华大基因5月连发两篇Nature子刊 获基因组新发现

　　生物通报道：作为测序的排头兵，华大基因不仅在中国序列研究领域占据首要地位，更是在全球基因组研究中占据一席之地。伴随着1999年“国际人类基因组计划 1% 项目”正式启动的深圳华大基因研究院不仅顺利完成国际人类基因组计划1%，而且在这几年里取得了飞跃式的发展。今年5月，这一研究院又联合其它科研单位，接连发表了猪脂肪和肌肉组织的基因组甲基化研究成果，以及通过基因测序全面揭示乙肝病毒整合机制。

在第一篇文章（Genome-wide Survey of Recurrent HBV Integration in Hepatocellular Carcinoma）中，深圳华大基因研究院与香港大学、新加坡国立大学等处合作，从全基因组水平上首次构建了一个高精度无偏差的乙肝病毒整合（HBV Integration）图谱，揭示了潜在的乙肝病毒整合机制，为肝癌的早期诊断、治疗及靶向药物研发等提供了非常宝贵的资源。

研究人员分别对来自81例HBV阳性患者和7例HBV阴性患者的癌组织样本和癌旁组织样本进行了全基因组测序及分析。结果发现HBV整合在肝癌中是一种普遍现象，HBV整合频率在癌组织中（86.4%）明显高于癌旁组织（30.7%）。结合转录组测序数据分析后，研究人员发现了3个新的HBV整合位点（CCNE1, SENP5, ROCK1），并推测这些基因可能在癌症的发生过程中起着非常重要的作用。

基于本研究成果，研究人员对潜在的HBV整合规律及其致癌机制进行了推测。他们发现HBV整合所具有的某些特征有助于病毒控制被感染的宿主基因，如HBV整合位点的偏向性以及HBV整合位点拷贝数目变异（CNV）增加等，这些变化将会影响染色体的稳定性及引起基因表达的改变。此外，研究还发现HBV整合与患者的临床表现密切相关。发生HBV整合的患者会更早地发展成为肝细胞癌而且治愈率更低。因此，通过对HBV整合的干预治疗可能有助于防止癌症的恶化，延长病人的生命。

第二篇文章（An atlas of DNA methylomes in porcine adipose and muscle tissues）由四川农业大学和深圳华大基因研究院主导，经过中、美、英、加四国共12个单位的50多位研究人员合作完成。

肥胖可以被视为一种流行病，在现代社会对人类健康有较大风险。肥胖已成为一些慢性疾病包括糖尿病、心血管疾病和癌症的一个重要的危险因素。据预测到2030年，全球成人人口中约58％的人可能超重或患有肥胖。

研究人员把猪作为研究模型。共选择三类猪种包括长白猪，藏族和荣昌猪。在表观数据的基础上，研究人员构建了全基因组DNA甲基化图以及研究脂肪和肌肉所需的基因表达图谱。

这项研究首次构建了猪不同部位脂肪和肌肉组织的DNA甲基化图谱，为预防人类肥胖疾病的发生和促进猪肌肉生长及脂肪沉积这一重要经济性状的研究，奠定了重要的表观遗传学基础。

这篇文章发表后，仅仅一天时间就被付费下载了2808次，而该杂志每篇文章平均每年的下载量也就1900―2800次。

（生物通：万纹）

原文摘要：

Genome-wide Survey of Recurrent HBV Integration in Hepatocellular Carcinoma

To survey hepatitis B virus (HBV) integration in liver cancer genomes, we conducted massively parallel sequencing of 81 HBV-positive and 7 HBV-negative hepatocellular carcinomas (HCCs) and adjacent normal tissues. We found that HBV integration is observed more frequently in the tumors (86.4%) than in adjacent liver tissues (30.7%). Copy-number variations (CNVs) were significantly increased at HBV breakpoint locations where chromosomal instability was likely induced. Approximately 40% of HBV breakpoints within the HBV genome were located within a 1,800-bp region where the viral enhancer, X gene and core gene are located. We also identified recurrent HBV integration events (in ≥4 HCCs) that were validated by RNA sequencing (RNA-seq) and Sanger sequencing at the known and putative cancer-related TERT, MLL4 and CCNE1 genes, which showed upregulated gene expression in tumor versus normal tissue. We also report evidence that suggests that the number of HBV integrations is associated with patient survival.

An atlas of DNA methylomes in porcine adipose and muscle tissues

It is evident that epigenetic factors, especially DNA methylation, have essential roles in obesity development. Here, using pig as a model, we investigate the systematic association between DNA methylation and obesity. We sample eight variant adipose and two distinct skeletal muscle tissues from three pig breeds living within comparable environments but displaying distinct fat level. We generate 1,381 Gb of sequence data from 180 methylated DNA immunoprecipitation libraries, and provide a genome-wide DNA methylation map as well as a gene expression map for adipose and muscle studies. The analysis shows global similarity and difference among breeds, sexes and anatomic locations, and identifies the differentially methylated regions. The differentially methylated regions in promoters are highly associated with obesity development via expression repression of both known obesity-related genes and novel genes. This comprehensive map provides a solid basis for exploring epigenetic mechanisms of adipose deposition and muscle growth.