BIO/CSC295 2011F, Class 04: The Central Dogma (1) Overview: * Reflection on the Chapter 1 programming lab. * Basics of the Central Dogma * Key Processes * Some Related Issues * Computational Problems * Web Exploration Admin: * For next Tuesday, read and respond to Altshcul et al. 1990. (BLAST!) * For Thursday, Read Chapter 3. * A friendly reminder for the FaceBook generation: What appears in the S&B stays on the Web for a long time. Do you want a potential employer or grad school committee to read "My goal is to make out with everyone in this house before the end of the year." (That's better than the alcohol comments that normally appear in house profiles. However, ....) * Pick new groups today. New partners. Still mixed background. * You do not need to turn in a writeup for today's lab or Thursday's lab. You will, however, have to due the on-your-own project (2.6). * EC for Gene Gaub's concert, Thursday, 11 a.m. * EC for Terian Koscik on Alice, Thursday, 4:30 p.m. in 3821 * EC for Summer MAP presentation on Robotic Education, Thursday the 15th 4:30, in 3821 * EC for volleyball home games this weekend * EC for cross country Les Duke home meet this weekend. Ride a bus to Oakland acres. * EC for football at home Saturday at 1pm. * Biochem picnic yesterday. Borrow the The Future House time machine to go. * Chem picnic Friday. * Go support the women's tennis team Saturday at 2pm * tabforacause.org - Drink sacchrine-ated diet soda to support nonprofits Thursday: * We wrote Python code to find the complement of a sequence * We use Python, book uses Perl. Which do you prefer?a * We use an interactive model in which you have procedures that you call with an interface to right Book - type input - Do you prefer one model more? Perl gives you more freedom to do what you want Perl has more stylistic freedom based on style of input Perl looked more complicated; Ditto Python seemed to be more logical. * Note: Some people felt that they understood very little of the programming. * Note: The first time through is really tough. * Expectations:we expect those with little CS experience won't be excellent amazing programmers, but will be able to communicate some of the ideas in Cs speak. We would like everyone to continue to write code all term, but it will take a while. Useful to reference Python on line. - Chase will come up with links * We are stepping out of our comfort zone. That's good. * Do things "with discplinary integritC" * In the end, we care that you are able to COMMUNICATE with those outside your discpline. * But with integrity Material from Chapter 2 * May be known to most of you. * But also unknown to some of you * Topic 1: Sickle Cell * People are facing the option of doing genetic testing * For yourself * Before having children * 23 and me: Send 'em $100 or so and they'll sequence your genome * Question from the book: Woman who knows she is a carrier of sickle cell and wants her husband to be tested. He is worried. Why? * Insurance problems: My insurer will find out I'm sick and will eliminate my insurance. * Worry about ethics of worrying about children. * I might get fired (although not legally) * HIPAA protects your medical information * Not from your insurer. * Maybe not from your employer. * Genetic Nondescrimination Act - American insurance companies cannot look at you genetic information before you enroll, change your premium based on genetic information, etc. Companies cannot change employment based on genetic information. * US Air Force restricted people from being pilots if they were sickle cell carriers. Argument: At high altitudes, there's less oxygen, and sickle cell carriers would be more likely to pass out. * There's some evidence that this worry is a reasonable one. * Is this different than discriminating based on height? * Is this an "unfit for the job" issue? * Do we worry more because the sickle cell trait is associated with race? * Note that military service is often a way out of poverty. * Why focus on one particular risk factor? There may be unknown risk factors. * Better to do a direct test (does this person perform less well at high altitudes) rather than an indirect test. * The genotype does not tell you about how much the trait is expressed. * Is there a meaningful distinction between doing the genetic test and doing another test that tells you "the same thing"? * Expression of genes is affected by physical environment. So they aren't really the same thing. * 23 and me's "You have a risk factor increase by 10% of ..." * There's not a direct correlation between individual genes and characteristic * Multiple genes working together * Other environmental factors * Genes + Environment = Phenotype * Back to the story from the book * Mary is a carrier. * For every gene except those on the X,Y chromosomes, you have two copies of the gene, one inherited from father, one inherited from mom. * A carrier has the mutation on one copy, but not the other. * Mary is a carrier, so we express her as Aa * Mary's Anonymous Husband could be AA * In this case, there's a 50% chance that a kid will be a carrier (Aa) * In this case, there's a 0% chance that a kid will have the disease * But this is simplified - There are complicating factors, e.g., cross-gene effects * Mary's Anonymous Husband