Syllabus

Course Overview

This course provides a foundation in the following four areas: evolutionary and population genetics; comparative genomics; structural genomics and proteomics; and functional genomics and regulation. Each module consists of four lectures providing key background material, one lecture providing clinical correlates, and one guest lecture from leaders in the field. This course is required for all HST students in the Bioinformatics and Integrative Genomics training program within the doctoral program in Medical Engineering and Medical Physics (MEMP).

Module 1: Evolutionary and Population Genetics

The basic forces of evolution: Mutation, recombination, mating, migration. Neutral evolution and drift, effective population size, coalescent theory.
Selection, fitness, and diffusion models. Selection at genetic and higher levels.
Phylogenetic analysis. Models of nucleotide evolution: Jukes-Cantor, Kimura, maximum likelihood models; Human/mouse/rate examples.
Measuring selection: From 'classical' methods to maximum likelihood (with applications to disease evolution, HIV and influenza).
Medical Lecture: Genetic diversity and evolution of hepatitis C virus.

Module 2: Comparative Genomics

Sequence comparison, substitution matrices, alignment methods, alignment statistics. Multiple alignments, profiles and PSSMs.
Genome comparison and genome evolution: Duplication, recombination, insertions, repeats. Orthologs, paralogs, in/out-paralogs. Algorithms of genome alignment. Conserved non-coding, positive selection. Motif discovery.
Prediction of gene function using: Homology, context, structure, networks.
SNPs: Microevolution, history of population, markers medical applications.
Medical Lecture: Finding the keys to human heart disease in the genomes of other animals.

Module 3: Structural Genomics and Proteomics

Overview of protein structures, domain architecture. Sequence-structure mapping, protein folding, forces and interactions.
Structure-based substitution matrices. Protein structure prediction. Threading.
Protein function: Binding and kinetics. Michaelis-Menthen kinetics, inhibition. Protein-DNA recognition: Models and algorithms.
Proteomics: Networks of protein-protein interactions, complexes, modules. Power-law distributions, clustering coefficient. Evolution of networks.
Medical Lecture: Hemoglobin and the anemias.

Module 4: Functional Genomics and Networks

Gene regulation and function, conservation, detecting regulatory elements.
RNA expression: Clustering and classification.
RNA expression: Classification, 2-way clustering, regulatory modules. Integration of expression and proteomic data.
Dynamics of biological networks metabolic, regulatory. FBA, signaling, regulation of gene expression.
Medical Lecture: Two examples: Phenylketonuria (monogenic) and diabetes type 2 (multigenic+). "Disease" genes vs. "susceptibility" genes. "Environmental" vs. "Developmental" regulation of gene expression.

Assignments

There are three problem sets for this course and a final project that includes an oral presentation.

Grading

Grading criteria.
ACTIVITIES	PERCENTAGES
Problem Sets	50%
Final Project	50%

Calendar

The calendar below provides information on the course's lecture (L) and recitation (R) sessions.

Except where indicated in the Topic specific fields, lectures are given by the faculty members listed next to the module names in the table below.

