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 Computational Biology: Genomes, Networks, Evolution

MIT 6.047 / 6.878 HSPH IMI.231 HST.507

 I. Administrivia

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$ Introductions # M   '  ()*+ ,  - .+- / M .    ,  0  +  +10 + 1,  +" .   +  

8 Course Information # *  M  , M$9 #    M :7 . $,  M    ( )< )"  #/ – All handouts, lectures, notes, etc will be posted here.

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; Course content

? Computation & Biology | Foundations & Frontiers # 2 .E(D5 D/ ,  - . M  b , 3  ,3   M  b  B+, ,  # 2 .E(.5 D/7  7 M  M  56,3  +     M 䇺   䇻6 6  M M 5,     , D+ ,3  +,B M  3 B   M ,,# +   

F Course organized around bio/comp modules # 1    ,  0  6   M  M M M M M # 7   7 6 6  M 2.  , +  +  + +1+ 33) , + + 6 +7   + )G+ 7+D57 +, .  +< , +0  .  +=)+  ,, # 7   )  6 6 M 10  . +  ,  .+  H+H 6    .+1,  +      

  .+   +  3 .+$2 I 9 Textbook / class notes / resources

 (Optional) Books for the Course

© Cambridge University Press. All rights reserved.This © Wiley-Interscience. All rights reserved. This content is excluded from our Creative Commons license. content is excluded from our Creative Commons For more information, see http://ocw.mit.edu/help/faq- !'!#$$%&'( license. For more information, see http://ocw.mit fair-use/. .edu/help/faq-fair-use/. 0  3 .-C,+   (JK895;9/   30   -C1 3  Courtesy of The MIT Press. Used with permission.  New this year!! Book for the Course

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$ Lectures and Scribing # 1     0   3        M "  , 36    3 ,   # - 6 ,0.  M 0  3  3 #  ,  66 336,0   M C 䇻 6 ,0. (  / # 7  66 3; . 6   M N ,  ,0 6  ,0.    ,  # )      ,  3 # )   35. # 3 M 16+6 + .+ + M 8 Scribing details – DropBox 6047_book LaTex



> Sign up here if you haven’t already

; Online material from last year

? Lecture feedback:  N 0 , 5>       .,5> $ ! .6,  M ! .6 5> M  6.6D,  5> M C6 6  5> M =B B  . 5> 8 "  M 266  .6    .5# 5  M  6   0  5# 5   M " 6    5# 56  >  , (6 , / M Q9R+9589R+895;9R+;95F9R+SF9R

 F Homeworks and quiz

I Details on Problem sets # 1 ,3   ,   (/ M "  ,3   D,  B+ +    + .  .+, . +   33 06,3  <   M   ,3  ,<, ,+D,    <   <    ,   <,  (., .   0  ,3  6;F?F/ # 2 . F,  M * ,  . 6 D3 +0  6  M 6   6 +,   + D., . +D ,,     # )3      M H 36.䇻0 0  +.  .  < 0< 0

9 Details on the in-class quiz

#䇻   + 䇻 6 D  M䇻 B+6 .+6++ +6. # 2   .6   8   M C ., ,    M C 3 0  , M 3 . ,, .  0,  ,3   # .,6B M ' B<7#6.+  ,    M 2, B   M "  ,3     ,    M 2,3  (/< 6  + 3    +      Final Project

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8 Final Project at a Glance   73 

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? Putting it all together

F Course Grading

#  

 # 8,3   M 1 ,3  ?59R+ 0$58  +  $58,3   M    ,3   ,   (")/ M   0   ,3      # 7 ,#  M      ,  3 .(?M/ M  ,50H 5. ,,    63  # ! M 5 B(H0>/H6 D  #  3 ,  . M  3  +3.  # =, . ,3  36  # = . #       3 H 

I Why Computational Biology ?

$9 Why Computational Biology: Last year䇻s answers # *6  (T 6  / #     # " 6 #䇻all 3   # 3 .0  # )  + ,   , # U06.(  ., 6/ # ",   < .D, 30  # H<  3 60  3  # 166  .( D,  ,  0/ # 6  6  ( 3 .  3  / #  +  5  , # . 6  .,    # *6 6 C     

