Mutation Analysis (MutSig v2.0)
Colon Adenocarcinoma (Primary solid tumor)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C13T9G65
Maintained by David Heiman (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2015): Mutation Analysis (MutSig v2.0). Broad Institute of MIT and Harvard. doi:10.7908/C13T9G65
Overview
Introduction

This report serves to describe the mutational landscape and properties of a given individual set, as well as rank genes and genesets according to mutational significance. MutSig v2.0 was used to generate the results found in this report.

  • Working with individual set: COAD-TP

  • Number of patients in set: 366

Input

The input for this pipeline is a set of individuals with the following files associated for each:

  1. An annotated .maf file describing the mutations called for the respective individual, and their properties.

  2. A .wig file that contains information about the coverage of the sample.

Summary

  • MAF used for this analysis:COAD-TP.final_analysis_set.maf

  • Blacklist used for this analysis: pancan_mutation_blacklist.v14.hg19.txt

  • Significantly mutated genes (q ≤ 0.1): 476

  • Mutations seen in COSMIC: 8536

  • Significantly mutated genes in COSMIC territory: 1547

  • Significantly mutated genesets: 0

  • Significantly mutated genesets: (excluding sig. mutated genes):0

Mutation Preprocessing

  • Read 102 MAFs of type "Broad"

  • Read 213 MAFs of type "Baylor-Illumina"

  • Read 52 MAFs of type "Baylor-SOLiD"

  • Total number of mutations in input MAFs: 199756

  • After removing 2 blacklisted mutations: 199754

  • After removing 48 noncoding mutations: 199706

  • After collapsing adjacent/redundant mutations: 196979

Mutation Filtering

  • Number of mutations before filtering: 196979

  • After removing 127 mutations outside patient set: 196852

  • After removing 6074 mutations outside gene set: 190778

  • After removing 982 mutations outside category set: 189796

  • After removing 2690 "impossible" mutations in

  • gene-patient-category bins of zero coverage: 179923

Results
Breakdown of Mutations by Type

Table 1.  Get Full Table Table representing breakdown of mutations by type.

type count
De_novo_Start_InFrame 16
De_novo_Start_OutOfFrame 125
Frame_Shift_Del 12543
Frame_Shift_Ins 3694
In_Frame_Del 1477
In_Frame_Ins 477
Missense_Mutation 114930
Nonsense_Mutation 8478
Nonstop_Mutation 30
Silent 46370
Splice_Site 1654
Translation_Start_Site 2
Total 189796
Breakdown of Mutation Rates by Category Type

Table 2.  Get Full Table A breakdown of mutation rates per category discovered for this individual set.

category n N rate rate_per_mb relative_rate exp_ns_s_ratio
*CpG->T 38701 491148035 0.000079 79 5.5 2.2
A->G 23912 4890661022 4.9e-06 4.9 0.34 2.3
*Cp(A/C/T)->T 17165 4398831250 3.9e-06 3.9 0.27 1.7
transver 33299 9780640307 3.4e-06 3.4 0.24 5.1
indel+null 27363 9780640307 2.8e-06 2.8 0.19 NaN
double_null 849 9780640307 8.7e-08 0.087 0.006 NaN
Total 141289 9780640307 0.000014 14 1 3.5
Target Coverage for Each Individual

The x axis represents the samples. The y axis represents the exons, one row per exon, and they are sorted by average coverage across samples. For exons with exactly the same average coverage, they are sorted next by the %GC of the exon. (The secondary sort is especially useful for the zero-coverage exons at the bottom). If the figure is unpopulated, then full coverage is assumed (e.g. MutSig CV doesn't use WIGs and assumes full coverage).

Figure 1. 

Distribution of Mutation Counts, Coverage, and Mutation Rates Across Samples

Figure 2.  Patients counts and rates file used to generate this plot: COAD-TP.patients.counts_and_rates.txt

Lego Plots

The mutation spectrum is depicted in the lego plots below in which the 96 possible mutation types are subdivided into six large blocks, color-coded to reflect the base substitution type. Each large block is further subdivided into the 16 possible pairs of 5' and 3' neighbors, as listed in the 4x4 trinucleotide context legend. The height of each block corresponds to the mutation frequency for that kind of mutation (counts of mutations normalized by the base coverage in a given bin). The shape of the spectrum is a signature for dominant mutational mechanisms in different tumor types.

