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Stanford CS 374 - Finding Elements in DNA Conserved by Evolution

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1. Motivation2. Basics.2.1. DNA multi-alignment and phylogenetic trees.2.2. Neutral theory, neutral rate of point substitution and MCSs:2.3. GC content and CpG2.4. Other definitions:3. First Paper: Characterization of Evolutionary rates and Constraints in the Three Mammalian Genomes.3.1. Overview3.2. Data3.3. Global Patterns of Nucleotide Substitution3.4. Rates of Transitions and Transversions in the Rodents3.5. Rates of Neutral Point Substitution3.6. Global Identification of Constrained Elements3.7. Regional Variability of Evolutionary Parameters4. Second Paper: Identification and Characterization of Multi-Species Conserved Sequences.4.1. Overview4.2. Data4.3. Binomial4.4. Parsimony4.5. Intersecting Methods4.6. Results5. Conclusion.Finding Elements in DNA Conserved by Evolution CS374 Fall 2004 Lecture 16, 11/18/04Lecturer: Penka Markova Scribe: Florian BuronFinding Elements in DNA Conserved by EvolutionBased on the following papers:1. Gregory Cooper, MichaelBrudno, Eric Stone, Inna Dubchak, Serafim Batzoglou and Arend Sidow.“Characterization of Evolutionary rates and Constraints in the Three Mammalian Genomes”,Genome Research 14: 539-548, 2004.2. Elliott Margulies, Mathieu Blanchette, David Haussler and Eric Green. “Identification andCharacterization of Multi-Species Conserved Sequences”, Genome Research 13: 2507-2518, 2003.Additional References:3. Jean-Vincent Chamary and Laurence D. Hurst. “Similar Rates but Different Modes of SequenceEvolution in Introns and at Exonic Silent Sites in Rodents: Evidence for Selectively Driven CodonUsage”, Molecular Biology and Evolution 21: 1014-1023, 2004.4. http://en.wikipedia.org/wiki/Exon 1. MotivationNow that the genomes of many mammals have been sequenced, one of the major tasks in Biologyis to interpret those data and especially to identify all functional elements in the human genome.To achieve this goal, comparative sequence analysis between different genome species hasbecome an essential component. Indeed, by finding which gene sequences are conserved byevolution from species to species, we can deduce that those genes have been selected by evolutionand such must have crucial biological functions. And such this lecture outlined the importance of those DNA sequences that are preserved byevolution. The first paper presents an analysis of rates and patterns of microevolutionaryphenomena that have shaped the human, mouse and rat genome since their last common ancestor.The second paper presents two algorithms to detect highly conserved region in a robust fashion.Interestingly, both to the same result that an important proportion of those DNA segmentspreserved by evolution belongs to the non-coding part of the DNA. This proves that some of thenon coding DNA must in fact play an important role in our organisms.1Finding Elements in DNA Conserved by Evolution CS374 Fall 2004 Lecture 16, 11/18/04Lecturer: Penka Markova Scribe: Florian Buron2. Basics.2.1. DNA multi-alignment and phylogenetic trees.We have already seen during the previous lecture (lecture14: Aligning Alignments) how we could align the variousDNA sequences of different species. There exist severalmethods to achieve this. Both paper are using pair wisealignment that are latter multi-aligned. (see figure 1bellow)Based on those alignments, we can build phylogenetictrees that reconstruct how each species have evolvedfrom common ancestors (see figure 2 on the right andlecture 10b: Phylogenetic Trees).Figure 1 and 2. DNA multi-alignment(left) and phylogenetictrees(right).2Finding Elements in DNA Conserved by Evolution CS374 Fall 2004 Lecture 16, 11/18/04Lecturer: Penka Markova Scribe: Florian Buron2.2. Neutral theory, neutral rate of point substitution and MCSs:The neutral theory of molecular evolution states that the majority of evolutionary changes atmolecular level are not maintained by natural selection. And thus, when we want to build a phylogenetic tree, to evaluate how far two species are fromthere common ancestor. This is done by computing the neutral rate of point substitution: therate of substitution that has happened since there common ancestor,. To be reliable, this rate mustonly take into account regions that are not maintained by natural selection. Indeed, as thoseevolutionary changes are not affected by evolution, they are only affected by the time separatingthe species from their common ancestor and such really represent the time distance to thiscommon ancestor.The MCSs (Multi-species Conserved Sequences) are exactly the contrary; they representsequences of the DNA that are so important that they have been fully maintained from species tospecies. The fact that they have been maintained by natural selection proved that those sequencesmust correspond to very important functions in our organisms.In both articles, one important hypotheses is that we supposed that there is no crucial biologicalfunction changes between the various species (human, rat mouse, etc.) and such that those MCSsrepresent the crucial biological functions of our organisms. For instance, if some very importantprotein has been created in the recent evolution of humanity, finding highly conserved geneticsequence between species is not going to reveal it.2.3. GC content and CpGThe guanine-cytosine content (GC content) is the ratio of guanine and cytosine to the totalnumber of nucleotides of a given genome. It ca be used, for example, to easily distinguishbetween different species when a doubt remains. The GC content can be measured by several means but one of the simplest methods is to measurewhat is called the melting temperature of the DNA with a spectrophotometer. The absorbance ofDNA at a wavelength of 260 nm increases fairly sharply when the double-stranded DNA separatesinto two single strands when sufficiently heated.CpG refers to a C nucleotide immediately followed by a G. The 'p' in 'CpG' refers to thephosphate group linking the two bases.Detection of regions of genomic sequences that are rich in the CpG pattern is important becausesuch regions are resistant to methylation and tend to be associated with genes which arefrequently switched on. Regions rich in the


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Stanford CS 374 - Finding Elements in DNA Conserved by Evolution

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