$ ATATTGAATTTTCAAAAATTCTTACTTTTTTTTTGGATGGACGCAAAGAAGTTTAATAATCATATTACATGGCATTACCACCATATA TATCCATATCTAATCTTACTTATATGTTGTGGAAATGTAAAGAGCCCCATTATCTTAGCCTAAAAAAACCTTCTCTTTGGAACTTTC TAATACGCTTAACTGCTCATTGCTATATTGAAGTACGGATTAGAAGCCGCCGAGCGGGCGACAGCCCTCCGACGGAAGACTCTCCTC TGCGTCCTCGTCTTCACCGGTCGCGTTCCTGAAACGCAGATGTGCCTCGCGCCGCACTGCTCCGAACAATAAAGATTCTACAATACT CTTTTATGGTTATGAAGAGGAAAAATTGGCAGTAACCTGGCCCCACAAACCTTCAAATTAACGAATCAAATTAACAACCATAGGATG AATGCGATTAGTTTTTTAGCCTTATTTCTGGGGTAATTAATCAGCGAAGCGATGATTTTTGATCTATTAACAGATATATAAATGGAA GCTGCATAACCACTTTAACTAATACTTTCAACATTTTCAGTTTGTATTACTTCTTATTCAAATGTCATAAAAGTATCAACAAAAAAT TTAATATACCTCTATACTTTAACGTCAAGGAGAAAAAACTATAATGACTAAATCTCATTCAGAAGAAGTGATTGTACCTGAGTTCAA CTAGCGCAAAGGAATTACCAAGACCATTGGCCGAAAAGTGCCCGAGCATAATTAAGAAATTTATAAGCGCTTATGATGCTAAACCGG TTTGTTGCTAGATCGCCTGGTAGAGTCAATCTAATTGGTGAACATATTGATTATTGTGACTTCTCGGTTTTACCTTTAGCTATTGAT TGATATGCTTTGCGCCGTCAAAGTTTTGAACGAGAAAAATCCATCCATTACCTTAATAAATGCTGATCCCAAATTTGCTCAAAGGAA TCGATTTGCCGTTGGACGGTTCTTATGTCACAATTGATCCTTCTGTGTCGGACTGGTCTAATTACTTTAAATGTGGTCTCCATGTTG CACTCTTTTCTAAAGAAACTTGCACCGGAAAGGTTTGCCAGTGCTCCTCTGGCCGGGCTGCAAGTCTTCTGTGAGGGTGATGTACCA TGGCAGTGGATTGTCTTCTTCGGCCGCATTCATTTGTGCCGTTGCTTTAGCTGTTGTTAAAGCGAATATGGGCCCTGGTTATCATAT CCAAGCAAAATTTAATGCGTATTACGGTCGTTGCAGAACATTATGTTGGTGTTAACAATGGCGGTATGGATCAGGCTGCCTCTGTTT GGTGAGGAAGATCATGCTCTATACGTTGAGTTCAAACCGCAGTTGAAGGCTACTCCGTTTAAATTTCCGCAATTAAAAAACCATGAA TAGCTTTGTTATTGCGAACACCCTTGTTGTATCTAACAAGTTTGAAACCGCCCCAACCAACTATAATTTAAGAGTGGTAGAAGTCAC CAGCTGCAAATGTTTTAGCTGCCACGTACGGTGTTGTTTTACTTTCTGGAAAAGAAGGATCGAGCACGAATAAAGGTAATCTAAGAG TTCATGAACGTTTATTATGCCAGATATCACAACATTTCCACACCCTGGAACGGCGATATTGAATCCGGCATCGAACGGTTAACAAAG GCTAGTACTAGTTGAAGAGTCTCTCGCCAATAAGAAACAGGGCTTTAGTGTTGACGATGTCGCACAATCCTTGAATTGTTCTCGCGA AATTCACAAGAGACTACTTAACAACATCTCCAGTGAGATTTCAAGTCTTAAAGCTATATCAGAGGGCTAAGCATGTGTATTCTGAAT TTAAGAGTCTTGAAGGCTGTGAAATTAATGACTACAGCGAGCTTTACTGCCGACGAAGACTTTTTCAAGCAATTTGGTGCCTTGATG CGAGTCTCAAGCTTCTTGCGATAAACTTTACGAATGTTCTTGTCCAGAGATTGACAAAATTTGTTCCATTGCTTTGTCAAATGGATC ATGGTTCCCGTTTGACCGGAGCTGGCTGGGGTGGTTGTACTGTTCACTTGGTTCCAGGGGGCCCAAATGGCAACATAGAAAAGGTAA GAAGCCCTTGCCAATGAGTTCTACAAGGTCAAGTACCCTAAGATCACTGATGCTGAGCTAGAAAATGCTATCATCGTCTCTAAACCA ATTGGGCAGCTGTCTATATGAATTATAAGTATACTTCTTTTTTTTACTTTGTTCAGAACAACTTCTCATTTTTTTCTACTCATAACT AGCATCACAAAATACGCAATAATAACGAGTAGTAACACTTTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATA GTTTTCAATGTAAGAGATTTCGATTATCCACAAACTTTAAAACACAGGGACAAAATTCTTGATATGCTTTCAACCGCTGCGTTTTGG ACCTATTCTTGACATGATATGACTACCATTTTGTTATTGTACGTGGGGCAGTTGACGTCTTATCATATGTCAAAGTCATTTGCGAAG CTTGGCAAGTTGCCAACTGACGAGATGCAGTAAAAAGAGATTGCCGTCTTGAAACTTTTTGTCCTTTTTTTTTTCCGGGGACTCTAC GAACCCTTTGTCCTACTGATTAATTTTGTACTGAATTTGGACAATTCAGATTTTAGTAGACAAGCGCGAGGAGGAAAAGAAATGACA AAAATTCCGATGGACAAGAAGATAGGAAAAAAAAAAAGCTTTCACCGATTTCCTAGACCGGAAAAAAGTCGTATGACATCAGAATGA AATTTTCAAGTTAGACAAGGACAAAATCAGGACAAATTGTAAAGATATAATAAACTATTTGATTCAGCGCCAATTTGCCCTTTTCCA