Figure 3.  Get High-res Image SNV Mutation rate lego plot for entire set. Each bin is normalized by base coverage for that bin. Colors represent the six SNV types on the upper right. The three-base context for each mutation is labeled in the 4x4 legend on the lower right. The fractional breakdown of SNV counts is shown in the pie chart on the upper left. If this figure is blank, not enough information was provided in the MAF to generate it.

Figure 4.  Get High-res Image SNV Mutation rate lego plots for 4 slices of mutation allele fraction (0<=AF<0.1, 0.1<=AF<0.25, 0.25<=AF<0.5, & 0.5<=AF) . The color code and three-base context legends are the same as the previous figure. If this figure is blank, not enough information was provided in the MAF to generate it.

CoMut Plot

Figure 5.  Get High-res Image The matrix in the center of the figure represents individual mutations in patient samples, color-coded by type of mutation, for the significantly mutated genes. The rate of synonymous and non-synonymous mutations is displayed at the top of the matrix. The barplot on the left of the matrix shows the number of mutations in each gene. The percentages represent the fraction of tumors with at least one mutation in the specified gene. The barplot to the right of the matrix displays the q-values for the most significantly mutated genes. The purple boxplots below the matrix (only displayed if required columns are present in the provided MAF) represent the distributions of allelic fractions observed in each sample. The plot at the bottom represents the base substitution distribution of individual samples, using the same categories that were used to calculate significance.

Significantly Mutated Genes

Column Descriptions:

  • N = number of sequenced bases in this gene across the individual set

  • n = number of (nonsilent) mutations in this gene across the individual set

  • npat = number of patients (individuals) with at least one nonsilent mutation

  • nsite = number of unique sites having a non-silent mutation

  • nsil = number of silent mutations in this gene across the individual set

  • n1 = number of nonsilent mutations of type: *CpG->T

  • n2 = number of nonsilent mutations of type: A->G

  • n3 = number of nonsilent mutations of type: *Cp(A/C/T)->T

  • n4 = number of nonsilent mutations of type: transver

  • n5 = number of nonsilent mutations of type: indel+null

  • n6 = number of nonsilent mutations of type: double_null

  • p_classic = p-value for the observed amount of nonsilent mutations being elevated in this gene

  • p_ns_s = p-value for the observed nonsilent/silent ratio being elevated in this gene

  • p_cons = p-value for enrichment of mutations at evolutionarily most-conserved sites in gene

  • p_joint = p-value for clustering + conservation

  • p = p-value (overall)

  • q = q-value, False Discovery Rate (Benjamini-Hochberg procedure)

Table 3.  Get Full Table A Ranked List of Significantly Mutated Genes. Number of significant genes found: 476. Number of genes displayed: 35. Click on a gene name to display its stick figure depicting the distribution of mutations and mutation types across the chosen gene (this feature may not be available for all significant genes).

