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by: Rupert Davis


Rupert Davis
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Joseph Felsenstein

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Joseph Felsenstein
Class Notes
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This 4 page Class Notes was uploaded by Rupert Davis on Wednesday September 9, 2015. The Class Notes belongs to GENOME 453 at University of Washington taught by Joseph Felsenstein in Fall. Since its upload, it has received 21 views. For similar materials see /class/192400/genome-453-university-of-washington in Genome Sciences at University of Washington.




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Date Created: 09/09/15
GENOME 453 Evolutionary Genetics J Felsenstein Autumn 2007 Outline of lectures 1315 Genetic Variation and Neutrality 1 F 9 7 U 03 Until 1966 evolutionary geneticists had a limited range of genetic variation they could examine and nothing like an unbiased sample of variation at the gene level 0 They could look at morphological variation but could not know how many loci were varying 0 They could look at tness variation uncovered by making whole chromosomes homozygous for example in Dmsophila but they did not know exactly how many loci were contributing to the effects They were by de nition concentrating on variation chosen because of its large tness effects so they couldn7t know whether these effects were at typical loci Previous to that time there were two major theories about variation at the genetic level H J Muller7s classical view was that most loci would have a very common wild type allele and mutation would maintain in a mutationselection balance low frequencies of mutant alleles that were deleterious Theodosius Dobzhansky7s balance view was that most loci would have multiple alleles maintained by strong overdominance or frequency dependent selection In the early 19607s people started using the technique of protein electrophoresis to study variation at individual enzyme loci Gel electrophoresis was invented by Oliver Smithies in 1957 the same guy who won the Nobel Prize 50 years later for unrelated work It was related to earlier paper electrophoresis methods A sample of blood is put in a gel made of potato starch or acrilamide and subject to an electric current for a few hours This is done under pH and temperature conditions that do not denature the proteins The gel is then stained for the product or the substrate of one particular protein and bands are seen where the active enzyme protein is on the gel These bands show how far the protein of that enzyme has migrated through the gel It is affected by both charge and conformation of its protein molecule The method can detect a single amino acid substitution though some are not detected and does so in a way that has nothing to do with the tness effect of the substitution The single locus studies in the early 19607s often found variation at such loci but there was no overall survey to see how typical this was People tended to publish lo and behold77 papers showing that they had found that their one locus showed variation lt 5 00 p O H F 9 wasn7t clear how many other people found no variation at the locus they studied and decided not to publish ln 19667 Lewontin and Hubby and independently Harry Harris surveyed populations respectively Dmsophz39la pseudoobscum and humans at multiple loci Both projects found a lot of variation7 which was a bit of a surprise The amount of variation is usually summarized in one of two kinds of statistic heterozygosity or polymorphism o Polymorphism is the fraction of loci at which the commonest allele is less than 95 in frequency ie all the rarer alleles add up to more than 5 o Heterozygosz39ty is measured by taking the gene frequencies at each locus7 and computing 1 PfP P Pfo which is the predicted heterozygosity7 as it is 1 the homozygosity This is then averaged across loci Typical values of heterozygosity seen by protein electrophoresis would be about 15 for invertebrates7 about 7 for vertebrates The variation of these typical values is big For example7 in amphibians one can nd groups with heterozygosity values around 15 These are for a variety of enzyme loci7 measured by electrophoresis One issue is whether these loci may be regarded as typical loci Polymorphism and Heterozygosity7 although both are measures of genetic variability7 do not necessarily show concordant patterns when we compare natural populations Enzyme polymorphism reveals only small fraction of the variability on the DNA level This began to be examined once DNA sequencing was available The alcohol dehydrogenase ADH locus in Dmsphz39la melanogaster has two electrophoretic alleles S and Marty Kreitman 1984 sequenced 11 different copies of the ADH gene at the time7 before PCR was invented7 about all that could be done with the time and resources he had with a total of 43 mutations One single site was responsible for the difference between the two electrophoretic alleles and was the only site that changed the protein sequence All the rest were synonymous substitutions The pattern of variation at the DNA level is similar to what is seen at the protein level 7 a lot of variation If we take two copies of the same chromosome say the two copies that an individual has we will see one difference about every 1000 bases This varies a bit from about 1 in 500 to 1 in 1500 depending on the species It is a slightly different gure from how often a SNP Single Nucleotide Polymorphism is found7 since that requires that more than two copies be looked at and that the variation is not rare among them H 00 H p D H The observations immediately contradicted Muller7s view as they projected that hundreds to thousands of loci would be heterozygous in a typical individual Later it was also realized that Dobzhansky7s mechanism of strong overdominant selection would not t the observations either With hundreds of loci becoming homozygous when a whole chromosome was made homozygous it would predict far stronger inbreeding depression than was actually observed Many surveys of patterns of variation nd suggestive patterns such as higher heterozygosity in invertebrates than in vertebrates but do not settle the issue of whether the variation is maintained by selection They also nd that some categories of loci such as enzymes in the glycolytic pathways are less variable Lewontin and Hubby had suggested that the data could be explained by either balancing selection or by neutral mutation Motoo Kimura the greatest population geneticist of his generation advocated and greatly developed the latter position using his formidable theoretical powers to greatly advance understanding of neutrality His colleague Tomoko Ohta has argued for the importance of nearly neutral mutations lf neutral mutations are occurring at a locus at a rate 1 per copy per generation and each one is to a new allele the in nite isoalleles77 model and the effective population size is N5 Crow and Kimura showed in 1964 that the expected amount of heterozygosity at the locus is 4Nep4Neu 1 The alleles continually turn over with no equilibrium gene frequencies of any allele but the level of variation is roughly predictable The effective population size is the population size corrected for other details of the life cycle that affect the rate of genetic drift Low selection coef cients can maintain alleles segregating in populations All that is required is that 4Nes gt 1 which means that for N5 106 s can be as low as 000000025 and still maintain the alleles Recall that for protein electrophoretic variation Lewontin and Hubby observed about 15 heterozygosity in Drosophila Harris observed about 7 in humans A 4N5 value of about 018 which would be obtained by having N5 106 and M 18 gtlt 10 7 will do this Less variability at some loci or in some parts of the genome is compatible with both theories as the neutral mutation theory says that the variation is not maintained by selection but it does not rule out there being selection against deleterious mutants It is thus not a statement that all mutations are neutral 7 purifying selection77 can remove deleterious mutants without invalidating the neutral theory Laboratory experiments such as population cages77 with Dmsophila can rule out large selection coef cients above 001 thus rejecting Dobzhansky7s view but they are totally incapable of detecting whether selection is 0 or 0001 as lab experiments involve smaller populations and much shorter time spans than apply in natural populations D D 3 9 3 Cf A selection coef cient as small as 14Ne can be e ective in nature7 and that can be far smaller than anything we can detect in the lab The controversy remains unresolved after 35 years7 although it is most likely that much of our junk77 DNA accumulates mostly neutral mutations For amino acid variations at protein loci the controversy is still unresolved Studies on pairs of whole human genomes nd hardly any regions where there is evidence of strong balancing selection At the same time7 genome comparisons of closely related organisms show signs of non neutral patterns of substitution at protein coding loci and this is argued to come down against the neutral mutation theory Whatever its ultimate fate7 the neutral theory has played a major role as a null hypothesis77 against which comparisons could be made


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