TTCCATTAAATCTCTGTTCTCTCTTACTTATATGATGATTAGGTATCATCTGTATAAAACTCCTTTCTTAATTTCACTCTAAAGCAT CCCATAGAGAAGATCTTTCGGTTCGAAGACATTCCTACGCATAATAAGAATAGGAGGGAATAATGCCAGACAATCTATCATTACATT AGCGGCTCTTCAAAAAGATTGAACTCTCGCCAACTTATGGAATCTTCCAATGAGACCTTTGCGCCAAATAATGTGGATTTGGAAAAA GTATAAGTCATCTCAGAGTAATATAACTACCGAAGTTTATGAGGCATCGAGCTTTGAAGAAAAAGTAAGCTCAGAAAAACCTCAATA GCTCATTCTGGAAGAAAATCTATTATGAATATGTGGTCGTTGACAAATCAATCTTGGGTGTTTCTATTCTGGATTCATTTATGTACA CAGGACTTGAAGCCCGTCGAAAAAGAAAGGCGGGTTTGGTCCTGGTACAATTATTGTTACTTCTGGCTTGCTGAATGTTTCAATATC CACTTGGCAAATTGCAGCTACAGGTCTACAACTGGGTCTAAATTGGTGGCAGTGTTGGATAACAATTTGGATTGGGTACGGTTTCG$T GTGCTTTTGTTGTTTTGGCCTCTAGAGTTGGATCTGCTTATCATTTGTCATTCCCTATATCATCTAGAGCATCATTCGGTATTTTCT ATATTGAATTTTCAAAAATTCTTACTTTTTTTTTGGATGGACGCAAAGAAGTTTAATAATCATATTACATGGCATTACCACCATATA TATCCATATCTAATCTTACTTATATGTTGTGGAAATGTAAAGAGCCCCATTATCTTAGCCTAAAAAAACCTTCTCTTTGGAACTTTC TAATACGCTTAACTGCTCATTGCTATATTGAAGTACGGATTAGAAGCCGCCGAGCGGGCGACAGCCCTCCGACGGAAGACTCTCCTC TGCGTCCTCGTCTTCACCGGTCGCGTTCCTGAAACGCAGATGTGCCTCGCGCCGCACTGCTCCGAACAATAAAGATTCTACAATACT CTTTTATGGTTATGAAGAGGAAAAATTGGCAGTAACCTGGCCCCACAAACCTTCAAATTAACGAATCAAATTAACAACCATAGGATG AATGCGATTAGTTTTTTAGCCTTATTTCTGGGGTAATTAATCAGCGAAGCGATGATTTTTGATCTATTAACAGATATATAAATGGAA GCTGCATAACCACTTTAACTAATACTTTCAACATTTTCAGTTTGTATTACTTCTTATTCAAATGTCATAAAAGTATCAACAAAAAAT TTAATATACCTCTATACTTTAACGTCAAGGAGAAAAAACTATAATGACTAAATCTCATTCAGAAGAAGTGATTGTACCTGAGTTCAA CTAGCGCAAAGGAATTACCAAGACCATTGGCCGAAAAGTGCCCGAGCATAATTAAGAAATTTATAAGCGCTTATGATGCTAAACCGG TTTGTTGCTAGATCGCCTGGTAGAGTCAATCTAATTGGTGAACATATTGATTATTGTGACTTCTCGGTTTTACCTTTAGCTATTGAT TGATATGCTTTGCGCCGTCAAAGTTTTGAACGAGAAAAATCCATCCATTACCTTAATAAATGCTGATCCCAAATTTGCTCAAAGGAA TCGATTTGCCGTTGGACGGTTCTTATGTCACAATTGATCCTTCTGTGTCGGACTGGTCTAATTACTTTAAATGTGGTCTCCATGTTG CACTCTTTTCTAAAGAAACTTGCACCGGAAAGGTTTGCCAGTGCTCCTCTGGCCGGGCTGCAAGTCTTCTGTGAGGGTGATGTACC A TGGCAGTGGATTGTCTTCTTCGGCCGCATTCATTTGTGCCGTTGCTTTAGCTGTTGTTAAAGCGAATATGGGCCCTGGTTATCATA  . 6 T CCAAGCAAAATTTAATGCGTATTACGGTCGTTGCAGAACATTATGTTGGTGTTAACAATGGCGGTATGGATCAGGCTGCCTCTGTTT GGTGAGGAAGATCATGCTCTATACGTTGAGTTCAAACCGCAGTTGAAGGCTACTCCGTTTAAATTTCCGCAATTAAAAAACCATGA 1  A TAGCTTTGTTATTGCGAACACCCTTGTTGTATCTAACAAGTTTGAAACCGCCCCAACCAACTATAATTTAAGAGTGGTAGAAGTCA   C CAGCTGCAAATGTTTTAGCTGCCACGTACGGTGTTGTTTTACTTTCTGGAAAAGAAGGATCGAGCACGAATAAAGGTAATCTAAGA , G TTCATGAACGTTTATTATGCCAGATATCACAACATTTCCACACCCTGGAACGGCGATATTGAATCCGGCATCGAACGGTTAACAAA D, G GCTAGTACTAGTTGAAGAGTCTCTCGCCAATAAGAAACAGGGCTTTAGTGTTGACGATGTCGCACAATCCTTGAATTGTTCTCGCGA AATTCACAAGAGACTACTTAACAACATCTCCAGTGAGATTTCAAGTCTTAAAGCTATATCAGAGGGCTAAGCATGTGTATTCTGAAT TTAAGAGTCTTGAAGGCTGTGAAATTAATGACTACAGCGAGCTTTACTGCCGACGAAGACTTTTTCAAGCAATTTGGTGCCTTGATG CGAGTCTCAAGCTTCTTGCGATAAACTTTACGAATGTTCTTGTCCAGAGATTGACAAAATTTGTTCCATTGCTTTGTCAAATGGATC ATGGTTCCCGTTTGACCGGAGCTGGCTGGGGTGGTTGTACTGTTCACTTGGTTCCAGGGGGCCCAAATGGCAACATAGAAAAGGTAA GAAGCCCTTGCCAATGAGTTCTACAAGGTCAAGTACCCTAAGATCACTGATGCTGAGCTAGAAAATGCTATCATCGTCTCTAAACCA