generating diversity: how genes and genomes evolve erin “they call me dr. worm” friedman 29...
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Generating Diversity: how genes and genomes evolve
Erin “They call me Dr. Worm” Friedman29 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?
• It’s not just about frog mating calls…
09_01_Germ_somatic1.jpg
09_02_Germ_somatic2.jpg
09_03_altered.genes_part1.jpg
Genetic Change Mutation
09_03_altered.genes_part2.jpg
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
Generating Point Mutations
• Replication Errors (Polymerase isn’t perfect)– Human rate 1 in 1010
• Chemical mutagens or radiation
• Repair failure after such DNA damage
Sickle Cell Anemia
• Caused by a point mutation in beta chain of hemoglobin (GAGGTG)
• 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
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
09_05_Gene.duplicate.jpg
Gene duplication / deletion
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…
09_06_globin.1.jpg
Gene duplication / deletion
09_07_globin.2.jpg
Duplication Divergence
• New gene copy is free to mutate
• Not all duplications lead to functional new genes (pseudogenes)
• Impact of gene deletions?
09_09_exon.jpg
Exon Duplication
Fig. 9-10
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)
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?
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
09_11_exon.arrange.jpg
Transposons
Transposable Elements in regulatory regions
Common human example of gene inactivation from transposon insertion: Factor VIII hemophilia
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
09_13_conjugation.jpg
Horizontal Transfer: organisms exchanging genes
Conjugation animation
09_14_promiscuous.jpg
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?
What Now?
• We can use this information to reconstruct an evolutionary tree
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
09_15_Phylogen.trees.jpg
Evolutionary descent
09_16_Ancestral.gene.jpg
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
09_17_Human_chimp.jpg
Conserved synteny
Rediers et. al., Microbiology 2004
Sample genome analysis
PST v PSB
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Synteny in Pseudomonas
PST v PP
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PST v PA
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09_19_human_mouse1.jpg
“Junk” DNA
Exons more highly conserved than introns: different evolutionary constraints in different parts of genome
What kind of selection is acting on the exons?
What phenomenon is taking place in the intron?
09_21_Fugu.introns.jpg
Introns (noncoding DNA) are non-essential
09_22_genetic.info.jpg
Conserved sequences: comparing distant genomes
Small subunit of rRNA
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