细胞基因组的诱导型修饰的制作方法

本申请根据35u.s.c.§119(e)要求于2015年10月16日提交的美国临时申请序列号62/242,884的优先权，该申请内容通过引用全文纳入本文。
背景技术：
：：基因组编辑是一种遗传工程改造，其中使用工程改造的核酸酶修饰基因组(例如，导入、移除或替换dna)。通常，核酸酶在基因组中所需位置产生特异性的双链断裂(dsb)，并且利用细胞的同源性机制以通过同源重组(hr)和非同源末端连接(nhej)的自然过程修复诱导的断裂。当前，人们使用四个家族的工程改造的核酸酶：锌指核酸酶(zfn)、转录激活物样效应物核酸酶(talen)、crispr/cas系统、和经工程改造的兆核酸酶重新工程改造的寻靶核酸内切酶。技术实现要素：在一些实施方式中，本文提供了工程改造的核酸构建体(“工程改造的构建体”)，其能够用于跨物种整合以及向基因组中导入诱导型基因组编辑系统。在一些实施方式中，在不另行导入载体(质粒)物质的情况下，将所述工程改造的构建体导入基因组。在一些实施方式中，本公开的工程改造的构建体在经非同源末端连接(nhej)途径位点特异性整合到基因组后，其允许空间控制且时间控制的靶基因表达活化(参见，例如，maresca等.genomeres.2013年3月；23(3):539-46，通过引用纳入本文)。不同于当前可用的系统，其通常通过使用至少两个独立的构建体来调整细胞基因组的靶向修饰，本公开的基因组编辑系统依赖于单个构建体的活化，该构建体包括用于表达调节蛋白的遗传因子以及用于表达靶基因的遗传因子。该单个构建体的构造导致严格调控且基本上无渗漏的靶基因表达，因而提供相对于当前可用的系统更加精确且有效的基因组编辑能力。因此，本公开的一些实施方式提供了工程改造的核酸构建体，其包括(a)启动子，其可操作地连接编码调节蛋白(例如，诱导物蛋白或阻遏物蛋白)的核酸；(b)诱导型启动子，其可操作地连接编码切割核酸的酶(例如，cas9核酸酶、cpf1核酸酶或其功能性等同物)的核酸，编码使核酸产生切口的酶(例如，cas9切口酶)的核酸，或编码催化核酸交换的酶(例如，cre重组酶)的核酸，其中，诱导型启动子的活性通过调节蛋白调整；(c)至少两个绝缘子(例如，哺乳动物绝缘子)，其位于(a)的下游且(b)的上游；至少一个绝缘子，其位于(b)的下游且(a)的上游；以及(e)至少一个脱氧核糖核酸(dna)-结合结构域识别序列，其位于(b)的下游且(a)的上游。在一些实施方式中，至少两个dna-结合结构域识别序列位于(b)的下游且(a)的上游。在一些实施方式中，诱导型启动子可操作地连接编码调节基因表达的酶的核酸(例如，融合krab的cas9，融合vp64的cas9，融合p300的cas9)，或编码修饰核苷酸碱基的酶的核酸(例如，融合aid/apobec结构域并且融合尿嘧啶糖苷酶抑制剂的无核酸酶活性cas9(cas9dead)或切口酶)。在一些实施方式中，本公开还提供包括工程改造的核酸构建体的载体，包括工程改造的核酸构建体的细胞，或包括包含工程改造的核酸构建体的载体的细胞。在一些实施方式中，本文还提供了修饰细胞基因组的方法。例如，本公开的方法可以用于使感兴趣的基因缺失(敲除)，导入(敲入)感兴趣的基因，或修饰感兴趣的基因。在一些实施方式中，酶是核酸酶、切口酶或重组酶。在一些实施方式中，诱导型启动子是组织特异性诱导型启动子或发育特异性诱导型启动子。在一些实施方式中，调节蛋白是四环素控制的反式激活因子(tta)蛋白、反向四环素控制的反式激活因子(rtta)蛋白或lac阻遏物蛋白。在一些实施方式中，dna-结合结构域识别序列被具有foki核酸酶结构域的核酸酶切割。这样的“杂化核酸酶”的非限制性示例包括锌指核酸酶(zfn)、转录激活物样效应物核酸酶(talen)和杂化cas9-foki核酸酶。在一些实施方式中，dna-结合结构域识别序列被不具有foki核酸酶结构域的核酸酶切割。例如，可以使用cpf1核酸酶切割dna-结合识别序列。与本文所述这些核酸酶在结构和功能相似的其它核酸酶也可用于本方法。本文提供了转基因小鼠，在该小鼠的基因组中包括本文提供的工程改造的核酸构建体(例如，toicas构建体)。在一些实施方式中，工程改造的核酸构建体被整合到小鼠基因组的rosa26基因座。应当理解的是尽管rosa26基因座在一些实施方式中详述，但是本公开并不限于位于rosa26基因座的基因组整合。本公开的工程改造的构建体可以被整合到小鼠基因组的任何基因座中(或人基因组，当适用于诸如toic人ipsc系的toic细胞系的产生时)。一些实施方式中，小鼠具有免疫能力。在一些实施方式中，在不存在诱导型启动子诱导的情况下(例如，不存在dox给予的情况下)，无法检测到酶(例如，cas9)的表达。在一些实施方式中，本公开的工程改造的核酸包括seqidno:8的序列。本文还提供了这样的转基因小鼠(例如，具有免疫能力的小鼠)，在该小鼠的基因组中包括工程改造的核酸构建体，该核酸构建体包括seqidno:8(toicas9)的序列。在一些实施方式中，将包括seqidno:8序列的工程改造的核酸构建体整合到小鼠基因组的rosa26基因座(或其它基因座)。附图简要说明本文附图并不是按照比例绘制。为了清楚的目的，并不是每一个组件可以在每一个附图中标记出来。图1是根据本公开工程改造的核酸构建体示例的示意图。启动子p1可操作地连接编码调节蛋白(例如，诱导物蛋白或阻遏物蛋白)的核酸，其位于两个(例如，至少两个)绝缘子的上游。绝缘子位于启动子p2的上游，其可操作地连接编码这样的酶的核酸，所述酶切割核酸(例如，cas9核酸酶、cpf1核酸酶，或其功能性等同物)或使核酸产生切口(例如，cas9切口酶)，或催化核酸交换(例如，cre重组酶)。该酶位于附加绝缘子上游，附加绝缘子位于(例如，至少一个)脱氧核糖核酸(dna)-结合结构域识别序列(bdrs)上游。工程改造的构建体的大小可以是例如至少15千碱基(kb)。图2是本公开工程改造的核酸构建体的示意图，其用于插入腺相关病毒整合位点1(aavs1)基因座(人)或rosaβgeo26(rosa26)基因座(小鼠)。工程改造的构建体的大小是17575kb。图3a-3b显示了包含本公开的多四环素(doxycycline)诱导型系统的诱导型多能干细胞(ipsc)的成像，如图3所示，在不存在多四环素(-dox)(图4a)和存在多四环素(+dox)的情况下。绿色荧光蛋白(gfp)是核酸酶(例如，cas9核酸酶、cpf1核酸酶或其功能性等同物)或重组酶(例如，cre)表达活化的指示物。gfp仅在多四环素存在的情况下表达，这表明该系统没有“渗漏”(图3b)。图4显示了表示dna水平的诱导的电泳凝胶图像。使用surveyor试验切除已知人基因usp14(注意：该概念适用于例如人基因组的任何序列)。该试验显示，只有当向细胞培养基添加多四环素并且存在引导rna(grna)时，诱导型系统在ipsc中活化。分析不同的细胞库或细胞的单个克隆(c6、c25、c41)，其各自包含本公开的诱导型cas9系统。通过电泳凝胶中其它较低的条带的释放来指示切割。在所有分析的细胞中观测到相同的切割效率。图5是根据本公开工程改造的核酸构建体示例的示意图。启动子p1可操作地连接编码进行切割的酶的核酸，编码使核酸产生切口的酶的核酸，或编码催化核酸交换的酶的核酸，其中，编码所述酶的核酸侧接雌激素受体(ert2)序列的修饰形式。该酶位于(例如，至少一个)脱氧核糖核酸(dna)-结合结构域识别序列(bdrs)上游。图6是用于靶向mthi基因的工程改造的核酸构建体示例的示意图。启动子p1可操作地连接编码调节蛋白(例如，诱导物蛋白或阻遏物蛋白)的核酸，其位于(例如，至少两个)绝缘子的上游。绝缘子位于启动子p2的上游，其可操作地连接编码进行切割的酶(例如，cas9核酸酶、cpf1核酸酶，或其功能性等同物)的核酸，编码使核酸产生切口的酶(例如，cas9切口酶)的核酸，或编码催化核酸交换的酶(例如，cre重组酶)的核酸。该酶位于编码引导rna(grna)的核酸上游，该引导rna(grna)位于附加绝缘子上游，该附加绝缘子位于(例如，至少一个)脱氧核糖核酸(dna)-结合结构域识别序列(bdrs)上游。在该示例中，grna对mth1基因具有特异性，其组成型表达并且结合cas9以在cas9表达后形成活性复合物。在该示例中的构建体包括dna-结合结构域识别序列，其对应于位于人基因组aavs1基因座中的序列。将构建体整合至avvs1基因座，并且选择重组克隆。检测重组克隆的诱导后内源性mth1基因座的切割。图7是显示通过tide软件确定的切割效率的图像。该分析显示，85％的细胞在mthi基因中包含缺失(敲除)，然而在不存在诱导的情况下没有观测到缺失。来自该分析的数据显示，当与存在于测试的细胞系中的特定突变结合时，mth1不是致命的。图8显示了不同的工程改造的核酸构建体的示意图，其中之一(顶端图)在用多四环素诱导后表达gfp。图9显示了确认图8顶端图所示工程改造的构建体的种系传递以及整合到rosa26基因座的数据。图10显示了工程改造的toicas构建体示例的示意图。cas9通过t2a肽融合gfp，并且由绝缘子侧接，用于严格调控。图11是电泳凝胶图，其显示了在dox和引导rna存在的情况下dna的高效切割。图12显示了使用aav-u6grna(p53-/-/krasg12d)构建体(顶端图)的基因靶向策略。kras靶位点位于内含子中，以在hdrssodn-介导的点突变“修复”失效的情况下使得对基因可能造成的损害较小。trp53crispr按照“常规”策略(底部图)。图13显示了在dox刺激(48h)和移除(112h)细胞后，gfp曲线随时间的变化。图14是显示来自对用dox刺激且用aav-grna-kras感染纤维母细胞以产生点突变和插入缺失(indel)的surveyor试验结果的电泳凝胶图。图15是显示了surveyor核酸酶试验结果的电泳凝胶图，其证明了气管内给予aav-grna-trp53(#37、#42、#52)的小鼠肺中trp53基因的精确切割(红色星号)，验证了toicas的功能。图16显示来自sanger测序分析的数据，其证明了在不存在dox的情况下没有观测到toicas9(诱导型cas9)切割。图17是这样的图表，其显示了作为亲本群体和稳定库(stablepool)一部分的gfp表达和cas9表达。图18是这样的图表，其显示了cas9表达对急性dna损伤的作用(gh2ax焦点形成)。图19是这样的图表，其显示了cas9表达对持续性dna损伤的作用(微核形成)。图20-28显示了本公开涵盖的toicas构建体示例的质粒图。图20-28中的序列分别对应于seqidno:12-20。具体实施方式本公开提供了工程改造的核酸构建体(例如，“toicas构建体”)，其能够用于跨物种整合以及向基因组中导入诱导型基因组编辑系统，在一些实施方式中，其不需要另行导入载体(质粒)物质。本公开的工程改造的构建体促进线性形式的构建体位点特异性地整合到基因组的单个基因座中，基因组的多个不同的基因座中，或不同基因组(来自不同的物种)的基因座中。这种直接整合依赖于构建体以及靶向的基因组基因组经协调的酶促切割，以及将线性的构建体连接到基因组基因座，例如，经非同源末端连接(nhej)途径(参见，例如，maresca等.genomeres.2013年3月；23(3):539-46，通过引用纳入本文)。定制的核酸酶，如cas9、cpf1、锌指核酸酶、tale核酸酶和其功能性同等物，包含dna切割结构域以及由最优化dna结合模块组装的dna结合结构域。在细胞中，这些核酸酶在基因组中位于或接近由核酸酶dna结合结构域识别的序列(“dna-结合结构域识别序列”)处生成双链断裂，并且诱导dna损伤修复本公开的工程改造的构建体是(部分)基于这样的结果，其显示游离构建体可以连接到靶基因组基因座，如果该构建体和该基因座包含相同的dna-结合结构域识别序列。在一些实施方式中，多个dna-结合结构域识别序列位于构建体中，因此它们侧接不需要的载体(例如，细菌质粒)dna。这样的结构导致构建体整合到基因组后载体dna被移除。本公开的工程改造的构建体(例如，“toicas构建体”)的多用性在于，在一些实施方式中，它们包括，用于以时间控制和空间控制的方式诱导基因表达的遗传因子，促进构建体位点特异性地整合到多个不同基因座的dna-结合结构域识别序列的阵列(例如，两个或更多个)，并且是基本无渗漏的。因此，相对于当前可用的基因组编辑系统，本公开的工程改造的构建体提供了更加精确和高效的基因组编辑能力。toicas构建体和转基因动物在一些实施方式中，本文所述工程改造的构建体指toi、toicas或toicas9构建体，其包括编码cas9酶的核酸。应当理解的是，在toic、toicas或toicas9构建体的任一中，编码cas9酶的核酸可以被替换成其它酶，其切割核酸，使核酸产生切口，催化核酸的交换，调节基因表达，或修饰核苷酸碱基。toic构建体的非限制性示例述于图20-28，其核酸序列分别由seqidno:12-20表示。在一些实施方式中，toic构建体包括图20-28中的任一种，例如，其分别具有seqidno:12-20中任一的序列。