ATTGGGCAGCTGTCTATATGAATTATAAGTATACTTCTTTTTTTTACTTTGTTCAGAACAACTTCTCATTTTTTTCTACTCATAACT AGCATCACAAAATACGCAATAATAACGAGTAGTAACACTTTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATA GTTTTCAATGTAAGAGATTTCGATTATCCACAAACTTTAAAACACAGGGACAAAATTCTTGATATGCTTTCAACCGCTGCGTTTTGG ACCTATTCTTGACATGATATGACTACCATTTTGTTATTGTACGTGGGGCAGTTGACGTCTTATCATATGTCAAAGTCATTTGCGAAG CTTGGCAAGTTGCCAACTGACGAGATGCAGTAAAAAGAGATTGCCGTCTTGAAACTTTTTGTCCTTTTTTTTTTCCGGGGACTCTAC GAACCCTTTGTCCTACTGATTAATTTTGTACTGAATTTGGACAATTCAGATTTTAGTAGACAAGCGCGAGGAGGAAAAGAAATGACA AAAATTCCGATGGACAAGAAGATAGGAAAAAAAAAAAGCTTTCACCGATTTCCTAGACCGGAAAAAAGTCGTATGACATCAGAATGA AATTTTCAAGTTAGACAAGGACAAAATCAGGACAAATTGTAAAGATATAATAAACTATTTGATTCAGCGCCAATTTGCCCTTTTCCA TTCCATTAAATCTCTGTTCTCTCTTACTTATATGATGATTAGGTATCATCTGTATAAAACTCCTTTCTTAATTTCACTCTAAAGCAT CCCATAGAGAAGATCTTTCGGTTCGAAGACATTCCTACGCATAATAAGAATAGGAGGGAATAATGCCAGACAATCTATCATTACATT AGCGGCTCTTCAAAAAGATTGAACTCTCGCCAACTTATGGAATCTTCCAATGAGACCTTTGCGCCAAATAATGTGGATTTGGAAAAA GTATAAGTCATCTCAGAGTAATATAACTACCGAAGTTTATGAGGCATCGAGCTTTGAAGAAAAAGTAAGCTCAGAAAAACCTCAATA GCTCATTCTGGAAGAAAATCTATTATGAATATGTGGTCGTTGACAAATCAATCTTGGGTGTTTCTATTCTGGATTCATTTATGTACA CAGGACTTGAAGCCCGTCGAAAAAGAAAGGCGGGTTTGGTCCTGGTACAATTATTGTTACTTCTGGCTTGCTGAATGTTTCAATATC CACTTGGCAAATTGCAGCTACAGGTCTACAACTGGGTCTAAATTGGTGGCAGTGTTGGATAACAATTTGGATTGGGTACGGTTTCG$$T GTGCTTTTGTTGTTTTGGCCTCTAGAGTTGGATCTGCTTATCATTTGTCATTCCCTATATCATCTAGAGCATCATTCGGTATTTTCT ATATTGAATTTTCAAAAATTCTTACTTTTTTTTTGGATGGACGCAAAGAAGTTTAATAATCATATTACATGGCATTACCACCATATA TATCCATATCTAATCTTACTTATATGTTGTGGAAATGTAAAGAGCCCCATTATCTTAGCCTAAAAAAACCTTCTCTTTGGAACTTTC TAATACGCTTAACTGCTCATTGCTATATTGAAGTACGGATTAGAAGCCGCCGAGCGGGCGACAGCCCTCCGACGGAAGACTCTCCTC TGCGTCCTCGTCTTCACCGGTCGCGTTCCTGAAACGCAGATGTGCCTCGCGCCGCACTGCTCCGAACAATAAAGATTCTACAATACT CTTTTATGGTTATGAAGAGGAAAAATTGGCAGTAACCTGGCCCCACAAACCTTCAAATTAACGAATCAAATTAACAACCATAGGATG AATGCGATTAGTTTTTTAGCCTTATTTCTGGGGTAATTAATCAGCGAAGCGATGATTTTTGATCTATTAACAGATATATAAATGGAA GCTGCATAACCACTTTAACTAATACTTTCAACATTTTCAGTTTGTATTACTTCTTATTCAAATGTCATAAAAGTATCAACAAAAAAT TTAATATACCTCTATACTTTAACGTCAAGGAGAAAAAACTATAATGACTAAATCTCATTCAGAAGAAGTGATTGTACCTGAGTTCAA CTAGCGCAAAGGAATTACCAAGACCATTGGCCGAAAAGTGCCCGAGCATAATTAAGAAATTTATAAGCGCTTATGATGCTAAACCGG TTTGTTGCTAGATCGCCTGGTAGAGTCAATCTAATTGGTGAACATATTGATTATTGTGACTTCTCGGTTTTACCTTTAGCTATTGAT TGATATGCTTTGCGCCGTCAAAGTTTTGAACGAGAAAAATCCATCCATTACCTTAATAAATGCTGATCCCAAATTTGCTCAAAGGAA TCGATTTGCCGTTGGACGGTTCTTATGTCACAATTGATCCTTCTGTGTCGGACTGGTCTAATTACTTTAAATGTGGTCTCCATGTTG CACTCTTTTCTAAAGAAACTTGCACCGGAAAGGTTTGCCAGTGCTCCTCTGGCCGGGCTGCAAGTCTTCTGTGAGGGTGATGTACCA TGGCAGTGGATTGTCTTCTTCGGCCGCATTCATTTGTGCCGTTGCTTTAGCTGTTGTTAAAGCGAATATGGGCCCTGGTTATCATAT CCAAGCAAAATTTAATGCGTATTACGGTCGTTGCAGAACATTATGTTGGTGTTAACAATGGCGGTATGGATCAGGCTGCCTCTGTTT GGTGAGGAAGATCATGCTCTATACGTTGAGTTCAAACCGCAGTTGAAGGCTACTCCGTTTAAATTTCCGCAATTAAAAAACCATGAA TAGCTTTGTTATTGCGAACACCCTTGTTGTATCTAACAAGTTTGAAACCGCCCCAACCAACTATAATTTAAGAGTGGTAGAAGTCAC