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Genome evolution: a sequence-centric approach

Genome evolution: a sequence-centric approach. Lecture 7: Brief evolutionary history of everything. (Probability, Calculus/Matrix theory, some graph theory, some statistics). Simple Tree Models HMMs and variants PhyloHMM,DBN Context-aware MM Factor Graphs. Probabilistic models.

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Genome evolution: a sequence-centric approach

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  1. Genome evolution: a sequence-centric approach Lecture 7: Brief evolutionary history of everything

  2. (Probability, Calculus/Matrix theory, some graph theory, some statistics) Simple Tree Models HMMs and variants PhyloHMM,DBN Context-aware MM Factor Graphs Probabilistic models Genome structure Inference Mutations DP Sampling Variational apx. LBP Parameter estimation Population EM Generalized EM (optimize free energy) Inferring Selection

  3. Genome Structure, Genome Information Mutation Genome structure Genomic information Selection

  4. Diversity: Brief description of the tree of life Genome structure: Size, Key features, Mobile elements Genome information: Proteins/RNA genes, regulatory elements Today: A lot of terminology, basic overview

  5. ? ? RNA Based Genomes Ribosome Proteins Genetic Code DNA Based Genomes Membranes Diversity! 3.4 – 3.8 BYA – fossils?? 3.2 BYA – good fossils 3 BYA – metanogenesis 2.8 BYA – photosynthesis .. .. 1.7-1.5 BYA – eukaryotes .. 0.55 BYA – camberian explosion 0.44 BYA – jawed vertebrates 0.4 – land plants 0.14 – flowering plants 0.10 - mammals

  6. Curated set of universal proteins Eliminating Lateral transfer Multiple alignment and removal of bad domains Maximum likelihood inference, with 4 classes of rate and a fixed matrix Bootstrap Validation Ciccarelli et al 2005

  7. Eukaryotes Uniknots Biknots

  8. Eukaryotes Uniknots – one flagela at some developmental stage Fungi Animals Animal parasites Amoebas Biknots – ancestrally two flagellas Green plants Red algea Ciliates, plasmoudium Brown algea More amobea Strange biology! A big bang phylogeny: speciations across a short time span? Ambiguity – and not much hope for really resolving it

  9. Vertebrates Fossil based, large scale phylogeny Sequenced Genomes phylogeny

  10. Primates 9% 1.2% 0.8% 3% 1.5% 0.5% 0.5% Gorilla Chimp Gibbon Baboon Human Macaque Marmoset Orangutan

  11. Flies

  12. Yeasts

  13. Genome Size

  14. Why larger genomes? • Selflish DNA – • larger genomes are a result of the proliferation of selfish DNA • Proliferation stops only when it is becoming too deleterious • Bulk DNA • Genome content is a consequence of natural selection • Larger genome is needed to allow larger cell size, larger nuclear membrane etc.

  15. Why smaller genomes? • Metabolic cost: maybe cells lose excess DNA for energetic efficiency • But DNA is only 2-5% of the dry mass • No genome size – replication time correlation in prokaryotes • Replication is much faster than transcription (10-20 times in E. coli)

  16. Mutational balance • Balance between deletions and insertions • May be different between species • Different balances may have been evolved • In flies, yeast laboratory evolution • 4-fold more 4kb spontaneous insertions • In mammals • More small deletions than insertions Can we model genome size evolution in a quantitative way? Mutational hazard • No loss of function for inert DNA • But is it truly not functional? • Gain of function mutations are still possible: • Transcription • Regulation Differences in population size may make DNA purging more effective for prokaryotes, small eukaryotes Differences in regulatory sophistication may make DNA mutational hazard less of a problem for metazoan

  17. Genome Structural features: centromeres/telomeres Human Rat – Partly acrocentric Centromeres are essential and universally important for proper cell division, but are highly diverging among speciesSattelites and repeats Pericentromeric regions – more repeats Telomeres are critical for genome maintenanceSub telomeric regions – also repetitive May be key to nuclear structure?

