Kimura Drift2 skenovat0001 40 200 100 400 500 a1 a2 z a1 Gg a2 d b substitution = replacement of one allele by other (tj. fixation of a new allele) if an individual do not reproduce, we call it genetic death J.B.S. Haldane (1957): advantageous mutation ® fixation and replacement of a deleterious allele as long as the original allele exists in the population, mean fitness is lower than maximal fitness Substitutional load and the cost of natural selection File:J. B. S. Haldane.jpg J.B.S. Haldane File:J. B. S. Haldane.jpg substitutional load*): ; when L = 0 in general it measures to what extent an average member of the population is less fit than the best fit genotype it expresses probability that an average individual dies before his/her reproduction *) in general = genetic load; other loads: mutational: emergence of a deleterious allele; segregational: cost of homozygotes under overdominance Cost of natural selection: We can envisage replacement of one allele in a population by another as a „selective death“ of the original allele The higher is the strength of selection, the more of the original (less advantageous) alleles are removed from the population (they „die“) If the natural selection was too strong it could cause extinction of the whole population Þ overproduction of the offspring necessary! eg. if the ratio of non-surviving to surviving alleles is 0,1/0,9, each survivor have to produce by 1/9 more descendants, but if the ratio is 0,999/0,001 ® by ~1000 more descendants! Haldane: upper limit of the cost of natural selection » substitution of 1 gene per 300 generations Þ evolution cannot run too fast, the cost of selection would be too high NEUTRAL THEORY OF MOLECULAR EVOLUTION Modern Synthesis: selection vs. drift debate beginning of the 1960s ® amino acid sequences in proteins 1966: protein elektrophoresis Richard Lewontin and Jack Hubby - Drosophila pseudoobscura; Harry Harris - humans ® high level of polymorphism Data gathered till the end of 1960s suggested that: Rate of evolution at the molecular level is constant Rate of evolution at the molecular level is constant comparison of AA differences between a- and b-globin human carp platypus shark Data gathered till the end of 1960s suggested that: Rate of molecular evolution is high Genetic variation in natural populations is too high ... both would require too high cost of natural selection Þ polymorphism cannot be maintained by selection Why so high polymorphism in populations? Motoo Kimura: because alleles are selectively neutral, it lasts many generations till a new mutation is fixed – meanwhile the population must be polymorphic = transient polymorphism During the process of fixation often a new allele appears by mutation Þ in a sufficiently large population at each point in time there is a large amount of variation Population is in equilibrium between drift and mutation M. Kimura (1968) J.L. King & T.H. Jukes (1969) neutral theory of molecular evolution Kimura M. Kimura skenovat0002 1. most allele substitutions in a population are neutral (Þ drift) Basic principles of the neutral theory: DFEnitely Different: The joint distribution of mutation fitness effe… Mol_sel.tif fast fixation of a beneficial mutation neutral allele is fixed randomly fast extinction of a deleterious mutation parallel occurrence of several alleles mostly only 1 allele in the population fibrinopeptides 8,3 pancreatic ribonuclease 2,1 lysozyme 2,0 alpha-globin 1,2 insulin 0,44 cytochrome c 0,3 histone H4 0,01 2. evolutionary rates in differently important proteins are different Grafika2 2. evolutionary rates in differently important proteins are different synonymous (´ 10-9/year) nonsynonymous (´ 10-9/year) Eg.: transient receptor potential vanilloid (TRPV) channel protein: 3. diverse evolutionary rate in different parts of proteins (binding sites ´ structural areas) http://www.epernicus.com/figures/1223/zoomed/1223.jpg?1243538696 binding sites are more conserved ATP molecule 4. different evolutionary rates at individual codone positions http://bio3400.nicerweb.com/Locked/media/ch13/13_07-genetic_code.jpg 64 codons... ... but 