CAGCTGCAAATGTTTTAGCTGCCACGTACGGTGTTGTTTTACTTTCTGGAAAAGAAGGATCGAGCACGAATAAAGGTAATCTAAGAG TTCATGAACGTTTATTATGCCAGATATCACAACATTTCCACACCCTGGAACGGCGATATTGAATCCGGCATCGAACGGTTAACAAAG GCTAGTACTAGTTGAAGAGTCTCTCGCCAATAAGAAACAGGGCTTTAGTGTTGACGATGTCGCACAATCCTTGAATTGTTCTCGCGA AATTCACAAGAGACTACTTAACAACATCTCCAGTGAGATTTCAAGTCTTAAAGCTATATCAGAGGGCTAAGCATGTGTATTCTGAAT TTAAGAGTCTTGAAGGCTGTGAAATTAATGACTACAGCGAGCTTTACTGCCGACGAAGACTTTTTCAAGCAATTTGGTGCCTTGATG CGAGTCTCAAGCTTCTTGCGATAAACTTTACGAATGTTCTTGTCCAGAGATTGACAAAATTTGTTCCATTGCTTTGTCAAATGGATC ATGGTTCCCGTTTGACCGGAGCTGGCTGGGGTGGTTGTACTGTTCACTTGGTTCCAGGGGGCCCAAATGGCAACATAGAAAAGGTAA GAAGCCCTTGCCAATGAGTTCTACAAGGTCAAGTACCCTAAGATCACTGATGCTGAGCTAGAAAATGCTATCATCGTCTCTAAACCA ATTGGGCAGCTGTCTATATGAATTATAAGTATACTTCTTTTTTTTACTTTGTTCAGAACAACTTCTCATTTTTTTCTACTCATAACT AGCATCACAAAATACGCAATAATAACGAGTAGTAACACTTTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATA GTTTTCAATGTAAGAGATTTCGATTATCCACAAACTTTAAAACACAGGGACAAAATTCTTGATATGCTTTCAACCGCTGCGTTTTGG ACCTATTCTTGACATGATATGACTACCATTTTGTTATTGTACGTGGGGCAGTTGACGTCTTATCATATGTCAAAGTCATTTGCGAAG CTTGGCAAGTTGCCAACTGACGAGATGCAGTAAAAAGAGATTGCCGTCTTGAAACTTTTTGTCCTTTTTTTTTTCCGGGGACTCTAC GAACCCTTTGTCCTACTGATTAATTTTGTACTGAATTTGGACAATTCAGATTTTAGTAGACAAGCGCGAGGAGGAAAAGAAATGACA AAAATTCCGATGGACAAGAAGATAGGAAAAAAAAAAAGCTTTCACCGATTTCCTAGACCGGAAAAAAGTCGTATGACATCAGAATGA AATTTTCAAGTTAGACAAGGACAAAATCAGGACAAATTGTAAAGATATAATAAACTATTTGATTCAGCGCCAATTTGCCCTTTTCCA TTCCATTAAATCTCTGTTCTCTCTTACTTATATGATGATTAGGTATCATCTGTATAAAACTCCTTTCTTAATTTCACTCTAAAGCAT CCCATAGAGAAGATCTTTCGGTTCGAAGACATTCCTACGCATAATAAGAATAGGAGGGAATAATGCCAGACAATCTATCATTACATT AGCGGCTCTTCAAAAAGATTGAACTCTCGCCAACTTATGGAATCTTCCAATGAGACCTTTGCGCCAAATAATGTGGATTTGGAAAAA GTATAAGTCATCTCAGAGTAATATAACTACCGAAGTTTATGAGGCATCGAGCTTTGAAGAAAAAGTAAGCTCAGAAAAACCTCAATA GCTCATTCTGGAAGAAAATCTATTATGAATATGTGGTCGTTGACAAATCAATCTTGGGTGTTTCTATTCTGGATTCATTTATGTACA CAGGACTTGAAGCCCGTCGAAAAAGAAAGGCGGGTTTGGTCCTGGTACAATTATTGTTACTTCTGGCTTGCTGAATGTTTCAATATC CACTTGGCAAATTGCAGCTACAGGTCTACAACTGGGTCTAAATTGGTGGCAGTGTTGGATAACAATTTGGATTGGGTACGGTTTCG$8T GTGCTTTTGTTGTTTTGGCCTCTAGAGTTGGATCTGCTTATCATTTGTCATTCCCTATATCATCTAGAGCATCATTCGGTATTTTCT ATATTGAATTTTCAAAAATTCTTACTTTTTTTTTGGATGGACGCAAAGAAGTTTAATAATCATATTACATGGCATTACCACCATATA TATCCATATCTAATCTTACTTATATGTTGTGGAAATGTAAAGAGCCCCATTATCTTAGCCTAAAAAAACCTTCTCTTTGGAACTTTC TAATACGCTTAACTGCTCATTGCTATATTGAAGTACGGATTAGAAGCCGCCGAGCGGGCGACAGCCCTCCGACGGAAGACTCTCCTC TGCGTCCTCGTCTTCACCGGTCGCGTTCCTGAAACGCAG1D  6 ATGTGCCTCGCGCCGCACTGCTCCGAACAATAAAGATTCTACAATACT CTTTTATGGTTATGAAGAGGAAAAATTGGCAGTAACCTGGCCCCACAAACCTTCAAATTAACGAATCAAATTAACAACCATAGGATG AATGCGATTAGTTTTTTAGCCTTATTTCTGGGGTAATTAATCAGCGAAGCGATGATTTTTGATCTATTAACAGATATATAAATGGAA GCTGCATAACCACTTTAACTAATACTTTCAACATTTTCAGTTTGTATTACTTCTTATTCAAATGTCATAAAAGTATCAACAAAAAAT TTAATATACCTCTATACTTTAACGTCAAGGAGAAAAAACTATAATGACTAAATCTCATTCAGAAGAAGTGATTGTACCTGAGTTCAA CTAGCGCAAAGGAATTACCAAGACCATTGGCCGAAAAGTGCCCGAGCATAATTAAGAAATTTATAAGCGCTTATGATGCTAAACCGG