-
DNA2: Last week's take home lessonsComparing types of alignments
& algorithmsDynamic programming (DP)Multi-sequence
alignmentSpace-time-accuracy tradeoffsFinding genes -- motif
profilesHidden Markov Model (HMM) for CpG Islands
-
RNA1: Today's story & goals Integration with previous topics
(HMM & DP for RNA structure) Goals of molecular quantitation
(maximal fold-changes, clustering & classification of genes
& conditions/cell types, causality) Genomics-grade measures of
RNA and protein and how we choose and integrate (SAGE,
oligo-arrays, gene-arrays)Sources of random and systematic errors
(reproducibilty of RNA source(s), biases in labeling, non-polyA
RNAs, effects of array geometry, cross-talk). Interpretation issues
(splicing, 5' & 3' ends, gene families, small RNAs, antisense,
apparent absence of RNA).Time series data: causality, mRNA decay,
time-warping
-
Discrete & continuous bell-curves
Chart4
0.000004050.00000000210.00000000150.00216057150
0.00001073710.00000004120.00000003110.00248327880
0.00002707760.00000041220.00000031720.00287133550
0.00006495570.00000274820.0000021550.00334145570
0.00014822120.0000137410.00001097630.00391548030
0.00032172780.00005496410.00004470350.00462217490
0.00066428140.00018321370.00015164560.00549970330.0000000006
0.00130467060.00052346760.00044071310.00659902010.0000000501
0.00243744560.0013086690.00112014590.00798846550.0000015662
0.0043316590.00290815330.00252944270.00975982960.0000235011
0.00732249130.00581630650.00513809020.01203593830.0001959731
0.01177466990.01057510280.00948352730.01497908720.0010216057
0.01801042230.01762517130.01603737920.01879775490.0036578757
0.02620500990.02711564810.02502180060.02374465780.0096988889
0.03626853670.03873664010.03623286710.03009051950.0202255944
0.04774864120.05164885350.04894486960.03804397930.0348071336
0.0597967080.06456106690.06195357540.04757621820.0513731574
0.07123260220.07595419640.07377003280.05813096580.0670609644
0.08071711290.08439355150.08291884160.06832325630.0793515697
0.08700369670.08883531740.08825280210.07596842620.0868038135
0.08920620580.08883531740.08918881670.07884787160.0891769814
0.08700369670.08460506420.08579972750.07596842620.0871287285
0.08071711290.07691369470.07874823470.06832325630.081777491
0.07123260220.06688147370.06909924150.05813096580.0743299235
0.0597967080.05573456140.05807709820.04757621820.0658483281
0.04774864120.04458764910.04683712650.03804397930.0571492957
0.03626853670.03429819160.03630150250.03009051950.0487919712
0.02620500990.02540606790.02708013310.02374465780.041113606
0.01801042230.01814719130.01946995140.01879775490.0342818828
0.01177466990.01251530440.01350893180.01497908720.0283464687
0.00732249130.00834353620.00905598760.01203593830.0232819189
0.0043316590.00538292660.00587208060.00975982960.019019893
0.00243744560.00336432910.00368673240.00798846550.0154715499
0.00130467060.00203898740.00224341110.00659902010.0125420761
0.00066428140.00119940430.0013243190.00549970330.0101394284
0.00032172780.00068537390.00075904690.00462217490.0081790847
0.00014822120.00038076330.00042275760.00391548030.0065861868
0.00006495570.0002058180.00022897930.00334145570.0052960752
0.00002707760.00010832530.0001206980.00287133550.0042538982
0.00001073710.00005555140.00006195890.00248327880.0034137403
0.000004050.00002777570.00003099510.00216057150.002737552
Normal (m=20, s=4.47)
Poisson (m=20, s^2=m)
Binomial (N=2020, p=.01, m=Np)
t-dist (m=20, s=4.47, dof=2)
ExtrVal(u=20, L=1/4.47)
ExtremeNorm
cum=1 means yes cumulative; cum=0 means No
Poisson(x,mean,cum)7E-019E-011E+00meanstdev
NormDist(x,mean,sd,cum)8E-011E+001E+000.57735026920.577215664101.28251.00
1E+021E+021E+0110.005.774.34E-1516.4510.00
mean5E-015E-015E-020.052E-022E-170.080.03
stdev5E-015E-011E-010.10778301079E-028E-020.11638219110.0899499444
xExtremeVal cumNorm (.58,1.3)
cumExtremeVal(L=1,u=0)Normal(m=.58,
s=1.3)NormExtr*XNorm*XExtr*(x-m)^2Norm*(x-m)^2
-101E+001E+000E+005E-168E-230E+00-8E-220E+008E-21
-9.91E+001E+000E+001E-152E-220E+00-2E-210E+002E-20
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06.32E-016.74E-013.68E-012.81E-013.99E-010.00E+000.00E+001.23E-010.00E+00
0.16E-016E-014E-013E-010.404E-024E-028E-024E-03
0.26E-016E-014E-013E-010.397E-028E-025E-022E-02
0.35E-016E-014E-013E-010.381E-011E-013E-023E-02
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0.55E-015E-013E-013E-010.352E-012E-012E-039E-02
0.64E-015E-013E-013E-010.332E-012E-012E-041E-01
0.74E-015E-013E-013E-010.312E-012E-015E-032E-01
0.84E-014E-013E-013E-010.292E-012E-011E-022E-01
0.93E-014E-013E-013E-010.272E-012E-013E-022E-01
13E-014E-013E-013E-010.243E-012E-015E-022E-01
1.13E-013E-012E-013E-010.223E-012E-017E-023E-01
1.23E-013E-012E-013E-010.193E-012E-019E-023E-01
1.32E-013E-012E-013E-010.173E-012E-011E-013E-01
1.42E-013E-012E-013E-010.153E-012E-011E-013E-01
1.52E-012E-012E-012E-010.133E-012E-012E-013E-01
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1.82E-012E-011E-012E-010.083E-011E-012E-013E-01
1.91E-012E-011E-012E-010.072E-011E-012E-012E-01
21E-011E-011E-012E-010.052E-011E-012E-012E-01
2.11E-011E-011E-012E-010.042E-019E-023E-012E-01
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3.14E-022E-024E-024E-020.001E-011E-023E-013E-02
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7.84E-049E-094E-044E-080.003E-032E-132E-021E-12
7.94E-046E-094E-043E-080.003E-039E-142E-027E-13
83E-044E-093E-042E-080.003E-034E-142E-023E-13
8.13E-042E-093E-041E-080.002E-032E-142E-021E-13
8.23E-041E-093E-047E-090.002E-038E-152E-027E-14
8.32E-049E-102E-044E-090.002E-034E-151E-023E-14
