全基因组重亚硫酸盐测序(whole genome bisulfite sequencing)用于全基因组DNA甲基化检测

2014-02-05 MedSci MedSci原创

表观遗传学研究已经证实了特定基因区域的DNA甲基化修饰对于染色体构象、基因表达调控机制有着重要影响,而全基因组DNA甲基化研究将是表观基因组学最为关注的内容之一。 Bisulfite处理能够将基因组中未发生甲基化的C碱基转换成U,进行PCR扩增后变成T,与原本具有甲基化修饰的C碱基区分开来,再结合高通量测序技术,可绘制单碱基分辨率的全基因组DNA甲基化图谱。 特定物种的高精确度甲基

表观遗传学研究已经证实了特定基因区域的DNA甲基化修饰对于染色体构象、基因表达调控机制有着重要影响,而全基因组DNA甲基化研究将是表观基因组学最为关注的内容之一。

Bisulfite处理能够将基因组中未发生甲基化的C碱基转换成U,进行PCR扩增后变成T,与原本具有甲基化修饰的C碱基区分开来,再结合高通量测序技术,可绘制单碱基分辨率的全基因组DNA甲基化图谱。

特定物种的高精确度甲基化修饰模式的分析,必将在表观基因组学研究中具有里程碑式的意义,并且为细胞分化、组织发育等基础机制研究,以及动植物育种、人类健康与疾病研究奠定基础。

技术优势:

■单碱基精确度:精确分析每一个C碱基的甲基化状态。

■里程碑式的研究:特定物种的表观基因组学研究的重要内容,适用于所有具有精确基因组图谱的物种。



实验流程:

● 基因组DNAA超声打断至100-500bp的片段

● DNA片段末端修复、3’端加A碱基,连接测序接头。

● 采用 EZ DNA Methylattion-Gold kit 进行 Bisulfite 处理

● 脱盐处理,PCR扩增后进行文库片段大小选择。

● 合格的文库用于上机测序。

信息分析流程图

生物信息分析:

1. Data Clean

测序结果进行去污染,去接头处理。根据测序产生的序列文件*.fq 统计read

长度,read数量,数据产量。


2. 标准信息分析

2.1 Bisulfite-seeq 序列与参考序列的比对

在信息分析过程中,首先将每一对reads中正链reads上的C碱基转换为T碱基,而反链 reads中的G碱基转换为A碱基。在此基础上使用SOAP软件,将reads与参考基因组序列进行比对,唯一比对reads将用于甲基化信息的分析。数据比对统计结果如下:



2.2 C碱基测序深度的累积分布

甲基化C碱基在基因组上的分布包含三种形式(CG, CHG和CHH,其中H代表A 或T或C碱基)。下述图表中反映了三种不同分布类型的C碱基的测序深度累积分布。其中横轴表示C碱基测序深度,纵轴表示一定测序深度下C碱基的累积比例( copynum <=1.5即uniquely mapped reads的判断标准之一)。

碱基测序深度的累积分布图

2.3 不同reads测序深度下的基因组覆盖度

横轴表示测序深度,纵轴表示特定测序深度下所对应的基因组覆盖度。



2.4 计算C碱基的甲基化水平

每一个甲基化C碱基的甲基化水平均按如下公式进行计算:100*reads/total reads(例如:CpG位点的甲基化率=100*支持CG甲基化的reads/支持甲基化的 reads+支持非甲基化的reads)全基因组平均甲基化水平反应了基因组甲基化图谱的总体特征。

Average methylation level for C, CG, CHG and CHH

Pattern

C

CG

CHG

CHH

Mathylation level

5.00

80.88

4.89

1.22


2.5 全基因组甲基化数据分布趋势

甲基化C碱基中CG, CHGG与CHH 的分布比例

不同分布类型的甲基化C位点在不同物种基因组中出现比例不同,因此,各类型mC( mCG、mCHG和mCHH ) 的位点数目,及其在全部mC的位点中所占的比例(例:mCHG所占比例= mCHG数目/mC的总数),在一定程度上反映了特定物种的全基因组甲基化图谱的特征。



不同分布类型甲基化 C 的数量及比例

Pattern

mCG

mCHG

mCHH

Number

1,409,380

4,890

47,583

Proportion

96.41

0.33

3.25

 

此外,还统计如下数据:

● CG、CHG和CHH中的所有C的甲基化水平

● 各个染色体中CG、CHG和CHH中C的甲基化水平

● 统计不同基因区域内CG、CHG和CHH中C的甲基化水平

● 不同基因元件区域中CG、CHG和CHH中C的甲基化水平

● CHG、CHH中甲基化C附近的9bp序列的序列特征分析

2.6 全基因组DNA甲基化图谱

染色体水平的甲基化C碱基的密度分布

从染色体水平来描述甲基C碱基的的分布情况。蓝点表示以10kb的窗口统计甲基化C碱基的密度在染色体上的分布情况,光滑曲线则表示不同类型甲基化C碱基( G、CHG和CHH )的密度分布。



染色体上甲基化C密度分布


全基国组不同功能元件区域的甲基化水平分布



2.7差异性甲基化区域(DMR)分析

在两个样品基因组相同位置上寻找包含5个CG的窗口,用CG甲基化水平的差异来寻找甲基化有差异的区域。确定每条染色体上有差异的区域长度和有差异的基 因,并对这些基因做 GO 聚类功能分析,以分析差异相关基因是否有明显的功能聚类,即是否针对性地调控行使某类功能。DMR分析须基于两个样品进行差异比较。



DMR相关基因的GO聚类分析



3. 个性化信息分析

根据客户的具体项目需求进行个性化分析。

质控

分离至受感染的E. coli, 是一段长488, 502bp的未甲基化修饰的DNA片段。在Bisulfite处理中可以作为阴性对照用于计算Bisulfite处理的转化率。在文库构建过程中,λ- DNA会被加入到样品中(5ngλ-DNA/μg样品DNA),在完成测序后,通过信息分析来计算转化率。

案例分析:

研究者采用全基因组重亚硫酸盐测序方法,对小鼠胚胎干细胞(ES)和神经元祖细胞(NP)进行分析,构建小鼠单碱基对精度全基因组甲基化图谱。该张图谱显 示,小鼠基因组中大部分区域(89.4%)呈现高甲基化状态,小部分区域(6.5%)呈现未甲基化状态,另外还有一部分区域(4.1%)呈现出低甲基化状 态(LMRs)。研究者对这小部分的低甲基化区域很感兴趣,对这些区域的特征进行详细的分析,他们发现转录因子以一种定向的方式促成LMRs模式出现。如 果没有这些转录因子的作用,DNA依然保持甲基化和紧凑包装。由此研究者提出一种全新的表观遗传模式--转录因子介导的低甲基化调控模式。



小鼠胚胎肝细胞甲基化谱


原始出处:
Stadler MB, Murr R, Burger L, Ivanek R, Lienert F, Schöler A, van Nimwegen E, Wirbelauer C, Oakeley EJ, Gaidatzis D, Tiwari VK, Schübeler D.DNA-binding factors shape the mouse methylome at distal regulatory regions.Nature. 2011 Dec 14;480(7378):490-5.

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    2014-05-31 neurowu
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    2014-06-13 kalseyzl
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    2014-07-15 gameplan

    都有点应接不暇了!更新太快了

    0

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    2014-02-05 36氪

    新技术太多

    0

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