如将在后续部分详细讨论的，本公开的toicas构建体包括可操作地连接调节蛋白的启动子(p1)(例如，cmv、cagg、cbh或ef1α或组织特异性启动子)，其处于串联的两个绝缘子(绝缘子1和绝缘子2)的上游，这两个绝缘子处于可操作地连接酶(例如，cas9)的启动子(p2)(例如，通过调节蛋白结合的顺序排列的序列)，启动子(p2)处于绝缘子(绝缘子3)的上游，该绝缘子处于dna-结合结构域识别位点(bdrs)(例如，核酸酶、重组酶或整合酶)的上游，该bdrs任选地位于可操作地连接编码选择蛋白(例如，药物选择蛋白或荧光标志物)的核酸的启动子(p3)的上游(参见，例如，图1和图10)。在一些实施方式中，toic构建体包括编码引导rna(grna)的核酸，其可以位于例如酶和绝缘子3之间，或绝缘子3和bdrs之间。本文还提供了包括toic构建体的转基因动物，如转基因小鼠模型。尽管本文所述许多实施方式指涉及基因小鼠模型，但是应当理解的是，本公开涵盖各种转基因动物模型(无脊椎动物和脊椎动物)，其包括但不限于：堡礁海绵(amphimedonqueenslandica)、阿巴海胆(arbaciapunctulata)、海兔(aplysia)、佛罗里达文昌鱼(branchiostomafloridae)、秀丽隐杆线虫、澳大利亚蝗虫(calediacaptive)、四纹豆象(callosobruchusmaculatus)、网翅蝗科雏蝗属雏(chorthippusparallelus)、玻璃海鞘(cionaintestinalis)、水蚤属(daphniaspp.)、扁蝇科、突眼蝇、果蝇、夏威夷短尾鱿鱼(euprymnascolopes)、大蜡螟(galleriamellonella)、双斑蟋、水螅、大西洋乌贼(loligopealei)、利加诺大口虫(macrostomumlignano)、梳状水母(mnemiopsisleidyi)、新星海葵(nematostellavectensis)、异体住囊虫(oikopleuradioica)、黏液海绵(oscarellacarmela)、哈维宁思明钩虾(parhyalehawaiensis)、沙蚕蠕虫(platynereisdumerilii)、短角蚱蜢属(podismaspp.)、太平洋蛔虫(pristionchuspacificus)、黄粪蝇、地中海圆头涡虫(schmidteamediterranea)、口胃动物(stomatogastric)、紫色球海胆海胆(strongylocentrotuspurpuratus)、薄荷酱蠕虫(symsagittiferaroscoffensis)、赤拟谷盗(triboliumcastaneum)，以及，丝盘虫(trichoplaxadhaerens)、正颤蚓(tubifextubifex)(无脊椎动物)；以及，铃蟾属(bombina)，卡罗来纳蜥(carolinaanole)(安乐蜥(anoliscarolinensis))、猫(猫属樟子松猫(felissylvestriscatus))、鸡(泰和鸡(gallusgallusdomesticus))-棉鼠(刚毛棉花鼠(sigmodonhispidus))、狗(家犬(canislupusfamiliaris))、金黄仓鼠(叙利亚仓鼠(mesocricetusauratus))、豚鼠(天竺鼠(caviaporcellus))、小型棕蝙蝠((小棕蝠myotislucifugus))、青鳉(青鳉(oryziaslatipes)，或日本异鳉科(japanesericefish))、鼠((musmusculus)小家鼠)、裸鼹鼠(nakedmole-rat)(裸鼹鼠(heterocephalusglaber))、弗氏假鳃鳉(nothobranchiusfurzeri)、鸽子(家鸽(columbaliviadomestica))、孔雀鱼、鼠((rattusnorvegicus)褐家鼠)、恒河猴(或猕猴)(猕猴(macacamulatta))、七鳃鳗(sealamprey)(海七鳃鳗(petromyzonmarinus))、东方鲀(takifugu)(红鳍东方鲀(takifugurubripes)，河豚)、三刺鱼(三刺鱼(gasterosteusaculeatus))、热带爪蟾(xenopustropicalis)和非洲爪蟾(xenopuslaevis)(非洲爪蛙)、斑胸草雀(珍珠鸟(taeniopygiaguttata))和斑马鱼(斑马鱼(daniorerio)，淡水鱼)。在一些实施方式中，转基因动物模型选自鱼、青蛙、鸟、小鼠、大鼠、仓鼠、猫、犬、猪、羊和猴。在一些实施方式中，转基因模型是小鼠模型。在一些实施方式中，本公开提供的工程改造的核酸包括seqidno:8的序列。本文还提供了转基因动物(例如，小鼠)，例如，具有免疫能力的动物(例如，小鼠)，在该动物(例如，小鼠)基因组中包括工程改造的核酸构建体，该工程改造的核酸构建体包括整合到例如动物(例如，小鼠)基因组rosa26基因座的seqidno:8的序列。在一些实施方式中，本公开提供的工程改造的核酸包括seqidno:12的序列。本文还提供了转基因动物(例如，小鼠)，例如，具有免疫能力的动物(例如，小鼠)，在该动物(例如，小鼠)基因组中包括工程改造的核酸构建体，该工程改造的核酸构建体包括整合到例如动物(例如，小鼠)基因组rosa26基因座的seqidno:12的序列。在一些实施方式中，本公开提供的工程改造的核酸包括seqidno:13的序列。本文还提供了转基因动物(例如，小鼠)，例如，具有免疫能力的动物(例如，小鼠)，在该动物(例如，小鼠)基因组中包括工程改造的核酸构建体，该工程改造的核酸构建体包括整合到例如动物(例如，小鼠)基因组rosa26基因座的seqidno:13的序列。在一些实施方式中，本公开提供的工程改造的核酸包括seqidno:14的序列。本文还提供了转基因动物(例如，小鼠)，例如，具有免疫能力的动物(例如，小鼠)，在该动物(例如，小鼠)基因组中包括工程改造的核酸构建体，该工程改造的核酸构建体包括整合到例如动物(例如，小鼠)基因组rosa26基因座的seqidno:14的序列。在一些实施方式中，本公开提供的工程改造的核酸包括seqidno:15的序列。本文还提供了转基因动物(例如，小鼠)，例如，具有免疫能力的动物(例如，小鼠)，在该动物(例如，小鼠)基因组中包括工程改造的核酸构建体，该工程改造的核酸构建体包括整合到例如动物(例如，小鼠)基因组rosa26基因座的seqidno:15的序列。在一些实施方式中，本公开提供的工程改造的核酸包括seqidno:16的序列。本文还提供了转基因动物(例如，小鼠)，例如，具有免疫能力的动物(例如，小鼠)，在该动物(例如，小鼠)基因组中包括工程改造的核酸构建体，该工程改造的核酸构建体包括整合到例如动物(例如，小鼠)基因组rosa26基因座的seqidno:16的序列。在一些实施方式中，本公开提供的工程改造的核酸包括seqidno:17的序列。本文还提供了转基因动物(例如，小鼠)，例如，具有免疫能力的动物(例如，小鼠)，在该动物(例如，小鼠)基因组中包括工程改造的核酸构建体，该工程改造的核酸构建体包括整合到例如动物(例如，小鼠)基因组rosa26基因座的seqidno:17的序列。在一些实施方式中，本公开提供的工程改造的核酸包括seqidno:18的序列。本文还提供了转基因动物(例如，小鼠)，例如，具有免疫能力的动物(例如，小鼠)，在该动物(例如，小鼠)基因组中包括工程改造的核酸构建体，该工程改造的核酸构建体包括整合到例如动物(例如，小鼠)基因组rosa26基因座的seqidno:18的序列。在一些实施方式中，本公开提供的工程改造的核酸包括seqidno:19的序列。本文还提供了转基因动物(例如，小鼠)，例如，具有免疫能力的动物(例如，小鼠)，在该动物(例如，小鼠)基因组中包括工程改造的核酸构建体，该工程改造的核酸构建体包括整合到例如动物(例如，小鼠)基因组rosa26基因座的seqidno:19的序列。在一些实施方式中，本公开提供的工程改造的核酸包括seqidno:20的序列。本文还提供了转基因动物(例如，小鼠)，例如，具有免疫能力的动物(例如，小鼠)，在该动物(例如，小鼠)基因组中包括工程改造的核酸构建体，该工程改造的核酸构建体包括整合到例如动物(例如，小鼠)基因组rosa26基因座的seqidno:29的序列。在动物模型中诱导酶(例如，cas9)表达可以通过给予多四环素或其它适当的诱导剂(取决于用于toic构建体的特定诱导系统)实现。在一些实施方式中，诱导剂(直接或间接激活toic构建体的诱导型启动子的物质)经由注射(例如，尾静脉注射)或口服灌胃给予动物。本文提供的转基因动物，通过同源重组或通过非同源末端连接，可以用于产生敲除或敲减等位基因，或用于过表达基因或将基因敲入特定的基因座。例如，这可以通过向动物给予模板dna(例如，包含感兴趣的修饰)以及核酸实现，所述核酸编码grna靶向的基因座和/或感兴趣的基因。感兴趣的基因的示例包括但不限于，致癌基因，如pik3ca、kras、braf、nras，和肿瘤抑制基因，如pten、p53、rb、apc、p16/p19、brca1、brca2、lkb1。通过将toic转基因小鼠与模板dna以及靶向基因和靶向一种或多种感兴趣的基因的grna组合，可以产生各种疾病模型。这样的模型包括但不限于，肺癌(例如，kras、lkb、p53和/或rb；例如，靶向mapk，新陈代谢)，胰腺癌(例如，kras、p53、p16/p19和/或pdx1；例如，靶向mapk)、前列腺癌(例如，pten、brca1、brca2和/或p53；例如，靶向pi3k、ar、aso、ddr)，乳腺癌(例如，pik2ca、p53和/或pten；例如，靶向pi3k、serd)，卵巢癌(例如，brca1、brca2、p53和/或rb；例如，靶向erk、mek、kras、aso、modp53)，黑素瘤(例如，braf和/或nras；例如，靶向mapk)以及结直肠癌(例如，pik3ca、kras和/或apc；例如，靶向mapk、pi3k)。例如，编码gran以及相关联的模板dna的核酸可以使用病毒(例如，腺相关病毒或腺病毒)经气管内、肾内或腹膜内转导给予动物。在一些实施方式中，将编码grna的核酸整合到转基因动物模型的基因组中。例如，组织特异性grna或组成型表达的grna可以被整合到转基因动物模型的基因组中。本文还提供了衍生自(获得自)本公开的转基因动物的类器官(organoid)(体外生长的三维器官芽(organ-bud))。因此，类器官可以包括任何toic构建体。例如，优选地，实例中描述的那些toic动物(例如，小鼠)可以具有免疫能力(能够在暴露于抗原后产生正常的免疫反应)。此外，本文开包括的是免疫功能不全的(具有弱化的免疫系统)toic动物。用于基因组整合的酶本公开的工程改造的构建体(例如，“tpicas构建体”)用于促进线性形式的构建体直接地、位点特异性地连接到单个基因组或多个不同的基因组的单个基因座或多个不同的基因座。这样的直接连接通过非同源的末端连接(nhej)途径发生(参见，例如maresca等genomeres.2013mar；23(3):539-46，通过引用纳入本文)。位点特异性连接依赖于杂化核酸酶的存在，所述杂化核酸酶包含dna结合结构域和dna切割结构域(通常是，foki结构域)，以及如下核酸的存在，所述核酸包含至少一个dna结合结构域识别序列。“dna结合结构域识别序列”是这样的核苷酸序列，核酸酶dna结合结构域与之结合，并且核酸酶dna切割结构域将其切割。工程改造的构建体包含至少一个dna结合结构域识别序列，其被杂化核酸酶识别和切割。对于工程改造的构建体的切割产生线性形式，然后可以将其以位点特异性的方式“连接”进入基因组。本公开的工程改造的构建体(例如，“toicas构建体”)，在一些实施方式中，包括单个dna-结合识别序列(bdrs)或dna-结合结构域识别序列的阵列(例如，两个或更多个)，其促进核酸的位点特异性基因组整合。优选地，本公开的工程改造的构建体可以用于促进线性形式的构建体位点特异性地连接到若干不同基因组的多个不同基因座，其能够用于相同构建体的跨物种整合。在一些实施方式中，工程改造的构建体的dna-结合识别序列对应于位于rosa26基因座中的序列，这样核酸可以被整合到小鼠基因组中。在一些实施方式中，工程改造的构建体的dna-结合识别序列对应于位于aavs1基因座中的序列，这样核酸可以被整合到人基因组中。位于其它基因组基因座中的其它dna-结合结构域识别序列涵盖在本公开的范围内。用于使工程改造的构建体线性化的杂化核酸酶的示例包括但不限于，锌指核酸酶(zfn)、tale核酸酶(talens)、dcas9-foki融合蛋白(融合至foki的催化失活的cas9)、cas9、融合至foki的cas9切口酶、以及经进化以生成突出端的cas9变体。在一些实施方式中，dna-结合结构域识别序列是zfndna结合结构域识别序列，其通过一个或多个锌指结合。个体zfn的dna-结合结构域可以包含3-6个单独的锌指重复，并且可以各自识别9-18个碱基对。如果锌指结构域对其意图的靶位置具有特异性，那么甚至识别总共18个碱基对的3-指zfn对亦可以靶向哺乳动物基因组中的单个基因座。在一些实施方式中，dna-结合结构域识别序列是talendna结合结构域识别序列，其通过一个或多个tal效应物单元结合。