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Introduction to Comparative Genomics
Dave UsseryBiological Sequence AnalysisDTU course # 2780315 May, 2006
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Outline
• Introduction - where are we? • Comparison of Genome Sizes• The Human Genome Project• A few words about speed of sequencing• DNA repeats• Brief intro. to genome atlases
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Where are we in the tree of life?
Du står her
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rRNA tree
HUMANS
maize (corn)
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Algae
Earth formed (~4.6 Bya)
4.5 Bya 4.0 Bya 3.5 Bya 3.0 Bya 2.5 Bya 2.0 Bya 1.5 Bya 1.0 Bya 0.5 Bya today
Oldest rocks
Time (Billions of years ago, Bya)
Oxygen levels rise
Methanogenic Archaebacteria
Sulfate reducing bacteria
Single-celled eukarotes Edicaran
fauna
Cambrian
Dinosaurs
Oldest bacteriafossils
Multi-cellular eukaryotes
Bacterialecosystems
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Earth formed (~4.6 Bya)
4.5 Bya 4.0 Bya 3.5 Bya 3.0 Bya 2.5 Bya 2.0 Bya 1.5 Bya 1.0 Bya 0.5 Bya today
Oldest rocks
Time (Billions of years ago, Bya)
Oxygen levels rise
Bacteria
Archaea4.0 Bya
Eukaryotic microbes
~2.0 Bya
maize (corn)
HUMANS
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rRNA tree
HUMANS
maize (corn)
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Comparative Microbial Genomics group
What is a genome?
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Organism # bp #genes
Φ-X174 5386 9
Escherichia coli 4,600,000 4288
Saccharomyces cerevisiae 13,000,000 5885
Caenorhabditis elegans ~100,000,000 ~14,000
Arabidopsis thaliana ~120,000,000 ~10,000
Drosophila melanogastor ~180,000,000 ~12,000
Homo sapiens ~3,400,000,000 ~25,000
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The Human Genome Project
Started ~1985
The U.S. government agreed to invest $200,000,000 U.S. per year for 20 years.
One base per second = 216 years!
~3,400,000,000 bp per haploid genome ~6,800,000,000 bp per haploid genome
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year# humangenes mapped
#years to sequence human genome
1970 none not possible
1980 3 ~4,000,000 years
1990 12 ~1000 years
2000 ~25,000 draft
2005 ~30,000
new draft + chimp, chicken, dog, mouse, pig,
rat...
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Why is the human genome so large?
One base per second = 216 years!
~3,400,000 bp per haploid genome ~6,800,000 bp per haploid genome
Discussion questions:
~2% or less codes for proteins.
Why is the human genome not finished yet?
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insects
fish
reptiles
higher
plantslower
plants
minerals
birdsm
amm
als
jellyfish
Aristotle’sladder ofcomplexity HUMANS
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The “C-value paradox”The genome size of an organism is defined as the amount of haploid DNA in a genomic set (e.g., an egg or sperm nucleus). This is also referred to as the "C-value"; the "C" means "constant" or "characteristic", since the size of a genome is usually constant for a given species. The large difference in genome sizes without any seeming relation to an organism’s complexity, is called the C-value paradox.
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What does all this DNA do?
90%
50%
2%
<1%
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The approximate size and characteristics of genomes was characterised in the 1960s, in a classic study of the kinetics of DNA reassociation by Britten and Kohne (1968).
1. foldback DNA2. highly repetitive DNA
3. middle-repetitive DNA4. single-copy DNA
The repetitive DNA can either be localised to discrete regions, or dispersed.
They found that the DNA could be divided into four fractions:
Britten,R.J., Kohne,D.E., "Repeated sequences in DNA", Science, 161:529-540, (1968).
