 2009, Bioinformatics)
* IGV: Integrative genomics viewer (Robinson et al, 2011, Nature Biotech)
7. Mo 2/18 FM Index & BWT Lecture Notes * PolyBayes: A general approach to single-nucleotide polymorphism discovery (Marth et al, 1999, Nature Genetics)
* GATK: A framework for variation discovery and genotyping using next-generation DNA sequencing data (Depristo et al, 2011, Nature Genetics)
* Scalpel: Accurate de novo and transmitted indel detection in exome-capture data using microassembly (Narzisi et al, 2014, Nature Methods)
Assignment 3
8. We 2/20 Snow Day!
9. Mo 2/25 Variant Analysis * Genome structural variation discovery and genotyping (Alkan et al, 2011, Nature Reviews Genetics)
* LUMPY: a probabilistic framework for structural variant discovery (Layer et al, 2014, Genome Biology)
* Assembly Reconciliation (Zimin et al, 2008, Bioinformatics)
* Resolving the complexity of the human genome using single-molecule sequencing (Chaisson et al, 2015, Nature)
* BEDTools: a flexible suite of utilities for comparing genomic features (Quinlan & Hall, 2010, Bioinformatics)
* A Parallel Algorithm for N-Way Interval Set Intersection (Layer & Quinlan, 2016, IEEE Proceedings)
Assignment 4
10. We 2/27 Functional Analysis 1: RNA-seq & Expectation-Maximization Worksheet * RNA-Seq: a revolutionary tool for transcriptomics (Wang et al, 2009. Nature Reviews Genetics)
* Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks (Trapnell et al, 2012, Nature Protocols)
* Salmon provides fast and bias-aware quantification of transcript expression (Patro et al, 2017, Nature Methods)
* Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications (Krueger and Andrews, 2011, Bioinformatics)
11. Mo 3/4 Functional Analysis 2: Annotation * BLAST: Basic Local Alignment Search Tool
* Glimmer: Microbial gene identification using interpolated Markov models
* MAKER2: an annotation pipeline and genome-database management tool for second-generation genome projects
Assignment 5
12. We 3/6 Functional Analysis 3: Gene Finding and HMMs * What is a hidden Markov model? Project Proposal
13. Mo 3/11 Functional Analysis 4: Methyl-seq, Chip-seq, and Hi-C * ChIP–seq and beyond: new and improved methodologies to detect and characterize protein–DNA interactions (Furey, 2012, Nature Reviews Genetics)
* PeakSeq enables systematic scoring of ChIP-seq experiments relative to controls (Rozowsky et al. 2009. Nature Biotech)
* Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome (Lieberman-Aiden et al, 2009, Science)
14. We 3/13 Functional Analysis 5: Regulatory States, ENCODE, GTEx, RoadMap * An integrated encyclopedia of DNA elements in the human genome (The ENCODE Project Consortium, Nature, 2012)
* Genetic effects on gene expression across human tissues (GTEx Consortium, Nature, 2017)
* Integrative analysis of 111 reference human epigenomes (Roadmap Epigenome Consortium, Nature, 2015)
* ChromHMM: automating chromatin-state discovery and characterization (Ernst & Kellis, 2012, Nature Methods)
* Segway: Unsupervised pattern discovery in human chromatin structure through genomic segmentation (Hoffman et al, 2012, Nature Methods)
Mo 3/18 Spring Break!
We 3/20 Spring Break!
15. Mo 3/25 Functional Analysis 6: Single Cell Genomics * Ginkgo: Interactive analysis and assessment of single-cell copy-number variations (Garvin et al, 2015, Nature Methods)
* The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells (Trapnell et al, Nature Biotech, 2014)
* Visualizing Data Using t-SNE
Assignment 6
16. We 3/27 Functional Analysis 7: Scalable methods for genomics * Cloud computing and the DNA data race (Schatz et al, Nature Biotech, 2010)
* Reproducible RNA-seq analysis using recount2 (Collado-Torres et al, Nature Biotech, 2017)
* Fast search of thousands of short-read sequencing experiments (Solomon et al. Nature Biotech, 2016)
17. Mo 4/1 Midterm Review
18. We 4/3 Midterm Exam In class exam
19. Mo 4/8 Human Evolution * An integrated map of genetic variation from 1,092 human genomes (1000 Genomes Consortium, 2012, Nature)
* Analysis of protein-coding genetic variation in 60,706 humans (Let et al, 2016, Nature)
* A Draft Sequence of the Neandertal Genome (Green et al. 2010, Science)
* Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals (Vernot et al. 2016. Science)
Preliminary Project Report
20. We 4/10 Human Genetic Diseases * Genome-Wide Association Studies (Bush & Moore, 2012, PLOS Comp Bio)
* The contribution of de novo coding mutations to autism spectrum disorder (Iossifov et al, 2014, Nature)
21. Mo 4/15 Microbiome and Metagenomics * Kraken: ultrafast metagenomic sequence classification using exact alignments (Wood and Salzberg, 2014, Genome Biology)
* Chapter 12: Human Microbiome Analysis (Morgan and Huttenhower)
22. We 4/17 Cancer Genomics * The Hallmarks of Cancer (Hanahan & Weinberg, 2000, Cell)
* Evolution of Cancer Genomes (Yates & Campbell, 2012, Nature Reviews Genetics)
* Comprehensive molecular portraits of human breast tumours (TCGA, 2012, Nature)
Project Presentations
23. Mo 4/22 Genomic Futures * "Snyderome" Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes (Chen et al, 2012, Cell)
* Identifying Personal Genomes by Surname Inference (Gymrek et al, 2013, Science)
Final Project Report
24. We 4/24 Project Presentations
25. Mo 4/29 Project Presentations
26. We 5/1 Project Presentations
27. Wed 5/15 Final Project Report Due! Final Project Report


Materials for Spring 2019 Applied Genomics Course






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