8.42E-045E-102E-043E-090.002E-032E-151E-021E-14
8.52E-043E-102E-042E-090.002E-037E-161E-026E-15
8.62E-042E-102E-041E-090.002E-033E-161E-023E-15
8.72E-041E-102E-046E-100.001E-031E-161E-021E-15
8.82E-047E-112E-044E-100.001E-035E-171E-025E-16
8.91E-044E-111E-042E-100.001E-032E-179E-032E-16
91E-043E-111E-041E-100.001E-039E-189E-038E-17
9.11E-042E-111E-048E-110.001E-034E-188E-033E-17
9.21E-049E-121E-045E-110.009E-042E-188E-031E-17
9.39E-055E-129E-053E-110.009E-046E-197E-036E-18
9.48E-053E-128E-052E-110.008E-042E-196E-032E-18
9.57E-052E-127E-051E-110.007E-041E-196E-039E-19
9.67E-051E-127E-056E-120.007E-044E-206E-034E-19
9.76E-056E-136E-053E-120.006E-041E-205E-031E-19
9.86E-053E-136E-052E-120.005E-045E-215E-035E-20
9.95E-052E-135E-051E-120.005E-042E-214E-032E-20
105E-051E-135E-056E-130.005E-048E-224E-038E-21
10.14E-056E-144E-053E-130.004E-043E-224E-033E-21
10.24E-053E-144E-052E-130.004E-041E-223E-031E-21
10.33E-052E-143E-051E-130.003E-044E-233E-034E-22
10.43E-059E-153E-056E-140.003E-041E-233E-031E-22
10.53E-055E-153E-053E-140.003E-045E-243E-035E-23
10.62E-053E-152E-052E-140.003E-042E-243E-032E-23
10.72E-050E+002E-059E-150.002E-046E-252E-036E-24
10.82E-050E+002E-055E-150.002E-042E-250.000.00
10.92E-050E+002E-053E-150.002E-047E-260.000.00
112E-050E+002E-051E-150.002E-042E-260.000.00
11.12E-050E+002E-058E-160.002E-048E-270.000.00
11.21E-050E+001E-054E-160.002E-043E-270.000.00
11.31E-050E+001E-052E-160.001E-048E-280.000.00
11.41E-050E+001E-051E-160.001E-043E-280.000.00
11.51E-050E+001E-056E-170.001E-049E-290.000.00
11.69E-060E+009E-063E-170.001E-043E-290.000.00
11.78E-060E+008E-061E-170.001E-049E-300.000.00
11.88E-060E+008E-067E-180.009E-053E-300.000.00
11.97E-060E+007E-064E-180.008E-058E-310.000.00
126E-060E+006E-062E-180.007E-053E-310.000.00
12.16E-060E+006E-069E-190.007E-058E-320.000.00
12.25E-060E+005E-065E-190.006E-052E-320.000.00
12.35E-060E+005E-062E-190.006E-057E-330.000.00
12.44E-060E+004E-061E-190.005E-052E-330.000.00
12.54E-060E+004E-065E-200.005E-056E-340.000.00
12.63E-060E+003E-063E-200.004E-052E-340.000.00
12.73E-060E+003E-061E-200.004E-055E-350.000.00
12.83E-060E+003E-066E-210.004E-051E-350.000.00
12.92E-060E+002E-063E-210.003E-054E-360.000.00
132E-060E+002E-061E-210.003E-051E-360.000.00
13.12E-060E+002E-066E-220.003E-053E-370.000.00
13.22E-060E+002E-063E-220.002E-058E-380.000.00
13.32E-060E+002E-061E-220.002E-052E-380.000.00
13.42E-060E+002E-066E-230.002E-055E-390.000.00
13.51E-060E+001E-063E-230.002E-051E-390.000.00
13.61E-060E+001E-061E-230.002E-054E-400.000.00
13.71E-060E+001E-066E-240.002E-051E-400.000.00
13.81E-060E+001E-063E-240.001E-052E-410.000.00
13.99E-070E+009E-071E-240.001E-056E-420.000.00
148E-070E+008E-075E-250.001E-052E-420.000.00
14.18E-070E+008E-072E-250.001E-054E-430.000.00
14.27E-070E+007E-071E-250.001E-059E-440.000.00
14.36E-070E+006E-074E-260.009E-062E-440.000.00
14.46E-070E+006E-072E-260.008E-065E-450.000.00
14.55E-070E+005E-078E-270.007E-061E-450.000.00
14.65E-070E+005E-073E-270.007E-063E-460.000.00
14.74E-070E+004E-071E-270.006E-067E-470.000.00
14.84E-070E+004E-076E-280.006E-062E-470.000.00
14.93E-070E+003E-073E-280.005E-064E-480.000.00
153E-070E+003E-071E-280.005E-068E-490.000.00
15.13E-070E+003E-074E-290.004E-062E-490.000.00
15.23E-070E+003E-072E-290.004E-064E-500.000.00
15.32E-070E+002E-078E-300.003E-069E-510.000.00
15.42E-070E+002E-073E-300.003E-062E-510.000.00
15.52E-070E+002E-071E-300.003E-064E-520.000.00
15.62E-070E+002E-075E-310.003E-069E-530.000.00
15.72E-070E+002E-072E-310.002E-062E-530.000.00
15.81E-070E+001E-078E-320.002E-064E-540.000.00
15.91E-070E+001E-073E-320.002E-068E-550.000.00
161E-070E+001E-071E-320.002E-062E-550.000.00
16.11E-070E+001E-075E-330.002E-063E-560.000.00
16.29E-080E+009E-082E-330.001E-067E-570.000.00
16.38E-080E+008E-087E-340.001E-061E-570.000.00
16.48E-080E+008E-083E-340.001E-063E-580.000.00
16.57E-080E+007E-081E-340.001E-065E-590.000.00
16.66E-080E+006E-084E-350.001E-061E-590.000.00
16.76E-080E+006E-082E-350.009E-072E-600.000.00
16.85E-080E+005E-086E-360.008E-073E-610.000.00
16.95E-080E+005E-082E-360.008E-076E-620.000.00
174E-080E+004E-088E-370.007E-071E-620.000.00
17.14E-080E+004E-083E-370.006E-072E-630.000.00
17.23E-080E+003E-081E-370.006E-074E-640.000.00
17.33E-080E+003E-084E-380.005E-077E-650.000.00
17.43E-080E+003E-081E-380.005E-071E-650.000.00
17.53E-080E+003E-085E-390.004E-072E-660.000.00
17.62E-080E+002E-082E-390.004E-074E-670.000.00
17.72E-080E+002E-086E-400.004E-077E-680.000.00
17.82E-080E+002E-082E-400.003E-071E-680.000.00
17.92E-080E+002E-088E-410.003E-072E-690.000.00
182E-080E+002E-083E-410.003E-073E-700.000.00
18.11E-080E+001E-089E-420.002E-075E-710.000.00
18.21E-080E+001E-083E-420.002E-079E-720.000.00
18.31E-080E+001E-081E-420.002E-071E-720.000.00
18.41E-080E+001E-084E-430.002E-072E-730.000.00
18.59E-090E+009E-091E-430.002E-074E-740.000.00
18.68E-090E+008E-094E-440.002E-076E-750.000.00
18.78E-090E+008E-091E-440.001E-079E-760.000.00
18.87E-090E+007E-095E-450.001E-071E-760.000.00
18.96E-090E+006E-091E-450.001E-072E-770.000.00
196E-090E+006E-095E-460.001E-073E-780.000.00
19.15E-090E+005E-092E-460.001E-075E-790.000.00
19.25E-090E+005E-095E-470.009E-087E-800.000.00
19.34E-090E+004E-092E-470.008E-081E-800.000.00
19.44E-090E+004E-095E-480.007E-081E-810.000.00
19.53E-090E+003E-092E-480.007E-082E-820.000.00
19.63E-090E+003E-095E-490.006E-083E-830.000.00
19.73E-090E+003E-092E-490.005E-084E-840.000.00
19.83E-090E+003E-095E-500.005E-086E-850.000.00
19.92E-090E+002E-092E-500.005E-088E-860.000.00
202E-090E+002E-095E-510.004E-081E-860.000.00
20.12E-090E+002E-092E-510.004E-081E-870.000.00
