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EVOLUTION OF EUKARYOTIC GENOME GENE 342 Lecture 14 – Molecular evolution MOLECULAR EVOLUTION I • Ability to clone, amplify, manipulate and sequence DNA molecules from organisms has had an enormous impact on the study of evolution • Darwin’s focus of evolution was on the traits of organisms, which are passed on more or less faithfully from parents to their offspring every generation, but which also undergo modifications as the organisms adapt to changing conditions • DNA molecules are passed from parents to offspring generation after generation. However, this process of genetic transmission is not perfect as mutation occur and modified DNA molecules are passed to the offspring • Over long periods of time mutations accumulate and the DNA sequence is changed, segments of DNA molecules may also be duplicated and re-arranged. Molecules as “Documents of Evolutionary History” • Fossils-mineralized remains of animals and plants long since dead, were avidly collected in Darwin’s day. Fossils – evidence of organisms once lived on earth • From detailed study of fossils, scientists could construct the phenotypes and behavior of ancient organisms MOLECULAR EVOLUTION I CONT… Molecules as “Documents of Evolutionary History” • Comparisons between currently living organisms and the fossilized remains of extinct organisms stimulated the speculation about the origin of species • DNA molecules, like fossils, contain information about life history. DNA molecules in creatures today are derived from their ancestors-parents, grandparents and so on, to the very first organisms • Each DNA molecule is the end result of a long historical process involving mutation, recombination, selection and genetic drift • In Metaphorical terms, the sequence of nucleotides in a DNA molecule in current version of an ancient text that has been altered (mutated), cut and pasted (recombined), preserved fro its value (selected), and randomly disseminated (subject to genetic drift) • Thus, DNA molecules are “documents of evolutionary history”. So, too, are protein molecules. Polypeptides are encoded by genes, which are segments of DNA molecules MOLECULAR EVOLUTION I CONT… Molecules as “Documents of Evolutionary History” • The analysis of DNA and protein sequences has several advantages over more traditional methods of studying evolution based on comparative anatomy, physiology and embryology: 1. DNA and Protein sequences follow simple rules of heredity. By contrast, anatomical physiological, and embryological traits are subject to all the vicissitudes of complex heredity 2. Molecular data sequence are easier to obtain and are amenable to quantitative analysis framed in the context of evolutionary genetics theory 3. The interpretation of quantitative analysis is usually much more straight forward than the interpretation of analysis based on morphological data 4. Molecular sequence data allow researchers to investigate evolutionary relationships among organisms that are phenotypical dissimilar, e.g. DNA and protein sequences from bacteria, yeast, protozoa, and humans can be compared to the study the evolutionary relationships among them Molecular Evolution I Cont… Molecules as “Documents of Evolutionary History” • One problem with the molecular approach to evolution is that researchers usually cannot obtain DNA or protein sequence data from extinct organisms • In a few exceptional cases, such data have been obtained from fossils. However, in none of these cases was the fossilized specimen more than a few tens of thousands of years old • Thus, truly ancient organisms are beyond the reach of any molecular investigation. Molecular Evolution I Cont… Molecular Phylogenies • Evolutionary relationships among organisms are summarized in diagrams called phylogenetic trees or phylogenies • A phylogeny that only shows the relationships is an unrooted tree, whereas the one that shows their derivation is a rooted tree • The branches at the tips of the tree-called terminal branches lead to the organisms that are under study Molecular Evolution I Cont… Molecular Phylogenies • Each branch point in a tree represents a common ancestor of the organisms farther out in the tree. • Some molecular analysis of evolutionary relationships are based on a single gene or gene product and other analysis combine data obtained by sequencing different genes and gene products • Descendants of an ancestral DNA or protein sequences are said to be homologous, even if they have diverged significantly from their ancestor and are different from each other Molecular Evolution I Cont… Molecular Phylogenies • Two sequences that come to resemble each other even though they are derived from entirely different ancestral sequences are said to be analogous • The construction of phylogenies should always be based on the analysis of homologous sequences. • Methods currently available to construction of phylogenies from DNA and protein sequence data have four features in common: 1. Aligning the sequences to allow comparisons among