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1、HowManyFunctionalSequencesAreThereinOurGenomes?Deng-KeNiuCollegeofLifeScience,BeijingNormalUniversity,Chinahttp:/ thaliana(27,029).Fromhttp:/www.ornl.gov/sci/techresources/Human_Genome/faq/genenumber.shtmlandhttp:/www.ncbi.nlm.nih.gov/pmc/articles/PMC2238962/Sequenceswithobviousfunctionsrepresentave
2、rysmallfractionofthehumangenome.Afterhumangenome:FindingTreasuresinJunkTheymusthavefunctionsthatstillremainstobediscovered.“FindingTreasureinJunk”wasaglobalattemptinmolecularbiology.ThejunkDNAwasthenmis-referredtosequenceswithnoidentifiedfunctionsbymanybiologists.Moreandmorealternativesplicingreveal
3、ed-almostallhumangeneshavealternativelysplicedmRNAsRegulatoryelementsfoundinintrons,enhancingeffectsofintronsongeneexpressionmiRNA,moreandmorenoncodingRNAsrevealedSomepseudogenesarefunctionalMoreandmoretreasuresfoundintransposableelements.ENCODE“revealed”thetreasuresTheEncyclopediaofDNAElements(ENCO
4、DE)istofindallfunctionalelementsinthehumangenome.ItisthemostcriticalprojectsbyUSNationalHumanGenomeResearchInstituteafteritssuccessinHumanGenomeProject.The“project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. Thes
5、e data enabled us to assign biochemical functions for 80% of the genome”.Theyassayedonly147ofthehundredsofhumancelltypes,someoftheexperimentswerecarriedoutinonlyafewcelltypes.Inaddition,theiranalysesdidnotconsidercircadianrhythm,seasonalvariationsandenvironmentalstresses(likeheat,starvation),whichar
6、ealsolikelytohavespecialpatternofgeneregulation.Thusonelikelyestimationisthatalmostallofthegenomeisbiochemicallyactive.In2010,themodENCODEprojectalso“revealed”thatthefractionoftheDrosophilagenomeassignedtocandidatefunctions:89%.ImpactofthetreasuresrevealedbyENCODEForbiologiststhatare“FindingTreasure
7、sinJunk”,itisatriumph.AdeclarationofthedeathofthejunkDNAconcept.Anentirelynewviewofourgenomeisemerging:everytinypartofourgenomeisfunctional;ourgenomeisperfectandthuswasdelicatelycreated.Butbywhat?BythenaturalselectioninDarwiniantheory?No.Itisawidelyheldwrongimpressiononevolution:all organisms are pe
8、rfect and everything within them is there for a function.ByGod,orothersupernaturalpowers(Intelligentdesign)?Supernaturalpowers,ifexist,candesignperfectgenomes.Itisnownotjustabiologicaldebate.Itinvolvesthebasisofnaturalsciences,atheismandmaterialism.Tangledwarfaresamongbiochemists,evolutionarybiologi
9、sts,andcreationists.没有一个完美的人：我们身体的十大设计缺陷自果壳网http:/ 不可靠的脊椎问题：我们的脊椎就是一团糟。我们能走路就是个奇迹，克利夫兰市凯斯西储大学人类起源中心主任布鲁斯拉蒂默（Bruce Latimer）说道。当我们的祖先四肢着地爬行时，他们的脊椎会像弓一样拱起，以承受悬空悬挂在下方的器官的重量。但接着，我们站起来了；这个90度的大转变让脊椎被迫成为了柱子。接下来，为了符合二足行走的需要，脊椎在后腰处向前弯曲；为了保持头部的平衡好让我们不至于走到哪儿都像在跳竹竿舞脊椎上部又向相反方向弯曲。这一变化让下脊椎承受了巨大的压力，据估计，让80%的成年人深受后腰