20.22E-090E+002E-095E-520.003E-082E-880.000.00
20.32E-090E+002E-091E-520.003E-083E-890.000.00
20.41E-090E+001E-094E-530.003E-083E-900.000.00
20.51E-090E+001E-091E-530.003E-085E-910.000.00
20.61E-090E+001E-094E-540.002E-086E-920.000.00
20.71E-090E+001E-091E-540.002E-087E-930.000.00
20.89E-100E+009E-103E-550.002E-089E-940.000.00
20.98E-100E+008E-109E-560.002E-081E-940.000.00
218E-100E+008E-103E-560.002E-081E-950.000.00
21.17E-100E+007E-108E-570.001E-082E-960.000.00
21.26E-100E+006E-102E-570.001E-082E-970.000.00
21.36E-100E+006E-106E-580.001E-083E-980.000.00
21.45E-100E+005E-102E-580.001E-083E-990.000.00
21.55E-100E+005E-105E-590.001E-084E-1000.000.00
21.64E-100E+004E-101E-590.009E-094E-1010.000.00
21.74E-100E+004E-104E-600.008E-095E-1020.000.00
21.83E-100E+003E-101E-600.007E-096E-1030.000.00
21.93E-100E+003E-103E-610.007E-096E-1040.000.00
223E-100E+003E-108E-620.006E-097E-1050.000.00
22.13E-100E+003E-102E-620.006E-098E-1060.000.00
22.22E-100E+002E-106E-630.005E-098E-1070.000.00
22.32E-100E+002E-102E-630.005E-099E-1080.000.00
22.42E-100E+002E-104E-640.004E-091E-1080.000.00
22.52E-100E+002E-101E-640.004E-091E-1090.000.00
22.62E-100E+002E-103E-650.003E-091E-1100.000.00
22.71E-100E+001E-108E-660.003E-091E-1110.000.00
22.81E-100E+001E-102E-660.003E-091E-1120.000.00
22.91E-100E+001E-105E-670.003E-091E-1130.000.00
231E-100E+001E-101E-670.002E-091E-1140.000.00
23.19E-110E+009E-113E-680.002E-091E-1150.000.00
23.28E-110E+008E-119E-690.002E-091E-1160.000.00
23.38E-110E+008E-112E-690.002E-091E-1170.000.00
23.47E-110E+007E-115E-700.002E-091E-1180.000.00
23.56E-110E+006E-111E-700.001E-091E-1190.000.00
23.66E-110E+006E-113E-710.001E-091E-1200.000.00
23.75E-110E+005E-118E-720.001E-091E-1210.000.00
23.85E-110E+005E-112E-720.001E-099E-1230.000.00
23.94E-110E+004E-115E-730.001E-099E-1240.000.00
244E-110E+004E-111E-730.009E-108E-1250.000.00
24.13E-110E+003E-113E-740.008E-107E-1260.000.00
ExtremeNorm
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
ExtremeVal cum
Norm (.58,1.3) cum
exp
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
ExtremeVal(L=1,u=0)
Normal(m=.58, s=1.3)
BiGaPotEv
texp(kt)exp(-kt)35exp(-x^2)0.2916666667
-3.50330.000167479135
-3.20833333330250.00118495
-2.91666666670180.0070721101
-2.6250140.0356047245
-2.33333333330100.1512083816
-2.0416666667080.5416936188
-1.75061.6369717834
-1.4583333333044.1729029737
-1.1666666667038.973151484
-0.8750216.2765115847
-0.58333333331224.9050422685
-0.29166666671132.1456975364
01135
0.29166666671132.1456975364
0.58333333332124.9050422685
0.8752016.2765115847
1.1666666667308.973151484
1.4583333333404.1729029737
1.75601.6369717834
2.0416666667800.5416936188
2.33333333331000.1512083816
2.6251400.0356047245
2.91666666671800.0070721101
3.20833333332500.00118495
3.53300.0001674791
BiGaPotEv
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
exp(kt)
exp(-kt)
Poisson (m=20, s^2=m)Binomial (N=2020, p=.01, m=Np)XNormal
(m=20, s=4.47)t-dist (m=20, s=4.47, dof=2)ExtrVal(u=20,
L=1/4.47)204.472
2.1E-091.5E-0904.0E-062.2E-032E-37meansddof
4.1E-083.1E-0811.1E-052.5E-037E-30
4.1E-073.2E-0722.7E-052.9E-037E-240.0120201
2.7E-062.2E-0636.5E-053.3E-034E-19pN=s*s/pqincrement
1.4E-051.1E-0541.5E-043.9E-032E-15
5.5E-054.5E-0553.2E-044.6E-033E-12note tdist is the derivative
with increment .001
1.8E-041.5E-0466.6E-045.5E-036E-10
5.2E-044.4E-0471.3E-036.6E-035E-08
1.3E-031.1E-0382.4E-038.0E-032E-06
2.9E-032.5E-0394.3E-039.8E-032E-05
5.8E-035.1E-03107.3E-031.2E-022E-04
1.1E-029.5E-03111.2E-021.5E-021E-03
1.8E-021.6E-02121.8E-021.9E-024E-03
2.7E-022.5E-02132.6E-022.4E-021E-02
3.9E-023.6E-02143.6E-023.0E-022E-02
5.2E-024.9E-02154.8E-023.8E-023E-02
6.5E-026.2E-02166.0E-024.8E-025E-02
7.6E-027.4E-02177.1E-025.8E-027E-02
8.4E-028.3E-02188.1E-026.8E-028E-02
8.9E-028.8E-02198.7E-027.6E-029E-02
8.88E-028.92E-02208.92E-027.9E-029E-02
8.5E-028.6E-02218.7E-027.6E-029E-02
7.7E-027.9E-02228.1E-026.8E-028E-02
6.7E-026.9E-02237.1E-025.8E-027E-02
5.6E-025.8E-02246.0E-024.8E-027E-02
4.5E-024.7E-02254.8E-023.8E-026E-02
3.4E-023.6E-02263.6E-023.0E-025E-02
2.5E-022.7E-02272.6E-022.4E-024E-02
1.8E-021.9E-02281.8E-021.9E-023E-02
1.3E-021.4E-02291.2E-021.5E-023E-02
8.3E-039.1E-03307.3E-031.2E-022E-02
5.4E-035.9E-03314.3E-039.8E-032E-02
3.4E-033.7E-03322.4E-038.0E-032E-02
2.0E-032.2E-03331.3E-036.6E-031E-02
1.2E-031.3E-03346.6E-045.5E-031E-02
6.9E-047.6E-04353.2E-044.6E-038E-03
3.8E-044.2E-04361.5E-043.9E-037E-03
2.1E-042.3E-04376.5E-053.3E-035E-03
1.1E-041.2E-04382.7E-052.9E-034E-03
5.6E-056.2E-05391.1E-052.5E-033E-03
2.8E-053.1E-05404.0E-062.2E-033E-03
&A
Page &P
Normal (m=20, s=4.47)
Poisson (m=20, s^2=m)
Binomial (N=2020, p=.01, m=Np)
t-dist (m=20, s=4.47, dof=2)
ExtrVal(u=20, L=1/4.47)
Normal (m=20, s=4.47)
t-dist (m=20, s=4.47, dof=2)
ExtrVal(u=20, L=1/4.47)
-
Primary to tertiary structuregggatttagctcagttgggagagcgccagactgaa
gatttg gaggtcctgtgttcgatccacagaattcgcacca
-
Non-watson-crick bpsref-CH3
-
Modified bases & bps in RNA" "ref1 72
-
Covariance
Mij= Sfxixjlog2[fxixj/(fxifxj)] M=0 to 2 bits; x=base type xixj
see Durbin et al p. 266-8.D-stemanticodonTyC3acc
-
Mutual InformationACUUAU M1,6= S = fAU
log2[fAU/(fA*fU)]...CCUUAG x1x6 GCUUGC
=4*.25log2[.25/(.25*.25)]=2UCUUGAi=1 j=6 M1,2=
4*.25log2[.25/(.25*1)]=0
Mij= Sfxixjlog2[fxixj/(fxifxj)] M=0 to 2 bits; x=base type xixj
see Durbin et al p. 266-8.See Shannon entropy, multinomial
Grendar
-
RNA secondary structure predictionMathews DH, Sabina J, Zuker M,
Turner DH J Mol Biol 1999 May 21;288(5):911-40
Expanded sequence dependence of thermodynamic parameters
improves prediction of RNA secondary structure.
