02-715 Advanced Topics in Computational Genomics

02-715 Advanced Topics in Computational Genomics, Spring 2013

Course Information

Instructor: Seyoung Kim (Lane Center for Computational Biology, School of Computer Science, Carnegie Mellon University)
Location: 2105 Doherty Hall
Time: Monday, Wednesday, and Friday 3:30-4:20pm
Office hours: Friday 4:30-5:30pm

Course Description

Research in biology and medicine is undergoing a revolution due to the availability of high-throughput technology for probing various aspects of a cell at a genome-wide scale. The next-generation sequencing technology is allowing researchers to inexpensively generate a large volume of genome sequence data. In combination with various other high-throughput techniques for epigenome, transcriptome, and proteome, we have unprecedented opportunities to answer fundamental questions in cell biology and understand the disease processes with the goal of finding treatments in medicine. The challenge in this new genomic era is to develop computational methods for integrating different data types and extracting complex patterns accurately and efficiently from a large volume of data. This course will discuss computational issues arising from high-throughput techniques recently introduced in biology, and cover very recent developments in computational genomics and population genetics, including genome structural variant discovery, association mapping, epigenome analysis, cancer genomics, and transcriptome analysis. The course material will be drawn from very recent literature. Class sessions will consist of lectures and discussions of recent papers led by the instructor. This course assumes a basic knowledge of machine learning and computational genomics (equivalent to 15-701 and 02-710).

Grading

The requirements of this course consists of short write-ups of summary/critique of the required readings for each class session, class participation, paper presentation, and final projects. The grading breakdown is as follows:

Write-ups for required reading (30%)
Class participation (20%)
Paper presentation (30%)
Final project (20%)

Write-ups for Required Reading: We expect students to read the papers listed as Required Readings in the course syllabus before the class meets. Students are required to submit a short write-up (less than 300 words for each paper) of summary/critique of the required readings by 12am on the day before each class. The write-ups should include both strengths and weaknesses of the paper. The write-ups should be submitted through the course blackboard.

Class Participation: We expect students to participate in discussions of the papers in each class session.

Paper Presentation: We expect students to present the paper and lead the discussion in some of the class sessions.

Final Project: In a class project, students will develop new computational methods and test them on genomic data. Also, students can take existing methods (or extend the existing methods) and apply them to genomic data. Students can work on a project either on their own or as a team of up to two students. A one-page project proposal is due by Monday, March 18, in class, and students will give a short presentation on projects during the last week of the course. The final project report is due by Friday (May 10th) (dropbox in the course blackboard will be made available).

Syllabus and Course Schedule (tentative)