rank gene description N n npat nsite nsil n1 n2 n3 n4 n5 n6 p_classic p_ns_s p_clust p_cons p_joint p q
1 TCF7L2 transcription factor 7-like 2 (T-cell specific, HMG-box) 675749 45 41 32 5 9 2 2 9 23 0 2.4e-14 0.031 0.0001 0.41 0.00036 3.33e-16 1.61e-13
2 CDH1 cadherin 1, type 1, E-cadherin (epithelial) 955680 87 74 65 19 7 35 13 11 20 1 2e-13 0.0037 0.000018 0.39 0.000069 5.55e-16 1.61e-13
3 APC adenomatous polyposis coli 3090421 530 296 320 167 17 141 43 69 145 115 1 0.065 0 0.97 0 <1.00e-15 <1.61e-13
4 TP53 tumor protein p53 456768 326 230 184 73 91 77 39 54 61 4 0.12 0.00027 0 0 0 <1.00e-15 <1.61e-13
5 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 1117023 288 175 143 115 21 138 72 45 12 0 1 0.29 0 0 0 <1.00e-15 <1.61e-13
6 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 255887 184 169 39 17 2 21 90 70 1 0 1.7e-15 2e-08 0 8e-07 0 <1.00e-15 <1.61e-13
7 SMAD4 SMAD family member 4 615341 166 120 106 54 25 68 21 32 18 2 1 0.039 0.000014 3.6e-06 0 <1.00e-15 <1.61e-13
8 FBXW7 F-box and WD repeat domain containing 7 939926 119 103 72 43 34 26 5 27 27 0 1 0.64 0 0.0011 0 <1.00e-15 <1.61e-13
9 BRAF v-raf murine sarcoma viral oncogene homolog B1 806321 111 96 50 38 4 38 8 53 8 0 1 0.37 0 0 0 <1.00e-15 <1.61e-13
10 NEFH neurofilament, heavy polypeptide 200kDa 653524 91 89 20 2 1 1 1 3 85 0 3.9e-15 0.66 0 0.71 0 <1.00e-15 <1.61e-13
11 EGFR epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian) 1397210 104 74 89 45 18 44 16 22 4 0 1 0.73 0 0 0 <1.00e-15 <1.61e-13
12 CTNNB1 catenin (cadherin-associated protein), beta 1, 88kDa 872821 99 73 64 43 5 45 13 29 7 0 1 0.49 0 0.17 0 <1.00e-15 <1.61e-13
13 MUC2 mucin 2, oligomeric mucus/gel-forming 1243760 66 59 29 13 5 4 4 7 45 1 4.2e-09 0.89 0 1 0 <1.00e-15 <1.61e-13
14 ACVR2A activin A receptor, type IIA 577842 64 58 21 3 4 2 1 4 51 2 8.4e-15 0.3 0 6e-07 0 <1.00e-15 <1.61e-13
15 RP1L1 retinitis pigmentosa 1-like 1 1728132 72 57 37 18 12 1 5 10 37 7 0.0041 0.89 0 1 0 <1.00e-15 <1.61e-13
16 FMN2 formin 2 1302530 61 52 38 14 8 6 4 11 32 0 5.8e-06 0.65 0 1 0 <1.00e-15 <1.61e-13
17 LIG1 ligase I, DNA, ATP-dependent 938287 52 50 13 8 3 45 1 1 2 0 4.6e-08 0.032 0 0.94 0 <1.00e-15 <1.61e-13
18 TNFAIP6 tumor necrosis factor, alpha-induced protein 6 311257 50 50 5 2 3 0 0 1 46 0 1.9e-15 0.75 0 1 0 <1.00e-15 <1.61e-13
19 CASP5 caspase 5, apoptosis-related cysteine peptidase 477307 48 47 13 3 3 5 1 2 37 0 4.8e-15 0.34 0 1 0 <1.00e-15 <1.61e-13
20 OR6C76 olfactory receptor, family 6, subfamily C, member 76 338797 48 47 5 0 0 1 2 1 44 0 7e-15 0.2 0 0.93 0 <1.00e-15 <1.61e-13
21 ADAM29 ADAM metallopeptidase domain 29 897265 52 46 30 15 21 6 4 7 14 0 1 0.65 0.000016 0.000051 0 <1.00e-15 <1.61e-13
22 RNF43 ring finger protein 43 808181 53 46 26 1 7 4 1 4 34 3 4.2e-15 0.041 0 0.16 0 <1.00e-15 <1.61e-13
23 RNF145 ring finger protein 145 738414 51 44 19 3 3 12 2 3 29 2 4.8e-15 0.049 0 1 0 <1.00e-15 <1.61e-13
24 TSHR thyroid stimulating hormone receptor 889065 55 44 37 9 8 28 6 12 1 0 1.1e-08 0.0063 4e-07 3.4e-06 0 <1.00e-15 <1.61e-13
25 JAK2 Janus kinase 2 (a protein tyrosine kinase) 1252671 48 42 37 21 6 30 3 6 1 2 1 0.63 4e-07 0.022 0 <1.00e-15 <1.61e-13
26 CRIPAK cysteine-rich PAK1 inhibitor 255575 43 40 19 5 3 3 2 3 24 8 5e-15 0.55 0 1 0 <1.00e-15 <1.61e-13
27 DDHD1 DDHD domain containing 1 838439 39 39 3 1 2 0 0 0 37 0 1.2e-14 0.76 0 1 0 <1.00e-15 <1.61e-13
28 SNX13 sorting nexin 13 785343 36 38 19 3 2 1 2 27 4 0 3.8e-07 0.11 0 1 0 <1.00e-15 <1.61e-13
29 ARHGAP5 Rho GTPase activating protein 5 1580432 43 37 20 2 4 22 2 1 14 0 0.000032 0.00016 2e-07 0.12 0 <1.00e-15 <1.61e-13
30 RUNX1 runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene) 328467 41 37 28 16 10 17 2 9 3 0 0.92 0.54 0.000012 2e-07 0 <1.00e-15 <1.61e-13
31 TCERG1 transcription elongation regulator 1 1183550 41 37 22 5 3 2 1 9 22 4 0.014 0.62 0.000072 0.000038 0 <1.00e-15 <1.61e-13
32 MYL1 myosin, light chain 1, alkali; skeletal, fast 223469 35 35 5 5 1 1 0 1 31 1 4.6e-15 1 0 0.13 0 <1.00e-15 <1.61e-13
33 FANCD2 Fanconi anemia, complementation group D2 1683879 35 34 16 4 3 4 3 1 24 0 0.00018 0.31 1.2e-06 0.00019 0 <1.00e-15 <1.61e-13
34 KRTAP4-1 keratin associated protein 4-1 92915 35 33 3 0 3 0 0 0 32 0 4.2e-15 1 0 0.55 0 <1.00e-15 <1.61e-13
35 NRAS neuroblastoma RAS viral (v-ras) oncogene homolog 214476 34 33 15 11 2 3 11 16 2 0 0.0092 0.5 0 0.016 0 <1.00e-15 <1.61e-13
COSMIC analyses

