`
`"RECEIVED
`
`P SEP03 2013
`
`UNIVERSITY LIBRARY
`;
`Dynamic DNA
`methylation indicates
`regulatoryfeatures
`across the human
`
`“genome PAGE477
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`
`
`
`
`
`
`
`DO NOT REMOVE FROM
`CURRENT PERIODICALS
`ROOM
`
`
`
` {UNIV. CHICAGO EX. 2029
`se
`See
`Bits
`a
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`? PLANT PHYSIOLOGY
`cit
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`

`CONTENTS
`
`22 August 2013 / Vol500 / Issue No 7463
`
` COMMENT
`
`NEWS IN FOCUS
`
`
`
`Sheep lock horns overfitness Pia
`
`388 POLICY
`Romanian science suffers as reversal
`of reforms begins to bite
`389 BIOTECHNOLOGY
`
`Researchers exploit loophole in US
`regulation of transgenic crops
`
`FEATURES
`
`STEM CELLS
`
`Egg
`engineers
`
`How to create sperm andegg cells
`
`in the laboratory PAGE 392
`
`THIS WEEK
`
`are in flux
`
`RESEARCH HIGHLIGHTS
`380 SELECTIONS FROM THE
`SCIENTIFIC LITERATURE
`Ant vibrations / Chemical yardstick
`for tumours / Hot news / Coping with
`temptation / Ebola potency / Bacterial
`cancer / Marine bone worm discovery
`
`SEVEN DAYS
`
`382 THE NEWS IN BRIEF
`
`Meetthe world’s latest carnivore: the
`olinguito / Ecuador gives green light to
`drilling in the Amazon / China launches
`bribery probe / NASAcalls time on
`Kepler / Guidelines issued for naming
`planets
`
`CAREERS
`
`491 RESEARCH IMPACT
`Altmetrics make their mark
`Alternatives to citation analysis have a
`role in career assessment — but handle
`them with care
`
`493 TURNING POINT
`Cancer researcher Jason Weber has
`propelled the issue of science funding
`into the US Senate
`
`HYORHRTTTHT
`385 WATER MANAGEMENT
`EDITORIALS
`377 RESEARCH
`HY
`Revampedforecasting system seeks
`ATTYHt
`to stop drinking water from silting up
`Subject to question
`AYATTYit
`Just how informed should informed
`386 PUBLISHING
`ITPURHERRORRTPRREY
`t
`consentactually be?
`Dramatic rise in number of research
`papers that are free to view
`WORLD VIEW
`
`HMPATERIRHAeadea erodeetretea ae
`
`387 EVOLUTIONARY GENETICS
`LUADHBERLULEEOREREALeaoucaLaaE
`379 Whatis to
`
`LLDAALDAAALSAAanaaaonad Seti
`be done about
`Russian science?
`Mikhail Gelfand
`Russia’s Academyof
`Sciences must reform
`but current proposals
`
`
`
`395 MEDICINE
`Trial unpredictability yields
`predictable therapy gains
`Benjamin Djulbegovic, Ambuj Kumar,
`Paul Glasziou, Branko Miladinovic
`& lain Chalmers
`Asurvey of 50 years of data shows the
`clinical trial system in a goodlight
`
`BOOKS & ARTS
`
`SCIENCE FICTION
`
`New world
`
`Paul McEuenon thefinalpart of
`Margaret Atwood’s dystopiantrilogy
`PAGE 398
`
`399 BOOKS IN BRIEF
`
`CORRESPONDENCE
`400 Antibiotics in agriculture / Fukushima
`fallout / REDD+ and indigenous people
`
`OBITUARY
`401 Michael John Morwood (1950-2013)
`Richard G Roberts & Thomas Sutikna
`
`
`FUTURES
`496 Alone
`Marko Jankovic
`
`22 AUGUST 2013 | VOL 500 | NATURE | 373
`
`

