Modeling Molecular Evolution

Learning Goals:

• CS students: To apply their knowledge of data structures and algorithms to a biological/bioinformatics domain
  
• Biology students: To apply their knowledge of the biology to design algorithms
  
• For the collaboration: To become familiar with modeling a biological process: requires "abstracting away" features of the biology; a simple model must be constructed and tested first.

This is appropriate for use in an upper level bioinformatics course in which the students have already become familiar with:

1. basic algorithm design
2. use of a scripting language such as Perl to implement an algorithm
3. Central Dogma, especially concepts of codons and protein translation
4. DNA single point mutations

Textbooks

1. Perl for Exploring DNA by LeBlanc and Dyer (Oxford University Press)
   
2. Understanding Bioinformatics by Zvelebil and Baum (Garland)

Week 1: Randomness, Sequence Alignment

Instructors provide background information (lectures and reading) on

1. Theory and practice of sequence alignment: A lecture on Sequence Alignment (PowerPoint 1.4MB Jun5 09)
2. Concept of randomness in the physical world as well as simulated by the computer: A lecture on Randomness (PowerPoint 139kB Jun5 09)

Students are given an assignment to acquire protein sequences from several genomic databases, then conduct sequence alignments using clustal.

1. Practice performing alignments using blast and clustal (Acrobat (PDF) 69kB Jun5 09)

Week 2: Creating models of DNA mutation

Discussion of the biology:Students discuss what they know about how DNA and protein sequences change over time, and the class discusses the process of DNA mutation, which is presented in the textbook as a primarily random process. The biology students, however, should be able to contribute information that the pattern of nucleotide substitution is probably not random, because alternation of an amino acid might affect the function of a protein, so the nucleotides that are most likely to vary are those in the the position of codons. Class discusses how the process of mutation may be random, but the process of selection will prevent most amino-acid altering substitutions from persisting.

Discussion of the algorithm:How might we model how protein evolution might look under two different scenarios: a random vs targeted nucleotide substitution approach. The Bio/CS pairs are given "starter code" that they must further modify and develop to model the effect of a random vs. targeted substitution on the the human Heat Shock Protein 70 (HSP70).

Assignment: Compare effects of substitutions that occur under a random vs. targeted to 3rd position of codons:

1. Model nucleotide substitution assignment
   
1. Assignment: Model random vs. targeted substitutions (Microsoft Word 25kB Jun5 09)
2. Substitution starter code ( 7kB Jun5 09)
3. Substitution data file (Text File 2kB Jun5 09)

Week 3: Using empirical data to test the models

The goal: use extant protein-coding genes to provide evidence to support or refute the students' attempts to model the evolution of protein-coding genes.

1. Construct a DNA sequence alignment of 5 animal homologs of the HSP70 gene
2. Write an algorithm to calculate the diversity of nt in each position of each codon
   
1. Starter Code for calculating codon diversity statistics ( 6kB Jun7 09)
2. Multiple fasta file of HSP70 DNA sequences (Text File 12kB Jun7 09)
3. Multiple fasta file of HSP70 amino acid sequences (Text File 4kB Jun7 09)
3. Compare the diversity statistics with the two models to assess whether one model more closely mirrors the evolution of the HSP70 gene.
   

Collaborative teaching:

This teaching activity was developed in the context of an upper level team-taught course (computer science and biology).

Pedagogical template:

1. Define a biological question or problem for the students to address. In this case, the problem to address was evolution of protein-coding DNA sequences.
   
2. We provided the students with "starter code" that did part of the job, or it was a first attempt at doing the job.
3. The students had to run and study the code and either improve the code or refine their original biological question or, usually, both.
4. To be successful, they had to collaborate, because they needed expertise in both the Bio and CS. The whole was greater than the sum of its parts.

• Pre/post survey to assess level of familiarity with genomics and bioinformatics Pre/post Attitude Survey (Microsoft Word 31kB Jun29 09)
• Completion of a "pre-assignment" that tested ability to acquire sequences from the databases, and familiarity and interpretation of protein sequence alignment Alignment Assignment (Acrobat (PDF) 69kB Jun5 09)
• Completion of an algorithm and perl script that modeled the evolution of DNA under random vs. targeted scenarios:

• Modeling assignment (Microsoft Word 25kB Jun5 09);
• Example of student code (substitution) ( 11kB Jun29 09);
• Example student results (substitution) (Excel 40kB Jun29 09)

• Completion of an algorithm and perl script that calculated the real nucleotide diversity at each position, using a dataset of 5 genes:

• Example of student code (diversity) ( 6kB Jun29 09)
  

Example student results (diversity) (Text File 559bytes Jun29 09)

• Instructor observation on the following aspects:

• collaboration and communication

• ability to identify and describe problems associated with the development and implementation of algorithms

• ability to interpret results after implementation and to discover problems that require re-thinking the approach

• increased sophistication in ability to understand molecular evolution (mutation occurs at the DNA level, but selection occurs at the protein level)
  

Textbooks

1. Perl for Exploring DNA by LeBlanc and Dyer (Oxford University Press)
   
2. Understanding Bioinformatics by Zvelebil and Baum (Garland)

Computing resources

Bioinformatics computing cluster (16 core Linux, SunGrid Engine) with a suite of open source bioinformatics tools (via iNquiry).

However, this module could be done entirely making use of open source web-based tools (clustalw) as well as any system that can run code (such as linux or dos).