tal效应物是由黄单胞菌属(xanthomonas)细菌分泌的蛋白质。dna结合结构域通常包含重复的高度保守的33-34氨基酸序列，除了第12和第13个氨基酸。这两个位置是高度可变的(复可变双残基，rvd)，并且显示出与特异性核苷酸识别的强相关性(boch等science326(5959):1509–12,2009；moscou等science326(5959):1501,2009，其各自通过应用纳入本文)。在一些实施方式中，通过对包含适当rvd的重复区段的组合进行选择来工程改造特异性dna-结合结构域(boch等naturebiotechnology29(2):135–6,2011)。在一些实施方式中，dna-结合结构域识别序列是与两个共表达的引导rna互补(例如，100％互补性)的序列。在一些实施方式中，dna-结合结构域识别序列是与两个共表达的引导rna至少80％、至少85％、至少90％、至少95％或至少98％互补的序列。在这样的实施方式中，融合foki核酸酶的催化失活的cas9(dcas9)可以被用于在工程改造的核酸中生成双链断裂。应当理解的是，本公开的工程改造的构建体可以包括编码核酸酶(例如，cas9核酸酶、cpf1核酸酶或其功能性等同物)的核酸，并且包含不一定由该工程改造的核酸的核酸酶识别的dna-结合核酸酶识别序列。例如，用于基因组编辑的工程改造的构建体可以编码cas9(例如，野生型或在其他情况下具有催化活性的cas9，出于编辑细胞基因组的目的)或cpf1核酸酶，并且还可以包含dna-结合核酸酶识别序列，其对锌指核酸酶或融合至foki核酸酶的催化失活的cas9(dcas)具有特异性。如果情况是这样的，那么可能需要向细胞导入编码特异性地识别并切割dna-结合核酸酶识别的融合foki的dcas9或锌指核酸酶的另一核酸。用于基因组编辑的酶本文同样描述了编码这样酶的核酸，所述酶切割核酸，使核酸产生切口，或催化核酸的交换。切割核酸的酶被称为核酸酶。使核酸产生切口的酶被称为切口酶。催化核酸交换的酶被称为重组酶。“切割”指这样的过程，其中核酸酶切开(水解)双链核酸的核酸主链(例如，糖-磷酸主链)。因此，该核酸酶产生两个切口：一个位于双链核酸一条链的核苷酸亚基之间的主链中，另一个位于双链核酸另一条链的核苷酸亚基之间的主链中。单个核酸分子的切割通常导致产生两个分开的核酸分子。与之相反，“使…产生切口”指这样的过程，其中切口酶仅切开双链核酸的一条链。“催化核酸的交换”指这样的过程，其中遗传物质经断裂，并且与其它遗传物质连接，并且包括基因重组。重组是将遗传物质通过例如染色体交叉或通过连接dna区段来对遗传物质进行重组或重排。在一些实施方式中，工程改造的核酸编码核酸酶。本公开的核酸酶可以经工程改造以切开预定的核苷酸序列，以允许例如遗传信息的高效工程改造以及各种不同核酸修饰的产生。工程改造的核酸酶的示例包括但不限于，dna-引导的内切酶，rna-引导的内切酶(rgen)，诸如cas9或cpf1，锌指核酸酶(zfn)(kim等procnatlacadsciusa93(3):1156–60,1996；bitinaite等procnatlacadsciusa95(18):10570–5,1998；以及cathomen等mol.ther.16(7):1200–7,2008)，tal效应物核酸酶(talen，转录激活物样效应物核酸内切酶)(boch等science326(5959):1509–12,2009；christian等.genetics186(2):757–61,2010)；以及miller等naturebiotechnology29(2):143–8,2011)(表1)，以及其功能性等同物。核酸酶通常包括dna结合结构域，其识别并结合特定dna序列，以及dna切割结构域，其在位于dna结合结构域或接近dna结合结构域(例如，在10个核苷酸内)的位置切割dna。例如，zfn包括锌指结构域，其结合dna，以及foki结构域，其切割dna(kim等natlacadsciusa93(3):1156–60,1996)。相似地，talen包括tal效应物单元，其结合a，以及foki结构域，其切割dna。rna-引导的cas9核酸酶切割dna，但是为了实现这样的切割，其必需首先由引导rna引导至靶切割位点，其与dna切割位点互补并结合，如本文其它地方所述。表1.工程改造的核酸酶系统cas9(crispr相关蛋白9)是rna-引导的dna核酸酶，其与诸如酿脓链球菌(streptococcuspyogenes)的细菌中的crispr(成簇且规律间隔的回文重复序列(clusteredregularlyinterspersedpalindromicrepeats))获得性免疫系统相关联。用于编辑、调节和靶向基因组的crispr系统可以包括至少两个不同的组件：(1)引导rna(grna)以及(2)cas9。grna是这样的单个嵌合转录本，其将内源性细菌crispr靶向rna(crrna)的靶向特异性与反式激活crrna(tracrrna)的折叠性质相结合。通常，用于基因组编辑的grna转录自细胞内的质粒或基因组基因座。grna转录本与cas9形成复合物，并且然后，例如，作为crrna序列与其基因组dna中互补靶序列之间碱基配对的结果，grna/cas9复合物被招募至靶序列。在典型的合成crispr/cas9基因组编辑系统中，感兴趣的基因序列(基因组靶序列)通过使用与感兴趣的序列互补的grna进行修饰，其将grna/cas9复合物引导至靶标(sanderjd等,2014naturebiotechnology32,247-355，通过引用纳入本文)。cas9内切核酸酶切开前间区序列邻近基序(pam)的基因组靶dna上游，产生双链断裂。双链断裂的修复常常导致双链断裂位点处的插入或缺失。crispr/cas9系统常常用于编辑细胞的基因组，各迭代需要设计和导入对感兴趣实施方式靶序列具有特异性的新的grna序列。在一些实施方式中，本公开的工程改造的构建体包括启动子(例如，诱导型启动子)，其可操作地连接编码引导rna的核酸(例如，位于编码cas9核酸酶的核酸下游)，其将cas9核酸酶引导至基因组靶(修饰)位点。与cas9功能性相似的酶可以根据本公开使用。cpf1是2型crispr-cas系统的单个rna-引导的内切核酸酶(zetsche等,2015,cell163:1-13，通过引用纳入本文)。cpf1与cas9类似，是一种两组件rna可编程的dna核酸酶。靶向的dna被切割成位于5’t富集的前间区序列邻近基序(pam)远端的5nt交错切口。两个cpf1同源物在人细胞中展现出强健的核酸酶活性，任何一种都可以在本文使用。与cpf1功能性相似的酶可以根据本公开使用。在其他实施方式中，将编码引导rna的核酸导入这样的宿主细胞中，该宿主细胞经修饰以在细胞基因组中表达(例如，稳定表达)本公开的工程改造的构建体(例如，编码cas9核酸酶的构建体)，并且将其用于替代在宿主细胞基因组的修饰期间导入宿主细胞的任何不需要的dna。例如，细胞，如干细胞(例如，多能干细胞)，可以经修饰以在细胞基因组中表达(例如，稳定表达)这样的工程改造的构建体，其包括(a)可操作地连接编码调节蛋白的核酸的启动子，(b)诱导型启动子，其可操作地连接编码cas9或cpf1的核酸，其中诱导型启动子的活性通过调节蛋白来调节，(c)至少两个绝缘子，其位于(a)的下游而在(b)的上游，和(d)至少一个绝缘子，其位于(b)的下游。对该宿主细胞的修饰可以使得在构建体的位点特异性整合后，载体(例如，细菌质粒)dna导入细胞的基因组，以及其它不需要的dna(例如，编码选择标志物的序列)的导入。该载体dna和任何其它不需要的dna可以被移除，例如，通过导入(a)编码由dna-结合结构域识别序列侧接的引导rna的工程改造的核酸，(b)编码杂交核酸酶的工程改造的核酸，所述杂交核酸酶识别并切割侧接引导rna的dna-结合结构域识别序列以及侧接位于细胞基因组中不需要的序列的dna-结合结构域识别序列，和(c)正交cas9(orthogonalcas9)(cas9来自与获得宿主细胞cas9的物种不同的物种)。例如，宿主细胞可以经工程改造以表达获自酿脓链球菌(streptococcuspyogenes)的cas9，以及获得自金黄色葡萄球菌(streptococcusaureus)、嗜热链球菌(streptococcusthermophilis)或脑膜炎奈瑟菌(neisseirameningitis)的正交cas9。其它正交cas9核酸酶包括在本公开内。杂化核酸酶、引导rna和正交cas9可以包括在相同的构建体(例如，载体)或各自位于单独的构建体上。引导rna替代载体dna或宿主细胞基因组中任何不需要的dna。在一些实施方式中，正交cas9用于用感兴趣的引导rna以及任选的选择标志物替代整合在宿主细胞基因组中的细菌质粒序列。在一些实施方式中，宿主细胞是多能干细胞(例如，人多能干细胞，如人诱导型多能干细胞)或胚胎干细胞(例如，小鼠胚胎干细胞，用于小鼠模型系统的产生)。在这些细胞类型中，细菌质粒序列具有使感兴趣的基因座失活的可能性，因此优选移除细菌质粒序列。在一些实施方式中，正交cas9或cpf1以及引导rna被用于在多能状态后，在分化的状态中使感兴趣的基因的表达缺失(敲除)、降低其表达(敲减)或增加其表达(过表达)。在一些实施方式中，载体dna或宿主细胞基因组中任何不需要的dna通过使用位点特异性重组酶(例如，cre、flp、dre、vike或其组合)移除。将工程改造的核酸构建体导入细胞基因组中并移除载体dna或不需要的dna的方法可以单一步骤(例如，所有的构建体同时递送至宿主细胞)或以多个步骤(例如，各构建体顺序地递送至宿主细胞)进行。本公开还包括使用本文所述任何核酸酶的催化失活形式。例如，在一些实施方式中，可以使用如本文所提供的cas9的催化失活形式(dcas9)或cpf1的催化失活形式，其可以通过干扰转录来敲减基因表达。在一些实施方式中，dcas9(或cpf1或其他核酸酶的催化失活形式)融合阻遏物肽(一种抑制转录的肽，例如，cas9-krab(urrutia2003genomebiol.4(10):231))。在一些实施方式中，dcas9(或cpf1或其他核酸酶的催化失活形式)融合激活物肽(一种激活或增强转录的肽，例如，cas9-vp64(beerli等1998procnatlacadsciusa.95(25):14628-33))。在一些实施方式中，dcas9(或cpf1或其他核酸酶的催化失活形式)融合表观基因组调节物(epigenomicregulator)(例如，cas9-dnmt或cas9-p500)。在一些实施方式中，dcas9(或cpf1或其他核酸酶的催化失活形式)融合foki核酸酶，以在与两个共表达的grna同源的序列处生成双链断裂。在一些实施方式中，表达dcas9(或其它催化失活的核酸酶)的工程改造的核酸被用于对基因组中特定序列进行成像(参见，例如.，chenb.,等(2013)cell155(7):1479-1491，通过引用纳入本文)。在一些实施方式中，融合阻遏物肽(例如，cas9-krab)或激活物肽(例如，cas9-vp64)的野生型或未修饰的cas9或cpf1(或其它催化失活的核酸酶)与短grna联用以调节基因表达(参见，例如，kianis,等(2015)"工程改造cas9grna用于基因组编辑、活化和抑制(cas9grnaengineeringforgenomeediting,activationandrepression)."naturemethods(2015)[出版前电子公开]，通过引用将其纳入本文)。在一些实施方式中，工程改造的核酸编码切口酶。切口酶是这样的酶，其在双链核酸中产生单链断裂。在一些实施方式中，切口酶是cas9切口酶(cong等2013science339(6121):819-823；shen等2014naturemethods11,399–402)。cas9切口酶根据共表达的grna定义的靶序列上在特定位置产生单链dna断裂(切口)，而不是通过野生型酶产生双链dna断裂(切割)。优选地，使用完整链作为模板，通过同源定向修复(hdr)在细胞中修复切口。hdr具有高保真度并且几乎不导致错误。两个相邻、相对链切口可以导致双链断裂(dsb)，并且引发易错非同源末端连接(nhej)修复；然而，在存在修复模板的情况下，可以通过hdr修复双切口。产生双切口通常降低不需要的脱靶作用。在一些实施方式中，工程改造的核酸编码重组酶。重组酶通常来自于细菌或真菌，其指向性地催化短(例如，30-40核苷酸)靶序列之间的敏感性dna交换反应，所述短靶序列对各重组酶具有特异性。这些反应实现四个基本功能——缺失/插入、倒位、易位和盒交换，并且其可以单独或组合使用。如本文所提供使用的重组酶的示例包括但不限于，cre重组酶、flp重组酶、hin重组酶(dhar等2004cell119(1):33–45；sanders等2004molbiol340(4):753–66；kamtekar等2006procnatlacadsciusa103(28):10642–7；li等2005science309(5738):1210–5)以及tre重组酶(sarkar等2007science316(5833):1912–15)。