could be Aa * 25% chance child will have the disease * 50% chance child will be a carrier A a --+------ A |AA Aa a |Aa aa * What about things on the X chromosome? * Reminder: Males are XY, Females are XX * Xf.XF x XF.Y Xf XF --+-------- XF|XfXF XFXF Y|XfY XFY * If the child is male, he gets the Y chromosome from dad and X from mom, so 50% chance of having the disease * If the child is female, she gets the XF chromose from dad and an X from mom, so 50% chance of being a carrier and NO CHANCE of disease. (Women are so lucky.) * This applies to color vision * Capital letters for "normal"/"wild type" * Lowercase letters for muties/abnormals/alleleic (sp?) variants * In some worlds, uppercase for dominant, lowercase for recessive * Detour: Dominant vs recessive * recessive genes are apparent in the person only when homozygous * dominant genes are apparent even if only one copy (or both) * But it's not always this simple. Some things that are dominant in one case may be recessive in another. The Central Dogma * What is it? A term coined by Francis Crick. * Used in chapter, but not defined. * Genes and DNA and stuff. * How information moves in a cell * From DNA to RNA - transcription * Both are nucleic acids. A scribe makes a copy * From RNA to Protein - translation * Are there exceptions to this? * RNA can be functional - you can read extra parts of the book to learn this * Cases in which RNA goes back to DNA. But those are just viruses. And they're not alive. * Insert stuff into the DNA to make new copies of themselves * Prions (and mad cow disease) * Bovine spongiform encephelitus (sp) * Spongy brains * Misfoled protein in the brain * And that protein can catalyze other proteins to misfold * And that clogs up your brains * Note: Information transmission from protein to protein * What is the rationale for the existence for prions? * We don't know * There is a corresponding human disease that cannibals get at high frequency DON'T EAT PEOPLE! * What does this mean in terms of the stuff insicde the cell? * Lots of biological processes: * Replication: Making a copy of your DNA to pass along to progeny. * Some chemistry 5' A T C G G C C T A ... 3' With a matched pair 3' T A G C C G G A T ... 5' * Strands run in opposite directions * Transcription: Make a one-stranded RNA copy of PART of the DNA. * Someone "cheated" in the design of RNA databases: They are too lazy to use U's for RNA, so they still use T's. * "DNA is a recipe book that makes the spoons and bowls and mixers!" -- Praitis 2011 * Translation: Every three letters encode an amino acid. There are 64 possible base combinations. Only 20 amino acids. What's going on? * There's some duplication: Some different codes encode the same amino acid. * There's a start codon and stop code. * There are some cool experiments that show that we really do encode with triplets. * We have now done BIO251 in twenty minutes by ignoring the underlying chemistry. * Some fun issues: * How do you recognize a gene? There are billions of base pairs, but only about 30K genes * Introns: Genes are not always contiguous, at least in humans. Predicting where the gene is can be complex. * What's going on with the multiple coding for the same amino acid? * Some tRNA that is a bit lazy about looking at the third base pair * It turns out that some organisms are biased towards particular encodings, and changing the encoding has a striking effect. * Silent mutation caused splicing. * What happens if a base pair is deleted? * The reading frame shifts - you change all the downstream stuff * So DNA repair mechanisms tend to avoid these kinds of circumstances * Single BP mutations are more likely. * Which strand does the RNA come from? And does it matter? * Yes, it matters. * We tend to call one as the coding strand and one as the template strand. * The cell uses the template strand to make the RNA. * But strands can switch roles |Code for Gene 1| 5' ................................................... 3' 3' ....................................................5' |2 eneG rof edoC| What are likely to be the straightforward and perhaps more interesting computational problems related to the central dogma? * What computational solutions come out of the central dogma? Find the start and stop codons? DNA to RNA - transcription RNA to amino Acids - translation Detecting mutations - compare sequences Predict 3-d structure from amino acid sequence - simulate physics; simpler problems - do transmembrane sequences have common elements. a-helices, b-sheets, common sequences? Identify introns within a sequence Identify combinations of introns detecting silent mutations The approaches we chose may make things harder than others. We might miss "silent" mutations, depending on assumptions we make in algorithms Determining genetic probabilities - This is really powerful when you have lots of genomic information (e.g. many genes) We will first start comparing nucleotide sequences We will later compare amino acid sequences BLAST - Basic local alignment Search tool Paper has some cool, complex programming components Thursday - how do we transcribe? How do we translate? Web exploration on HBB. page 25 of your text. * The file called sicklecell_dna_modified.txt should suffice for sicklecell_dna.txt * *