TTTGTTGCTAGATCGCCTGGTAGAGTCAATCTAATTGGTGAACATATTGATTATTGTGACTTCTCGGTTTTACCTTTAGCTATTGAT TGATATGCTTTGCGCCGTCAAAGTTTTGAACGAGAAAAATCCATCCATTACCTTAATAAATGCTGATCCCAAATTTGCTCAAAGGAA TCGATTTGCCGTTGGACGGTTCTTATGTCACAATTGATCCTTCTGTGTCGGACTGGTCTAATTACTTTAAATGTGGTCTCCATGTTG CACTCTTTTCTAAAGAAACTTGCACCGGAAAGGTTTGCCAGTGCTCCTCTGGCCGGGCTGCAAGTCTTCTGTGAGGGTGATGTACCA TGGCAGTGGATTGTCTTCTTCGGCCGCATTCATTTGTGCCGTTGCTTTAGCTGTTGTTAAAGCGAATATGGGCCCTGGTTATCATAT CCAAGCAAAATTTAATGCGTATTACGGTCGTTGCAGAACATTATGTTGGTGTTAACAATGGCGGTATGGATCAGGCTGCCTCTGTTT GGTGAGGAAGATCATGCTCTATACGTTGAGTTCAAACCGCAGTTGAAGGCTACTCCGTTTAAATTTCCGCAATTAAAAAACCATGAA TAGCTTTGTTATTGCGAACACCCTTGTTGTATCTAACAAGTTTGAAACCGCCCCAACCAACTATAATTTAAGAGTGGTAGAAGTCAC CAGCTGCAAATGTTTTAGCTGCCACGTACGGTGTTGTTTTACTTTCTGGAAAAGAAGGATCGAGCACGAATAAAGGTAATCTAAGAG TTCATGAACGTTTATTATGCCAGATATCACAACATTTCCACACCCTGGAACGGCGATATTGAATCCGGCATCGAACGGTTAACAAAG GCTAGTACTAGTTGAAGAGTCTCTCGCCAATAAGAAACAGGGCTTTAGTGTTGACGATGTCGCACAATCCTTGAATTGTTCTCGCGA AATTCACAAGAGACTACTTAACAACATCTCCAGTGAGATTTCAAGTCTTAAAGCTATATCAGAGGGCTAAGCATGTGTATTCTGAAT TTAAGAGTCTTGAAGGCTGTGAAATTAATGACTACAGCGAGCTTTACTGCCGACGAAGACTTTTTCAAGCAATTTGGTGCCTTGATG CGAGTCTCAAGCTTCTTGCGATAAACTTTACGAATGTTCTTGTCCAGAGATTGACAAAATTTGTTCCATTGCTTTGTCAAATGGATC ATGGTTCCCGTTTGACCGGAGCTGGCTGGGGTGGTTGTACTGTTCACTTGGTTCCAGGGGGCCCAAATGGCAACATAGAAAAGGTAA GAAGCCCTTGCCAATGAGTTCTACAAGGTCAAGTACCCTAAGATCACTGATGCTGAGCTAGAAAATGCTATCATCGTCTCTAAACCA ATTGGGCAGCTGTCTATATGAATTATAAGTATACTTCTTTTTTTTACTTTGTTCAGAACAACTTCTCATTTTTTTCTACTCATAACT AGCATCACAAAATACGCAATAATAACGAGTAGTAACACTTTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATA GTTTTCAATGTAAGAGATTTCGATTATCCACAAACTTTAAAACACAGGGACAAAATTCTTGATATGCTTTCAACCGCTGCGTTTTGG ACCTATTCTTGACATGATATGACTACCATTTTGTTATTGTACGTGGGGCAGTTGACGTCTTATCATATGTCAAAGTCATTTGCGAAG CTTGGCAAGTTGCCAACTGACGAGATGCAGTAAAAAGAGATTGCCGTCTTGAAACTTTTTGTCCTTTTTTTTTTCCGGGGACTCTAC GAACCCTTTGTCCTACTGATTAATTTTGTACTGAATTTGGACAATTCAGATTTTAGTAGACAAGCGCGAGGAGGAAAAGAAATGACA AAAATTCCGATGGACAAGAAGATAGGAAAAAAAAAAAGCTTTCACCGATTTCCTAGACCGGAAAAAAGTCGTATGACATCAGAATGA AATTTTCAAGTTAGACAAGGACAAAATCAGGACAAATTGTAAAGATATAATAAACTATTTGATTCAGCGCCAATTTGCCCTTTTCCA TTCCATTAAATCTCTGTTCTCTCTTACTTATATGATGATTAGGTATCATCTGTATAAAACTCCTTTCTTAATTTCACTCTAAAGCAT CCCATAGAGAAGATCTTTCGGTTCGAAGACATTCCTACGCATAATAAGAATAGGAGGGAATAATGCCAGACAATCTATCATTACATT AGCGGCTCTTCAAAAAGATTGAACTCTCGCCAACTTATGGAATCTTCCAATGAGACCTTTGCGCCAAATAATGTGGATTTGGAAAAA GTATAAGTCATCTCAGAGTAATATAACTACCGAAGTTTATGAGGCATCGAGCTTTGAAGAAAAAGTAAGCTCAGAAAAACCTCAATA GCTCATTCTGGAAGAAAATCTATTATGAATATGTGGTCGTTGACAAATCAATCTTGGGTGTTTCTATTCTGGATTCATTTATGTACA CAGGACTTGAAGCCCGTCGAAAAAGAAAGGCGGGTTTGGTCCTGGTACAATTATTGTTACTTCTGGCTTGCTGAATGTTTCAATATC CACTTGGCAAATTGCAGCTACAGGTCTACAACTGGGTCTAAATTGGTGGCAGTGTTGGATAACAATTTGGATTGGGTACGGTTTCGT GTGCTTTTGTTGTTTTGGCCTCTAGAGTTGGATCTGCTTATCATTTGTCATTCCCTATATCATCTAGAGCATCATTCGGTATTTTCT$> The components of genomes and gene regulation