DNA repeats
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Highly repetitive DNADispersed - e.g., Alu family
• about 300 bp long • 500,000 copies in humans • (about 5% of the human genome) • dispersed throughout the chromosomes
Localised highly repetitive sequences • about 2-10 bp long • present in millions of copies, often in large blocks • (about 6% of the human genome) • associated with heterochromatin • usually very high A+T content
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Often, satellite DNA consists of long tandem arrays of repeated sequences, all localised to one or a few discrete regions in the chromosomes. For example, in the kangaroo rat (Dipodomys ordii), more than 50% of the genome consists of three families of repeated sequences:
(AAG)n, where n = ~2.24 x 10
9
(TTAGGG)n, where n = ~2.2 x 10
9
(ACACAGCGGG)n, where n = ~1.2 x 10
9
Localised repetitive DNA
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Middle repetitive DNA
• makes up more than 40% of the human genome
• position varies due to transposable elements
• Includes the following types of sequences:
- Dinucleotide repeats - microsatellite DNA - TRInucleotide repeats
- associated with many diseases - (e.g., Fragile X, muscular distrophy)
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What about bacteria?
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A decade of sequencing prokaryotic genomes.
Num
ber
Gen
omes
Pub
lish
ed
Year
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genomeprj 929 genomes
unfinished
(14-May-2006)
Hjælp!
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Kronborg Castle
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What is Bioinformatics?
Bioinformatics is the application of machine learning processes to
biological information.
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1978 P. HOGEWEG in Simulation 31 90/1 Since 1970 she has been a staff member at the Subfaculty ofBiology of the University of Utrecht, with her main field of research in bioinformatics. 1985 Jrnl. Theoret.Biol. 113 719 (heading) Tumor escape from immune elimination... R. J. De Beer, Bioinformatics Group,University of Utrecht. 1986 Philos. Trans. Royal Soc. A. 317 324 The area of modelling mutants from aknown structure has been revolutionized by the latest tools of molecular graphics... This is a key elementin the whole technology and has attracted much interest (for example, the recent E.E.C. ‘Bioinformatics’programme). 1987 Science 4 Sept. 1108/3 One of the latest developments [at the European MolecularBiology Laboratory] has been the creation of a new research program in bioinformatics. This is intendedto bring together research in computing science, structural biology, and molecular genetics. 1996 FastCompany Aug.-Sept. 32/3 A lot of breakthroughs in medicine will come out of the efforts of bio-informatics. 2001 N.Y. Times 4 Jan. B6/2 The hope..is to make New York a leader in cutting-edge fieldslike bioinformatics, in which computers are used to decipher genes and proteins.
The science of information and information flow in biological systems, esp. the use of computational methods in genetics and genomics.
bioinformatics, n.
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What is Biological Information?
Genome -> Transcriptome ->Proteome
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The DNA sequence contains information.