`

`ONTENTS
`
`22 August 2013 / Vol 500 / Issue No 7463
`
`RESEARCH
`
`NEW ONLINE
`403 Papers published this week at
`nature.com
`
`NEWS& VIEWS
`404 PLANT BIOLOGY
`Electric defence
`Herbivory inducesan electrical wave
`that triggers jasmonate formation
`Alexander Christmann & Erwin Grill
`SEE LETTER P. 422
`
`405 ASTROPHYSICS
`Twinkling stars
`Correlation betweenstellar brightness
`variations and surface gravity
`Jargen Christensen-Dalsgaard
`SEE LETTER P. 427
`
`406 BIOTECHNOLOGY
`Programming genomeswithlight
`Using optogenetics to regulate
`genetranscription
`Andreas Méglich & Peter Hegemann
`SEE LETTER P. 472
`
`408 CONDENSED-MATTER PHYSICS
`A solid triple point
`A coexistence of twoinsulating phases
`and a conducting phase in VO,
`Douglas Natelson
`SEE LETTERP. 431
`
`409 METABOLISM
`Sweetenticements to move
`PFK2 activity in endothelial cells
`accelerates glycolysis and angiogenesis
`Cholsoon Jang & Zoltan Arany
`ECOLOGY
`Abundant equals nested
`Network nestednessis linked to
`community abundance
`Colin Fontaine
`SEE LETTER P. 449
`
`411
`
`412 EVOLUTIONARY BIOLOGY
`A gut feeling for isolation
`A malfunctioning host-microbiome
`interface can cause hybrid inviability
`Gregory D D Hurst & Chris D Jiggins
`
`ARTICLES
`415 CANCER Signatures of mutational
`processes in human cancer
`L B Alexandrovetal.
`
`422 PLANT SCIENCES GLUTAMATE
`RECEPTOR-LIKE genes mediate
`
`
`
`ON THE COVER
`
`Methyl m
`The dynamic methylation landscape
`of the human genome: the x axis(left)
`
`leaf-to-leaf wound signalling
`SAR Mousavi, A Chauvin, F Pascaud,
`S Kellenberger & E E Farmer
`SEE N&V P. 404
`
`LETTERS
`427 ASTRONOMY An observational
`correlation betweenstellar brightness
`variations and surface gravity
`F A Bastien, K G Stassun, G Basri
`& J Pepper SEE N&V P. 405
`PHYSICS Measurementof a solid-state
`triple point at the metal-insulator
`transition in VO,
`JH Park etal. SEE N&V P. 408
`
`43—
`
`43 an
`
`44 o
`
`Ad on
`
`OPTICS AND PHOTONICS Therole of spin
`in the kinetic control of recombination
`in organic photovoltaics
`A Raoet al.
`
`CLIMATE SCIENCES Onsetof deglacial
`warmingin West Antarctica driven
`by local orbital forcing
`WAIS Divide Project Members
`
`EVO-DEVO Digit loss in archosaur
`evolution and the interplay between
`selection and constraints
`
`it feorrespondsto the maximal observed
`
`
`
`
`
`
`BANGWONG&MICHAELZILLER
`
`MAG de Bakkeretal.
`
`449 ECOLOGY Emergenceofstructural and
`dynamical propertiesof ecological
`mutualistic networks
`S Suweis, F Simini, J R Banavar
`& A Maritan SEE N&V P. 411
`
`ow
`
`o
`
`oo
`
`o
`
`rR
`
`EVOLUTIONARY GENETICS Genomic
`evidence for ameiotic evolution
`in the bdelloid rotifer Adineta vaga
`J-F Flot etal.
`
`NEUROSCIENCE Oxytocin enhances
`hippocampalspike transmission by
`modulating fast-spiking interneurons
`SF Owen etal.
`
`BIOPHYSICS Non-vesicular trafficking
`by a ceramide-1-phosphatetransfer
`protein regulates eicosanoids
`DK Simanshu etal.
`
`CELL BIOLOGY The histone H4 lysine 16
`acetyltransferase hMOFregulates the
`outcomeof autophagy
`J Fiillgrabe etal.
`
`BIOTECHNOLOGY Optical controlof
`mammalian endogenoustranscription
`and epigenetic states
`S Konermannet al. SEE N&V P. 406
`
`47=~!
`
`48Ro
`
`48a
`
`EPIGENOMICS Charting a dynamic
`DNA methylation landscapeof
`the human genome
`MJ Ziller etal.
`
`BIOPHYSICS DNA unwinding
`heterogeneity by RecBCDresults from
`static molecules able to equilibrate
`B Liu, RJ Baskin & S C Kowalczykowski
`STRUCTURAL BIOLOGY Structural basis
`for molecular recognition of
`folic acid by folate receptors
`C Chen etal.
`
`490 CORRIGENDUM Replication stress links
`structural and numerical cancer
`chromosomal instability
`RA Burrell et al.
`
`490 RETRACTION Oligosaccharide ligands
`for NKR-P1 protein activate NK cells
`and cytotoxicity
`K Bezouskaetal.
`
`490 ERRATUM The importanceof feldspar
`for ice nucleation by mineral dust in
`mixed-phase clouds
`J D Atkinsonetal.
`
`22 AUGUST 2013 | VOL 500 | NATURE | 375
`
`