In this analysis, COSMIC is used as a filter to increase power by restricting the territory of each gene. Cosmic version: v48.

Table 4.  Get Full Table Significantly mutated genes (COSMIC territory only). To access the database please go to: COSMIC. Number of significant genes found: 1547. Number of genes displayed: 10

rank gene description n cos n_cos N_cos cos_ev p q
1 APC adenomatous polyposis coli 532 839 455 307074 9471 0 0
2 TP53 tumor protein p53 328 824 328 301584 85364 0 0
3 PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 286 767 276 280722 4062 0 0
4 NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease) 118 285 99 104310 167 0 0
5 EGFR epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian) 104 293 84 107238 1323 0 0
6 VHL von Hippel-Lindau tumor suppressor 83 541 82 198006 1604 0 0
7 NF2 neurofibromin 2 (merlin) 76 550 71 201300 377 0 0
8 KRTAP5-5 keratin associated protein 5-5 12 1 10 366 10 1.4e-15 3.6e-13
9 EHBP1 EH domain binding protein 1 23 1 9 366 9 1.4e-15 3.6e-13
10 ETNK2 ethanolamine kinase 2 11 1 8 366 8 1.4e-15 3.6e-13

Note:

n - number of (nonsilent) mutations in this gene across the individual set.

cos = number of unique mutated sites in this gene in COSMIC

n_cos = overlap between n and cos.

N_cos = number of individuals times cos.

cos_ev = total evidence: number of reports in COSMIC for mutations seen in this gene.

p = p-value for seeing the observed amount of overlap in this gene)

q = q-value, False Discovery Rate (Benjamini-Hochberg procedure)