Course calendar.
SES #	TOPICS	KEY DATES
L0	Introduction - Prof. Leonid Mirny
Module 1: Evolutionary and Population Genetics - Lectures by Prof. Robert Berwick
L1	The Basic Forces of Evolution: Mutation, Recombination and Mating, Migration, Neutral Evolution and Drift, Effective Population Size
L2	Selection, Fitness, Probability of Fixation, Coalescent Theory Parameter Estimation
R1	The Basic Forces of Evolution: Mutation, Recombination and Mating, Migration, Neutral Evolution and Drift, Effective Population Size Selection, Fitness, Probability of Fixation, Coalescent Theory Parameter Estimation
L3	Selection, Fitness, and Diffusion Models Molecular Evolution, Jukes-Cantor Model, Kimura Model
L4	Human/Mouse/Rat Examples Measuring Selection: From 'Classical' Methods to Maximum Likelihood (With Applications to Disease Evolution, HIV and Influenza) McDonald-Kreitman Test	Problem set 1 out
R2	Discussion of Problem Set 1
L5	Medical Lecture: Genetic Diversity and Evolution of Hepatitis C Virus - Prof. Isaac Kohane
L6	Guest Lecture - Prof. Richard Lewontin	Final projects discussed with class faculty after the lecture
Module 2: Comparative Genomics - Lectures by Prof. Shamil Sunyaev
L7	Domain Structure of Proteins, Sequence-Structure-Function Relationships Orthologs, Paralogs, In/Out-Paralogs Pairwise Sequence Comparison - Substitution Matrices (PAM, BLOSUM, Gonnet) - Alignment Methods - Alignment Statistics	Problem set 1 due
L8	Structure of the Genome Genome Comparison and Genome Evolution: Duplication, Recombination, Insertions, Repeats Finding Genome Elements: Genes, Regulatory Regions Motif Searching Conserved Non-coding
R3	Infinite Site Model: Nucleotide Diversity, Allele Frequency	Problem set 2 out
L9	Multiple Alignments, Profiles and PSSM, HMMs, Domain Databases Prediction of Gene Function Using: Homology, Context, Structure
L10	SNPs: Microevolution, Inference of Population History LD, Haplotypes, Medical Applications Effect of SNPs on Function
R4	Recitation: SNPs
L11	Medical Lecture: Human Variations Genes, Genotypes and Generations - Dr. Marco Ramoni	Summary of final projects due
Module 3: Structural Genomics and Proteomics - Lectures by Prof. Leonid Mirny
L12	Overview of Protein Structures, Domain Architecture Sequence-structure Mapping, Protein Folding, Forces and Interactions	Problem set 2 due
L13	Structure-based Substitution Matrices Protein Structure Prediction Threading Protein Function: Binding and Kinetics, Michaelis-Menthen Kinetics, Inhibition Protein-DNA Recognition: Models and Algorithms
L14	Proteomics: Networks of Protein-protein Interactions, Complexes, Modules Power-law Distributions, Clustering Coefficient
L15	Proteomics: Evolution of Protein and Regulatory Networks, Function and Misfunction of Genes in Networks
R5	Recitation
L16	Medical Lecture: Hemoglobin and the Anemias - Prof. Isaac Kohane	Problem set 3 out
L17	Guest Lecture	Final projects progress report due
Module 4: Functional Genomics and Networks - Lectures by Prof. Alvin Kho
L18	Gene Regulation and Function, Conservation, Detecting Regulatory Elements
L19	RNA Expression: Clustering and Classification	Problem Set 3 due
L20	RNA Expression: Classification, 2-way Clustering, Regulatory Modules Integration of Expression and Proteomic Data	Problem set 4 out
R6	Recitation
L21	Dynamics of Biological Networks Metabolic, Regulatory FBA, Signaling, Regulation of Gene Expression
L22	Medical Lectures - Prof. Isaac Kohane Two Examples: Phenylketonuria (monogenic) and Diabetes Type 2 (multigenic+) "Disease" Genes vs. "Susceptibility" Genes "Environmental" vs. "Developmental" Regulation of Gene Expression
L23	Guest Lecture	Problem set 4 due
L24	Final Presentations

Readings

Suggested Papers

Gould, Stephen Jay, and Richard C. Lewontin. "The Spandrels of San Marco and the Panglossian Paradigm: A Critique of the Adaptationist P." Proc Roy Soc London B 205 (1979): 581-598.

Prediction of Protein Function

Korbel, J. O., L. J. Jensen, Mering C. Von, and P. Bork. "Analysis of genomic context: Prediction of functional associations from conserved bidirect." Nat Biotechnol 22, no. 7 (July 2004): 911-7.

Pellegrini, M., E. M. Marcotte, M. J. Thompson, D. Eisenberg, and T. O. Yeates. "Assigning protein functions by comparative genome analysis: Protein phylogenetic profiles." Proc Natl Acad Sci U.S.A. 96, no. 8 (April 13, 1999): 4285-8.

Sonnhammer, E. L., S. R. Eddy, E. Birney, A. Bateman, and R. Durbin. "Pfam: Multiple sequence alignments and HMM-profiles of protein domains." Nucleic Acids Res 26, no. 1 (January 1, 1998): 320-2.

Medical Lecture 2 (Dr. Marco Ramoni)

Hoh, J., and J. Ott. "Mathematical multi-locus approaches to localizing complex human trait genes." Nat Rev Genet 4, no. 9 (September 2003): 701-9.

Sebastiani, P., M. F. Ramoni, V. Nolan, C. T. Baldwin, and M. H. Steinberg. "Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia." Nat Genet 37, no. 4 (April 2005): 435-40.

Module 4: Functional Genomics

Turing, A. M. "The Chemical Basis of Morphogenesis Philosophical Transactions of the Royal Society of London." Series B, Biological Sciences 237, no. 641 (August 14, 1952): 37-72.

Online Resources

A Population Genetics Primer Online

Pfam Database