`

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`376 | NATURE | VOL 500 | 22 AUGUST 2013
`
`|
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`doi:10.1038/nature12477
`
`Signatures of mutational processes in
`human cancer
`
`A list of authors andtheiraffiliations appears at the end of the paper
`
`All cancers are caused by somatic mutations; however, understanding of the biological processes generating these
`mutations is limited. The catalogue of somatic mutations from a cancer genomebears the signatures of the mutational
`processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than
`20 distinct mutational signatures. Some are present in manycancertypes, notably a signature attributed to the APOBEC
`family of cytidine deaminases, whereas others are confinedto a single cancer class. Certain signatures are associated
`with age ofthe patientat cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of
`cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic
`regions, ‘kataegis’, is found in many cancer types. Theresults reveal the diversity of mutational processes underlying
`the developmentof cancer, with potential implications for understandingof canceraetiology, prevention and therapy.
`
`Somatic mutations found in cancer genomes’ maybe the consequence
`of the intrinsic slight infidelity of the DNA replication machinery,
`exogenous or endogenous mutagen exposures, enzymatic modifica-
`tion of DNA,or defective DNA repair. In some cancertypes, a sub-
`stantial proportion of somatic mutations are knownto be generated
`by exposures, for example, tobacco smoking in lung cancers and
`ultraviolet light in skin cancers’, or by abnormalities of DNA main-
`tenance,
`for example, defective DNA mismatch repair in some
`colorectal cancers*. However, our understanding of the mutational
`processes that cause somatic mutations in most cancer classes is
`remarkably limited.
`Different mutational processes often generate different combinations
`of mutation types, termed ‘signatures’. Until recently, mutational sig-
`natures in human cancer have been explored through a small number
`
`of frequently mutated cancer genes, notably TP53 (ref. 4). Although
`informative, these studies have limitations. To generate a mutational
`signature, a single mutation from each cancer sample is entered into a
`mutationset aggregated from several cases of a particular cancertype. A
`signature that contributes the large majority ofsomatic mutations in the
`tumourclass is accurately reported. However, if multiple mutational
`processes are operative, a jumbled composite signature is generated.
`Furthermore, because such studies are based on ‘driver’ mutations’,
`signatures ofselection are superimposed onthe signatures ofmutational
`processes,
`Recent advancesin sequencing technology have overcomepastlimi-
`tations of scale’. Thousands of somatic mutations can now be iden-
`tified in a single cancer sample,offering the possibility of deciphering
`mutational signatures even when several mutational processes are
`
`
`
`
`
`
`
`(numbermutationspermegabase)
`
`
`
`
`
`Somaticmutationprevalence
`
`Figure 1 | The prevalence of somatic mutations across humancancertypes.
`Every dot represents a sample whereas the red horizontallines are the median
`numbers of mutations in the respective cancer types. The vertical axis (log
`scaled) shows the number of mutations per megabase whereas the different
`
`cancertypes are ordered on the horizontal axis based on their median numbers
`of somatic mutations, Wethank G.Getz andcolleagues for the design ofthis
`figure*®. ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia;
`CLL, chronic lymphocytic leukaemia.
`
`22 AUGUST 2013 | VOL 500 | NATURE | 415
`
`