cre是衍生自p1噬菌体的酪氨酸重组酶。该酶使用拓扑异构酶i样机制进行位点特异性重组。该酶(例如，38kda)是位点特异性重组酶整合酶家族的成员，并且催化位于两个dna识别位点(loxp位点)之间的位点特异性重组。这一约34碱基对(bp)的loxp识别位点包含两个约13bp的回文序列，其侧接约8bp的间隔物区域。cre介导的重组在loxp位点的产物依赖于loxp位点的位置和相对方向。作为cre介导的重组的结果，均包含loxp位点的两个单独的dna物质可以进行融合。位于两个loxp位点之间的dna序列被称为“floxed”。cre介导的重组的产物依赖于loxp位点的取向。位于以相同方向取向的两个loxp位点的dna被切成dna圆环，而位于反相取向的两个loxp位点之间的间插dna被反转。cre重组酶的功能不需要其辅因子(如atp)或辅助蛋白。flp-frt重组是与cre-lox重组类似的定点重组技术。flp-frt重组包括通过衍生自面包酵母酿酒酵母2μm质粒的重组酶(flp)重组位于短翻转酶识别靶标(frt)位点之间的序列(zhu等1995journalofbiologicalchemistry270(39):23044–54；schlake等1994biochemistry33(43):12746–12751；以及turan等2010j.mol.biol.402(1):52–69)。在一些实施方式中，工程改造的核酸编码碱基编辑酶。碱基编辑酶是这样的融合体，其融合dna结合蛋白(例如，cas9、tale、zf)至在dna结合位点附近诱导碱基交换(例如，c交换成t)的特定效应物(参见，例如，komor,a.c.,等nature,2016；和nishida,k.,等science353:6305,2016)。基因表达的控制本公开的工程改造的构建体(例如，“toicas构建体”)允许基因组编辑的空间控制，基因组编辑的时间控制，以及空间和时间控制的组合。空间控制通常指在器官的特定组织中转录的激活。时间控制通常指在发育期间的特定时间激活转录。空间控制和/或时间控制可能是由例如以下所导致：来自使用细胞特异性或组织特异性启动子驱动核酸表达，来自对将效应物物质递送至细胞或器官以诱导或抑制核酸表达的时间的控制，或者来自其组合。在一些实施方式中，细胞特异性或组织特异性启动子驱动核酸的表达，以使其仅在细胞特化或细胞分化的特定阶段期间可操作地连接。在一些实施方式中，仅在细胞特化或细胞分化的特定阶段期间，向细胞或组织递送效应物物质(例如，dox)。此外，本文公开的工程改造的构建体(例如，“toicas构建体”)基本上降低渗漏基因表达。如果转录在不存在调节蛋白的情况下或以非受控的方式开始，基因表达系统可能会被认为是“渗漏的”。如本文其它地方所述，调节蛋白结合启动子以调节转录活性。如果表达以不存在这样的调节蛋白的情况出现，基因表达被认为是“渗漏的”，所述调节蛋白旨在结合控制基因表达的启动子。如果在不存在调节蛋白的基因表达的水平是存在条件蛋白的基因表达的水平的小于15％(例如，小于10％，小于5％，小于2％，小于1％，小于0.5％)，基因表达被认为是“基本上无渗透的”。如图1和2所述，例如，至少一个绝缘子(例如，一个、两个或更多个绝缘子)位于编码调节蛋白的核酸以及控制酶(例如，核酸酶或重组蛋白酶)表达的下游启动子(p2)(调节蛋白与之结合)之间。“绝缘子”是阻断增强子和启动子之间相互作用的核苷酸序列。应当理解的是，在一些实施方式中，绝缘子可能位于驱动基因表达的任意两个启动子之间，从而防止在上游启动子转录激活时，下游启动子的转录激活。因此，在一些实施方式中，工程改造的构建体(例如，“toicas构建体”)包括至少一个绝缘子。在一些实施方式中，工程改造的构建体包括至少2个、至少3个或至少4个绝缘子。在一些实施方式中，绝缘子包括哺乳动物绝缘子。例如，绝缘子可能包括(至少一个)人绝缘子，如5’hs5、dmd/icr、bead-1、apob(-57kb)、apob(+43kb)或dm1位点1或dm1位点2(表2)。在一些实施方式中，绝缘子可能包括(至少一个)小家鼠(musmusculus)绝缘子，如bead-1、hs2-6或dmr/icr。参见，例如，bell等,curropingenetdev.1999年4月；9(2):191-8；science.2001年1月19日；291(5503):447-50；west等,genesdev.2002年2月1日；16(3):271-88；以及ziebarth等,nucleicacidsresearch.2013；41(d1):d188-d194，其各自内容通过引用纳入本文。在一些实施方式中，绝缘子包括(至少一个)非哺乳动物绝缘子。例如，绝缘子可能包括(至少一个)黑腹果蝇(drosophilamelanogaster)绝缘子，如scs/scs’、gypsy、fab-7、fab-8、faswb或eve启动子。在一些实施方式中，绝缘体可能包括酿酒酵(scharomycescerevisiae)绝缘子，包括hmrtrnathr,chaluas、uasrpg或star。在一些实施方式中，绝缘子可能包括(至少一个)原鸡(gallusgallus)绝缘子，如lys5’a、hs4或3’hs。在一些实施方式中，绝缘子包括sns、普通海胆(parancentrotuslividus)绝缘子、ur1、马粪海胆(hemicentrotuspulcherrimus)绝缘子、或ro、非洲爪蟾(xenopuslaevis)绝缘子。表2“下游”和“上游”指核酸(例如，dna或rna)的相对位置。dna或rna的各条链具有5'端和3'端，据此命名脱氧核糖(或核糖)链上的碳位置。。按照惯例，上游和下游相对5'-3'方向处发生rna转录。上游朝向rna分子的5'端，下游朝向3'端。当考虑双链dna时，上游朝向感兴趣基因编码链的5'端，下游朝向3'端。诱导型基因编辑系统诱导型基因编辑系统能够用于时间控制的、空间控制的、或时间控制且空间控制的基因修饰。一些实施方式利用tet-关闭(tet-off)或tet-开启(tet-on)诱导型系统。其它实施方式利用他莫昔芬诱导型系统。而其它一些实施方式利用异丙基β-d-1-硫代半乳糖苷(iptg)诱导型系统。四环素诱导型系统tet技术包括两个互补的控制电路，最初被描述为tta依赖型(gossen等procnatlacadsciusa.1992年6月15日；89(12):5547-51)以及rtta依赖型(gossen等science.1995年6月23日；268(5218):1766-9)表达系统。它们现在常被称为tet-关闭系统(tta依赖型)和tet-开启系统(rtta依赖型)。在各系统中，重组四环素控制的转录因子(tta或rtta)与tta/rtta响应性启动子ptet相互作用以驱动感兴趣基因的表达。表达受到效应物物质四环素(tc)或其衍生物中的一种的调控。tet-开启系统响应多四环素(dox)。四环素在四环素控制的反式激活因子(tta)与反式四环素控制的反式激活因子(rtta)的转录因子的dna结合水平作用。rtta需要四环素配体用于dna结合和转录。与之相反，tta和dna之间的相互作用被四环素阻止。因此，这两种形式的tet系统差异性地响应四环素，并且可以互补的方式使用。tta是这样的杂化转录因子，其来自于原核tet阻遏物tetr与真核转录反式激活结构域(例如，hsvvp16)的融合。tetr部分提供序列特异性dna结合，对四环素的敏感性，以及与tta融合蛋白的二聚化。相应地，tetr和tta对四环素的响应是相似的：抗生素的结合低于其对其常见关联结合位点tet操纵子的亲和力。rtta与tta在tetr中的几个点突变处不同。然而，这导致该转录因子四环素响应性的完全反转。rtta需要四环素用于结合teto。特定的四环素衍生物，诸如多四环素(dox)或无水四环素(atc)可以用于研究rtta表型。ptet是响应tta和rtta两者的合成启动子。其包含融合至多聚化teto序列的最小rna聚合酶ii启动子(在不存在其它转录结合位点的情况下转录沉默)。这样的排布使得ptet的活性依赖于tta或rtta的结合。设计这样的合成tta/rtta响应性启动子就以下而言是灵活的：最小启动子的起点以及操纵子的准确布置。例如，由融合至7个teto序列阵列的cmv最小启动子组成的原始形式被称为ptet-1。其被作为ptre载体系列的部分销售(用于四环素响应性元件)，一定程度上符合主流真核命名法。在一些实施方式中，多四环素(四环素衍生物)是用于tet-开启或tet-关闭系统的效应物物质。多四环素以高亲和力结合tta以及rtta，并且因此在例如tta的情况中，其在低至1-2ng/ml的浓度时在tet-关闭系统中完全有效。在tet-开启系统中，在例如rtta2-syn1的情况下，低至80ng/ml的浓度是有效的。在本公开的一些实施方式中，工程改造的构建体包括可操作地连接编码rtta的核酸(例如，基因)的启动子(例如，cag)，其位于ptet启动子的上游，所述ptet启动子可操作地连接编码产生切割的酶(例如，cas9核酸酶)的核酸，编码使核酸产生切口的酶(例如，cas9切口酶)的核酸，或编码催化核酸交换的酶(例如，cre重组酶)的核酸。通常，至少一个(例如，一个、两个或更多个)绝缘子位于编码rtta的核酸和ptet启动子之间，这样在不存在合适效应物物质(如多四环素)的情况下，激活编码rtta的核酸的转录并不会另激活该酶的转录。在本公开的一些实施方式中，工程改造的构建体包括可操作地连接编码rta的核酸(例如，基因)的启动子(例如，cag)，其位于ptet启动子的上游，所述ptet启动子可操作地连接编码产生切割的酶(例如，cas9核酸酶)的核酸，编码使核酸产生切口的酶(例如，cas9切口酶)的核酸，或编码催化核酸交换的酶(例如，cre重组酶)的核酸。通常，至少一个(例如，一个、两个或更多个)绝缘子位于编码rtta的核酸和ptet启动子之间，这样在不存在合适效应物物质(如多四环素)的情况下，激活编码tta的核酸的转录并不会另激活该酶的转录。iptg诱导型系统本公开的一些实施方式利用依赖于乳糖(lac)阻遏物蛋白和lac操纵子存在的系统。lac阻遏物是结合lac操纵子的dna-结合蛋白，并且抑制可操作地连接lac操纵子的核酸的表达。异乳糖或异乳糖模拟物(如异丙基β-d-1-硫代半乳糖苷(iptg))的存在抑制lac阻遏物蛋白的dna结合能力。通过lac阻遏物造成的dna结合的缺失被用于lac操纵子的转录活化以及与该操纵子连接的任何核酸的表达。lac操纵子包含三个结构基因，以及启动子，终止子，调控子，以及操纵子。三个结构基因是lacz、lacy和laca。lacz编码β-半乳糖苷酶(lacz)，其是将二糖乳糖切割成葡萄糖和半乳糖的胞内酶；lacy编码乳糖透性酶(lacy)，其是以相同方向的质子梯度将β-半乳糖苷泵入细胞的跨膜同向转移物；并且laca编码半乳糖苷o-乙酰转移酶(laca)，其是将乙酰基团由乙酰辅酶a转移至β-半乳糖苷的酶。在本公开的一些实施方式中，工程改造的构建体包括可操作地连接编码lac阻遏物蛋白的核酸(例如，基因)的启动子(例如，cag)，其位于lac操纵子的上游，所述lac操纵子可操作地连接编码产生切割的酶(例如，cas9核酸酶)的核酸，编码使核酸产生切口的酶(例如，cas9切口酶)的核酸，或编码催化核酸交换的酶(例如，cre重组酶)的核酸。通常，至少一个(例如，一个、两个或更多个)绝缘子位于编码lac阻遏物蛋白的核酸和lac操纵子之间，这样在不存在合适效应物物质(如iptg)的情况下，激活编码lac阻遏物蛋白的核酸的转录并不会另激活该酶的转录。他莫昔芬诱导型系统本文还提供了工程改造的构建体，其包括(a)可操作地连接编码这样cas9核酸酶的核酸的启动子，所述cas9核酸酶并不包括核定位信号，其中，编码该酶的核酸侧接雌激素受体(ert2)序列，以及(b)脱氧核糖核酸(dna)-结合识别序列。核定位信号或序列(nls)是这样的氨基酸序列，其“标记”通过核转运输入到细胞核的蛋白质。通常，该信号包含暴露于蛋白质表面的带正电荷的赖氨酸残基或精氨酸残基的一个或多个短序列。不同核定位的蛋白质可能共享相同的nls。nls具有与核输出信号相反的作用，其以将蛋白质输出核作为目标。不包括核定位信号的cas9核酸酶是修饰的cas9蛋白质，其没有通过核转运输入到细胞核中。cas9活性可以通过将核酸酶融合至雌激素受体(ert2)经修饰的片段来进行调节。在一些实施方式中，ert2是er受体的修饰形式，其对他莫昔芬结合相对于内源性雌性激素具有高选择性。cas9与经修饰的片段的融合被隔离在核的外部，不能指导重组。在存在雌激素受体拮抗剂(例如，他莫昔芬)的情况下，可以将cas9重新定位到核中，其在那里能够发挥功能。在一些实施方式中，工程改造的核酸侧接ert2片段(包括位于该蛋白质各末端的ert2片段(ert2cas9ert2；seqidno:7))。如果ert2cas9ert2表达由阻止特异性启动子驱动(控制)，感兴趣的基因可以在其发育的任何时间在感兴趣的组织中修饰。一旦记录该信息，可以在动物的整个生命周期监测该细胞。在一些实施方式中，工程改造的构建体包括编码不包括核定位信号的cas9核酸酶的核酸，其中，编码该酶的核酸侧接雌激素受体(ert2)序列(例如，seqidno:7)。