Date	Lectures and Require Readings	Additional Readings
Overview, review
Mon 1/14	Course overview and introduction [slides]
Wed 1/16	Course overview and introduction II
Fri 1/18	Analysis of population structure: a unifying framework and novel methods based on sparse factor analysis. PLoS Genetics, 2010. (B. Engelhardt and M. Stephens) [slides]
Mon 1/21	No class (Martin Luther King's day)
Wed 1/23	Inference of population structure using multilocus genotype data. Genetics, 2000. (J.K. Pritchard et al.)
Genetic basis of complex phenotypes
Fri 1/25	Lecture [slides]	A tutorial on statistical methods for population association studies. Nature Reviews Genetics, 2006. (D.J. Balding)
Mon 1/28	Integrating large-scale functional genomic data to dissect the complexity of yeast regulatory networks. Nature Genetics, 2008. (J. Zhu et al.)
Wed 1/30	Learning a prior on regulatory potential from eQTL data. PLoS Genetics, 2009. (S-I. Lee et al.) [slides]
Fri 2/1	Using Network Component Analysis to Dissect Regulatory Networks Mediated by Transcription Factors in Yeast. [slides] PLoS Computational Biology, 2009. (C. Ye et al.)
Mon 2/4	Statistical estimation of correlated genome associations to a quantitative trait network. PLoS Genetics, 2009. (S. Kim and E.P. Xing) [slides]	Network-constrained regularization and variable selection for analysis of genomic data. Bioinformatics, 2008. (C. Li and H. Li)
Wed 2/6	Association mapping in structured populations. AJHG 2000. (J.K. Pritchard et al.) [slides]	Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics, 2006. (A. Price et al.)
Fri 2/8	Lecture: Epistasis Bayesian inference of epistatic interactions in case-control studies. Nature Genetics, 2007. (Y. Zhang and J. Liu) [slides]	Screen and clean: a tool for identifying interactions in genome-wide association studies. Genetic Epidemiology, 2010. (J. Wu et al.)
Mon 2/11	Lecture: structured GWAS [slides]
Structural variations in genomes
Wed 2/13	Lecture [slides]
Fri 2/15	Lecture [slides]	Computational methods for discovering structural variation with next-generation sequencing. Nature Methods, 2009. (P. Medvedev, M. Stanciu, M. Brudno) Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics, 2009. (K. Ye et al.)
*Mon 2/18	MoDIL: detecting small indels from clone-end sequencing with mixtures of distributions. Nature Methods, 2009. (S. Lee et al.) [slides]	Breakdancer: an algorithm for high-resolution mapping of genomic structural variation. Nature Methods, 2009. (K. Chen et al.)
Wed 2/20	Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nature Genetics, 2008. (J. Korn et al.) [slides]	Copy-number variation and association studies of human disease. Nature Genetics, 2007. (S. A. McCarroll and D. M. Altshuler)
Epigenetics
Fri 2/22	Lecture [slides]
Mon 2/25	Contribution of histone sequence preferences to nucleosome organization: proposed definitions and methodology. Genome Biology, 2010. (N. Kaplan et al.) [slides]
Wed 2/27	Learning a weighted sequence model of the nucleosome core and linker yields more accurate predictions in Saccharomyces cerevisiae and Homo sapiens. PLoS Computational Biology, 2010. (S. Reynolds et al.) [slides]	Predicting nucleosome positioning using multiple evidence tracks. RECOMB 2010. (S. Reynolds et al.)
Fri 3/1 (Benny)	Chromatin: constructing the big picture. The EMBO Journal, 2011. (B. van Steensel)
*Mon 3/4	Discovery and characterization of chromatin states for systematic annotation of the human genome. Nature Biotechnology, 2010. (J. Ernst and M. Kellis) [slides]	Comprehensive analysis of the chromatin landscape in Drosophila melanogaster. Nature, 2010. (P. Kharchenko et al.) Histone modification levels are predictive for gene expression. PNAS, 2010. (R. Karlic et al.)
Cancer Genomics
Wed 3/6	Lecture [slides]	The Hallmarks of Cancer. Cell, 2000. (D. Hanahan and R. Weinberg) Hallmarks of Cancer: The Next Generation. Cell, 2011. (D. Hanahan and R. Weinberg)
Fri 3/8 - Fri 3/15	No class (mid semester break, spring break)
*Mon 3/18 (SH)	Cancer-specific high-throughput annotation of somatic mutations: computational prediction of driver missense mutations. Cancer Research, 2009. (H. Carter et al.)
Wed 3/20	An integrated approach to uncover drivers of cancer. Cell, 2010. (U. Akavia et al.) [slides]
Fri 3/22	Inference of patient-specific pathway activities from multi-dimensional cancer genomics data using PARADIGM. Bioinformatics, 2010. (C. J. Vaske et al.) [slides]
Mon 3/25	Inferring transcriptional and microRNA-mediated regulatory programs in glioblastoma. Molecular Systems Biology, 2012. (M. Setty et al.) [slides]
*Wed 3/27 (Sid)	Mutual exclusivity analysis identifies oncogenic network modules. Genome Research, 2012. (G. Ciriello et al.)
Evolution and natural selection
Fri 3/29	Positive Natural Selection in the Human Lineage. Science, 2006. (P. Sabeti et al.) [slides]
Mon 4/1	Genomic scans for selective sweeps using SNP data. Genome Research, 2005. (R. Nielsen et al.) [slides]	Genome-wide detection and characterization of positive selection in human populations. Nature, 2007. (P. C. Sabeti et al.)
*Wed 4/3	Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Research, 2005. (A. Siepel et al.) [slides]
*Fri 4/5 (Sid)	Phylogenetic motif detection by expectation-maximization on evolutionary mixtures. Pac Symp Biocomput, 2004. (A.M. Moses, D.Y. Chiang, and M.B. Eisen)
Mon 4/8	Phylogenomics of primates and their ancestral populations. Genome Research, 2009. (A. Siepel)
Wed 4/10	A Bayesian Approach for Fast and Accurate Gene Tree Reconstruction. Molecular Biology and Evolution, 2011. (M. Rasmussen and M. Kellis) [slides]
Systems biology
Fri 4/12	High resolution models of transcription factor-DNA affinities improve in vitro and in vivo binding predictions. PLoS Computational Biology, 2010. (P. Agius et al.) [slides]	Mismatch string kernels for discriminative protein classification. Bioinformatics, 2004. (C. Leslie et al.) A feature-based approach to modeling protein−DNA interactions. PLoS Computational Biology, 2008. (E. Sharon, S. Lubliner, E. Segal)
*Mon 4/15 (Benny)	Cooperative transcription factor associations discovered using regulatory variation. PNAS, 2011. (K. Karczewski et al.)	Breast cancer risk–associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression. Nature Genetics, 2012. (R. Cowper-Sal-lari et al.)
Wed 4/17	Global alignment of multiple protein interaction networks with application to functional orthology detection. PNAS, 2008. (R. Singh, J. Xu, B. Berger) [slides]	IsoRankN: spectral methods for global alignment of multiple protein networks. Bioinformatics, 2009. (C. Liao et al.)
Fri 4/19	No class (spring carnival)
Metaganomics
Mon 4/22	Lecture [slides]	A human gut microbial gene catalogue established by metagenomic sequencing. Nature, 2010. (J. Qin et al.) A Primer on Metagenomics. PLoS Computational Biology, 2010. (J. Wooley et al.)
Wed 4/24	Genovo: de novo assembly for metagenomes. RECOMB, 2010. (J. Laserson, V. Jojic, D. Koller) [slides]
*Fri 4/26 (SH)	Variable selection for sparse Dirichlet-multinomial regression with an application to microbiome data analysis. AOAS, 2013. (Chen and Li)
Mon 4/29	Project presentation
Wed 5/1	Project presentation
Fri 5/3	Project presentation

Resources

International HapMap Project
Model organism ENCyclopedia Of DNA Elements (modENCODE) Project
1000 Genomes Project: a deep catalog of human genetic variation
Sage Bionetworks: a repository of various genomic datasets
The Cancer Genome Atlas (TCGA)