10、疼痛所苦。解决方法：像祖先一样把脊椎拱起来。“想想你的狗，” 拉蒂默说道，“它从骶骨到颈部都是一个弓状的弧。这是个很棒的系统。”简单。强壮。无痛。只有一个问题：要想不因为头部的重量一头向前栽去，我们得回到四肢爬行。没有一个完美的人：我们身体的十大设计缺陷自果壳网http:/ 不灵活的膝盖问题：正如拉蒂默所说，“把全身上下最复杂的关节放在两个巨大的杠杆股骨和胫骨之间，这纯属是在找麻烦。”这么做的结果就是，你的膝盖只能向两个方向转动：向前和向后。这就是为什么所有主要体育项目，大概除橄榄球外，都禁止从侧面别住对手的膝盖，或是击打对手膝盖的侧面。解决方法：用球窝关节取代这个杠杆系统，就像肩膀和髋部那样
11、。我们的膝盖从未演化出这样的关节，是因为“过去的我们并不需要，” 拉蒂默解释道，“我们不知道会有橄榄球这回事。”没有一个完美的人：我们身体的十大设计缺陷自果壳网http:/ 过窄的骨盆问题：生育很痛苦。雪上加霜的是，女性骨盆的宽度已经有大约20万年没发生过变化了，这使我们的大脑尺寸也无法继续增加。解决方法：拉伸骨盆当然是个办法，拉蒂默回答，但技术专家们大概已经找到了更好的解决方法。“我敢打赌，在一万年内，或者甚至一千年内，发达国家的女性都再也不会自然生产了。诊所会混合精子和卵子，然后你只要来一趟就可以把孩子领回家了。”没有一个完美的人：我们身体的十大设计缺陷自果壳网http:/ 暴露的睾丸问题
12、：男性生殖器官脆弱地暴露在体外。解决方法：把睾丸移到体内能让男人们免受被一脚踢中蛋蛋的痛苦。为了实现这一目标，首先要改变精子，纽约州立大学奥尔巴尼分校的演化心理学家戈登加鲁普（Gordon Gallup）说道。显然，睾丸（与卵巢不同）被扔出体外的原因是，精子必须储存在比体温低2.5-3华氏度的温度下。加鲁普的猜想是，这是因为较低的温度能让精子在进入温暖的阴道开始受精赛跑前，保持较低的活跃程度 。这一演化小花招防止了精子过早失去活力。所以，换种方法思路来实现这一目的吧，加鲁普提出：在体温下保存精子，但升高阴道的温度（以及顺便说，我们并不需要从头绘制新的蓝图：大象就是不错的模型）。没有一个完美的人
13、：我们身体的十大设计缺陷自果壳网http:/ 蜿蜒的动脉问题：血液通过一条主动脉流进你的四肢，这条动脉从身体前侧的二头肌或髋屈肌处进入四肢。而为了给四肢后侧的组织，比如三头肌和后腿腱供血，这条主动脉分岔开去，迂回地绕过骨头，并和神经捆绑在一起。这种绕弯的布线方式可能会造成一些很是烦人的差错。比如说，在肘部，一条动脉分支与负责小指活动的尺骨神经就在皮肤下方交会。正因为如此，你上臂的骨头，也就是肱骨或“麻骨”被打到的时候，你的手臂就会发麻。解决方法：用一条新的动脉，从肩胛骨或臀部给四肢后侧供血，华盛顿特区霍华德大学的解剖学助理教授瑞迪奥戈（Rui Diogo）回答道；他的研究方向是灵长动物的肌肉演
14、化。这根额外的血管能为肩膀到手背提供一条更直接的路径，防止血管和神经离皮肤过近。没有一个完美的人：我们身体的十大设计缺陷自果壳网http:/ 装反了的视网膜问题：视网膜上的感光细胞就像放反了的麦克风，纽约州立大学的分子生物学副教授纳桑伦茨（Nathan Lents）写道。这一设计迫使光线必须穿过整个细胞，以及血液和组织，才能到达细胞后部的相当于接收器的部分。这一结构可能会导致视网膜从其支持组织上脱离这也是失明的主要原因之一。它还导致了细胞纤维相当于麦克风电线与视神经交汇处的盲点，让大脑不得不自行填补这一空白。解决方法：可以从章鱼或者乌贼那里剽窃来把视网膜反过来就行。没有一个完美的人：我们身体的
15、十大设计缺陷自果壳网http:/ Z. German）说说道。在胎儿还在子宫的时候，在把那堆讨厌的血管组织降进胸腔之后再发育喉返神经。这样，喉返神经就不会被它拖下去了。没有一个完美的人：我们身体的十大设计缺陷自果壳网http:/ 放错位置的发声器官问题：人的食道和气管共同开口到一个地方：咽。咽上接鼻腔和口腔，下接喉（发声器官）。为了阻止食物进入气管，当你吞咽的时候，会厌（一片叶状的皮瓣）会反射性地盖住通往喉的开口。但有时候，比如你在吃饭时聊天或者大笑，会厌的反应就没那么快，这时，食物就会滑进你的气管并滞留在那，让你噎住。解决方法：鲸鱼的喉部位于气孔，我们从这儿找到了灵感。热尔曼说，如果将咽部挪
16、到鼻子，我们就会有两根独立的管子。当然，这样的话，我们就丧失说话的能力了。但我们还可以用歌声来交流，就像鲸鱼一样，振动我们的鼻孔来发声。没有一个完美的人：我们身体的十大设计缺陷自果壳网http:/ 七拼八凑的大脑问题：人类的进化是阶段性的。心理学家盖瑞马库斯（Gary Marcus）在他的书Kluge: The Haphazard Evolution of the Mind中解释到，在新的模块还在组建的时候，我们依然需要旧的模块在线，让大脑维持运转。一边建造一边使用的后果就是各种偷懒草率抄近道，就好像大脑是一个混乱失调的车间，年轻的工人（前脑）处理诸如语言的新技能的同时，老保安（中脑和后脑）则
17、在管理着系统记忆和地下室的保险丝。姑举几个后果为例：抑郁，疯狂，不可靠的记忆，证实偏见。解决方法：没救。英文原著链接：http:/nautil.us/issue/24/error/top-10-design-flaws-in-the-human-bodyNautil，这个网络科普期刊挺不错。WhatiswrongwithENCODE?Theirreason:Regionsoftranscription,transcriptionfactorassociation,chromatinstructure,histonemodificationandDNAmethylationareactive.B