核酸“工程改造的构建体”指用于导入细胞的人工构建的核酸区段(线性或环状)。工程改造的构建体(例如，“toicas构建体”)通常包含至少一个启动子，其可操作地连接编码感兴趣的蛋白质的核酸。本公开的实施方式提供了工程改造的核酸分子，其编码诱导型核酸表达系统的元件。“工程改造的核酸”是不存在于自然的核酸(例如，共价连接在一起的至少两个核苷酸，并且在一些实施方式中，包含磷酸二酯键，称之为磷酸二酯“主链”)。工程改造的核酸包括重组核酸和合成核酸。“重组核酸”是通过连接核酸(例如，分离的核酸、合成的核酸、或其组合)构建的分子，并且在一些实施方式中，其可以在活细胞中复制。“合成的核酸”是放大的或以化学方式或其它方法合成的分子。合成的核酸包括经化学修饰或以其他方式修饰，但是可以与天然产生的核酸分子碱基配对(也称为“结合”，例如，瞬时地或稳定的)的那些核酸。重组的和合成的核酸还包括产生自复制上述两种情况之一的那些分子。尽管工程改造的核酸作为一个整体不是天然产生的，但是其可以包括野生型核苷酸序列。在一些实施方式中，工程改造的核酸包括获得自不同生物(例如，获得自不同物种)的核苷酸序列。例如，在一些实施方式中，工程改造的核酸包括小鼠核苷酸序列、细菌核苷酸序列、人核苷酸序列、病毒核苷酸序列、或上述序列中任意两种或更多种的组合。在一些实施方式中，本公开的工程改造的核酸可以包括不同于磷酸二酯主链的主链。例如，在一些实施方式中，工程改造的核酸可以包括磷酰胺、硫代磷酸酯、二硫代磷酸酯、o-甲基亚磷酰胺连接、肽核酸或上述连接中任意两种或更多种的组合。工程改造的核酸可以是单链或双链的，如本文具体所示，或者工程改造的核酸可以同时含有双链或单链序列的部分。在一些实施方式中，工程改造的核酸包含三链序列的部分。工程改造的核酸可以包括dna(例如，基因组dna、cdna、或基因组dna和cdna的组合)，rna或杂化分子，例如，其中核酸包含脱氧核糖核苷酸和核糖核苷酸(例如，人工或天然的)的任意组合，以及两种或更多种碱基的任意组合，包括尿嘧啶、腺嘌呤、胸腺嘧啶、胞嘧啶、鸟嘌呤、肌苷、黄嘌呤、次黄嘌呤、异胞嘧啶、异鸟嘌呤等。本公开的工程改造的核酸可以使用标准分子生物学方法生产(参见，例如，green和sambrook,《分子克隆：实验室手册(molecularcloning,alaboratorymanual)》,2012,冷泉港实验室出版社(coldspringharborpress))。在一些实施方式中，使用gibson克隆生产核酸(参见，例如，gibson,d.g.等naturemethods,343–345,2009；和gibson,d.g.等naturemethods,901–903,2010，其各自通过引用纳入本文)。gibson通常在单管反应中使用3种酶活性：5′外切核酸酶、dna聚合酶的3′延伸活性以及dna连接酶活性。5′外切核酸酶活性回嚼(chewback)5′短序列，并且将互补序列暴露用于退火。聚合酶活性随后填补退火区域的间隙。然后dna连接物将切口封闭，并且将dna片段共价连接在一起。邻近片段的重叠序列比在goldengate装配中使用的那些要长许多，并且因此导致较高比例的正确装配。生产工程改造的核酸的其它方法是本领域已知的并且可根据本公开使用。遗传因子本公开的工程改造的核酸可以包括一个或多个遗传因子。“遗传因子”指这样的核苷酸序列，其在核酸表达中起作用(例如，启动子、绝缘子、增强子、终止子和分子(例如，dna或蛋白质)结合区域)或者编码核酸的产物(例如，编码调节蛋白的核苷酸序列或编码切割核酸的酶的核苷酸序列，编码使核酸产生缺口的酶的核酸，或编码催化核酸交换的酶的核酸)。工程改造的核酸的表达通常通过可操作地连接该工程改造的核酸的启动子驱动。“启动子”指这样一种核酸的控制序列，在其中控制核酸序列剩余物转录的起始和速率。启动子驱动转录或其调控的核酸序列的转录，因此，其通常位于或靠近基因转录起始位点。在一些实施方式中，启动子是100-1000个核苷酸长度。启动子还包括亚区域，其调节蛋白质和其它可能结合的分子，如rna聚合酶和其它转录因子。启动子可以是组成型(例如，cag启动子、巨细胞病毒(cmv)启动子)、诱导型(也称为激活型)、抑制型、组织特异型、发育阶段特异型或上述一种或多种的任意组合。当启动子相对于其调节(例如，控制(“驱动”)转录开始和/或表达序列)的核酸序列处于正确的功能性位置和方向时，可以认为该启动子是“可操作地连接”的。在一些实施方式中，启动子与核酸天然地相关联，并且可以通过分离位于给定核酸的编码区域上游的5'非编码序列获得。这种启动子称为“内源性”启动子。在一些实施方式中，启动子与核酸并不天然相关联。这种启动子称为“异源性”启动子，并且包括例如调节其它核酸的启动子以及获得自其它细胞的启动子。异源性启动子可以是合成的或重组的。在一些实施方式中，合成的异源性启动子包含获得自已知转录调控区域的各种元件。在一些实施方式中，合成的异源性启动子包含这样的突变，其通过本领域已知的遗传工程改造方法改变表达。在一些实施方式中，重组异源性启动子是这样产生的：通过重组克隆、核酸扩增(例如，聚合酶链反应(pcr))、或重组克隆和核酸扩增的组合(参见，美国专利号4,683,202和美国专利号5,928,906)。本文考虑了产生合成和重组异源性启动子的其他方法。在一些实施方式中，启动子是诱导型启动子。当启动子受到相应调节蛋白的影响或接触时，“诱导型启动子”调节(例如，激活或灭活)其可操作地连接的核酸的转录活性。因此，本文所用“调节蛋白”是这样的蛋白质，其调节(例如，激活或灭活)来自启动子(例如，诱导型启动子)的转录活性。在一些所述方法中，调节蛋白直接结合诱导型启动子(例如，至启动子内的核苷酸的序列)。在一些实施方式中，调节蛋白结合位于诱导型启动子上游的区域(例如，位于诱导型启动子上游50-100个核苷酸)。在一些所述方法中，调节蛋白结合在诱导型启动子邻近(例如，附近)。调节蛋白的示例包括但不限于，四环素控制的反式激活因子(tta)转录因子、反向四环素控制的反式激活因子(rtta)转录因子、和lac阻遏物蛋白。根据使用的系统，调整转录的调节蛋白可以激活或灭活转录。转录的激活可能涉及在启动子上直接作用以驱动转录，或通过灭活阻遏物元件(例如，阻遏物蛋白)来间接作用在启动子上，所述阻遏物元件阻止启动子驱动转录。相反，转录的灭活可能涉及在启动子上直接作用以阻止转录或通过激活作用于启动子的阻遏物元件来间接作用在启动子上。调节蛋白的活性常常有效应物物质调节。“效应物物质”是任何调整(例如，激活或灭活)调节蛋白活性的物质。效应物物质可以是内源性或外源性条件(例如，光或热)、化合物(例如，化学或非化学化合物)或调节(例如，直接或间接)调节蛋白活性的其它蛋白质。例如，在tet-关闭系统(也称之为tta依赖型系统)和tet-开启系统(也称之为rtta依赖型系统)中，重组四环素控制的转录因子(tta或rtta)(“调节蛋白”)与tta/rtta诱导型启动子ptet相互作用以驱动可操作地连接启动子的基因的表达。基因表达受到效应物物质四环素或其衍生物中的一种的调控。四环素在tta和rtta转录因子的dna结合水平作用。rtta需要四环素配体用于dna结合，并且因此转录。相反，tta和dna之间的相互作用被四环素阻止。因此，tet系统的两种形式tet-关闭系统和tet-开启系统对于四环素(以及其衍生物，如多四环素)响应不同。通常，效应物物质的给予或去除将导致可操作连接的核酸序列的转录在激活或灭活之间转换。因此，可操作地连接核酸序列的启动子的活化状态指当该启动子积极地调节核酸序列转录(例如，表达连接的核酸序列)的状态。相反，可操作地连接核酸序列的启动子的灭活状态指当该启动子不积极地调节核酸序列转录(例如，不表达连接的核酸序列)的状态。调节诱导型启动子(例如，经由调节蛋白的调节)的效应物物质的示例包括但不限于，生理条件，如光、ph、温度、辐射、渗透压、盐梯度和细胞表面结合中的改变。诱导型启动子还可以通过改变外在或内在效应物物质的浓度来调节。外在效应物物质的示例包括但不限于，氨基酸和氨基酸类似物、糖和多糖、核酸、蛋白质转录激活物和阻遏物、细胞因子、毒素、基于石油的化合物、包含金属(例如，铜)的化合物、盐、离子、酶底物类似物、激素或上述任意两种或多种的组合。其它效应物物质是本领域已知的并且可根据本公开使用。诱导型启动子的示例包括但不限于，化学或生物化学调节的和物理调节的启动子，如醇调节的启动子，四环素调节的启动子(例如，无水四环素(atc)响应性启动子和其他四环素响应性启动子系统，这包括四环素阻遏物蛋白(tetr)、四环素操纵子序列(teto)和四环素反式激活因子融合蛋白(tta))，类固醇调节的启动子(例如，基于大鼠糖皮质激素受体的启动子，人雌激素受体，蛾蜕皮激素受体，以及来自类固醇/类维生素a/甲状腺受体超家族的启动子)，金属调节的启动子(例如，来自酵母、小鼠和人的金属硫蛋白(结合和隔离金属离子的蛋白)基因的启动子)，发病原调节的启动子(例如，由水杨酸、乙烯或苯并噻二唑(bth)诱导的，温度/热诱导型启动子(例如，热休克启动子)和光调节的启动子(例如，来自植物细胞的光响应性启动子)。其它诱导型启动子是本领域已知的并且可根据本公开使用。增强子在一些实施方式中，工程改造的核酸包括增强子。“增强子”是顺式作用核苷酸调控序列，其涉及可操作地连接启动子的核酸序列的转录活化。增强子可以位于启动子上游或下游的任何功能性位置。终止子在一些实施方式中，工程改造的核酸包括终止子。“终止子”是导致转录停止的核苷酸序列。终止子可以是单向的或双向的。终止子包括这样的dna序列，其涉及通过rna聚合酶特异性终止rna转录本，并且防止下游核酸序列被上游启动子转录活化。最常用类型的终止子是正向终止子。当将正向转录终止子置于通常转录的核酸序列下游时，正向转录终止子将会导致转录中止。在一些实施方式中，使用了双向转录终止子，其通常导致在正向和反相链上的转录终止。在一些实施方式中，提供了法向转录终止子，其通常仅终止在反相链上的转录。根据本公开使用的终止子的示例包括但不限于，基因的终止序列，例如，牛生长激素终止子，和病毒终止序列，例如，存在于细菌系统中的t0终止子、te终止子、λt1和t1t2终止子。在一些实施方式中，终止信号可能是不可以被转录或翻译的信号，诸如来自序列截短的那些。选择性标志物在一些实施方式中，工程改造的构建体(例如，“toicas构建体”)包括编码选择性标志物蛋白的核酸。选择性标志物是导入细胞的基因，其赋予适合人工选择的特征。例如，选择性标志物可以是抗生素抗性基因。抗生素抗摔基因非限制性的示例包括编码对氨苄青霉素、氯霉素、四环素或卡那霉素抗性的基因。例如，β-内酰胺酶赋予对细菌宿主的氨苄青霉素抗性，获自tn5的neo基因赋予细菌中的卡那霉素以及真核细胞中的遗传霉素的抗性，获自大肠杆菌基因组的突变fabi基因(mfabi)赋予对宿主的三氯生抗性，并且获自酵母的乳清苷-5'磷酸脱羧酶ura3是阳性和阴性选择性标记物。载体本公开的实施方式提供了包含工程改造的核酸分子的载体，所述工程改造的核酸编码诱导型核酸表达系统的元件。“载体”指用做载剂的核酸(例如，dna)以将遗传物质(例如，工程改造的核酸)运送到细胞中，在其中其可以例如复制和/或表达。应当理解的是，本文所用属于“载体”不包括慢病毒载体。因此，在一些实施方式中，本公开的工程改造的核酸是被克隆到载体中，或经由载体(非慢病毒载体)递送至细胞。提供使用的载体通常是经工程改造的，并且包括附加型表达载体。附加型表达载体的示例包括但不限于，质粒，其是能够在宿主细胞中自动复制的双链常环状的dna序列，以及病毒载体，其可以基于来自dna病毒的序列，如bk病毒、牛乳头瘤病毒1和eb病毒。本文也提供了杆状病毒载体(kost等2005natbiotechnol.2005年5月；23(5):567–575)。杆状病毒基因表达系统和基因递送系统是已知的(参见，例如，makelaar等coldspringharbprotoc.2010年3月；2010(3)，通过引用纳入本文)，并且可以根据本公开使用。在一些实施方式中，使用杆状病毒载体将如本文所提供的toicas构建体递送至细胞，如哺乳动物细胞。载体还可能是工程改造的细菌人工染色体(bac)(o’connerm.等1989science244(4910):1307–1312；shizuyah.等1992procnatlacadsciusa89(18):8794–8797；和shizuyah等2001keiojmed.50(1):26–30，其各自通过引用纳入本文)或酵母人工染色体(yac)(struhlk等1979pnas76(3):1035-39，通过引用纳入本文)，其中，例如编码调节蛋白的核酸、编码核酸酶的核酸或编码重组酶的核酸被置于诱导型启动子(例如，组织特异性启动子)或管家基因启动子控制下。在一些实施方式中，存在于bac或yac中的启动子可调节下游基因。在一些实施方式中，包括工程改造的核酸的载体(或工程改造的核酸本身)比典型的表达构建体大。在一些实施方式中，本公开的工程改造的核酸(或包括工程改造的核酸的载体)是至少12千碱基(kb)。例如，工程改造的核酸(或包括工程改造的核酸的载体)可以是至少13kb、至少14kb、至少15kb、至少16kb、至少17kb、至少18kb、至少19kb或至少20kb。