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given profile matrix  # easy to find starting position probabilities

8F Multivariate HMM for Chromatin States Transcription Enhancer Transcribed Region Start Site DNA

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Courtesy of Macmillan Publishers Limited. Used with permission. Source: Ernst, Jason and Manolis Kellis. "Discovery and characterization of chromatin states for systematic annotation of the human genome." Nature Biotechnology 28, no. 8 (2010): 817-825. 8I Modules IV and V: Evolution/phylogeny/populations

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© source unknown. All rights reserved. This content is excluded from our Creative Commons license. For more information, see http://ocw.mit.edu/help/faq- fair-use/.

Courtesy of Macmillan Publishers Limited. Used with permission. Source: Arking, Dan E. et al. "Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization." Nature Genetics 46, no. 8 (2014): 826-836. Focus on sub-threshold variants (e.g. rs1743292 P=10-4.2) Trait: QRS/QT interval (1) Large cohorts, (2) many known hits

(3) well-characterized tissue drivers > Evidence of NeanderthalbHuman gene flow

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Coalescence Duplication & Loss



 -   -  # Coalescent models of alleles in populations # DL models of genes in species Deal with 1-to-1 orthologs Deal with paralogous families Estimate divergence times, pop sizes, etc Estimate birth death rates Models move backward in time Models move forward in time Cannot cope with duplication and loss Cannot cope with incomplete lineage sorting >; >? Biology primer

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>I DNA: The double helix #       

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;$ Alignment: all species/genes share common ancestry

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© Neal Olander. All rights reserved. This content is excluded from our Creative Commons license. For more information, see http://ocw.mit.edu/help/faq-fair-use/. ;> Tree of life 

© Neal Olander. All rights reserved. This content is excluded from our Creative Commons license. For more information, see http://ocw.mit.edu/help/faq-fair-use/. ;; Extinctions part of life

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;I Chromosomes inside the cell

Eukaryote DNA Prokaryote

Nucleus DNA organized in a single chromosome. No nucleus. No mitosis. DNA organized in multiple chromosomes inside a nucleus. Mitotic division

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#7< < <7<    ,?$ Epigenomics Roadmap across 100+ tissues/cell types

Diverse epigenomic assays: 1. Histone modifications # H3K4me3, H3K4me1 # H3K36me3 Art: Rae Senarighi, Richard Sandstrom # H3K27me3, H3K9me3 # H3K27/9ac, +20 more 2. Open chromatin: # DNase

Courtesy of Macmillan Publishers Limited. Used with permission. 3. DNA methylation: Source: Roadmap Epigenomics Consortium et al. "Integrative analysis of 111 # WGBS, RRBS, MRE/MeDIP reference human epigenomes." Nature 518, no. 7539 (2015): 317-330. 4. Gene expression Diverse tissues and cells: # RNA-seq, Exon Arrays 1.Adult tissues and cells (brain, muscle, heart, digestive, skin, adipose, lung, blood…) 2.Fetal tissues (brain, skeletal muscle, heart, digestive, lung, cord blood…)

3.ES cells, iPS, differentiated cells (meso/endo/ectoderm, neural, mesench, trophobl) ?8 Deep sampling of 9 reference epigenomes (e.g. IMR90)

Courtesy of Ting Wang. Used with permission. UWash Epigenome Browser, Ting Wang Chromatin state+RNA+DNAse+28 histone marks+WGBS+Hi-C ?> 20    ,   

Enhancers Promoters Transcribed Repressed # H3K4me1 # H3K4me3 # H3K36me3 # H3K9me3 # H3K27ac # H3K9ac # H3K79me2 # H3K27me3 # DNase # DNase # H4K20me1 # DNAmethyl # H3K4me3 # H3K4me1 # H3K27ac # H3K36me3 # H4K20me1 # H3K79me3 # H3K27me3 # H3K9me3 # H3K9ac # H3K18ac

© source unknown. All rights reserved. This contentis excluded from our Creative

Courtesy of Broad Communications. Used with permission. Commons license. Formore information, # 996 6 + . see http://ocw.mit.edu/help/faq-fair-use/  .

#).   ,, "5+- 65+2H 5)B ?; Chromatin state annotations across 127 epigenomes

Courtesy of Anshul Kundaje. Used with permission. Reveal epigenomic variability: enh/prom/tx/repr/het Anshul Kundaje ?? 䇾Central dogma䇿 of Molecular Biology





?F Genes control the making of cell parts

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?I mRNA: The messenger

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F9 From DNA to RNA: Transcription

Image removed due to copyright restrictions.Please see: Figure 7-9 from Alberts, Bruce, and Martin Raff. Essential Cell Biology. New York, NY: Garland Publishing Inc., 1997. ISBN: 0815320450.