them 2. Ascertaining the amount of similarity between any two sequences 3. Grouping the sequences on the basis of similarity 4. Placing the sequences at the tip of a tree Molecular Evolution I Cont… Rates of Molecular Evolution • By linking the branch points of a tree to a specific times in the evolutionary history of the sequences, we can determine the rate at which the sequences have been evolving • An example of this kind of analysis consider α-globin – one of the two peptide in the blood protein hemoglobin. α-globin is 141 amino acid long Number of dissimilar amino acids in the α-globin of representative vertebrates Mouse Human Mouse Chicken Newt Carp 16 Chicken 35 39 Newt 62 63 63 Carp 68 68 72 74 Shark 79 79 83 84 85 • The fossil records of these organisms provide information about key events in the evolutionary history Molecular Evolution I Cont… Rates of Molecular Evolution 100 200 300 400 500 Million years ago Tree constructed using the evidence from fossil records Molecular Evolution I Cont… Rates of Molecular Evolution • The topology of the tree is consistent with the molecular data presented in the table above • The extent to which the amino acid sequences of these organisms differ can be used to estimate the rate at which α-globin has been evolving •To obtain this rate: 1. Need to determine the average number of amino acid changes occurred since the split of any two lineages from a common ancestor 2. Start with the two closely related organisms (humans & mice), which are different in 16 of the 141 amino acid sites in α-globin the proportion of different site in α-globin of these two species is 16/141 = 0.11 i.e., 0.11 is the average number of differences per amino acid site 3. Consider very distantly related organisms (Humans & Carps) – differ in 68 0f 141 amino acid sites = 68/141=0.48 i.e., almost half of the site have changed during the evolution of the lineage that produced these species with such high frequency of changed site, we might expect that some of the sites have changed multiple times Molecular Evolution I Cont… Rates of Molecular Evolution • The observed proportion (0.48) must therefore underestimate the average number of changes that have occurred during the long time since the human and carp lineages split • observed proportions can be adjusted upwards to account for multiple amino acid substitution at particular sites. The adjustment involves Poisson Correction • Poisson corrected differences (values) estimates the average number of changes that have occurred per amino acid site in α-globin during the time since the evolving lineages split from a common ancestor Number of dissimilar amino acids in the α-globin of representative vertebrates Mouse Chicken Newt Carp Shark Human 16/141= 0.11 35/141=0.24 62/141=0.44 68/141=0.48 79/141=0.56 0.25 0.45 Mouse 0.46 0.56 0.45 Chicken 0.51 0.58 Newt 0.52 0.59 Carp 0.60 Poisson-Corrected Average Number of Amino Acid Differences In The α-globin of representative vertebrates and Associated Evolutionary Rates Human Mouse Chicken Newt Carp Mouse Chicken 0.2 0.28 0.33 Newt 0.58 0.59 0.59 Carp 0.66 0.66 0.66 0.74 Shark 0.82 0.82 0.89 0.91 0.92 Molecular Evolution I Cont… Rates of Molecular Evolution • The observed proportion (0.48) must therefore underestimate the average number of changes that have occurred during the long time since the human and carp lineages split • observed proportions can be adjusted upwards to account for multiple amino acid substitution at particular sites. The adjustment involves Poisson Correction • Poisson corrected differences (values) estimates the average number of changes that have occurred per amino acid site in α-globin during the time since the evolving lineages split from a common ancestor • Note that the human and Carp lineages, the average number of changes per amino acid site is 0.66 (0.48), which is almost 1.4 times the observed proportion of amino acid differences between the human and carp α-globins • The rate of which α-globin has evolved can be calculated from the average number of changes per amino acid site from each pair of organism • This rate is the average number of changes per amino acid site divided by the total time that the two lineages have been evolving Calculation of the α-globin Evolving Rate For example: the lineages that produced humans and mice from a common ancestor 80mya 100 200 300 400 500 Million years ago Calculation of the α-globin Evolving Rate For example: the lineages that produced humans and mice from a common ancestor 80mya the total time that these lineages have been evolving is therefore 2 x 80 million years = 160 mln yrs Using the Poisson corrected average number of amino acid (a.a.) changes per site from the table above, we have: Av. Number of a.a. changes per site Total Evolution Time = 0.12 a.a. changes per site 160 mln yrs = 0.74 x 10-9 a.a. changes per year • From this rate, it is clear that α-globin has been evolving at a little less than one amino acid change per site every billion years MOLECULAR EVOLUTION II Variation In Evolutionary