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 Quantitative Genomics  posted by  duggu   on 11/24/2007  Add Courseware to favorites Add To Favorites  
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Kohane, Isaac, Leonid Mirny, Robert Berwick, and Alvin Kho, HST.508 Quantitative Genomics, Fall 2005. (Massachusetts Institute of Technology: MIT OpenCourseWare), (Accessed 09 Jul, 2010). License: Creative Commons BY-NC-SA



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.


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


Problem Sets 50%
Final Project 50%




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.

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


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   Tell A Friend