`

`ARTICLE
`
`
`
`
`
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`Figure 2 | Validated mutational signatures found in humancancer. Each
`signatureis displayed accordingto the 96 substitutionclassification defined by
`the substitution class and sequence context immediately 3’ and 5’ to the
`mutated base. The probability bars for the six types of substitutions are
`displayed in different colours. The mutationtypes are on the horizontal axes,
`
`whereas vertical axes depict the percentage of mutationsattributedto a specific
`mutation type. All mutational signatures are displayed on thebasis of the
`trinucleotide frequency of the human genome.A higherresolution of each
`panelis found respectively in Supplementary Figs 2-23. Asterisk indicates
`mutation type exceeding 20%.
`
`operative. Moreover, because most mutations in cancer genomesare
`‘passengers”they do not bear strong imprints ofselection.
`Werecently developed an algorithm to extract mutational signa-
`tures from catalogues of somatic mutations and appliedit to 21 breast
`cancer whole-genome sequences”®. Novel and knownsignatures were
`revealed, with the contribution ofeach signatureto each cancer sample
`and the timingofits activity estimated®”. Further studies have demon-
`strated that the approachcanalso beapplied,albeit with less power,to
`mutational catalogues from sequencesofall coding exons (exomes)’.
`Global sequencinginitiatives are now yielding catalogues of somatic
`mutations from thousandsof cancers*. We have therefore applied this
`methodto survey the repertoire ofmutational signatures andprocesses
`operating across the spectrum of humanneoplasia.
`
`Mutational catalogues
`Wecompiled 4,938,362 somatic substitutions and small insertions/
`deletions (indels) from the mutational catalogues of 7,042 primary
`cancers of30 different classes (507 from whole genomeand 6,535 from
`exome sequences) (Supplementary Fig. 1). In all cases, normal DNA
`416 | NATURE | VOL 500 | 22 AUGUST 2013
`
`from the sameindividuals had been sequencedtoestablish the somatic
`origin of variants.
`The prevalence of somatic mutations was highly variable between
`and within cancerclasses, ranging from about 0.001 per megabase
`(Mb) to more than 400 per Mb (Fig. 1). Certain childhood cancers
`carried fewest mutations whereas cancersrelated to chronic mutagenic
`exposures such as lung (tobacco smoking) and malignant melanoma
`(exposure to ultraviolet light) exhibited the highest prevalence. This
`variation in mutation prevalenceis attributable to differences between
`cancersin the durationofthecellularlineage betweenthefertilized egg
`andthe sequencedcancercell and/or to differences in somatic muta-
`tion rates during the wholeorpartsofthat cellular lineage’.
`
`The landscape of mutational signatures
`Inprinciple, all classes of mutation (such as substitutions, indels, rear-
`rangements) and any accessory mutation characteristic, for example, the
`sequence contextofthe mutationorthetranscriptional strand on which
`it occurs, can be incorporatedinto thesetof features by which a muta-
`tional signatureis defined. In thefirst instance, we extracted mutational
`
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`@® Total cancer types in which a signature is operative
`Figure 3 | The presence of mutational signatures across human cancer
`percentage ofsamples from ourdataset of7,042 cancers in which the signature
`types. Cancertypes are ordered alphabetically as columns whereas mutational
`contributed significant numberof somatic mutations, For most signatures,
`signaturesare displayed as rows. ‘Other’ indicates mutational signaturesfor
`significant numberof mutationsin a sampleis defined as more than 100
`which we were notable to performvalidation or for which validation failed
`substitutions or more than 25% ofall mutationsin that sample. MMR,
`(Supplementary Figs 24-28). Prevalence in cancer samples indicates the
`mismatchrepair.
`
`Qe
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`
`signatures using base substitutions and additionally included informa-
`tion on the sequence context of each mutation, Because there are six
`classes ofbase substitution—C>A, C>G, C>T, T>A, T>C, T>G(all
`substitutionsare referred to by the pyrimidine of the mutated Watson-
`Crick base pair)—and as weincorporated information on the bases
`immediately 5’ and 3' to each mutatedbase,there are 96 possible muta-
`tionsin this classification. This 96 substitution classificationis particu-
`larly useful for distinguishing mutational signatures that cause the same
`substitutions butin different sequencecontexts,
`Applying this approach to the 30 cancer typesrevealed 21 distinct
`validated mutational signatures (Supplementary Table 1 and Sup-
`plementary Figs 2-28). These show substantial diversity (Fig. 2 and
`Supplementary Figs 2-23). There are signatures characterized by
`Prominence ofonly oneortwoofthe 96 possible substitution muta-
`tions, indicating remarkable specificity ofmutation type and sequence
`context(signature 10). By contrast, others exhibit a more-or-less equal
`representation ofall 96 mutations(signature 3). There are signatures
`characterized predominantly by C>T (signatures 1A/B, 6, 7, 11,15,
`19), C>A (4, 8, 18), T>C (5,12, 16, 21) and T>G mutations(9, 17),
`with others showing distinctive combinations of mutation classes
`(2, 13, 14),
`Signatures 1A and 1B were observed in 25 outof 30 cancerclasses
`(Fig. 3). Both are characterized by prominence of C>T substitutions
`at NpCpGtrinucleotides, Because they are almost mutually exclusive
`among tumour types they probably represent the same underlying
`process, with signature 1B representingless efficient separation from
`other signatures in some cancer types. Signature 1A/B is probably
`related to the relatively elevated rate of spontaneous deamination
`of 5-methyl-cytosine which results in C>T transitions and which
`predominantly occurs at NpCpGtrinucleotides’, This mutational
`Process operates in the germline, whereit has resulted in substantial
`depletion of NpCpG sequences, and in normal somaticcells",
`Signature2 is characterized primarily by C>T and C>G mutations
`at TpCpN trinucleotides and was foundin 16 out of30 cancer types
`
`(Fig. 3). On the basis ofsimilarities in mutation type and sequence
`context we previously proposedthatsignature2 is due to over activity
`of members of the APOBEC family of cytidine deaminases, which
`convert cytidine to uracil, coupled to activity of the base excision
`repair and DNAreplication machineries",
`In most cancerclasses at least two mutational signatures were
`observed, with a maximum ofsix in cancers of the liver, uterus and
`stomach. Although these differences may, in part, be attributable to
`differences in the powerto extract signatures,it seemslikely that some
`cancers have a more complexrepertoire of mutational processes than
`others.
`Mostindividual cancer genomesexhibit more than one mutational
`signature and manydifferent combinations ofsignatures were observed
`(Fig. 4 and Supplementary Figs 29-88), The patternsof contribution to
`individual cancer samples vary markedly betweensignatures. Signature
`1A/B contributesrelativelysimilar numbers ofmutationsto most cancer
`cases whereas other signatures contribute overwhelming numbers of
`mutations to somecancer samples but very few to others of the same
`cancerclass, for example, signatures2, 3, 4, 6,7, 9, 10, 11, 13 (Fig. 4).
`Mutational signatures and age of cancer diagnosis
`Weexamined eachcancertypefor correlations between age of dia-
`gnosis and the numberof mutationsattributable to each signature in
`each sample. Signature 1A/B exhibited strong positive correlations
`with age in the majority of cancer types of childhood and adulthood
`(Supplementary Table 2), No other mutational signature showed a
`consistentcorrelation with age of diagnosis.
`The mutations in a cancer genome maybe acquiredat anystage in
`the cellular lineage from thefertilized egg to the sequenced cancercell.
`The correlation with ageofdiagnosis is consistent with the hypothesis
`that a substantial proportion of signature 1A/B mutations in cancer
`genomes have beenacquired overthelifetime ofthe cancer patient, at
`a relatively constantrate thatis similarin different people, probably in
`normal somatic tissues. The absence of consistent correlation of all
`
`[rrr
`
`22 AUGUST 2013 | VOL 500 | NATURE | 417
`
`