Geneset Analyses

Table 5.  Get Full Table A Ranked List of Significantly Mutated Genesets. (Source: MSigDB GSEA Cannonical Pathway Set).Number of significant genesets found: 0. Number of genesets displayed: 10

rank geneset description genes N_genes mut_tally N n npat nsite nsil n1 n2 n3 n4 n5 n6 p_ns_s p q
1 TCRMOLECULE T Cell Receptor and CD3 Complex CD3D, CD3E, CD3G, CD3Z, TRA@, TRB@ 3 CD3D(4), CD3E(2), CD3G(15) 634073 21 19 8 3 1 4 2 0 14 0 0.53 0.058 1
2 SA_BONE_MORPHOGENETIC Bone morphogenetic protein binds to its receptor to induce ectopic bone formation and promote development of the viscera. BMP1, BMPR1A, BMPR1B, BMPR2, MADH1, MADH4, MADH6 4 BMP1(17), BMPR1A(18), BMPR1B(14), BMPR2(46) 3229801 95 69 78 13 20 14 5 20 26 10 0.014 0.074 1
3 HSA00785_LIPOIC_ACID_METABOLISM Genes involved in lipoic acid metabolism LIAS, LIPT1, LOC387787 2 LIAS(8), LIPT1(11) 821172 19 17 14 0 0 3 2 3 11 0 0.055 0.15 1
4 HSA00472_D_ARGININE_AND_D_ORNITHINE_METABOLISM Genes involved in D-arginine and D-ornithine metabolism DAO 1 DAO(7) 384581 7 8 7 1 6 0 0 1 0 0 0.33 0.37 1
5 INOSITOL_METABOLISM ALDH6A1, ALDOA, ALDOB, ALDOC, TPI1 5 ALDH6A1(5), ALDOA(2), ALDOB(16), ALDOC(1), TPI1(3) 1926826 27 26 23 3 4 5 2 15 1 0 0.052 0.53 1
6 HSA00430_TAURINE_AND_HYPOTAURINE_METABOLISM Genes involved in taurine and hypotaurine metabolism BAAT, CDO1, CSAD, GAD1, GAD2, GGT1, GGTL3, GGTL4 6 BAAT(3), CDO1(3), CSAD(4), GAD1(15), GAD2(15), GGT1(9) 2900087 49 43 37 8 16 6 5 11 11 0 0.035 0.57 1
7 SA_G1_AND_S_PHASES Cdk2, 4, and 6 bind cyclin D in G1, while cdk2/cyclin E promotes the G1/S transition. ARF1, ARF3, CCND1, CDK2, CDK4, CDKN1A, CDKN1B, CDKN2A, CFL1, E2F1, E2F2, MDM2, NXT1, PRB1, TP53 15 ARF1(1), CCND1(2), CDK2(5), CDK4(3), CDKN1A(2), CDKN1B(4), CDKN2A(7), CFL1(2), E2F2(7), MDM2(11), NXT1(5), PRB1(3), TP53(326) 3973129 378 245 232 89 99 90 47 65 73 4 0.000073 0.6 1
8 HSA00031_INOSITOL_METABOLISM Genes involved in inositol metabolism ALDH6A1, TPI1 2 ALDH6A1(5), TPI1(3) 802771 8 8 8 1 0 0 1 7 0 0 0.4 0.71 1
9 HSA00830_RETINOL_METABOLISM Genes involved in retinol metabolism ALDH1A1, ALDH1A2, BCMO1, RDH5 4 ALDH1A1(11), ALDH1A2(17), BCMO1(5), RDH5(2) 2048461 35 32 34 7 10 8 5 8 4 0 0.077 0.73 1
10 TCAPOPTOSISPATHWAY HIV infection upregulates Fas ligand in macrophages and CD4 in helper T cells, leading to widespread Fas-induced T cell apoptosis. CCR5, CD28, CD3D, CD3E, CD3G, CD3Z, CD4, TNFRSF6, TNFSF6, TRA@, TRB@ 6 CCR5(11), CD28(4), CD3D(4), CD3E(2), CD3G(15), CD4(4) 1777677 40 32 26 8 4 4 6 8 18 0 0.4 0.78 1