  18. Genome Structural features: nuclear organization The nucleus must be organized to allow functional transcription and replicationIncredibly dense mesh of chromosomes, cytoskeleton, membranesTranscription factories / chromosomal territories“spacer DNA” may affect physical organization in unexpected waysInter- and Intra- chromosomal interactionsEntire genome may participate in regulating interactions

  19. Genomic information: Protein coding genes

  20. Modeling protein structure/function Modeling protein coding genes Structure is complex Dependencies are not confined by gene linear coding http://predictioncenter.org/

  21. Genomic information: the gene repertoire is evolving by duplication and loss

  22. Genome information: Introns/Exons

  23. Genome information: RNA genes mRNA – messenger RNA. Mature gene transcripts after introns have been processed out of the mRNA precursor miRNA – micro-RNA. 20-30bp in length, processed from transcribed “hair-pin” precursors RNAs. Regulate gene expression by binding nearly perfect matches in the 3’ UTR of transcripts siRNA – small interfering RNAs. 20-30bp in length, processed from double stranded RNA by the RNAi machinary. Used for posttranscriptional silencing rRNA – ribosomal RNA, part of the ribosome machine (with proteins) snRNA – small nuclear RNAs. Heterogeneous set with function confined to the nucleus. Including RNAs involved in the Splicesome machinery. snoRNA – small nucleolar RNA. Involved in the chemical modifications made in the construction of ribosomes. Often encode within the introns of ribosomal proteins genes tRNA – transfer RNA. Delivering amino-acid to the ribosome. piRNA - ???

  24. miRNA clusters

  25. snRNA works by binding other RNAsRNA structure affects function

  26. Computational perspective: finding and understanding RNAs and their evolution

  27. Ultra-high throughput sequencing is transforming all aspects of biology

  28. Ultra-high throughput sequencing is transforming all aspects of biology

  29. Genome information: regulatory elements Specialized proteins can bind DNA in a sequence specific fashion Genomes can therefore control the level of affinity of each region to a large set of DNA binding proteins DNA binding sites are typically short (<20bp) Multiple binding sites at different affinities participate in regulation Computational perspective: finding and understanding TFBSs

  30. The regulatory process is likely to less deterministic and discrete the this beautiful idealized sea urchin regulatory network Each regulatory interaction is parameterized and many additional weak interaction participate in the Process Evolution of regulatory regions involve more than a small set of discrete 20bp sites

  31. Chromatin Immunoprecipitation is mapping DNA binding sites

  32. Structure meets information: packaging and chromosomal interactions are critical for proper genome function

  33. Structure meets information: HOX clusters as an example Hox genes are important developmental regulators Present in linear clusters, preserving order Their expression is frequently coordinate with the gene order 4 HOX clusters are present in the human genome Additional gene clusters: Protocadherins, Olfactory receptors, MAGE genes, Zinc fingers Additional smaller groups of related regulators are co-located

  34. Mapping chromosomal interactions: 4C

  35. Repeats: selfish DNA Repetitive elements in the human genome

  36. Retrotransposition via RNA

  37. Repeats: short tandems, satellites DNA-based transposons do not involve an RNA intermediate, and are quite rare. Satellite DNA duplicate by Replication slippages which is enhanced for specific sequences. Abundant near telomeres and centromeres. Some of these are still a mystery. Retrotransposition is generally sloppy and noisy – so elements die out quickly Element proliferation appears in evolutionary bursts.

  38. Pseudogenes Genes that are becoming inactive due to mutations are called pseudogenes mRNAs that jump back into the genome are called processed pseudogenes (they therefore lack introns)

  39. Summary – • History/Phylogeny: • Early phylogenetics can be inferred using genome sequences, but conclusions are not always reliable • Maximum likelihood models sometime depends on the gene/genomic region analyzed, genome is highly heterogeneous at all levels. • The major clades, phylogeny of model organisms and sequenced genomes • Genome structure • Size and its consequences • Packaging and nuclear organization • Mutational effects and differences • Selfish DNA • Genome information • Protein coding genes • RNA genes • Transcription factor binding sites • Chromosomal organization and DNA codes that affect it

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