Rates • Rates of amino acid sequence evolution range over three orders of magnitudes: 1. At extremes, fibrinopeptide, derived from a protein involved in blood clotting evolves at a rate of greater than 8 a.a. substitutions per site every billion years 2. Histones-interact intimately with DNA, evolve at a rate of only 0.01 a.a. substitutions per site every billion years 3. Amino acids on the surface of α-globin change at a rate of about 1.3 substitutions per site every billion years where as a.a. in the interior of the molecule change at a rate of only 0.17 substitution per site every billion years • Observed variation in evolutionary rates is explained by the hypothesis: In more evolving proteins, the exact a.a. sequence is not as important as it is in more slowly evolving proteins • The hypothesis speculate that in some proteins, amino acid changes can occur with relatively impunity, whereas other, are rigorously selected against Molecular Evolution II Cont.. Variation In Evolutionary Rates • The rate of evolution depends on the degree to which are amino acid sequence of a protein is constrained by selection to preserve that protein function • Slowly evolving proteins are more constrained than rapidly evolving proteins • Variation in evolutionary rates is therefore explained by the amount of functional constraint on the a.a sequence • e.g. the specific a.a. at or near the active site of enzymes might be expected to be more rigorously constrained by selection than a.a. that simply less important ones • Functionally more important proteins, or parts of proteins, evolve more slowly than functionally less important ones • Variation in the evolutionary rate is also seen when DNA sequences are examined DNA sequences in pseudogenes-duplicated genes that do not encoded functional products because they have sustained one or more lesions such as such as frameshifting or nonsense mutations, have the highest evolutionary rate Molecular Evolution II Cont… Variation In Evolutionary Rates • The nucleotides in a pseudogene are not constrained by selection because the function of the pseudogene has already been destroyed • However, the nucleotides in the first & second position of a codon in a functional gene are re-constrained because changing them will almost always change the amino acid specified by that codon • Some of these changes will be conservative in the sense that the new amino acid will be structural and functionally life the original amino acid • e.g. if the first nucleotide in the codon CTT mutates to A, the amino acids specified by this codon will change from leucine to isoleucin, which similar proteins • However, other substitutions in this codon may cause a non-consrvative change in the amino acid sequence. E.g. if CTT mutates, TTT, the a.a. specified the code will change from leucine to phenyalanine, which has very duufferent chemical properties • Nucleotides in the third position of codons within function genes evolve much faster than nucleotides in either the he first or second position Molecular Evolution II Cont… Variation In Evolutionary Rates • This is due to the genetic code being degenerate. Many amino acids are specified by more than codon e.g. prolong by four different codons: CCT, CCC, CCA, and CCG • As long as the two nucleotides in a codon are both C, any nucleotide can be present in the third position and the codon will specify proline-that is, the third nucleotide position is fourfold degenerate • Changing the last nucleotide in a proline codon, should therefore be inconsequential for the structure and the function of the poplypeptide encoded by a gene. • The high level of degeneracy accounts for the faster evolutionary rate of third position nucleotides • A nucleotide substitution that does not change the a.a. specified by a codon is called synonymous substitution otherwise non-synonymous substitution Molecular Evolution II Neutral Theory of Molecular Evolution • Neutral Theory was developed to explain the evolution of DNA and protein sequences. This theory focuses on three processes: mutation, purifying selection, and random genetic drift • Mutation is at the root of all nucleotide and amino acid substitution that occur during evolution. Without mutation, and protein molecules could not evolve. • Some of the mutations that occur spontaneously improve the fitness of organisms, i.e., they are beneficial mutations that might, over time, spread through a population and become fixed • Other mutations depress fitness and are eliminated from a population by the force of purifying selection • Many mutations, like random changes in a piece of a complex machinery, are likely to impair function. However, some mutations may have little or no effect on fitness. Such mutations are selectively neutral • Synonymous nucleotide substitutions in the third position of codons and any other type of nucleotide substitution in a pseudogene might be selectively neutral Molecular Evolution II Cont… Neutral Theory of Molecular Evolution • The rate of a selectively neutral mutation depends