Dyschromatosis universalis hereditaria (DUH) is a pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules distributed randomly over the body. No causative genes have been reported to date. In this study, we investigated a large five-generation Chinese family with DUH. After excluding the two known DUH loci, we performed genome-wide linkage analysis and identified a DUH locus on chromosome 2q33.3-q36.1 with a maximum LOD score of 3.49 with marker D2S2382. Exome sequencing identified a c.1067T>C (p.Leu356Pro) mutation in exon 3 of ABCB6 (ATP-binding cassette subfamily B, member 6) in the DUH family. Two additional missense mutations, c.508A>G (p.Ser170Gly) in exon 1 and c.1736G>A (p.Gly579Glu) in exon 12 of ABCB6, were found in two out of six patients by mutational screening using sporadic DUH patients. Immunohistologic examination in biopsy specimens showed that ABCB6 is expressed in the epidermis and had a diffuse cytoplasmic distribution. Examination of subcellular localization of wild-type ABCB6 in a B16 mouse melanoma cell line revealed that it is localized to the endosome-like compartment and dendrite tips, whereas disease-causing mutations of ABCB6 resulted in its retention in the Golgi apparatus. Our studies identified ABCB6 as the first pathogenic gene associated with DUH. These findings suggest that ABCB6 may be a physiological factor for skin pigmentation. © 2013 The Society for Investigative Dermatology.

Zhang Caie    Li Duanzhuo    Jianguo Zhang    Chen    Huang Mi    Archacki Stephen R.    Yuke Tian    Ren Weiping    Mei Aihua    Zhang Qing-yan    Fang Mingyan    Su Zheng    Ye Yin    Liu Dongxian    Chen Yingling    Cui Xiukun    Li Chang    杨焕明     王擎    Jun Wang    刘木根    Deng Yun-Hua   

Journal of Investigative Dermatology

2013

There are remarkable disparities among patients of different races with prostate cancer; however, the mechanism underlying this difference remains unclear. Here, we present a comprehensive landscape of the transcriptome profiles of 14 primary prostate cancers and their paired normal counterparts from the Chinese population using RNA-seq, revealing tremendous diversity across prostate cancer transcriptomes with respect to gene fusions, long noncoding RNAs (long ncRNA), alternative splicing and somatic mutations. Three of the 14 tumors (21.4%) harbored a TMPRSS2-ERG fusion, and the low prevalence of this fusion in Chinese patients was further confirmed in an additional tumor set (10/54=18.5%). Notably, two novel gene fusions, CTAGE5-KHDRBS3 (20/54=37%) and USP9Y-TTTY15 (19/54=35.2%), occurred frequently in our patient cohort. Further systematic transcriptional profiling identified numerous long ncRNAs that were differentially expressed in the tumors. An analysis of the correlation between expression of long ncRNA and genes suggested that long ncRNAs may have functions beyond transcriptional regulation. This study yielded new insights into the pathogenesis of prostate cancer in the Chinese population. © 2012 IBCB, SIBS, CAS All rights reserved.

Shancheng Ren    Zhiyu Peng    Jianhua Mao    Yongwei Yu    Changjun Yin    Xin Gao    Cui Zilian    Zhang Jibin    Yi Kang    徐卫东    陈超    Fubo Wang    Guo Xinwu    Ji Lu    Yang Jun    Wei Min    Tian Zhijian    Guan Yinghui    Liang Tang    许传亮    王林辉    Gao Xu    Wei Tian    Jian Wang    杨焕明     Jun Wang    孙颖浩   

Cell Research

2012

The utility of induced pluripotent stem cells (iPSCs) as models to study diseases and as sources for cell therapy depends on the integrity of their genomes. Despite recent publications of DNA sequence variations in the iPSCs, the true scope of such changes for the entire genome is not clear. Here we report the whole-genome sequencing of three human iPSC lines derived from two cell types of an adult donor by episomal vectors. The vector sequence was undetectable in the deeply sequenced iPSC lines. We identified 1,058-1,808 heterozygous single-nucleotide variants (SNVs), but no copy-number variants, in each iPSC line. Six to twelve of these SNVs were within coding regions in each iPSC line, but ∼50% of them are synonymous changes and the remaining are not selectively enriched for known genes associated with cancers. Our data thus suggest that episome-mediated reprogramming is not inherently mutagenic during integration-free iPSC induction. © 2012 Elsevier Inc.

