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Bi 1 “Drugs and the Brain” Lecture 27 Thursday, May 26, 2006 Evolution 1. Inferences from molecular biology. Mechanisms of speciation 5/23/2017 1 What is a theory (as in, “Theory of Evolution)? Wikipedia In 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. HAL A theory is not a mathematical theorem. A reminder of Henry Lester’s office hours Monday & Thursday, 1-1:30, outside the Red Door 2 DNA changes that might lead to speciation 1. “Break and join” events 2. Repeated elements can lead to gene and exon duplication. 3. How transposable elements move 5. What is the selective advantage of repetitive elements? 5. Point mutations What is a species? Populations of the same species can interbreed, exchange genes, and pass on traits to their offspring. 3 Number of base pairs in Genbank, 1982 - present 60 56 52 48 44 40 36 32 28 24 20 16 12 8 4 0 1.E+11 Semilogarithmic plot 1.E+10 Base Pairs Base Pairs (billions) http://www.ncbi.nlm.nih.gov/Genbank/genbankstats.html 1.E+09 1.E+08 1.E+07 2-fold / 18 mo 10-fold / 5 yr 1.E+06 1980 1985 1990 1995 2000 2005 1980 1985 1990 1995 2000 2005 Year Year These 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. 4 like Lecture 15: Polymerase Chain Reaction (PCR) gives access to genomes of many rare organisms heat to separate DNA strands cool to bind primers heat to separate DNA strands cool to bind primers DNA synthesis heat to separate DNA strands DNA synthesis cool to bind primers DNA synthesis fragment of DNA to be detected 5 from Lecture 15: Lander et al 6 1. “Break and join” events produce conserved synteny. ~180 events between mouse and human, 75 mY ago Regions where corresponding genes that began as neighbors have remained as neighbors, strung together in the same sequence in both species. “synteny” Human Little Alberts 9-28 © Garland Mouse 7 See also Lectures 15, 18 Repetitive elements in the human genome SINE = Short INterspered Element (L1-like) (Alu-like) from Lander Figure 17 8 The human Alu sequences are SINEs 1,090,000 copies (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 regions 9 from Lecture 20 A Reminder that recombination at meiosis is based on cross-strand exchange The process involves (a) Enzymes that nick (b) Base pairing (c) Enzymes that ligate 10 Gene and exon duplication due to repeated elements Figure 9-11 shows how individual exons would be duplicated by the same mechanism Misalignment at meiosis leads to . . . . “Unequal” crossing over Little Alberts 9-5 © Garland This chromosome would not survive 11 Long introns may increase the probability that shuffling maintains functional exons From Lecture 15: Exons don’t differ much among organisms, but human introns are longer 12 See also Lecture 18 Globin paralogs in the human genome Two 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. Myr BP Orthologs often retain the same function in the course of evolution, whereas paralogs may evolve new functions, even if related to the original one. © Garland publishing Based on Little Alberts 9-7 (Hemoglobin is a tetramer, a2b2) 13 new mouse-human split, produces orthologs Globin paralogs in the mouse genome Globin paralogs in the human genome chromosome 7 Myr BP Myr BP 14 Hemoglobin paralogs in the mouse genome Hemoglobin paralogs in the human genome no duplication duplication chromosome 7 Myr BP Myr BP 15 orthologs resemble each other across species (mouse b vs human b) Hemoglobin paralogs in the mouse genome mouse e vs b paralogs resemble each other, distant or closely, within a species Hemoglobin paralogs in the human genome human e vs b gG vs gA chromosome 7 Myr BP Myr BP 16 Here are remaining repetitive elements that may have produced these duplications Alu (SINE) L1 (LINE) Little Alberts 9-18 © Garland 1998 17 3. How transposable elements move, so that they become repetitive “Move” is the common term, but “copy” is a better term. 18 3a. DNA-mediated transposable elements: long-distance movements “Many details are known, but the process is too complex to be illustrated here”--Big Alberts base pairing and enzymes 19 3b. RNA-mediated transposable elements are retrotransposons. 1,090,000 copies 20 3b. RNA-mediated transposable elements are retrotransposons. Discovered by David Baltimore in retroviruses, where it functions much more frequently. A virus is a “fully mobile genetic element that can escape from cells” Reverse transcriptase encoded by the LINE-1 element Little Alberts 6-34 © Garland 21 4. Selective advantage, if any, of repetitive elements? A. None, just “selfish” DNA B. 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 synthesis Therefore, 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! 22 DNA changes that might lead to speciation 1. “Break and join” events 2. Repeated elements can lead to gene and exon duplication. 3. How transposable elements move 4. What is the selective advantage of repetitive elements? 5. Point mutations 23 To assess the importance of point mutations vs repetitive elements and other changes in speciation, we need the complete sequences of two closely related genomes. Human / chimpanzee (draft available now; full sequence underway) http://www.genome.gov/11008056 Molecular functions showing the strongest evidence for positive selection. Highly represented: olfactory receptors; transcription factors & structural proteins in speech and hearing; immune defenses; tumor suppression; sperm development. “Human-chimp DNA sequence divergence is roughly 10 times the divergence between random pairs of humans.” G. Clark et al (2003), Science 302, 1960; Nielsen et al, PLoS Biology 3, epub Mouse / rat are now available, April 2004. 24 from lecture 15: While we await full sequences . . . Physical Chemistry of DNA Hybridization: Studied at Caltech in ‘60’s and ‘70’s by Norman Davidson 1. The hydrogen bonds that form double-stranded DNA are easily disrupted by heating. 2. Some dyes fluoresce when they bind to double-stranded DNA. 25 DNA Hybridization: a conventional method to assess homology 1. heating. If there are some mismatches, the structure is less stable. It therefore melts at a lower temperature than perfectly paired DNA. 2. Alternatively, the hydrogen bonds are disrupted at lowered ionic strength, because the negatively charged phosphate groups exert stronger forces on each other through the lower dielectric constant of the solution. 3. These hybridization phenomena form the basis for several quantitative measurements of DNA homology. 26 Hybridization is appropriate for assessing random mutations: ~ 1% / 9 Myr bonobo Alberts Figure 9-15 © Garland 27 Bonobos (pigmy chimpanzees) 28 Bi 1 “Drugs and the Brain” End of Lecture 27 5/23/2017 29 Bonobos (pigmy chimpanzees) 30