completely on random genetic drift • Most selectively neutral mutations are lost from a population shortly after they first appear but a smaller fraction of them survive generations and ultimately spread throughout the population and become fixed • The rate of fixation of selectively neutral mutations in a population is equal to the rate at which genes mutate to selectively neutral allelles. • To see that the rate of fixation is equal to the neutral mutation rate:- Calculation - Suppose the population size is N, and that each generation a fraction µ of the 2N copies of a gene mutate to a selectively neutral alleles - Let us assume that each new mutant is unique; Given the large number of nucleotides that can mutate with a gene, and the extremely low probability that exactly the same nucleotide change will occur more than once - Therefore, each generation the number of selectively neutral mutations that appear in the population will be 2Nµ because each mutant is unique, its frequency will be 1/2N - Therefore, the probability that a particular mutation will ultimately be fixed is 1/2N - The rate at which selectively neutral mutants of any sort are fixed is simply the number of such mutants that appear each generation (2Nµ) x probability that any one of them will ultimately be fixed (1/2N) -Thus, the rate of fixation of selectively neutral mutants is 2Nµ x (1/2N) = µ Molecular Evolution II Cont… Neutral Theory of Molecular Evolution • The rate of a selectively neutral mutation depends completely on random genetic drift • Most selectively neutral mutations are lost from a population shortly after they first appear but a smaller fraction of them survive generations and ultimately spread throughout the population and become fixed • The rate of fixation of selectively neutral mutations in a population is equal to the rate at which genes mutate to selectively neutral alleles. • To see that the rate of fixation is equal to the neutral mutation rate:See the calculation above • Neutral Theory says that for selectively neutral mutations, the rate of molecular evolution is equal to the rate at which these mutants occur in the population • The rate of evolution does not depend on population size, the efficiency of selection, or peculiarities, of the mating system. Molecular Evolution II Cont… Neutral Theory of Molecular Evolution • Neutral Theory explains:1. Why substitution rates are approximately constant in many lineages over long period of evolution time 2. Why substitution rate differ among proteins and DNA regions 3. The variation in eveolutionary rates that is observed among proteins and DNA regions by revoking differences in functional conditions Molecular Evolution II Cont… Molecular Evolution and Phenotypic Evolution • By definition, the Neutral theory has nothing to say about the evolution of traits that are adaptive • The giraffe’s long neck, the elephant trunk, and the camel’s hump are all adaptations that enhance fitness. So to, is the large, highly convoluted brain of humans • The phenotypic changes that occur during this process produce new varieties and eventually new species • Q? Can the evolution of adaptation and the diversification of organisms be explained by the relentless accumulation of nucleotide and amino acid substitutions • A Probaly in some case it can. However, change at the molecular level is not a guarantee that phenotypic evolution will occur -Nile Crocodiles (Crocoduylud nulotias - great White Shark (Carcha rodon canrcharrs -House shoe crab Molecular Evolution II Cont… Molecular Evolution and Phenotype Evolution • e.g. Crocodiles, sharks, and horseshoe crabs have accumulated amino acid and nucleotide changes at rates similar to highly diversified groups of animals such as birds, mammals, and inserts • Fossil records of these type organisms have a very little change in phenotype since they first appeared hundreds of million of years ago • Q? What sort of genetic changes might be responsible for the evolution of novel phenotypes? Some possible answers are coming from the genome sequencing projects and studies in developmental genetics • A: Genes often become duplicated during evolution and that the duplicates sometimes acquire different functions. 2. Portions of genes maybe be duplicated and recombined with other genes. Eukaryote genes are segmented into exons and introns – Exones in a gene encodes a separate functional domain in the gene’s polypeptide product Molecular Evolution II Cont… Molecular Evolution and Phenotype Evolution • Exons from a gene could be combined with exons from another gene to create a coding sequence that would specify a protein with some of the properties of each of the original gene products therefore, novel proteins could be created by combining exons in modular fashion – a process now called exon shifting 3. In addition to gene duplication and exon shifting, evolutionary diversification seems to have benefited from spatial and temporal changes in the expression of genes, especially those whose products regulate the expression of other genes