Each set of 750 generated structures contains one structure
that, on average, has 86 % of known base-pairs.
-
Stacked bp & ss
-
Initial 1981 O(N2) DP methods: Circular Representation of RNA
StructureDid not handle pseudoknots5
3
-
RNA pseudoknots, important biologically, but challenging for
structure searches
-
Dynamic programming finally handles RNA pseudoknots too.Rivas E,
Eddy SR J Mol Biol 1999 Feb 5;285(5):2053-68 A dynamic programming
algorithm for RNA structure prediction includingpseudoknots.
(ref)
Worst case complexity of O(N6) in time and O(N4) in memory
space.
Bioinformatics 2000 Apr;16(4):334-40 (ref)
-
CpG Island + in a ocean of - First order Markov
ModelC+A+G+T+P(G+|C+) >P(A+|A+)MM=16, HMM= 64 transition
probabilities (adjacent bp)
-
Small nucleolar (sno)RNA structure & functionLowe et al.
Science (ref)
-
SnoRNA Search
-
Performance of RNA-fold matching algorithmsAlgorithmCPU
bp/secTrue pos.False pos.
TRNASCAN9140095.1% 0.4x10-6TRNASCAN-SE 9730,000 99.5%93%
-
Putative Sno RNA gene disruption effects on rRNA
modificationPrimer extension pauses at 2'O-Me positions forming
bands at low dNTP.Lowe et al. Science 1999 283:1168-71 (ref)
-
RNA1: Today's story & goals Integration with previous topics
(HMM & DP for RNA structure) Goals of molecular quantitation
(maximal fold-changes, clustering & classification of genes
& conditions/cell types, causality) Genomics-grade measures of
RNA and protein and how we choose and integrate (SAGE,
oligo-arrays, gene-arrays)Sources of random and systematic errors
(reproducibilty of RNA source(s), biases in labeling, non-polyA
RNAs, effects of array geometry, cross-talk). Interpretation issues
(splicing, 5' & 3' ends, gene families, small RNAs, antisense,
apparent absence of RNA).Time series data: causality, mRNA
decay
-
RNA (array) & Protein/metabolite (MS) quantitation
RNA measures are closer to genomic regulatory motifs &
transcriptional control
Protein/metabolite measures are closer to Flux & growth
phenotypes.
-
8 cross-checks for regulon quantitationProtein fusionsMicroarray
dataPhylogenetic profilesMetabolic pathwaysConserved operonsKnown
regulons in other organismsTCAcycleIn vivo crosslinking&
selection (1-hybrid)In vitroarray binding or selection
-
B. subtilispurEpurKpurBpurCpurLpurFpurMpurNpurHpurDIn E. coli,
each color above is a separate but coregulated operon:C.
acetobutylicumpurEpurCpurFpurMpurNpurHpurDpurEpurKpurBpurCpurLpurFpurMpurNpurHpurDE.
coli PurR motifCheck regulons from conserved operons (chromosomal
proximity)Predicting regulons and their cis-regulatory motifs by
comparative genomics. Mcguire & Church, (2000) Nucleic Acids
Research 28:4523-30.
-
M. janaschiipurEpurKpurMpurNpurHpurDP. furiosusC. jejuniP.
horokoshiiM. tuberculosisE.
colipurMpurFpurHpurNpurFpurCpurQpurCpurLpurHpurMpurFpurCpurYpurQpurLpurYFCMNHDEKLQYThe
above predicts regulonconnections among these genes:Predicting the
PurR regulon by piecing together smaller operons
-
(Whole genome) RNA quantitation objectivesRNAs showing maximum
changeminimum change detectable/meaningful
RNA absolute levels (compare protein levels)minimum amount
detectable/meaningful
Network -- direct causality-- motifs
Classify (e.g. stress, drug effects, cancers)
-
(Sub)cellular inhomogeneity( see figure)Dissected tissues have
mixed cell types.
Cell-cycle differences in expression.
XIST RNA localized on inactive X-chromosome
-
Fluorescent in situ hybridization (FISH)Time resolution:
1msecSensitivity: 1 moleculeMultiplicity: >24Space: 10 nm
(3-dimensional, in vivo)
10 nm accuracy with far-field optics energy-transfer fluorescent
beads nanocrystal quantum dots,closed-loop piezo-scanner (ref)
-
RNA1: Today's story & goals Integration with previous topics
(HMM & DP for RNA structure) Goals of molecular quantitation
(maximal fold-changes, clustering & classification of genes
& conditions/cell types, causality) Genomics-grade measures of
RNA and protein and how we choose and integrate (SAGE,
oligo-arrays, gene-arrays)Sources of random and systematic errors
(reproducibilty of RNA source(s), biases in labeling, non-polyA
RNAs, effects of array geometry, cross-talk). Interpretation issues
(splicing, 5' & 3' ends, gene families, small RNAs, antisense,
apparent absence of RNA).Time series data: causality, mRNA decay,
time-warping
-
Steady-state population-average RNA quantitation
methodologyMicroarrays1~1000 bp hybridization
experimentcontrolR/G ratiosR, G valuesquality indicatorsORF1
DeRisi, et.al., Science 278:680-686 (1997) 4 Brenner et al, 2
Lockhart, et.al., Nat Biotech 14:1675-1680 (1996)3 Velculescu,
et.al, Serial Analysis of Gene Expression, Science 270:484-487
(1995)MPSS4
-
Biotinylated RNAfrom experimentGeneChip expressionanalysis probe
arrayImage of hybridized probe arrayEach probe cell
containsmillions of copies of a specific oligonucleotide
probeStreptavidin-phycoerythrinconjugate
-
Most RNAs < 1 molecule per cell.Yeast RNA25-mer arrayWodicka,
Lockhart, et al. (1997) Nature Biotech
15:1359-67(ref)Reproducibilityconfidence intervalsto find
significantdeviations.
