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Intro/Background

Generating Diversity: how genes and genomes evolve Erin “They call me Dr. Worm” Friedman 29 September 2005. Intro/Background. Why do we care about generating diversity? What exactly is mutation? How does evolution act on mutations? How does evolution work on a molecular scale?

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Intro/Background

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  1. Generating Diversity: how genes and genomes evolveErin “They call me Dr. Worm” Friedman29 September 2005

  2. Intro/Background • Why do we care about generating diversity? • What exactly is mutation? • How does evolution act on mutations? • How does evolution work on a molecular scale? • It’s not just about frog mating calls…

  3. 09_01_Germ_somatic1.jpg

  4. 09_02_Germ_somatic2.jpg

  5. Genetic Change  Mutation 09_03_altered.genes_part1.jpg

  6. 09_03_altered.genes_part2.jpg

  7. Point Mutations • Nucleotide change, addition, deletion • Silent Mutation – same AA (synonymous) • Sense Mutation – different AA (nonsynonymous) • Nonsense Mutation – stop codon (translation termination) Plotkin et. al., Nature 2004

  8. Generating Point Mutations • Replication Errors (Polymerase isn’t perfect) • Human rate 1 in 1010 • Chemical mutagens or radiation • Repair failure after such DNA damage

  9. Sickle Cell Anemia • Caused by a point mutation in beta chain of hemoglobin (GAGGTG) • Changes glutamic acid to valine • What kind of mutation is this? • Autosomal Recessive Disorder • Cell morphology http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/M/Mutations.html

  10. Sickle Cell Evolution • Sickle cell anemia vs. sickle cell trait (het) • Low oxygen  Acidity  sickling • Link between sickle cell trait and malaria • Positive selection for sickle cell trait in some regions with high malaria incidence http://www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_WhatIs.html

  11. Gene duplication / deletion 09_05_Gene.duplicate.jpg

  12. Globin Gene Evolution • Especially important in larger, multicellular organisms • Diffusion doesn’t cut it • Multiple duplication events • Primitive animals have one globin chain; higher vertebrates have two • Beta-globin duplicated / mutated again (fetal, adult) and each product duplicated…

  13. Gene duplication / deletion 09_06_globin.1.jpg

  14. 09_07_globin.2.jpg

  15. Duplication  Divergence • New gene copy is free to mutate • Not all duplications lead to functional new genes (pseudogenes) • Impact of gene deletions?

  16. Exon Duplication 09_09_exon.jpg

  17. Exon Shuffling • Recombination between non-homologous genes • A few thousand exons could explain protein variability today • Combinations of different exon elements • (symbols = different protein domains) Fig. 9-10

  18. Exon shuffling • Can bacteria use exon duplication / shuffling to form a functional gene? • Why would big introns be beneficial for generating diversity in this manner?

  19. Transposable Elements • Parasitic DNA sequences • Can disrupt function, alter regulation, or make new genes by bringing along gene segments with it • Inverted repeats • Transposase binding domains http://engels.genetics.wisc.edu/Pelements/fig1.html

  20. Transposons 09_11_exon.arrange.jpg

  21. Transposable Elements in regulatory regions Common human example of gene inactivation from transposon insertion: Factor VIII  hemophilia

  22. Transposons as a tool • Transposable elements can be used to study particular genes • Knock out genes and look for a phenotype (reverse genetics) • Drosophila P-Element (transposon) • Can carry different genes, map insertion by phenotype

  23. Horizontal Transfer: organisms exchanging genes 09_13_conjugation.jpg

  24. Conjugation animation

  25. 09_14_promiscuous.jpg

  26. Consequences of Horizontal Transfer • Gene duplication • Rapid evolution • Bacterial antibiotic resistance • Some strains of TB are resistant to 9 antibiotics • “Drug resistance may have contributed to the 58 percent rise in infectious disease deaths among Americans between 1980 and 1992.” (Mayo Clinic) • Where in genome would resistance genes live?

  27. What Now? • We can use this information to reconstruct an evolutionary tree

  28. Analyzing Genomes • Homologous genes have common ancestry, similar nt sequences • Finding homologues with BLAST • Different genome segments evolve differently • Highly conserved / essential genes = constrained • Purifying selection removes dysfunctional individuals • Positive selection preserves beneficial mutations • Genetic Drift: random, unconstrained mutation • How we measure mutation rate

  29. Evolutionary descent 09_15_Phylogen.trees.jpg

  30. 09_16_Ancestral.gene.jpg

  31. Why reconstruct ancestor sequences? • Can be used to study evolution rates • Why can’t you just compare 2 genes? • Measuring rates with dN/dS, PAML • Evolution rate is a good screen for looking for candidate genes (compare gene to ancestor, not to homologous gene): • Some genes likely evolve rapidly (e.g. those involved in infection, defense) • Highly conserved, essential genes likely evolve slowly

  32. Conserved synteny 09_17_Human_chimp.jpg

  33. Sample genome analysis Rediers et. al., Microbiology 2004

  34. Synteny in Pseudomonas

  35. “Junk” DNA Exons more highly conserved than introns: different evolutionary constraints in different parts of genome 09_19_human_mouse1.jpg What kind of selection is acting on the exons? What phenomenon is taking place in the intron?

  36. Introns (noncoding DNA) are non-essential 09_21_Fugu.introns.jpg

  37. Conserved sequences: comparing distant genomes Small subunit of rRNA 09_22_genetic.info.jpg

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