在一些实施方式中，工程改造的核酸(或包括工程改造的核酸的载体)是15kb-20kb、15kb-30kb、15kb-40kb、20kb-30kb或20kb-40kb。细胞本公开的工程改造的构建体(例如，“toicas构建体”)可以导入各种不同的细胞中。工程改造的构建体可以被导入的细胞的示例包括但不限于，哺乳动物细胞、昆虫细胞、细菌细胞和酵母细胞。例如，哺乳动物细胞可以是人细胞、灵长类动物细胞(例如，vero细胞)、大鼠细胞(例如，gh3细胞、c23细胞)或小鼠细胞(例如，mc3t3细胞)。存在各种人细胞系，其包括但不限于hek细胞(例如，hek293或hek293t细胞)、hela细胞、来自国家癌症研究所60癌症细胞系(nci60)的癌症细胞、du145(前列腺癌症)细胞、lncap(前列腺癌症)细胞、mcf-7(乳腺癌)细胞、mda-mb-438(乳腺癌)细胞、pc3(前列腺癌症)细胞、t47d(乳腺癌)细胞、thp-1(急性骨髓性白血病)细胞、u87(恶性胶质瘤)细胞、shsy5y人神经母细胞瘤细胞(克隆自骨髓瘤)和saos-2(骨癌)细胞。在一些实施方式中，工程改造的构建体表达在干细胞中(例如，人干细胞)，如多能干细胞(例如，人多能干细胞，其包括人诱导型多能干细胞(hipscs))。“干细胞”指在培养中不确定的时期具有分裂能力且产生特化细胞的细胞。“多能干细胞”指这样类型的干细胞，其能够分化成器官的所有组织，但是其单独不能够持续完整器官发育。“人诱导型多能干细胞”指这样的体(例如，成熟或成体)细胞，其已经通过被强制表达对于维持胚胎干细胞限定特性重要的因子和基因来重编程至胚胎干细胞样状态(参见，例如，takahashi和yamanaka,2006cell126(4):663–76，通过引用纳入本文)。人诱导型多能干细胞表达干细胞标志物，并且能够生产所有三胚层(外胚层、内胚层、中胚层)的细胞特性。可以更加本公开使用的细胞系的其它非限制性示例包括293-t、293-t、3t3、4t1、721、9l、a-549、a172、a20、a253、a2780、a2780adr、a2780cis、a431、alc、b16、b35、bcp-1、beas-2b、bend.3、bhk-21、br293、bxpc3、c2c12、c3h-10t1/2、c6、c6/36、cal-27、cgr8、cho、cmlt1、cmt、cor-l23、cor-l23/5010、cor-l23/cpr、cor-l23/r23、cos-7、cov-434、ct26、d17、dh82、du145、ducap、e14tg2a、el4、em2、em3、emt6/ar1、emt6/ar10.0、fm3、h1299、h69、hb54、hb55、hca2、hepa1c1c7、highfive细胞、hl-60、hmec、ht-29、huvec、j558l细胞、jurkat、jy细胞、k562细胞、kcl22、kg1、ku812、kyo1、lncap、ma-mel1、2、3....48、mc-38、mcf-10a、mcf-7、mda-mb-231、mda-mb-435、mda-mb-468、mdckii、mg63、mono-mac6、mor/0.2r、mrc5、mtd-1a、myend、nalm-1、nci-h69/cpr、nci-h69/lx10、nci-h69/lx20、nci-h69/lx4、nih-3t3、nw-145、opcn/opctpeer、pnt-1a/pnt2、ptk2、raji、rbl细胞、renca、rin-5f、rma/rmas、s2、saos-2细胞、sf21、sf9、siha、skbr3、skov-3、t-47d、t2、t84、thp1、u373、u87、u937、vcap、wm39、wt-49、x63、yac-1和yar细胞。在一些实施方式中，本公开的工程改造的构建体被导入人细胞，例如，淋巴细胞，如t细胞(例如，cd8+细胞、cd4+细胞)、b细胞或自然杀伤细胞(nk细胞)。在一些实施方式中，本公开的细胞是修饰的。修饰的细胞是这样的细胞，其包含外源性核酸或自然不存在的核酸。在一些实施方式中，修饰的细胞包含基因组核酸中的突变。在一些实施方式中，修饰的核酸包含外源性独立复制的核酸(例如，存在于附加型载体的工程改造的核酸)。在一些实施方式中，修饰的细胞通过将外来或外源性核酸导入细胞产生。工程改造的构建体可以通过诸如下述方法导入细胞：例如，电穿孔(参见，例如，heiserw.c.转录因子方案:分子生物学方法tm2000(transcriptionfactorprotocols:methodsinmolecularbiologytm2000)；130:117-134)、化学法(例如，磷酸钙或脂质法)、转染(参见，例如，lewisw.h.,等,somaticcellgenet.1980年5月；6(3):333-47；chenc.,等,molcellbiol.1987年8月；7(8):2745–2752)、与包含重组质粒的细菌原生质体融合(参见，例如，schaffnerw.procnatlacadsciusa.1980年4月；77(4):2163-7)、或将纯化的dna直接显微镜下注射到细胞的核内(参见，例如，capecchim.r.cell.1980年11月；22(2pt2):479-88)。经修饰以包括本公开的工程改造的构建体的哺乳动物细胞(例如，人细胞)可以使用传统哺乳动物细胞培养方法培养(例如，维持在细胞培养中)(参见，例如，phelanm.c.currprotoccellbiol.2007年9月；第1章:1.1单元，通过引用纳入本文)。例如，细胞可以在细胞培养箱中以适当的温度和气体混合物(例如，37℃、5％co2针对哺乳动物细胞)生长和维持。培养条件对于各种细胞类型可能不同。例如，细胞培养基的ph、葡萄糖浓度、生长因子和存在的其它营养素可能不同。用于补充培养基的生长因子通常来自自动物血液的血清，如胎牛血清(fbs)、小牛血清和/或猪血清。在一些实施方式中，本文所提供的使用的培养基可以是市售可得和/或已详细描述的(参见，例如，birchj.r.,r.g.spier(ed.)细胞技术百科全书(encyclopediaofcelltechnology),wiley.411-424,2000；keenm.j.cytotechnology17:125-132,1995；zang,等bio/technology.13:389-392,1995)。在一些实施方式中，使用化学限定的培养基。本公开的诱导型基因组编辑系统允许空间控制的和时间控制的基因组修饰，这可以用于各种应用。例如，起可以被用于生成动物模型、细胞系和诱导型多能干细胞(ipsc)，其中在分化阶段必需严格控制靶基因的调节。诱导型基因组编辑细胞还可以用于生长组织特异性诱导型敲除或敲入。其它应用包括基因治疗。实施例实施例1:插入诱导型盒的方案1.培养细胞，并且在转染前一天将约500000个细胞分至6孔板的新孔中。2.以靶向核酸酶结合位点基因座的zfn和toicas诱导型构建体并使用适当的转染剂(通常是lipofectamineltx或fugenehd(通常以3:1的zfns/toicas比例)转染细胞。3.转染后3天，将细胞分至20cm孔内，并利用适当的选择(g418针对dox诱导型、嘌呤霉素针对c9ert2)进行选择。4.选择后3周，挑取克隆并且针对安全港基因座中的整合进行检查。5.grna可以慢病毒感染或用诱导型构建体再次靶向基因座的方式插入或瞬时转染。6.通过向培养基添加多四环素(10μg/ml)或他莫昔芬(0.5um)进行诱导。7.诱导后3天评价切割。实施例2:使用toicas构建体生成细胞系人诱导型多能干细胞(hipsc)是研究多步骤分化过程的宝贵工具，并且用于生成基于细胞的体外疾病模型。它们还以被用于化学筛选和细胞治疗。这些应用中的每一种都可以通过基因组工程显著增强；特别是感兴趣基因的诱导型敲入或敲减促进了对于其功能在不同分化阶段或不需要使用动物模型的疾病进程的研究。使用严格调控的一个载体系统将toicas构建体(图10)靶向位于hipsc中的人安全港aavs1基因座以获得多四环素(dox)诱导型cas9。在存在dox的情况下，反式激活因子(3g)结合响应元件，并且驱动感兴趣的蛋白质cas9t2agfp的表达。生成的ipsc系显示在不存在dox的情况下无可检测的gfp表达，而在存在dox的情况下，检测到清楚的gfp信号(数据未显示)。可以用低至5ng/ml的dox检测gfp，并且在40小时的周期内信号随着渐增的浓度(0ng/ml、1ng/ml、5ng/ml、10ng/ml、50ng/ml和100ng/ml)增强，这表明系统可以如所需调整(未显示荧光数据图像)。在不存在dox或靶向引导rna的情况下，grna靶基因座上并不存在可检测的基因组切割(通过入缺失标记指示)，然而在存在dox和引导rna的情况下，观察到高效切割，这表明该系统是高效的并且没有cas9的渗漏表达(图11)。可以使用本公开的方法插入构建体的单个或多个拷贝。较高拷贝数对于较高蛋白质(例如，gfp)表达水平。染色体组型在用于分化过程的细胞中特别重要，如诱导型多能干细胞(ipsc)和小鼠胚胎干细胞(mesc)。对来自人诱导型多能干细胞系的固定细胞悬浮液的染色体分析显示在检测的20个细胞中的明显正常染色体组型，这表明如本文所提供的整合方法并不干扰包含诱导型cas9系统的诱导型多能干细胞中的多能性(数据未显示)。dox处理细胞后进行cas9诱导的时间-过程，其在6小时后显示了可检测的gfp水平并且持续了至少40小时，在第30小时观察到最大表达(数据未显示)。使用相同的toicas系统，还生成了表达cas9变体的诱导型多能干细胞(ipsc)系，所述cas9变体是酶失活的(cas9死亡)。当与相同toicas系统中的cas9系比较时，仅在系统过表达时(100ng/ml，表达2周)观测到cas9的毒性。毒性通过ipsc系分化的诱导来指示，如通过形态学改变以及通过多能性基因(例如，oct4)表达的降低所指示的。这表明cas9的核酸酶活性与诱导型多能干细胞中的毒性相关联。接着，基因敲除效率在ipsc或衍生自ipsc的细胞中评估。高效基因敲除通过转染在表达质粒中编码的合成grna、合成crrna/tracr和grna而获得。通过使用靶向附近序列(相距约10-400bp)的2个或更多个grna构建体，效率和缺失精度有所增加。实施例3:人内源性大麻素受体缺失内源性大麻素(ecb)在不同范围的生理或病理过程中有重要作用，其中包括神经发育、免疫功能、疼痛、能量平衡、脂质和葡萄糖代谢。尽管内源性大麻素需求以及在小鼠中详细地研究过，但是这些小信号转导脂质在人神经元发育和病理中的作用却极为少知。为了研究在人系统中内源性大麻素信号转导的需求，使用toicas生成人诱导型多能干细胞(hipsc)库，其中人内源性大麻素受体1和2基因(cnr1和cnr2)被单独或组合靶向(分别为单个或两个敲除)。hipsc中进行单个doxa诱导后，在cas9存在的情况下使用双引导rna在cnr1和2基因中实现精确缺失(数据未显示)。细胞培养1周后，传代细胞，并且提取基因组dna。cnr1和cnr2编码序列中的精确缺失通过连接pcr、细胞试验和sanger测序确认(数据未显示)。实施例4:针对crisprko和crispri的toicas-krab生成包含toic修饰形式的ipsc细胞系。正常的cas9融合至krab结构域。使用具有正常/常规原型间隔子长度的grna或具有短原型间隔子长度的grna分别诱导crisprko或crispri(参见，例如，kiani,s.,等naturemethods12(11):1051-1054,2015中的方法)。该系统还用于靶向oct4基因，并且通过使用如上所示的替代性grna实现oct4基因的敲除或敲减。该系统一般适用于其它修饰，如crispra，碱基编辑和适用于其它正交cas9酶。实施例5:在具有免疫能力的小鼠中生成功能性小鼠模型用于离体原代细胞建模的tet-开启诱导型cas9(icas9)小鼠。crispr-cas9是用于遗传干扰的模块化且通用工具。其由核糖核蛋白内切核酸酶(cas9)和引导rna(grna)组成。培养的细胞对于crispr-cas9工程是相对可修改的。然而，应用于活体动物产生了一些重大挑战，鉴于将所有组件精确且同时递送到感兴趣的组织中的复杂性。此外，常规的敲除策略会影响动物中的每种细胞，因此，在复制表型中区分主要和次要改变常常是不可能的。最后，任何基因的改变在小鼠发育上都具有潜在的后果，这使得在成体动物上的研究被妨碍或被复杂化(例如，胚胎致死性、畸型、代谢缺陷、癌症)。因此，存在对用于体内精确且时间编辑系统的日益增长的需求。本文提供的是一种严格的一组件系统，以在没有其它任何表型序列下在具有免疫能力的小鼠中实现cas9的多四环素诱导型表达。将本公开的工程改造的toicas构建体(图10)插入小鼠胚胎干细胞(mes)中的安全(safe)r26基因座中。以r26基因座中的单个或多个拷贝整合成功生成克隆。多四环素诱导且进一步确认cas9表达后，选择不同的克隆注入胚泡以产生嵌合小鼠(数据未显示)。将dox处理后的cas的表达与r26基因座中tpicas构建体的拷贝数量关联。