20 aminoacids all nonsynonymous! Evolutionary Genetics - ppt download skenovat0004 ... and in different parts of genome likewise M. Grunstein (1976): evolutionary rate of Histone H4 in 2 sea urchin species 84 bp mtDNA ® 9 of 10 differences synonymous http://images.gizmag.com/hero/nissans-leather-seats-like-human-skin-4.jpg https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcSbEXZJ3IFYe5I4_F2mBefY6k4YNaQg7mLIpCn9-5A0Je4 uQKwE http://eatsomethingsexy.com/wordpress/wp-content/uploads/2010/10/seaurchin.jpg http://www.365daysofdining.com/wp-content/uploads/sea-urchin.jpg excess of synonymous nucleotide substitutions ® esp. at the 3rd position M. Kimura (1977): mRNA sequences of humans and rabbits ® of 53 nucleotide positions 6 differences, of them only 1 nonsynonymous ´ theoretically only 24% of differences should be synonymous Clock2 5. evolutionary rate of a given protein in various species roughly constant Kimura (1983), vertebrates, a-globin: Wilson (1977), mammals, 7 proteins: mostly does not concern morphological, physiological, and behavioural trais cannot explain adaptations many deleterious mutations, however, these rapidly removed by selection selection acts also at the molecular level but most mutations have only small effects on fitness Þ important role of drift Haldane´s cost of selection was overestimated: selection mostly soft, not hard frequency-dependent selection rather than overdominance selection does not affect individual loci independently (epistasis) Mol_drift.tif Mean time to fixation of a novel mutation = 4Ne moderately sized population: mutations more frequent small population: mutations infrequent Mean interval between fixations = 1/m In small populations faster fixations but longer interval between them: Theoretical principles of neutral theory: Mol_drift.tif Frequency of substitutions (replacements of one allele by another in populations): 1/(2Ne) ´ 2Nem = m Þ rate of neutral evolution is independent of Ne, depends only on frequency of neutral mutations m ! Mean time to fixation of a novel mutation = 4Ne Mean interval between fixations = 1/m Theoretical principles of neutral theory: , where q = 4Nem Mean balanced heterozygosity: continual emergence of new mutations Þ increase of variation ´ its erosion by drift Þ continual replacement of one allele by another Equilibrium between mutation and drift Þ polymorphism (contrary to the mutation-selection eq.) is transient larger populations Þ higher heterozygosity mutace advantageous deleterious Rate of neutral mutations: Zeyl & DeVisser (2001): yeast Saccharomyces cerevisiae 50 replicated populations, 1 individual in each generation the experiment does not detect extremely deleterious (lethal) mutations bimodal distribution of mutations DFEnitely Different: The joint distribution of mutation fitness effe… yeast RNA viruses Observed heterozygosity lower than predicted by NT Test of neutral theory: range of heterozygosity Expected heterozygosity heterozygosity according to NT Given the enormous range of population sizes, the range of heterozygosities is too small Test of neutral theory: range of heterozygosity Population size (log) Tomoko Ohta tried to explain the deviations of the observed range of heterozygosity from predictions: slightly deleterious mutations (SDM) Ohta also substitutions of slightly deleterious alleles http://authors.library.caltech.edu/5456/1/hrst.mit.edu/hrs/evolution/public/images/TOhta.JPG in small populations alleles behave as effectively neutral neutralism slightly deleterious mutations Pozn.: protože q = 1/(2N), bude čitatel v rovnici zjednodušen na 1 – e^2s Fixation probability of neutral, beneficial, and deleterious mutation: Eg.: What is the fixation probability of a mutation in a population of Ne = 1000? neutral mutation (s = 0): P = 0,05% advantageous mutation (s = 0,01): P = 20% advantageous mutation (s = 0,001): P = 2% deleterious mutation (s = -0,001): P = 0,004% as s ® 0 higher „neutrality“ Pozn.: protože q = 1/(2N), bude čitatel v rovnici zjednodušen na 1 – e^2s We can conclude that 1) Not all advantageous mutations may be fixed in the