-
Microarray data analyses (web)AFMAMADA ChurchillCLUSFAVOR
CLUSTER, D-CHIP GENE-CLUSTERJ-EXPRESSPAGE PLAID SAM SMA
SVDMANTREE-ARRANGE & TREEPSVERA &SAM XCLUSTERArrayTools
ARRAY-VIEWERF-SCAN P-SCAN SCAN-ALYZEGENEXMAPS
-
Statistical models for repeated array dataLi & Wong (2001)
Model-based analysis of oligonucleotide arrays: model validation,
design issues and standard error application. Genome Biol
2(8):0032
Kuo et al. (2002) Analysis of matched mRNA measurements from two
different microarray technologies. Bioinformatics 18(3):405-12
Tusher, Tibshirani and Chu (2001) Significance analysis of
microarrays applied to the ionizing radiation response. PNAS
98(9):5116-21. Selinger, et al. (2000) RNA expression analysis
using a 30 base pair resolution Escherichia coli genome array.
Nature Biotech. 18, 1262-7.
-
Significant distributions t-test t= ( Mean / SD ) * sqrt( N ).
Degrees of freedom = N-1H0: The mean value of the difference =0. If
difference distribution is not normal, use the Wilcoxon
Matched-Pairs Signed-Ranks Test. graph
Chart1
0.00000401330.00215878960
0.000010650.00248126220
0.00002688160.00286904540
0.00006453950.00333884650
0.00014738760.00391249890
0.00032015540.004618760
0.00066149320.00549578610.0000000006
0.00130003290.00659452680.0000000489
0.00243023280.00798332340.0000015397
0.00432121540.00975398130.0000232183
0.00730850370.01202936820.0001943228
0.0117575150.01497187280.0010157394
0.01799149010.01879015580.0036440621
0.02618684910.02373726310.0096760874
0.03625466330.0300844620.0201986244
0.04774292520.03804117490.0347854684
0.05980241060.0475794540.0513659409
0.07125131370.05814342250.0670724486
0.08074796380.06834698660.0793799175
0.08704319060.07600206350.0868429663
0.08924883230.07888554840.0892195939
0.08704319060.07600206350.0871684957
0.08074796380.06834698660.0818102622
0.07125131370.05814342250.0743537907
0.05980241060.0475794540.0658631478
0.04774292520.03804117490.057156045
0.03625466330.0300844620.0487921749
0.02618684910.02373726310.0411089224
0.01799149010.01879015580.0342738534
0.0117575150.01497187280.028336395
0.00730850370.01202936820.0232708249
0.00432121540.00975398130.0190085374
0.00243023280.00798332340.0154604625
0.00130003290.00659452680.0125316021
0.00066149320.00549578610.0101297718
0.00032015540.004618760.0081703455
0.00014738760.00391249890.0065783925
0.00006453950.00333884650.0052892046
0.00002688160.00286904540.0042478992
0.000010650.00248126220.0034085437
0.00000401330.00215878960.0027330802
Normal (m=0, s=4.47)
t-dist (m=0, s=4.47, dof=2)
ExtrVal(u=0, L=1/4.47)
ExtremeNorm
cum=1 means yes cumulative; cum=0 means No
Poisson(x,mean,cum)7E-019E-011E+00meanstdev
NormDist(x,mean,sd,cum)8E-011E+001E+000.57735026920.577215664101.28251.00
1E+021E+021E+0110.005.774.34E-1516.4510.00
mean5E-015E-015E-020.052E-022E-170.080.03
stdev5E-015E-011E-010.10778301079E-028E-020.11638219110.0899499444
xExtremeVal cumNorm (.58,1.3)
cumExtremeVal(L=1,u=0)Normal(m=.58,
s=1.3)NormExtr*XNorm*XExtr*(x-m)^2Norm*(x-m)^2
-101E+001E+000E+005E-168E-230E+00-8E-220E+008E-21
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0.74E-015E-013E-013E-010.312E-012E-015E-032E-01
0.84E-014E-013E-013E-010.292E-012E-011E-022E-01
0.93E-014E-013E-013E-010.272E-012E-013E-022E-01
13E-014E-013E-013E-010.243E-012E-015E-022E-01
1.13E-013E-012E-013E-010.223E-012E-017E-023E-01
1.23E-013E-012E-013E-010.193E-012E-019E-023E-01
1.32E-013E-012E-013E-010.173E-012E-011E-013E-01
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1.82E-012E-011E-012E-010.083E-011E-012E-013E-01
1.91E-012E-011E-012E-010.072E-011E-012E-012E-01
21E-011E-011E-012E-010.052E-011E-012E-012E-01
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2.95E-024E-025E-026E-020.012E-012E-023E-015E-02
35E-023E-025E-025E-020.001E-011E-023E-014E-02
3.14E-022E-024E-024E-020.001E-011E-023E-013E-02
3.24E-022E-024E-024E-020.001E-018E-033E-012E-02
3.34E-022E-024E-023E-020.001E-016E-033E-012E-02
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4.12E-023E-032E-027E-030.007E-024E-042E-012E-03
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4.61E-029E-041E-022E-030.005E-025E-052E-012E-04
4.79E-037E-049E-032E-030.004E-023E-052E-011E-04
4.88E-035E-048E-031E-030.004E-022E-051E-019E-05
4.97E-034E-047E-031E-030.004E-021E-051E-016E-05
57E-033E-047E-038E-040.003E-027E-061E-014E-05
5.16E-032E-046E-036E-040.003E-025E-061E-012E-05
5.26E-032E-045E-035E-040.003E-023E-061E-011E-05
5.35E-031E-045E-034E-040.003E-022E-061E-019E-06
5.45E-038E-054E-033E-040.002E-021E-061E-015E-06
5.54E-036E-054E-032E-040.002E-026E-071E-013E-06
5.64E-034E-054E-031E-040.002E-023E-079E-022E-06
5.73E-033E-053E-031E-040.002E-022E-079E-021E-06
5.83E-032E-053E-038E-050.002E-021E-078E-027E-07
5.93E-032E-053E-036E-050.002E-026E-088E-024E-07
62E-031E-052E-034E-050.001E-024E-087E-022E-07
6.12E-038E-062E-033E-050.001E-022E-087E-021E-07
6.22E-036E-062E-032E-050.001E-021E-086E-027E-08
6.32E-034E-062E-031E-050.001E-026E-096E-024E-08
6.42E-033E-062E-031E-050.001E-023E-096E-022E-08
6.52E-032E-062E-037E-060.001E-022E-095E-021E-08
6.61E-031E-061E-035E-060.009E-039E-105E-026E-09
6.71E-039E-071E-033E-060.008E-035E-105E-023E-09
6.81E-036E-071E-032E-060.008E-032E-104E-022E-09
6.91E-034E-071E-032E-060.007E-031E-104E-029E-10
79E-043E-079E-041E-060.006E-036E-114E-024E-10
7.18E-042E-078E-048E-070.006E-033E-114E-022E-10