18、iochemicalactivitiesareentirelydifferentfrombiologicalfunctions.Theyneglectednumerouspreviousstudies:nonsense-mediatedmRNAdecay,repressivetranscription,stochasticnatureofgeneexpression,etc.Anotherreason:OverlappingbetweenGWASdisease-relatedSNPsandnoncodingregions.Diseasesarenotnecessarily1)selecteda
19、gainst,2)loss-of-function.Howtodefinefunction?SelectedeffectandCausalroleFromDoolittleWF.GenomeBiolEvol(2014)doi:10.1093/gbe/evu098Howtodefinefunction?SelectedeffectandCausalroleTypesofcausalrolesandselectedeffectfunctionareconsideredherefortheleveloforganisms,thatwhichisusuallyimplicitingenomicbiol
20、ogy.“Mereeffects”areconsequencesofthepresenceofageneticelementorsequencethatmightnotgenerallybeconsidereda“phenotype”attheorganismallevel,orto“contributetothecapacityofthesystemthatcontainsit”inanybiologicallymeaningfulway.Beingsensitivetorestrictionnucleasesin vitro ortemplatingitsownreplicationin
21、vivo,apropertyofeverynucleotide,areexamples.Asphenotypebecomesmoresignificantorcharacteristicallyprominentattheorganismlevel,thedistinctionbetweenmereeffectsandspandrelsbecomeshardertomake.Theabilitytosupporteyeglasses,clearlynotaselectedeffect,isneverthelessanimportantphenotypicconsequenceofnoses,f
22、orinstance.Indeedtheboundariesbetweenallslicesofthispiearenegotiable,anddependonparametersthatvaryorotherdefinitionsaboutwhichthereisnoconsensus.Whenpopulationsizesarereduced,functionsunderweakselectionmightretaincausalrolesforsometime,orquicklybecomemereeffects.Productsoftheevolutionaryratchetcalle
23、dConstructiveNeutralEvolutionbydefinitionariseneutrallybutaremaintainedbypurifyingselection.Whether“selectedeffects”shouldbeconstruedasembracingsuchelementshasnotbeenseriouslyaddressed.Andtheeffectsofselfishelementsattheorganismalandspecieslevels(negativeandpositive,respectively)mightalsobetakenassp
24、andrelsorcausalrolefunctionsatthoselevels.Selectedeffect:Adaptiverole,Exaptation,Constructiveneutralevolution-Conservative;Ablation,knockoutHowtodefinefunction?SelectedeffectandCausalroleWhatcouldwelearnfromthedebate?“We classify the functional impact attributed to TE insertions into four categories
25、 of increasing complexity and argue that so far very few studies have conclusively demonstrated exaptation of TEs as transcriptional regulatory regions. We also contend that many genome-wide studies dealing with TE exaptation in recent lineages of mammals are still inconclusive and that the hypothes
26、is of rapid transcriptional regulatory rewiring mediated by TE mobilization must be taken with caution.” (deSouzaetal2013)“We found that mRNA levels are much better conserved than individual transcription factor binding events, and that changes in a genes expression were poorly explained by changes