But what kind of information?
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ΦX174 gagttttatc gcttccatga cgcagaagtt aacactttcg gatatttctg atgagtcgaa aaattatctt gataaagcag gaattactac tgcttgttta cgaattaaat
cgaagtggac tgctggcgga aaatgagaaa attcgaccta tccttgcgca gctcgagaag ctcttacttt gcgacctttc gccatcaact aacgattctg tcaaaaactg acgcgttgga tgaggagaag tggcttaata tgcttggcac gttcgtcaag gactggttta gatatgagtc acattttgtt catggtagag attctcttgt tgacatttta aaagagcgtg gattactatc tgagtccgat gctgttcaac cactaatagg taagaaatca tgagtcaagt tactgaacaa tccgtacgtt tccagaccgc tttggcctct attaagctca ttcaggcttc tgccgttttg gatttaaccg aagatgattt cgattttctg acgagtaaca aagtttggat tgctactgac cgctctcgtg ctcgtcgctg cgttgaggct tgcgtttatg gtacgctgga ctttgtggga taccctcgct ttcctgctcc tgttgagttt attgctgccg tcattgctta ttatgttcat cccgtcaaca ttcaaacggc ctgtctcatc atggaaggcg ctgaatttac ggaaaacatt attaatggcg tcgagcgtcc ggttaaagcc gctgaattgt tcgcgtttac cttgcgtgta cgcgcaggaa acactgacgt tcttactgac gcagaagaaa acgtgcgtca aaaattacgt gcggaaggag tgatgtaatg tctaaaggta aaaaacgttc tggcgctcgc cctggtcgtc cgcagccgtt gcgaggtact aaaggcaagc gtaaaggcgc tcgtctttgg tatgtaggtg gtcaacaatt ttaattgcag gggcttcggc cccttacttg aggataaatt atgtctaata ttcaaactgg cgccgagcgt atgccgcatg acctttccca tcttggcttc cttgctggtc agattggtcg tcttattacc atttcaacta ctccggttat cgctggcgac tccttcgaga tggacgccgt tggcgctctc cgtctttctc cattgcgtcg tggccttgct attgactcta ctgtagacat ttttactttt tatgtccctc atcgtcacgt ttatggtgaa cagtggatta agttcatgaa ggatggtgtt aatgccactc ctctcccgac tgttaacact actggttata ttgaccatgc cgcttttctt ggcacgatta accctgatac caataaaatc cctaagcatt tgtttcaggg ttatttgaat atctataaca actattttaa agcgccgtgg atgcctgacc gtaccgaggc taaccctaat gagcttaatc aagatgatgc tcgttatggt ttccgttgct gccatctcaa aaacatttgg actgctccgc ttcctcctga gactgagctt tctcgccaaa tgacgacttc taccacatct attgacatta tgggtctgca agctgcttat gctaatttgc atactgacca agaacgtgat tacttcatgc agcgttacca tgatgttatt tcttcatttg gaggtaaaac ctcttatgac gctgacaacc gtcctttact tgtcatgcgc tctaatctct gggcatctgg ctatgatgtt gatggaactg accaaacgtc gttaggccag ttttctggtc gtgttcaaca gacctataaa cattctgtgc cgcgtttctt tgttcctgag catggcacta tgtttactct tgcgcttgtt cgttttccgc ctactgcgac taaagagatt cagtacctta acgctaaagg tgctttgact tataccgata ttgctggcga ccctgttttg tatggcaact tgccgccgcg tgaaatttct atgaaggatg ttttccgttc tggtgattcg tctaagaagt ttaagattgc tgagggtcag tggtatcgtt atgcgccttc gtatgtttct cctgcttatc accttcttga aggcttccca ttcattcagg aaccgccttc tggtgatttg caagaacgcg tacttattcg ccaccatgat tatgaccagt gtttccagtc cgttcagttg ttgcagtgga atagtcaggt taaatttaat gtgaccgttt atcgcaatct gccgaccact cgcgattcaa tcatgacttc gtgataaaag attgagtgtg aggttataac gccgaagcgg taaaaatttt aatttttgcc gctgaggggt tgaccaagcg aagcgcggta ggttttctgc ttaggagttt aatcatgttt cagactttta tttctcgcca taattcaaac tttttttctg ataagctggt tctcacttct gttactccag cttcttcggc acctgtttta cagacaccta aagctacatc gtcaacgtta tattttgata gtttgacggt taatgctggt aatggtggtt ttcttcattg cattcagatg gatacatctg tcaacgccgc taatcaggtt gtttctgttg gtgctgatat tgcttttgat gccgacccta aattttttgc ctgtttggtt cgctttgagt cttcttcggt tccgactacc ctcccgactg cctatgatgt ttatcctttg aatggtcgcc atgatggtgg ttattatacc gtcaaggact gtgtgactat tgacgtcctt ccccgtacgc cgggcaataa cgtttatgtt ggtttcatgg tttggtctaa ctttaccgct actaaatgcc gcggattggt ttcgctgaat aagagattat ttgtctccag ccacttaagt gaggtgattt atgtttggtg ctattgctgg cggtattgct tctgctcttg ctggtggcgc catgtctaaa