`

`SEsence
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`Figure 5 | Selected mutational signatures with strong transcriptional strand
`bias. Mutations are shownaccordingto the 192 mutation classification
`incorporating the substitution type, the sequence context immediately 5' and 3’
`to the mutated base and whether the mutated pyrimidineis on the transcribed
`or untranscribed strand. The mutation types are displayed on the horizontal
`axis, whereasthe vertical axis depicts the percentage ofmutations attributed toa
`specific mutation type. A higherresolution versionofall mutationalsignatures
`with strong transcriptional strandbias is found respectively in Supplementary
`Figs 89-95.
`
`(Fig. 5). Similarly, signature 12, which features T>C mutationsat
`NpTpNtrinucleotides, also found in hepatocellular carcinomas,
`showsstrong transcriptional strand bias with more T>C mutations
`on the transcribed than untranscribed strands (Supplementary Fig. 94).
`Onthe assumption that the transcriptional strand biases in signa-
`tures 12 and 16 are introduced by transcription-coupled NER, these
`currently unexplained signatures may be the result of bulky DNA
`helix-distorting adducts on adenine. However, there is no previous
`basis for invoking transcription-coupled NERin the genesis of these
`signatures and othercausesoftranscriptional strand bias mayexist.
`
`Mutational signatures with insertions and deletions
`Were-extracted the mutational signatures including, in addition