27、in adjacent transcription factor binding. However, highly bound sites, sites in regions bound by multiple factors and sites near genes are conserved more frequently than other binding, suggesting that a considerable amount of transcription factor binding is weakly or non-functional and not subject t
28、o purifying selection.” (Parisetal2013)We speculate on the meaning of the differences observed and discuss that although ChIP experiments identify the biochemical event of proteinDNA interaction, it cannot determine whether the event results in a biological function, and therefore more studies are r
29、equired to establish the effect of divergence of binding events on species-specific gene expression. (SakabeandNobrega,2013)One of the major findings of ENCODE, and other genome analysis projects, is that the human transcriptome is far larger and more complex than previously thought.The question as
30、to what proportion of this complexity is truly functional remains open, however, and this ambiguity presents a serious challenge to genome scientists.We propose that an understanding of the true overlap between transcriptional complexity and functionality will not be gained in the short term.(Mudgee
31、tal2013)WhydidENCODEconsortiumneglectsomuchbiologicalknowledge?Whatcouldwelearnfromthedebate?RNAeditingisaposttranscriptionalmodificationthatcanleadtoachangeintheencodedproteinsequenceofagene.AlthoughafewcasesofmammaliancodingRNAeditingareknowntobefunctionallyimportant,thevastmajorityofover2,000A-to
32、-Ieditingsitesthathavebeenidentifiedfromthecodingregionsofthehumangenomearelikelynonadaptive,representingtolerablepromiscuoustargetingofeditingenzymes.Findingthepotentiallytinyfractionofbeneficialeditingsitesfromtheseaofmostlynearlyneutraleditingisadifficultbutimportanttask(XuandZhang,2014,PNAS).Num
33、erouseukaryoticgenesarealternativelyspliced.Recently,deeptranscriptomesequencinghasskyrocketedproportionofalternativelysplicedgenes;over95%humanmulti-exongenesarealternativelyspliced.Onefundamentalquestionis:areallthesealternativesplicing(AS)eventsfunctional?(Wangetal2014NAR).Whatcouldwelearnfromthe
34、debate?ReferencesBrennerS.1998.Refugeofspandrels.Curr. Biol.8:R669.DanielHillisW.1993.Whyphysicistslikemodelsandwhybiologistsshould.Curr. Biol.3:79-81.MerkinJ,etal.2012.EvolutionaryDynamicsofGeneandIsoformRegulationinMammalianTissues.Science338:1593-1599.StamatoyannopoulosJA.2012.Whatdoesourgenomeen
35、code?Genome Res.22:1602-1611.TheENCODEProjectConsortium.2007.Identificationandanalysisoffunctionalelementsin1%ofthehumangenomebytheENCODEpilotproject.Nature447:799-816.TheENCODEProjectConsortium.2012.AnintegratedencyclopediaofDNAelementsinthehumangenome.Nature489:57-74.ThemodENCODEConsortium,etal.20