Table 6.  Get Full Table A Ranked List of Significantly Mutated Genesets (Excluding Significantly Mutated Genes). Number of significant genesets found: 0. Number of genesets displayed: 10

rank geneset description genes N_genes mut_tally N n npat nsite nsil n1 n2 n3 n4 n5 n6 p_ns_s p q
1 HSA00785_LIPOIC_ACID_METABOLISM Genes involved in lipoic acid metabolism LIAS, LIPT1, LOC387787 2 LIAS(8), LIPT1(11) 821172 19 17 14 0 0 3 2 3 11 0 0.055 0.15 1
2 HSA00472_D_ARGININE_AND_D_ORNITHINE_METABOLISM Genes involved in D-arginine and D-ornithine metabolism DAO 1 DAO(7) 384581 7 8 7 1 6 0 0 1 0 0 0.33 0.37 1
3 HSA00031_INOSITOL_METABOLISM Genes involved in inositol metabolism ALDH6A1, TPI1 2 ALDH6A1(5), TPI1(3) 802771 8 8 8 1 0 0 1 7 0 0 0.4 0.71 1
4 SLRPPATHWAY Small leucine-rich proteoglycans (SLRPs) interact with and reorganize collagen fibers in the extracellular matrix. BGN, DCN, DSPG3, FMOD, KERA, LUM 5 BGN(7), DCN(7), FMOD(8), KERA(7), LUM(12) 1873748 41 36 40 9 10 12 1 14 4 0 0.21 0.82 1
5 1_2_DICHLOROETHANE_DEGRADATION ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH2, ALDH3A1, ALDH3A2, ALDH9A1 6 ALDH1A1(11), ALDH1A3(18), ALDH1B1(8), ALDH3A1(7), ALDH3A2(10), ALDH9A1(4) 3071928 58 44 52 9 19 9 7 15 8 0 0.01 0.86 1
6 ASCORBATE_AND_ALDARATE_METABOLISM ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH2, ALDH3A1, ALDH3A2, ALDH9A1 6 ALDH1A1(11), ALDH1A3(18), ALDH1B1(8), ALDH3A1(7), ALDH3A2(10), ALDH9A1(4) 3071928 58 44 52 9 19 9 7 15 8 0 0.01 0.86 1
7 BBCELLPATHWAY Fas ligand expression by T cells induces apoptosis in Fas-expressing, inactive B cells. CD28, CD4, HLA-DRA, HLA-DRB1, TNFRSF5, TNFRSF6, TNFSF5, TNFSF6 3 CD28(4), CD4(4), HLA-DRB1(6) 912125 14 12 13 7 1 0 2 5 4 2 0.96 0.86 1
8 HSA00430_TAURINE_AND_HYPOTAURINE_METABOLISM Genes involved in taurine and hypotaurine metabolism BAAT, CDO1, CSAD, GAD1, GAD2, GGT1, GGTL3, GGTL4 5 BAAT(3), CDO1(3), CSAD(4), GAD1(15), GAD2(15) 2490512 40 36 33 8 16 6 4 11 3 0 0.07 0.94 1
9 SA_FAS_SIGNALING The TNF-type receptor Fas induces apoptosis on ligand binding. BCL2, CASP3, CASP8, CFL1, CFLAR, P11, PDE6D, TNFRSF6, TNFSF6 6 BCL2(2), CASP3(3), CASP8(19), CFL1(2), CFLAR(2), PDE6D(2) 1974946 30 28 28 5 5 2 3 8 12 0 0.19 0.95 1
10 PEPIPATHWAY Proepithelin (PEPI) induces epithelial cells to secrete IL-8, which promotes elastase secretion by neutrophils. ELA1, ELA2, ELA2A, ELA2B, ELA3B, GRN, IL8, SLPI 3 GRN(9), IL8(5), SLPI(2) 832960 16 15 15 7 2 3 2 3 6 0 0.79 0.96 1
Methods & Data
Methods

In brief, we tabulate the number of mutations and the number of covered bases for each gene. The counts are broken down by mutation context category: four context categories that are discovered by MutSig, and one for indel and 'null' mutations, which include indels, nonsense mutations, splice-site mutations, and non-stop (read-through) mutations. For each gene, we calculate the probability of seeing the observed constellation of mutations, i.e. the product P1 x P2 x ... x Pm, or a more extreme one, given the background mutation rates calculated across the dataset. [1]

Download Results

In addition to the links below, the full results of the analysis summarized in this report can also be downloaded programmatically using firehose_get, or interactively from either the Broad GDAC website or TCGA Data Coordination Center Portal.

References
[1] TCGA, Integrated genomic analyses of ovarian carcinoma, Nature 474:609 - 615 (2011)
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