population 2) Conversely, with low probability also deleterious mutations can be fixed What is the fixation probability of a mutation in a population of Ne = 10 000? neutral mutation (s = 0): P = 0,005% advantageous mutation (s = 0,01): P = 20% advantageous mutation (s = 0,001): P = 2% deleterious mutation (s = -0,001): P = 2.10-17% in a large population P of an advantegous allele is the same as in a small one but for a deleterious allele P ® 0 Conclusions: 1) In large populations selection plays a much more important role; conversely, with decreasing population size the role of drift is increasing 2) Harmfulness of a mutation is inversely proportional to population size: the more it approaches zero, the larger the population may be for allele fixation (drift exceeds negative selection) and vice versa: the stronger selection against an allele, the smaller the population must be to allow drift to play a substantial role 3) This means that in small populations slightly deleterious mutations behave as effectively neutral Clock2 MOLECULAR CLOCK Zuckerkandl & Pauling (1962-65) AA and/or nucleotide substitution rate is constant effect of generation time: dependency on absolute or generation time? AA sequences of the a-chain of hemoglobin of 6 vertebrate species: XY = XZ despite being morphologically more similar, the distance of the shark from humans is the same as from the carp Þ AA differences are cumulating constantly in time regardless of the phenotypic evolution http://static.squarespace.com/static/5181d5b7e4b07b8c66ed5614/t/528eeee2e4b0fc15797f8ebf/1385098979 427/chicken.jpg http://images.yourdictionary.com/images/definitions/lg/house-mouse.jpg http://www.warrenphotographic.co.uk/photography/bigs/04804-Common-Newt-white-background.jpg http://www.dpi.nsw.gov.au/__data/assets/image/0015/318300/Common-carp-Pat-Tully.jpg http://interactivemedia.seancohen.com/fa2012/Lam_Joan/web2/assignment6/sliding-horizontal-parallax/ images/shark.png http://pixabay.com/static/uploads/photo/2014/02/20/08/45/man-270415_640.png the same distance between the human or mouse from the shark as between the carp and shark Þ no generation time effect both dating methods show almost constant rate independent of generation time Generation or absolute time? Accumulation of neutral substitutions in placental mammals: species with larger populations tend to have shorter generation times Population size and generation time: Þ potential explanation of absolute time dependence: in smaller populations also slightly deleterious alleles are fixed http://upload.wikimedia.org/wikipedia/commons/thumb/7/7e/SNP_saturation.PNG/300px-SNP_saturation.PN G Scan20001.TIF But molecular clock does not „tick“ with the same pace in different groups eg. cetaceans < „artiodactyls“< primates < murine rodents in primates Old World monkeys > „apes“ > humans Problem of sequence saturation: ® using an appropriate evolutionary model („straightening“ of the curve) relaxed molecular clock method CONCERTED EVOLUTION AND MOLECULAR DRIVE ribosomal DNA globin genes 40 200 100 400 500 a1 a2 z e Gg a2 d b current genes have emerged through a series of duplications the ape species pairs differ by ~ 2,5 AA substitutions in the a1 i a2 gene ... ... only few differences accumulated between the a1 a a2 gene ... ... in fact this duplication is older than 300 million years Þ molecular clock is invalid in this case, the genes do not evolve independently – the evolution is concerted Mechanisms of concerted evolution: Gabriel Dover (1982): Molecular drive mechanism different from selection and drift 1. unequal crossing-over 1 2 3 1 2 3 ´ 2 3 1 1 2 3 3 copy loss copy gain ´ ´ ´ gain of a mutant copy loss of a normal copy gain of a mutant copy ... etc. ... 2. replication slippage http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/wp-content/uploads/2011/02/f_q05slippage.gif Výsledek obrázku pro polymeraseslippage image 3. gene conversion File:Conversion and crossover.jpg Conclusions: a consequence of unequal crossing-over and slippage = change of a copy number a consequence of unequal c-o and gene conversion = sequence homogenization