36、10.IdentificationoffunctionalelementsandregulatorycircuitsbyDrosophila modENCODE.Science330:1787-1797.JohnSMattickandMarcelEDinger2013.Theextentoffunctionalityinthehumangenome.The HUGO Journal2013,7:2EddySR.2012.TheC-valueparadox,junkDNAandENCODE.Curr. Biol.22:R898-R899.NiuDK,JiangL.2013.CanENCODEte
37、llushowmuchjunkDNAwecarryinourgenome?Biochem. Biophys. Res. Commun.430:1340-1343.GraurD,etal.2013.OntheImmortalityofTelevisionSets:“Function”intheHumanGenomeAccordingtotheEvolution-FreeGospelofENCODE.Genome Biol. Evol.5:578-590.DoolittleWF.2013.IsjunkDNAbunk?AcritiqueofENCODE.Proc. Natl. Acad. Sci.
38、USA110:5294-5300.LAURENCEA.MORAN.2013.TheJunkDNAControversy:JohnMattickDefendsDesign.Sandwalkblog.SeanEddy:ENCODE says what?DanGraur:http:/ or functional DNA? ENCODE and the function controversy.Biol Philos 2014:1-25.ReferencesParisM,etal.MB.2013.Extensive divergence of transcription factor binding
39、in Drosophila embryos with highly conserved gene expression.PLoSGenet9:e1003748.SakabeNJ,NobregaMA:2013.Beyond the ENCODE project: using genomics and epigenomics strategies to study enhancer evolution.Philosophical Transactions of the Royal Society B: Biological Sciences 368(1632):20130022.MudgeJM,F
40、rankishA,HarrowJ:Functional transcriptomics in the post-ENCODE era.Genome Res 2013,23:1961-1973.KellisM,etal.:Defining functional DNA elements in the human genome.Proc Natl Acad Sci USA 2014,111:6131-6138.PalazzoAF,GregoryTR:The case for junk DNA.PLoS Genet 2014,10:e1004351.DoolittleWF,BrunetTDP,Lin
41、quistS,GregoryTR:Distinguishing between “function” and “effect” in genome biology.Genome Biol Evol 2014.doi:10.1093/gbe/evu098.ReferencesReferencesParisM,etal.MB.2013.Extensive divergence of transcription factor binding in Drosophila embryos with highly conserved gene expression.PLoSGenet9:e1003748.
42、MudgeJM,FrankishA,HarrowJ:Functional transcriptomics in the post-ENCODE era.Genome Res 2013,23:1961-1973.deSouzaFSJ,FranchiniLF,RubinsteinM.2013.Exaptation of Transposable Elements into Novel Cis-Regulatory Elements: Is the Evidence Always Strong? Mol. Biol. Evol.30:1239-1251.XuGX,ZhangJZ:Human codi
43、ng RNA editing is generally nonadaptive. Proc Natl Acad Sci USA 2014,111:3769-3774.WangM,et al: Alternative splicing at GYNNGY 5 splice sites: more noise, less regulation. Nucleic Acids Res 2014,42:13969-13980.Elliott,T.A.,Linquist,S.,andGregory,T.R.(2014).Conceptualandempiricalchallengesofascribingfunctionstotransposableelements.Am.Nat.184,1424.PalazzoAF,LeeES:Non-coding RNA, what is functional and what is junk? Underreview.