F From pre-mRNA to mRNA: Splicing

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Courtesy of SStructView F8 Splicing machinery made of RNA

Image removed due to copyright restrictions. Please see: Figure 7-16 from Alberts, Bruce, and Martin Raff. Essential Cell Biology. New York, NY: Garland Publishing Inc., 1997. ISBN: 0815320450.

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F; Proteins carry out the cell䇻s chemistry

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I9 The Genetic Code

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Image by MIT OpenCourseWare. I Cellular dynamics and regulation How cells move through this Central Dogma





I$ Animal/Human gene regulation: One genome  Many cell types

ACCAGTTACGACGGTCA GGGTACTGATACCCCAA ACCGTTGACCGCATTTA CAGACGGGGTTTGGGTT TTGCCCCACACAGGTAC GTTAGCTACTGGTTTAG Images of a heart, red blood cell, and a brain CAATTTACCGTTACAAC removed due to copyright restrictions. GTTTACAGGGTTACGGT TGGGATTTGAAAAAAAG TTTGAGTTGGTTTTTTC ACGGTAGAACGTACCGT TACCAGTA Image in the public domain.

 ) , I8 Eukaryotic Gene Regulation

Cartoon depicting eukaryotic gene regulation removed due to copyright restrictions.

I> Diverse roles for regulatory non-coding RNAs

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I; Regulation of Gene Expression

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I? Predicted motif drivers of enhancer modules

# Activator and repressor motifs consistent with tissues

Courtesy of Macmillan Publishers Limited. Used with permission. Pouya Kheradpour 98 IF Network components reveal functional modules

© Cold Spring Harbor Laboratory Press. All rights reserved. This content is excluded from our Creative Commons license. For more information, see http://ocw.mit.edu/help/faq-fair-use/. Source: Zeitlinger, Julia et al. "Whole-genome ChIP–chip analysis of Dorsal, Twist, and Snail suggests integration of diverse patterning prcesses in the Drosophila embryo." Genes & # 756  ,0 ,Development 21, no. 4 (2007): 385-390.  ,  # , 6 W 

aet al& II Systematic motif dissection in 2000 enhancers: 5 activators and 2 repressors in 2 cell lines

Figure 1: selection of activator and repressor motifs removed due to copyright restrictions. Source: Kheradpour, Pouya et al. "Systematic dissection of regulatory motifs in 2000 predicted human enhancers using a massively parallel reporter assay." Genome Research 23, no. 5 (2013): 800-811.



Kheradpour et al Genome Research 2013 99 Emerging properties of regulatory networks

Figures removed due to copyright restrictions.

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98 The role of genetic alterations





9> Brief intro to human genetics # $- + ,+$   + 9+J$  )H"+J>99 , .,3  

www.genome.gov/GWAStudies www.ebi.ac.uk/fgpt/gwas/

Figure in the public domain. Created by Darryl Leja and Teri Manolio, NHGRI; Tony Burdett, Dani Welter, and Helen Parkinson, EBI.

9; The power and challenge of disease-association studies

'7'* + (011'1(12331 Slide credit: Luke Ward, Mark Daly # Large associated blocks with many variants: Fine-mapping challenge # No information on cell type/mechanism, most variants non-coding  Epigenomic annotations help find relevant cell types / nucleotides 9? The power of GWAS: reveal new disease genes

© ADAM, Inc. All rights reserved. This content is excluded from our Creative Commons license. For more information, see http://ocw.mit.edu/help/faq-fair-use/. Courtesy of Macmillan Publishers Limited. Used with permission. Source: Cho, Judy H. "The genetics and immunopathogenesis of inflammatory bowel disease." Nature Reviews Immunology 8, no. 6 (2008): 458-466.

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9F Genomewide association in schizophrenia with 40,000 cases

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Courtesy of Macmillan Publishers Limited. Used with permission. Source: Ripke, Stephan et al. "Biological insights from 108 schizophrenia-associated genetic loci." Nature 511, no. 7510 (2014): 421. 9I Interpreting non- DD coding variants

# Disease-associated SNPs enriched for enhancers in relevant cell types # E.g. lupus SNP in GM enhancer disrupts Ets1 predicted activator '7'* +(011'1(12331 9 Mechanistic predictions for top disease-associated SNPs

Figures removed due to copyright restrictions.

Disrupt activator Ets-1 motif Creation of repressor Gfi1 motif  Loss of GM-specific activation  Gain K562-specific repression  Loss of enhancer function  Loss of enhancer function  Loss of HLA-DRB1 expression  Loss of CCDC162 expression Chromatin state annotations across 127 epigenomes

Figures removed due to copyright restrictions.

Reveal epigenomic variability: enh/prom/tx/repr/het Anshul Kundaje  Characterizing sub-threshold variants in heart arrhythmia

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Focus on sub-threshold variants -4.2 (e.g. rs1743292 P=10 ) Courtesy of Macmillan Publishers Limited. Used with permission. Source: Arking, Dan E. et al. "Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization." Nature Genetics 46, no. 8 (2014): 826-836. Trait: QRS/QT interval (1) Large cohorts, (2) many known hits

(3) well-characterized tissue drivers $ Courtesy of Macmillan Publishers Limited. Used with permission. Source: Roadmap Epigenomics Consortium et al. "Integrative analysis of 111 reference human epigenomes." Nature 518, no. 7539 (2015): 317-330. 8 Linking traits to their relevant cell/tissue types

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