7.27E-041E-077E-045E-070.005E-032E-113E-021E-10
7.37E-048E-087E-043E-070.005E-038E-123E-026E-11
7.46E-045E-086E-042E-070.005E-034E-123E-023E-11
7.56E-043E-086E-041E-070.004E-032E-123E-021E-11
7.65E-042E-085E-041E-070.004E-039E-132E-027E-12
7.75E-041E-085E-046E-080.003E-034E-132E-023E-12
7.84E-049E-094E-044E-080.003E-032E-132E-021E-12
7.94E-046E-094E-043E-080.003E-039E-142E-027E-13
83E-044E-093E-042E-080.003E-034E-142E-023E-13
8.13E-042E-093E-041E-080.002E-032E-142E-021E-13
8.23E-041E-093E-047E-090.002E-038E-152E-027E-14
8.32E-049E-102E-044E-090.002E-034E-151E-023E-14
8.42E-045E-102E-043E-090.002E-032E-151E-021E-14
8.52E-043E-102E-042E-090.002E-037E-161E-026E-15
8.62E-042E-102E-041E-090.002E-033E-161E-023E-15
8.72E-041E-102E-046E-100.001E-031E-161E-021E-15
8.82E-047E-112E-044E-100.001E-035E-171E-025E-16
8.91E-044E-111E-042E-100.001E-032E-179E-032E-16
91E-043E-111E-041E-100.001E-039E-189E-038E-17
9.11E-042E-111E-048E-110.001E-034E-188E-033E-17
9.21E-049E-121E-045E-110.009E-042E-188E-031E-17
9.39E-055E-129E-053E-110.009E-046E-197E-036E-18
9.48E-053E-128E-052E-110.008E-042E-196E-032E-18
9.57E-052E-127E-051E-110.007E-041E-196E-039E-19
9.67E-051E-127E-056E-120.007E-044E-206E-034E-19
9.76E-056E-136E-053E-120.006E-041E-205E-031E-19
9.86E-053E-136E-052E-120.005E-045E-215E-035E-20
9.95E-052E-135E-051E-120.005E-042E-214E-032E-20
105E-051E-135E-056E-130.005E-048E-224E-038E-21
10.14E-056E-144E-053E-130.004E-043E-224E-033E-21
10.24E-053E-144E-052E-130.004E-041E-223E-031E-21
10.33E-052E-143E-051E-130.003E-044E-233E-034E-22
10.43E-059E-153E-056E-140.003E-041E-233E-031E-22
10.53E-055E-153E-053E-140.003E-045E-243E-035E-23
10.62E-053E-152E-052E-140.003E-042E-243E-032E-23
10.72E-050E+002E-059E-150.002E-046E-252E-036E-24
10.82E-050E+002E-055E-150.002E-042E-250.000.00
10.92E-050E+002E-053E-150.002E-047E-260.000.00
112E-050E+002E-051E-150.002E-042E-260.000.00
11.12E-050E+002E-058E-160.002E-048E-270.000.00
11.21E-050E+001E-054E-160.002E-043E-270.000.00
11.31E-050E+001E-052E-160.001E-048E-280.000.00
11.41E-050E+001E-051E-160.001E-043E-280.000.00
11.51E-050E+001E-056E-170.001E-049E-290.000.00
11.69E-060E+009E-063E-170.001E-043E-290.000.00
11.78E-060E+008E-061E-170.001E-049E-300.000.00
11.88E-060E+008E-067E-180.009E-053E-300.000.00
11.97E-060E+007E-064E-180.008E-058E-310.000.00
126E-060E+006E-062E-180.007E-053E-310.000.00
12.16E-060E+006E-069E-190.007E-058E-320.000.00
12.25E-060E+005E-065E-190.006E-052E-320.000.00
12.35E-060E+005E-062E-190.006E-057E-330.000.00
12.44E-060E+004E-061E-190.005E-052E-330.000.00
12.54E-060E+004E-065E-200.005E-056E-340.000.00
12.63E-060E+003E-063E-200.004E-052E-340.000.00
12.73E-060E+003E-061E-200.004E-055E-350.000.00
12.83E-060E+003E-066E-210.004E-051E-350.000.00
12.92E-060E+002E-063E-210.003E-054E-360.000.00
132E-060E+002E-061E-210.003E-051E-360.000.00
13.12E-060E+002E-066E-220.003E-053E-370.000.00
13.22E-060E+002E-063E-220.002E-058E-380.000.00
13.32E-060E+002E-061E-220.002E-052E-380.000.00
13.42E-060E+002E-066E-230.002E-055E-390.000.00
13.51E-060E+001E-063E-230.002E-051E-390.000.00
13.61E-060E+001E-061E-230.002E-054E-400.000.00
13.71E-060E+001E-066E-240.002E-051E-400.000.00
13.81E-060E+001E-063E-240.001E-052E-410.000.00
13.99E-070E+009E-071E-240.001E-056E-420.000.00
148E-070E+008E-075E-250.001E-052E-420.000.00
14.18E-070E+008E-072E-250.001E-054E-430.000.00
14.27E-070E+007E-071E-250.001E-059E-440.000.00
14.36E-070E+006E-074E-260.009E-062E-440.000.00
14.46E-070E+006E-072E-260.008E-065E-450.000.00
14.55E-070E+005E-078E-270.007E-061E-450.000.00
14.65E-070E+005E-073E-270.007E-063E-460.000.00
14.74E-070E+004E-071E-270.006E-067E-470.000.00
14.84E-070E+004E-076E-280.006E-062E-470.000.00
14.93E-070E+003E-073E-280.005E-064E-480.000.00
153E-070E+003E-071E-280.005E-068E-490.000.00
15.13E-070E+003E-074E-290.004E-062E-490.000.00
15.23E-070E+003E-072E-290.004E-064E-500.000.00
15.32E-070E+002E-078E-300.003E-069E-510.000.00
15.42E-070E+002E-073E-300.003E-062E-510.000.00
15.52E-070E+002E-071E-300.003E-064E-520.000.00
15.62E-070E+002E-075E-310.003E-069E-530.000.00
15.72E-070E+002E-072E-310.002E-062E-530.000.00
15.81E-070E+001E-078E-320.002E-064E-540.000.00
15.91E-070E+001E-073E-320.002E-068E-550.000.00
161E-070E+001E-071E-320.002E-062E-550.000.00
16.11E-070E+001E-075E-330.002E-063E-560.000.00
16.29E-080E+009E-082E-330.001E-067E-570.000.00
16.38E-080E+008E-087E-340.001E-061E-570.000.00
16.48E-080E+008E-083E-340.001E-063E-580.000.00
16.57E-080E+007E-081E-340.001E-065E-590.000.00
16.66E-080E+006E-084E-350.001E-061E-590.000.00
16.76E-080E+006E-082E-350.009E-072E-600.000.00
16.85E-080E+005E-086E-360.008E-073E-610.000.00
16.95E-080E+005E-082E-360.008E-076E-620.000.00
174E-080E+004E-088E-370.007E-071E-620.000.00
17.14E-080E+004E-083E-370.006E-072E-630.000.00
17.23E-080E+003E-081E-370.006E-074E-640.000.00
17.33E-080E+003E-084E-380.005E-077E-650.000.00
17.43E-080E+003E-081E-380.005E-071E-650.000.00
17.53E-080E+003E-085E-390.004E-072E-660.000.00
17.62E-080E+002E-082E-390.004E-074E-670.000.00
17.72E-080E+002E-086E-400.004E-077E-680.000.00
17.82E-080E+002E-082E-400.003E-071E-680.000.00
17.92E-080E+002E-088E-410.003E-072E-690.000.00
182E-080E+002E-083E-410.003E-073E-700.000.00
18.11E-080E+001E-089E-420.002E-075E-710.000.00
18.21E-080E+001E-083E-420.002E-079E-720.000.00
18.31E-080E+001E-081E-420.002E-071E-720.000.00