将多个拷贝导入特定基因座只有通过使用用于整合的基于nhej的方法才可以实现。这是通过该方法产生的第一个动物模型。为了证明tpicas在小鼠细胞中的功能性，分离来自初创小鼠耳成纤维细胞，并且进行离体培养。然后使用dox刺激细胞。在荧光显微镜下成像后，确认gfp表达(数据未显示)。用于aav介导的体内基因组编辑和癌症建模的tet-开启诱导型cas9(icas9)小鼠。crispr-cas9将基因组编辑的边界移动至复杂的体内应用。crispr对于基因治疗的快速途径的前景受制于对更加可译且有效动物模型逐渐增长的需求。小鼠分子遗传学具有复制人疾病的潜能，但是常规的敲除策略不具有选择性，也不具有足以空间或时间方式控制的通用性。最近几年，对于更加灵活的体内基因工具的需求急剧增长，特别是在成体小鼠中复杂建模的领域。cas9表达在toicas小鼠中被严格调控，并且只有在多四环素处理后，才在大部分组织中观察到cas9表达。toic小鼠具有免疫能力背景，因此可以用于例如免疫-肿瘤学应用。因此，向具有免疫能力的toicas小鼠(一组6只)给予溶于饮用水的2mg/ml的多四环素(dox)，自由摄取，持续3天。处理后，将toicas小鼠与未处理的(-dox)toicas对照小鼠(一组6只)一起进行安乐死。立即分离来自两种小鼠的6个组织，并且用落射荧光立体显微镜成像，以便基准cas9表达(数据未显示)。dox诱导3天后，在心脏、肺、气管、肝脏、脾脏、胰腺和大脑中观测到体内toicas活化/gfp表达，然而并没有在来自未处理的对照小鼠的组织中检测到gfp(数据未显示)。组织病理学分析显示小鼠肿瘤与人肿瘤类似。可以在肺的所有区域观测到低分化腺瘤。生长模式包括显示乳头状、小梁状、腺状和紧凑生长模式的上皮肿瘤细胞，以及在肺泡腔和邻近组织中的局部浸润。观测到偶尔存在的近乎鳞状上皮样的转换。肿瘤组织中以及存在典型有丝分裂的少数支气管区域出现高有丝分裂活性。同样存在具有多倍性、各向异性和异型核型以及显著增加的肺泡巨噬细胞的高度分化的细胞。没有血管浸润或转移的迹象。观察到支气管肺泡的生长模式以及通过肺泡和细支气管间隙中多灶性结节所鉴定的小梁和腺体生长模式的区域。整体观察到高有丝分裂活性，特别是在所有肿瘤结节(基于针对增殖标志物ki67的免疫组织化学试验)以及随机的支气管上皮细胞中。令人惊讶的是，被我们视为阴性对照的脑(通过药物治疗最难以到达的器官)也呈gfp阳性。为了生成体内癌症小鼠模型，使用了针对trp53和kras的grna以及模板以导入krasg12d突变。用带有靶向kras的grna的aav感染细胞(图12，顶图)。.通过gfp表达的时间-过程监测来评估cas9内切核酸酶活性(图13)。在收集自感染4或9周后细胞的基因组dna上进行的surveyor试验确认由靶向策略所预期的独特模式表示的精确编辑(插入缺失和点突变-图14)。在纤维母细胞和成年小鼠中确认了p53敲除(ko)和kras诱变两者。然后，用aav经由气管内注射来感染toicas小鼠，所述aav具有靶向trp53基因的引导rna(图12，底图)。感染前24小时，在#37、#42和#52小鼠中激活cas9，而不处理#98小鼠#99(-dox)。感染4周后，从所有小鼠处收集肺部，并且提取dna以进行surveyor核酸酶试验。如图15所示，然后在经处理和感染的小鼠中确认trp53基因中精确突变的存在。实施例6:组织特异性敲除针对本公开tpicas系统中crispr的空间和时间调控研发了若干种策略。一种策略是在组织特异性启动子下驱动rtta的表达。使用α肌球蛋白重链(amhc)驱动rtta的表达并且因此调节cas9；该策略通常适合使用任何其它组织启动子，并且只在特定组织中诱导cas9的表达。另一策略是引入由polii启动子(例如，组织特异性)驱动的组织特异性转录本中的grna盒。grna被整合到内含子中，并且可以具有核酶(rybozyme)或后续待由原始转录本切割的其它rna加工序列。再一个策略是基于在组织特异性重组酶或组织特异性正交cas9/crispr诱导后的grna激活。在该情况中，grna的表达是通过停止盒(stopcassette)阻止，该停止盒位于启动子和grna的功能性部分之间。正交cas9/crispr或位点特异性重组酶的存在诱导停止盒的去除，因此使得grna仅在正交cas9/crispr或位点特异性重组酶表达的组织中表达。上述实施例实现了空间和时间调节cas9/crispr系统，因此，有可能在成体动物以及分化的细胞中产生组织特异性敲除、敲减和碱基编辑，由胚胎干细胞或诱导型多能干细胞开始。toicas系统的一个应用是感兴趣组织或细胞的诱导型消融，以研究细胞/组织的功能或模拟疾病的状态。在该情况中，toicas系统中cas9的时间表达(通过dox调节)与grna的组织特异性表达组合，所述grna靶向靶基因组中多个重复。作为靶位置的重复的两个非限制示例是小鼠基因组中的重复b1(ctcactatgtagaccaggc(seqidno:10))，以及在人基因组中的重复alui(cctgtaatcccagcactttcactttgggaggccgaggcgagtctcgctctgtcgccc(seqidno:11))。系统的组织特异性和时间性活化促进在多个位点的切割，因此靶基因组的降解只在tpicas系统被表达的组织内且只在dox处理的情况中。实施例7:grna克隆方法开发了三种策略以在表达cas9的细胞或质粒中克隆针对特定基因的grna。t第一种策略使用重组工程以插入这样的盒，所述盒包含位点特异性grna，以及细菌选择标志物和驱动grna表达的poliii启动子。通过在细菌中选择接受grna和选择标志物的细胞，grna可以高通量方式插入。第二种策略是使用来自脑膜炎奈瑟菌(neisseriameningitis)的cas9以靶向包含toicas构建体的细胞中的neo基因，并且导入grna，以及neo选择标志物内的哺乳动物选择标志物。该策略并不限于neo选择标志物以及cas9nm，因为grna整合可以使用任何其它正交cas9和插入点。第三种策略是使用cas9核糖核蛋白(cas9ribonucleoprotein)以通过同源重组方法或基于nhej的方法在精确的基因座中递送grna。其它方法是通过慢病毒和转座子插入。实施例8:toicas系统的进一步分析如图16-19所示，尽管在不存在多四环素的情况下偶尔会有表达cas9的细胞，但是cas9诱导非常干净。仅在多四环素暴露24小时后，表达最大量的cas9。此外，在a549细胞中，cas9表达的诱导似乎以下作用：细胞生长、dna损伤的发生率(通过gh2ax焦点测量)、或dna损伤的持续性(通过微核形成测量)。通常，cas9表达似乎不增强对于ir的敏感性，也不增强ir所导致的dna损伤。序列用于根据本公开使用的哺乳动物绝缘子序列的其它示例：ctagagggacagcccccccccaaagcccccagggatgtaattacgtccctcccccgctaggggcagcagcgagccgcccggggctccgctccggtccggcgctccccccgcatccccgagccggcagcgtgcggggacagcccgggcacggggaaggtggcacgggatcgctttcctctgaacgcttctcgctgctctttgagcctgcagacacctggggggatacggggaaaaagctttaggctgaaagagagatttagaatgacagaatcatagaacggcctgggttgcaaaggagcacagtgctcatccagatccaaccccctgctatgtgcagggtcatcaaccagcagcccaggctgcccagagccacatccagcctggccttgaatgcctgcagggatggggcatccacagcctccttgggcaacctgttcagtgcgtcaccaccctctgggggaaaaactgcctcctcatatccaacccaaacctcccctgtctcagtgtaaagccattcccccttgtcctatcaagggggagtttgctgtgacattgttggtctggggtgacacatgtttgccaattcagtgcatcacggagaggcagatcttggggataaggaagtgcaggacagcatggacgtgggacatgcaggtgttgagggctctgggacactctccaagtcacagcgttcagaacagccttaaggataagaagataggatagaaggacaaagagcaagttaaaacccagcatggagaggagcacaaaaaggccacagacactgctggtccctgtgtctgagcctgcatgtttgatggtgtctggatgcaagcagaaggggtggaagagcttgcctggagagatacagctgggtcagtaggactgggacaggcagctggagaattgccatgtagatgttcatacaatcgtcaaatcatgaaggctggaaaagccctccaagatccccaagaccaaccccaacccacccaccgtgcccactggccatgtccctcagtgccacatccccacagttcttcatcacctccagggacggtgacccccccacctccgtgggcagctgtgccactgcagcaccgctctttggagaaggtaaatcttgctaaatccagcccgaccctcccctggcacaacgtaaggccattatctctcatccaactccaggacggagtcagtgaggatggggct(seqidno:6)cas9ert2:atggctctcgagccatctgctggagacatgagagctgccaacctttggccaagcccgctcatgatcaaacgctctaagaagaacagcctggccttgtccctgacggccgaccagatggtcagtgccttgttggatgctgagccccccatactctattccgagtatgatcctaccagacccttcagtgaagcttcgatgatgggcttactgaccaacctggcagacagggagctggttcacatgatcaactgggcgaagagggtgccaggctttgtggatttgaccctccatgatcaggtccaccttctggaatgtgcctggctagagatcctgatgattggtctcgtctggcgctctatggagcacccagtgaagctactgtttgctcctaacttgctcttggacaggaaccagggaaaatgtgtagagggcatggtggagatcttcgacatgctgctggctacatcatctcggttccgcatgatgaatctgcagggagaggagtttgtgtgcctcaaatctattattttgcttaattctggagtgtacacatttctgtccagcaccctgaagtctctggaagagaaggaccatatccaccgagtcctggacaagatcacagacactttgatccacctgatggccaaggcaggcctgaccctgcagcagcagcaccagcggctggcccagctcctcctcatcctctcccacatcaggcacatgagtaacaaaggcatggagcatctgtacagcatgaagtgcaagaacgtggtgcccctctatgacctgctgctggaggcggcggacgcccaccgcctacatgcgcccactagccgtggaggggcatccgtggaggagacggaccaaagccacttggccactgcgggctctacttcatcgcattccttgcaaaagtattacatcacgggggaggcagagggtttccctgccacagctgacaagaaatactcaatcgggctggacatcggaactaactcagtggggtgggcagtcattactgacgagtacaaagtgccaagcaagaaatttaaggtcctgggcaacaccgataggcactccatcaagaaaaatctgattggggccctgctgttcgactctggagagacagctgaagcaactagactgaaaaggactgctagaaggcgctatacccggcgaaagaatcgcatctgctacctgcaggagattttctctaacgaaatggccaaggtggacgatagtttctttcatcggctggaggaatcattcctggtcgaggaagataagaaacacgagagacatcctatctttggaaacattgtggacgaggtcgcttatcacgaaaaataccccaccatctatcatctgcgcaagaaactggtggactctacagataaagcagacctgcggctgatctatctggccctggctcacatgattaagttcagaggccattttctgatcgagggagatctgaacccagacaatagcgatgtggacaagctgttcatccagctggtccagacatacaatcagctgtttgaggaaaaccctattaatgcatctggcgtggacgcaaaagccatcctgagtgccaggctgtctaagagtagaaggctggagaacctgatcgctcagctgccaggcgaaaagaaaaacggcctgtttggaaatctgattgcactgtcactgggactgacacctaacttcaagagcaattttgatctggccgaggacgctaaactgcagctgagcaaggacacttatgacgatgacctggataacctgctggctcagatcggagatcagtacgcagacctgttcctggccgctaagaatctgtctgacgctatcctgctgagtgatattctgcgggtgaacaccgagattacaaaagcccctctgtcagctagcatgatcaagagatatgacgagcaccatcaggatctgaccctgctgaaggcactggtgcgccagcagctgcccgagaagtacaaggaaatcttctttgatcagagtaagaacgggtacgccggttatattgacggcggagctt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cagcctacacaatcgctcaagacgtgtaatgcttttattatatattagtcacgatatctataacaagaaaatatatatataataagttatcacgtaagtagaacatgaaataacaatataattatcgtatgagttaaatcttaaaagtcacgtaaaagataatcatgcgtcattttgactcacgcggtcgttatagttcaaaatcagtgacacttaccgcattgacaagcacgcctcacgggagctccaagcggcgactgagatgtcctaaatgcacagcgacggattcgcgctatttagaaagagagagcaatatttcaagaatgcatgcgtcaattttacgcagactatctttctagggttaaaaaagatttgcgctttactcgacctaaactttaaacacgtcatagaatcttcgtttgacaaaaaccacattgtggggtaccgagctcttaattaaggcgcgccggggaggttccctttagtgagggttaattgcgggtcgccctatagtgagtcgtattacaattcactggccgtcgttttacaacgtcgtgactgggaaaaccctggcgttacccaacttaatcgccttgcagcacatccccctttcgccagctggcgtaatagcgaagaggcccgcaccgatcgcccttcccaacagttgcgcagcctgaatggcgaatggcaaattgtaagcgttaatattttgttaaaattcgcgttaaatttttgttaaatcagctcattttttaaccaataggccgaaatcggcaaaatcccttataaatcaaaagaatagaccgagatagggttgagtgttgttccagtttggaacaagagtccactattaaagaacgtggactccaacgtcaaagggcgaaaaaccgtctatcagggcgatggcccactacgtgaaccatcaccctaatcaagttttttggggtcgaggtgccgtaaagcactaaatcggaaccctaaagggagcccccgatttagagcttgacggggaaagccggcgaacgtggcgagaaaggaagggaagaaagcgaaaggagcgggcgctagggcgctggcaagtgtagcggtcacgctgcgcgtaaccaccacacccgccgcgcttaatgcgccgctacagggcgcgtcag(seqidno:20)本文公开的所有参考文献、专利和专利申请通过引用每一个被引用的主题纳入，其中在一些情况中，可以包括整个文件。在本申请的说明书和权利要求书中，除非有明确的相反说明，不定冠词“一个”和“一种”应理解为“至少一个(种)”。还应理解，除非清楚表明相反，在本文要求权利的包括多于一个步骤或行动的任何方法中，所述方法的步骤或行动的顺序不必限定是列举该方法步骤或行为的顺序。在权利要求以及上述说明书中，所有连接词例如“包括”、“含有”、“带有”、、“具有”、“包含”、“涉及”、“持有”、“由……组成”等应被理解为是开放式的，即，指包括但不限于。如美国专利局的专利审查程序手册中2111.03部分所列举，仅连接词“由……组成”和“基本由……组成”分别应是封闭或半封闭的连接词。序列表<110>阿斯特拉捷利康股份公司(astrazenecaab)<120>细胞基因组的诱导型修饰<130>a1106.70000wo00<140>notyetassigned<141>2016-10-14<150>us62/242,884<151>2015-10-16<160>20<170>patentinversion3.5<210>1<211>72<212>dna<213>智人(homosapiens)<400>1catcttggaccattagctccacaggtatcttcttccctctagtggtcataacagcagctt60cagctacctctc72<210>2<211>32<212>dna<213>智人(homosapiens)<400>2caaattatcctgccccctagacataacctccc32<210>3<211>70<212>dna<213>智人(homosapiens)<400>3tgcattggctgcccaggcctgcactgccgcctgccggcaggggtccagtccacgagaccc60agctccctgc70<210>4<211>61<212>dna<213>智人(homosapiens)<400>4gccggccgcggacccggcccctccctccccggccgctagggggcgggcccggatcacagg60a61<210>5<211>61<212>dna<213>智人(homosapiens)<400>5catgcacaagaaagctttgcactttgcgaaccaacgataggtgggggtgcgtggaggatg60g61<210>6<211>1209<212>dna<213>人工序列<220><223>合成的多核苷酸<400>6ctagagggacagcccccccccaaagcccccagggatgtaattacgtccctcccccgctag60gggcagcagcgagccgcccggggctccgctccggtccggcgctccccccgcatccccgag120ccggcagcgtgcggggacagcccgggcacggggaaggtggcacgggatcgctttcctctg180aacgcttctcgctgctctttgagcctgcagacacctggggggatacggggaaaaagcttt240aggctgaaagagagatttagaatgacagaatcatagaacggcctgggttgcaaaggagca300cagtgctcatccagatccaaccccctgctatgtgcagggtcatcaaccagcagcccaggc360tgcccagagccacatccagcctggccttgaatgcctgcagggatggggcatccacagcct420ccttgggcaacctgttcagtgcgtcaccaccctctgggggaaaaactgcctcctcatatc480caacccaaacctcccctgtctcagtgtaaagccattcccccttgtcctatcaagggggag540tttgctgtgacattgttggtctggggtgacacatgtttgccaattcagtgcatcacggag600aggcagatcttggggataaggaagtgcaggacagcatggacgtgggacatgcaggtgttg660agggctctgggacactctccaagtcacagcgttcagaacagccttaaggataagaagata720ggatagaaggacaaagagcaagttaaaacccagcatggagaggagcacaaaaaggccaca780gacactgctggtccctgtgtctgagcctgcatgtttgatggtgtctggatgcaagcagaa840ggggtggaagagcttgcctggagagatacagctgggtcagtaggactgggacaggcagct900ggagaattgccatgtagatgttcatacaatcgtcaaatcatgaaggctggaaaagccctc960caagatccccaagaccaaccccaacccacccaccgtgcccactggccatgtccctcagtg1020ccacatccccacagttcttcatcacctccagggacggtgacccccccacctccgtgggca1080gctgtgccactgcagcaccgctctttggagaaggtaaatcttgctaaatccagcccgacc1140ctcccctggcacaacgtaaggccattatctctcatccaactccaggacggagtcagtgag1200gatggggct1209<210>7<211>6012<212>dna<213>人工序列<220><223>合成的多核苷酸<400>7atggctctcgagccatctgctggagacatgagagctgccaacctttggccaagcccgctc60atgatcaaacgctctaagaagaacagcctggccttgtccctgacggccgaccagatggtc120agtgccttgttggatgctgagccccccatactctattccgagtatgatcctaccagaccc180ttcagtgaagcttcgatgatgggcttactgaccaacctggcagacagggagctggttcac240atgatcaactgggcgaagagggtgccaggctttgtggatttgaccctccatgatcaggtc300caccttctggaatgtgcctggctagagatcctgatgattggtctcgtctggcgctctatg360gagcacccagtgaagctactgtttgctcctaacttgctcttggacaggaaccagggaaaa420tgtgtagagggcatggtggagatcttcgacatgctgctggctacatcatctcggttccgc480atgatgaatctgcagggagaggagtttgtgtgcctcaaatctattattttgcttaattct540ggagtgtacacatttctgtccagcaccctgaagtctctggaagagaaggaccatatccac600cgagtcctggacaagatcacagacactttgatccacctgatggccaaggcaggcctgacc660ctgcagcagcagcaccagcggctggcccagctcctcctcatcctctcccacatcaggcac720atgagtaacaaaggcatggagcatctgtacagcatgaagtgcaagaacgtggtgcccctc780tatgacctgctgctggaggcggcggacgcccaccgcctacatgcgcccactagccgtgga840ggggcatccgtggaggagacggaccaaagccacttggccactgcgggctctacttcatcg900cattccttgcaaaagtattacatcacgggggaggcagagggtttccctgccacagctgac960aagaaatactcaatcgggctggacatcggaactaactcagtggggtgggcagtcattact1020gacgagtacaaagtgccaagcaagaaatttaaggtcctgggcaacaccgataggcactcc1080atcaagaaaaatctgattggggccctgctgttcgactctggagagacagctgaagcaact1140agactgaaaaggactgctagaaggcgctatacccggcgaaagaatcgcatctgctacctg1200caggagattttctctaacgaaatggccaaggtggacgatagtttctttcatcggctggag1260gaatcattcctggtcgaggaagataagaaacacgagagacatcctatctttggaaacatt1320gtggacgaggtcgcttat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