ttgtttggag gcggtcaaaa agccgcctcc ggtggcattc aaggtgatgt gcttgctacc gataacaata ctgtaggcat gggtgatgct ggtattaaat ctgccattca aggctctaat gttcctaacc ctgatgaggc cgcccctagt tttgtttctg gtgctatggc taaagctggt aaaggacttc ttgaaggtac gttgcaggct ggcacttctg ccgtttctga taagttgctt gatttggttg gacttggtgg caagtctgcc gctgataaag gaaaggatac tcgtgattat cttgctgctg catttcctga gcttaatgct tgggagcgtg ctggtgctga tgcttcctct gctggtatgg ttgacgccgg atttgagaat caaaaagagc ttactaaaat gcaactggac aatcagaaag agattgccga gatgcaaaat gagactcaaa aagagattgc tggcattcag tcggcgactt cacgccagaa tacgaaagac caggtatatg cacaaaatga gatgcttgct tatcaacaga aggagtctac tgctcgcgtt gcgtctatta tggaaaacac caatctttcc aagcaacagc aggtttccga gattatgcgc caaatgctta ctcaagctca aacggctggt cagtatttta ccaatgacca aatcaaagaa atgactcgca aggttagtgc tgaggttgac ttagttcatc agcaaacgca gaatcagcgg tatggctctt ctcatattgg cgctactgca aaggatattt ctaatgtcgt cactgatgct gcttctggtg tggttgatat ttttcatggt attgataaag ctgttgccga tacttggaac aatttctgga aagacggtaa agctgatggt attggctcta atttgtctag gaaataaccg tcaggattga caccctccca attgtatgtt ttcatgcctc caaatcttgg aggctttttt atggttcgtt cttattaccc ttctgaatgt cacgctgatt attttgactt tgagcgtatc gaggctctta aacctgctat tgaggcttgt ggcatttcta ctctttctca atccccaatg cttggcttcc ataagcagat ggataaccgc atcaagctct tggaagagat tctgtctttt cgtatgcagg gcgttgagtt cgataatggt gatatgtatg ttgacggcca taaggctgct tctgacgttc gtgatgagtt tgtatctgtt actgagaagt taatggatga attggcacaa tgctacaatg tgctccccca acttgatatt aataacacta tagaccaccg ccccgaaggg gacgaaaaat ggtttttaga gaacgagaag acggttacgc agttttgccg caagctggct gctgaacgcc ctcttaagga tattcgcgat gagtataatt accccaaaaa gaaaggtatt aaggatgagt gttcaagatt gctggaggcc tccactatga aatcgcgtag aggctttgct attcagcgtt tgatgaatgc aatgcgacag gctcatgctg atggttggtt tatcgttttt gacactctca cgttggctga cgaccgatta gaggcgtttt atgataatcc caatgctttg cgtgactatt ttcgtgatat tggtcgtatg gttcttgctg ccgagggtcg caaggctaat gattcacacg ccgactgcta tcagtatttt tgtgtgcctg agtatggtac agctaatggc cgtcttcatt tccatgcggt gcactttatg cggacacttc ctacaggtag cgttgaccct aattttggtc gtcgggtacg caatcgccgc cagttaaata gcttgcaaaa tacgtggcct tatggttaca gtatgcccat cgcagttcgc tacacgcagg acgctttttc acgttctggt tggttgtggc ctgttgatgc taaaggtgag ccgcttaaag ctaccagtta tatggctgtt ggtttctatg tggctaaata cgttaacaaa aagtcagata tggaccttgc tgctaaaggt ctaggagcta aagaatggaa caactcacta aaaaccaagc tgtcgctact tcccaagaag ctgttcagaa tcagaatgag ccgcaacttc gggatgaaaa tgctcacaat gacaaatctg tccacggagt gcttaatcca acttaccaag ctgggttacg acgcgacgcc gttcaaccag atattgaagc agaacgcaaa aagagagatg agattgaggc tgggaaaagt tactgtagcc gacgttttgg cggcgcaacc tgtgacgaca aatctgctca aatttatgcg cgcttcgata aaaatgattg gcgtatccaa cctgca
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mark D
TU
Comparative Microbial Genomics group
Cen
ter fo
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eq
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sis Th
e T
ech
nica
l Un
iversity
of D
en
mark D
TU
Comparative Microbial Genomics group
Summary
1. A “genome” is sum of all the DNA sequences (chromosomes) in an organism.
2. The sizes of genomes range about 100,000,000 fold - from small viruses to very large amoebas.
3. Many eukaryotic genomes contain large fractions of repeated DNA sequences, and there is no apparent correlation between the size of an organism and its biological complexity (”C-value Paradox”)
4. Sequence databases are growing faster than computational power!