18.41E-080E+001E-084E-430.002E-072E-730.000.00
18.59E-090E+009E-091E-430.002E-074E-740.000.00
18.68E-090E+008E-094E-440.002E-076E-750.000.00
18.78E-090E+008E-091E-440.001E-079E-760.000.00
18.87E-090E+007E-095E-450.001E-071E-760.000.00
18.96E-090E+006E-091E-450.001E-072E-770.000.00
196E-090E+006E-095E-460.001E-073E-780.000.00
19.15E-090E+005E-092E-460.001E-075E-790.000.00
19.25E-090E+005E-095E-470.009E-087E-800.000.00
19.34E-090E+004E-092E-470.008E-081E-800.000.00
19.44E-090E+004E-095E-480.007E-081E-810.000.00
19.53E-090E+003E-092E-480.007E-082E-820.000.00
19.63E-090E+003E-095E-490.006E-083E-830.000.00
19.73E-090E+003E-092E-490.005E-084E-840.000.00
19.83E-090E+003E-095E-500.005E-086E-850.000.00
19.92E-090E+002E-092E-500.005E-088E-860.000.00
202E-090E+002E-095E-510.004E-081E-860.000.00
20.12E-090E+002E-092E-510.004E-081E-870.000.00
20.22E-090E+002E-095E-520.003E-082E-880.000.00
20.32E-090E+002E-091E-520.003E-083E-890.000.00
20.41E-090E+001E-094E-530.003E-083E-900.000.00
20.51E-090E+001E-091E-530.003E-085E-910.000.00
20.61E-090E+001E-094E-540.002E-086E-920.000.00
20.71E-090E+001E-091E-540.002E-087E-930.000.00
20.89E-100E+009E-103E-550.002E-089E-940.000.00
20.98E-100E+008E-109E-560.002E-081E-940.000.00
218E-100E+008E-103E-560.002E-081E-950.000.00
21.17E-100E+007E-108E-570.001E-082E-960.000.00
21.26E-100E+006E-102E-570.001E-082E-970.000.00
21.36E-100E+006E-106E-580.001E-083E-980.000.00
21.45E-100E+005E-102E-580.001E-083E-990.000.00
21.55E-100E+005E-105E-590.001E-084E-1000.000.00
21.64E-100E+004E-101E-590.009E-094E-1010.000.00
21.74E-100E+004E-104E-600.008E-095E-1020.000.00
21.83E-100E+003E-101E-600.007E-096E-1030.000.00
21.93E-100E+003E-103E-610.007E-096E-1040.000.00
223E-100E+003E-108E-620.006E-097E-1050.000.00
22.13E-100E+003E-102E-620.006E-098E-1060.000.00
22.22E-100E+002E-106E-630.005E-098E-1070.000.00
22.32E-100E+002E-102E-630.005E-099E-1080.000.00
22.42E-100E+002E-104E-640.004E-091E-1080.000.00
22.52E-100E+002E-101E-640.004E-091E-1090.000.00
22.62E-100E+002E-103E-650.003E-091E-1100.000.00
22.71E-100E+001E-108E-660.003E-091E-1110.000.00
22.81E-100E+001E-102E-660.003E-091E-1120.000.00
22.91E-100E+001E-105E-670.003E-091E-1130.000.00
231E-100E+001E-101E-670.002E-091E-1140.000.00
23.19E-110E+009E-113E-680.002E-091E-1150.000.00
23.28E-110E+008E-119E-690.002E-091E-1160.000.00
23.38E-110E+008E-112E-690.002E-091E-1170.000.00
23.47E-110E+007E-115E-700.002E-091E-1180.000.00
23.56E-110E+006E-111E-700.001E-091E-1190.000.00
23.66E-110E+006E-113E-710.001E-091E-1200.000.00
23.75E-110E+005E-118E-720.001E-091E-1210.000.00
23.85E-110E+005E-112E-720.001E-099E-1230.000.00
23.94E-110E+004E-115E-730.001E-099E-1240.000.00
244E-110E+004E-111E-730.009E-108E-1250.000.00
24.13E-110E+003E-113E-740.008E-107E-1260.000.00
ExtremeNorm
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
ExtremeVal cum
Norm (.58,1.3) cum
exp
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
ExtremeVal(L=1,u=0)
Normal(m=.58, s=1.3)
BiGaPotEv
texp(kt)exp(-kt)35exp(-x^2)0.2916666667
-3.50330.000167479135
-3.20833333330250.00118495
-2.91666666670180.0070721101
-2.6250140.0356047245
-2.33333333330100.1512083816
-2.0416666667080.5416936188
-1.75061.6369717834
-1.4583333333044.1729029737
-1.1666666667038.973151484
-0.8750216.2765115847
-0.58333333331224.9050422685
-0.29166666671132.1456975364
01135
0.29166666671132.1456975364
0.58333333332124.9050422685
0.8752016.2765115847
1.1666666667308.973151484
1.4583333333404.1729029737
1.75601.6369717834
2.0416666667800.5416936188
2.33333333331000.1512083816
2.6251400.0356047245
2.91666666671800.0070721101
3.20833333332500.00118495
3.53300.0001674791
BiGaPotEv
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
exp(kt)
exp(-kt)
Poisson (m=20, s^2=m)Binomial (N=2020, p=.01, m=Np)XNormal (m=0,
s=4.47)t-dist (m=0, s=4.47, dof=2)ExtrVal(u=0, L=1/4.47)04.472
0.0E+000.0E+00-204.0E-062.2E-032E-37meansddof
0.0E+000.0E+00-191.1E-052.5E-036E-30
0.0E+000.0E+00-182.7E-052.9E-036E-240.0120181
0.0E+000.0E+00-176.5E-053.3E-034E-19pN=s*s/pqincrement
0.0E+000.0E+00-161.5E-043.9E-032E-15
0.0E+000.0E+00-153.2E-044.6E-032E-12note tdist is the derivative
with increment .001
0.0E+000.0E+00-146.6E-045.5E-036E-10
0.0E+000.0E+00-131.3E-036.6E-035E-08
0.0E+000.0E+00-122.4E-038.0E-032E-06
0.0E+000.0E+00-114.3E-039.8E-032E-05
0.0E+000.0E+00-107.3E-031.2E-022E-04
0.0E+000.0E+00-91.2E-021.5E-021E-03
0.0E+000.0E+00-81.8E-021.9E-024E-03
0.0E+000.0E+00-72.6E-022.4E-021E-02
0.0E+000.0E+00-63.6E-023.0E-022E-02
0.0E+000.0E+00-54.8E-023.8E-023E-02
0.0E+000.0E+00-46.0E-024.8E-025E-02
0.0E+000.0E+00-37.1E-025.8E-027E-02
0.0E+000.0E+00-28.1E-026.8E-028E-02
0.0E+000.0E+00-18.7E-027.6E-029E-02
1.00E+001.56E-0908.92E-027.9E-029E-02
0.0E+003.2E-0818.7E-027.6E-029E-02
0.0E+003.2E-0728.1E-026.8E-028E-02
0.0E+002.2E-0637.1E-025.8E-027E-02
0.0E+001.1E-0546.0E-024.8E-027E-02
0.0E+004.5E-0554.8E-023.8E-026E-02
0.0E+001.5E-0463.6E-023.0E-025E-02
0.0E+004.5E-0472.6E-022.4E-024E-02
0.0E+001.1E-0381.8E-021.9E-023E-02
0.0E+002.6E-0391.2E-021.5E-023E-02
0.0E+005.2E-03107.3E-031.2E-022E-02
0.0E+009.6E-03114.3E-039.8E-032E-02
0.0E+001.6E-02122.4E-038.0E-032E-02
0.0E+002.5E-02131.3E-036.6E-031E-02
0.0E+003.6E-02146.6E-045.5E-031E-02
0.0E+004.9E-02153.2E-044.6E-038E-03
0.0E+006.2E-02161.5E-043.9E-037E-03
0.0E+007.4E-02176.5E-053.3E-035E-03
0.0E+008.3E-02182.7E-052.9E-034E-03
0.0E+008.8E-02191.1E-052.5E-033E-03
0.0E+008.9E-02204.0E-062.2E-033E-03
&A
Page &P
Normal (m=0, s=4.47)
Poisson (m=20, s^2=m)
Binomial (N=2020, p=.01, m=Np)
t-dist (m=0, s=4.47, dof=2)
ExtrVal(u=0, L=1/4.47)
Normal (m=0, s=4.47)
t-dist (m=0, s=4.47, dof=2)
ExtrVal(u=0, L=1/4.47)
-
Independent ExperimentsMicroarray analysis of the
transcriptional network controlled by the photoreceptor homeobox
gene Crx.Livesay, et al. (2000) Current Biology
-
RNA quantitationIs less than a 2-fold RNA-ratio ever important?
Yes; 1.5-fold in trisomies.
Why oligonucleotides rather than cDNAs? Alternative splicing, 5'
& 3' ends; gene families.
What about using a subset of the genomeor ratios to a variety of
control RNAs? It makes trouble for later (meta) analyses.
-
(Whole genome) RNA quantitation methodsMethodAdvantages
Genes immobilized labeled RNAChip manufactureRNAs immobilized
labeled genes- Northern gel blot RNA sizesQRT-PCRSensitivity
1e-10Reporter constructsNo crosshybridizationFluorescent In Situ
HybridizationSpatial relationsTag counting (SAGE)Gene
discoveryDifferential display & subtraction"Selective"
discovery
-
Microarray to Northern
-
Genomic oligonucleotide microarrays Non-coding sequencesProtein
coding 25-mers(12% of genome)
295,936 oligonucleotides (including controls)Intergenic regions:
~6bp spacing Genes: ~70 bp spacingNot polyA (or 3' end) biased
Strengths: Gene family paralogs, RNA fine structure (adjacent
promoters), untranslated & antisense RNAs, DNA-protein
interactions.Affymetrix: Mei, Gentalen, Johansen, Lockhart(Novartis
Inst)HMS: Church, Bulyk, Cheung, Tavazoie, Petti, SelingertRNAs,
rRNAsE. coli25-mer array
-
Random & Systematic Errors in RNA quantitation Secondary
structure Position on array (mixing, scattering) Amount of target
per spot Cross-hybridization Unanticipated transcripts
-
Spatial Variation in Control IntensityExperiment 1experiment
2Selinger et al
-
Detection of Antisense and Untranslated RNAsb0671 - ORF of
unknown function, tiled in the opposite orientationExpression Chip
Reverse Complement Chipintergenic region 1725 - is actually a small
untranslated RNA (csrB)Crick StrandWatson Strand (same chip)
-
Mapping deviations from expected repeat ratiosLi & Wong
-
RNA1: Today's story & goals Integration with previous topics
(HMM & DP for RNA structure) Goals of molecular quantitation
(maximal fold-changes, clustering & classification of genes
& conditions/cell types, causality) Genomics-grade measures of
RNA and protein and how we choose and integrate (SAGE,
oligo-arrays, gene-arrays)Sources of random and systematic errors
(reproducibilty of RNA source(s), biases in labeling, non-polyA
RNAs, effects of array geometry, cross-talk). Interpretation issues
(splicing, 5' & 3' ends, gene families, small RNAs, antisense,
apparent absence of RNA).Time series data: causality, mRNA decay,
time-warping
-
Independent oligos analysis of RNA structureSelinger et al
-
Predicting RNA-RNA interactions
-
Human RNA-splice junctions sequence matrix
http://www-lmmb.ncifcrf.gov/~toms/sequencelogo.html
-
Experimental annotation of the human genome using microarray
technology.Shoemaker, et al. (2001) Nature 409:922-7.
-
RNA1: Today's story & goals Integration with previous topics
(HMM & DP for RNA structure) Goals of molecular quantitation
(maximal fold-changes, clustering & classification of genes
& conditions/cell types, causality) Genomics-grade measures of
RNA and protein and how we choose and integrate (SAGE,
oligo-arrays, gene-arrays)Sources of random and systematic errors
(reproducibilty of RNA source(s), biases in labeling, non-polyA
RNAs, effects of array geometry, cross-talk). Interpretation issues
(splicing, 5' & 3' ends, gene families, small RNAs, antisense,
apparent absence of RNA).Time series data: causality, mRNA decay,
time-warping
-
Time coursesTo discriminate primary vs secondary effects we need
conditional gene knockouts .
Conditional control via transcription/translation is slow
(>60 sec up & much longer for down regulation)
Chemical knockouts can be more specific than temperature
(ts-mutants).
-
Beyond steady state: mRNA turnover rates (rifampicin
time-course)00.20.40.60.811.21.4024681012141618Time (min)Fraction
of Initial (16S normalized)cspE Chiplpp ChipcspE Northernlpp
NortherncspE half lifechip 2.4 minNorthern 2.9 min lpp half
lifechip >20 minNorthern >300 min Chip metric = Smaxlpp
Northernlpp ChipcspE NortherncspE Chip
-
TimeWarp: pairs of expression series, discrete or
interpolativeAach & Church
-
TimeWarp: cell-cycle experiments
-
TimeWarp: alignment example
-
RNA1: Today's story & goals Integration with previous topics
(HMM & DP for RNA structure) Goals of molecular quantitation
(maximal fold-changes, clustering & classification of genes
& conditions/cell types, causality) Genomics-grade measures of
RNA and protein and how we choose and integrate (SAGE,
oligo-arrays, gene-arrays)Sources of random and systematic errors
(reproducibilty of RNA source(s), biases in labeling, non-polyA
RNAs, effects of array geometry, cross-talk). Interpretation issues
(splicing, 5' & 3' ends, gene families, small RNAs, antisense,
apparent absence of RNA).Time series data: causality, mRNA decay,
time-warping
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