Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 3001/14/191Bi 1 “Drugs and the Brain” Lecture 27Thursday, May 26, 2006Evolution 1. Inferences from molecular biology. Mechanisms of speciation2What is a theory (as in, “Theory of Evolution)?WikipediaIn common usage, people use the word "theory" to signify "conjecture", "speculation", or "opinion." In this sense, "theories" are opposed to "facts" — parts of the world, or claims about the world, that are real or true regardless of what people think.In science, a theory is a proposed description, explanation, or model of the manner of interaction of a set of natural phenomena, capable of predicting future occurrences or observations of the same kind, and capable of being tested through experiment or otherwise verified through empirical observation. It follows from this that for scientists "theory" and "fact" do not necessarily stand in opposition. For example, it is a fact that an apple dropped on earth has been observed to fall towards the center of the planet, and the theory which explains why the apple behaves so is the current theory of gravitation.HALA theory is not a mathematical theorem. A reminder of Henry Lester’s office hoursMonday & Thursday, 1-1:30, outside the Red Door3DNA changes that might lead to speciation1. “Break and join” events2. Repeated elements can lead to gene and exon duplication.3. How transposable elements move5. What is the selective advantage of repetitive elements?5. Point mutationsWhat is a species?Populations of the same species can interbreed, exchange genes, and pass on traits to their offspring.4Number of base pairs in Genbank, 1982 - presentThese graphs provide one example of the rapidly accumulating data in biology, leading to entire new fields of study.Today’s topic, evolution, is one such field. 2-fold / 18 mo10-fold / 5 yrSemilogarithmic plothttp://www.ncbi.nlm.nih.gov/Genbank/genbankstats.html5Polymerase Chain Reaction (PCR) gives access to genomes of many rare organismsDNAsynthesiscool tobind primersDNAsynthesiscool tobind primersDNAsynthesiscool tobind primersfragment of DNAto be detectedheat to separate DNAstrandsheat to separate DNAstrandsheat to separate DNAstrandslike Lecture 15:6Lander et al from Lecture 15:71. “Break and join” events produce conserved synteny.~180 events between mouse and human, 75 mY agoRegions where corresponding genes that began as neighbors have remained as neighbors, strung together in the same sequence in both species.Little Alberts 9-28© GarlandHumanMouse“synteny”8from Lander Figure 17Repetitive elements in the human genome(L1-like)(Alu-like)SINE = Short INterspered ElementSee also Lectures 15, 189(1) length ~ 300 bp(2) account for 13% of the genome(3) require reverse transcriptase and an RNA intermediate to transpose.(4) occur primarily in GC-rich regions1,090,000copiesThe human Alu sequences are SINEs10The process involves (a) Enzymes that nick(b) Base pairing(c) Enzymes that ligatefrom Lecture 20A Reminder that recombination at meiosis is based on cross-strand exchange11Gene and exon duplication due to repeated elementsMisalignment at meiosis leads to . . . .“Unequal” crossing overLittle Alberts 9-5© GarlandThis chromosome would not surviveFigure 9-11 shows how individual exons would be duplicated by the same mechanism12Exons don’t differ much among organisms, From Lecture 15:but human introns are longerLong introns may increase the probability that shuffling maintains functional exons13Myr BP(Hemoglobin is a tetramer, )Globin paralogs in the human genome© Garland publishingBased on Little Alberts 9-7Two categories of sequence-related genes:Orthologs are pairs of genes in different species that evolved from a common ancestral gene by speciation. Orthologs are “the same gene” in two different genomes. >90% of genes have orthologs in human – rat – mouse.Paralogs are pairs of genes related by duplication within a genome. Orthologs often retain the same function in the course of evolution, whereas paralogs may evolve new functions, even if related to the original one. See also Lecture 1814mouse-human split, produces orthologsnewMyr BPGlobin paralogs in the human genomeMyr BPGlobin paralogs in the mouse genomechromosome 715Myr BPHemoglobin paralogs in the human genomeMyr BPHemoglobin paralogs in the mouse genomechromosome 7 no duplication duplication16Myr BPHemoglobin paralogs in the human genomeMyr BPHemoglobin paralogs in the mouse genomechromosome 7 orthologs resemble each otheracross species (mouse  vs human ) human  vs mouse  vs paralogs resemble each other, distant or closely, within a species G vs A17Little Alberts 9-18© Garland 1998Alu (SINE)L1 (LINE)Here are remaining repetitive elements that may have produced these duplications183. How transposable elements move, so that they become repetitive“Move” is the common term, but “copy” is a better term.193a. DNA-mediated transposable elements: long-distance movements“Many details are known, but the process is too complex to be illustrated here”--Big Albertsbase pairingand enzymes203b. RNA-mediated transposable elements are retrotransposons.1,090,000copies213b. RNA-mediated transposable elements are retrotransposons.Little Alberts 6-34© Garland Discovered by David Baltimorein retroviruses, where it functions much more frequently.A virus is a “fully mobile genetic element that can escape from cells”Reverse transcriptaseencoded by the LINE-1 element22A. None, just “selfish” DNAB. In many species, Alu-like sequences are expressed under conditions of stress.The resulting RNAs specifically bind and block a protein kinase called PKR.PKR ordinarily blocks protein synthesisTherefore, SINE RNAs would promote protein translation under stress. A Bi1 irony: Some biologists suggest that repetitive elements play roles resembling those played by lithium and the SSRIs!4. Selective advantage, if any, of repetitive elements?23DNA changes that might lead to speciation1. “Break and join” events2. Repeated elements can lead to gene and exon duplication.3. How transposable elements move4. What is the selective advantage of repetitive elements?5. Point mutations24Human / chimpanzee (draft available now; full