程临钊    Nancy fisher Hansen    Zhao Ling    Yutao Du    Zou Chun-Lin    Donovan Frank X.    Chou Bin-Kuan    Zhou Guangyu    Li Shijie    Dowey Sarah N.    Zhaohui Ye    Chandrasekharappa Settara    杨焕明     James Mullikin    Paul Liu   

Cell Stem Cell

2012

Tumor heterogeneity presents a challenge for inferring clonal evolution and driver gene identification. Here, we describe a method for analyzing the cancer genome at a single-cell nucleotide level. To perform our analyses, we first devised and validated a high-throughput whole-genome single-cell sequencing method using two lymphoblastoid cell line single cells. We then carried out whole-exome single-cell sequencing of 90 cells from a JAK2-negative myeloproliferative neoplasm patient. The sequencing data from 58 cells passed our quality control criteria, and these data indicated that this neoplasm represented a monoclonal evolution. We further identified essential thrombocythemia (ET)-related candidate mutations such as SESN2 and NTRK1, which may be involved in neoplasm progression. This pilot study allowed the initial characterization of the disease-related genetic architecture at the single-cell nucleotide level. Further, we established a single-cell sequencing method that opens the way for detailed analyses of a variety of tumor types, including those with high genetic complex between patients. © 2012 Elsevier Inc.

Yong Hou    Song Luting    Zhu Ping    Bo Zhang    Ye Tao    许迅    Li Fuqiang    Kui Wu    Liang Jie    Shao Di    Wu Hanjie    Ye Xiaofei    Chen Ye    Renhua Wu    Min Jian    Yan Chen    Wei Xie    Zhang Ruren    Lei Chen    Xin Liu    Yao Xiaotian    Hancheng Zheng    Chang Yu    Qibin Li    Gong Zhuolin    Mao Mao    Yang Xu    Lin Yang    Jingxiang Li    Wen Wang    陆祖宏    顾宁    Laurie Goodman    Lars Bolund    Karsten Kristiansen    Jian Wang    杨焕明     李英睿    Xiuqing Zhang    王军   

Cell

2012

Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer and has very few mutations that are shared between different patients. To better understand the intratumoral genetics underlying mutations of ccRCC, we carried out single-cell exome sequencing on a ccRCC tumor and its adjacent kidney tissue. Our data indicate that this tumor was unlikely to have resulted from mutations in VHL and PBRM1. Quantitative population genetic analysis indicates that the tumor did not contain any significant clonal subpopulations and also showed that mutations that had different allele frequencies within the population also had different mutation spectrums. Analyses of these data allowed us to delineate a detailed intratumoral genetic landscape at a single-cell level. Our pilot study demonstrates that ccRCC may be more genetically complex than previously thought and provides information that can lead to new ways to investigate individual tumors, with the aim of developing more effective cellular targeted therapies. © 2012 Elsevier Inc.

许迅    Yong Hou    Yin Xuyang    Bao Li    Aifa Tang    Song Luting    Li Fuqiang    Tsang Shirley    Kui Wu    Wu Hanjie    Weiming He    Liang Zeng    Xing Manjie    Renhua Wu    Hui Jiang    Xiao Liu    Dandan Cao    Guangwu Guo    Xueda Hu    桂耀庭    Zesong Li    Xie Wenyue    Xiaojuan Sun    Min Shi    Zhiming Cai    Wang Bin    Zhong Meiming    Jingxiang Li    陆祖宏    顾宁    Xiuqing Zhang    Goodman Laurie    Lars Bolund    Jian Wang    杨焕明     Karsten Kristiansen    Michael Dean    李英睿    王军   

Cell

2012

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. © 2012 Macmillan Publishers Limited. All rights reserved.

Mingzhou Li    Wu Honglong    Luo Zonggang    Xia Yudong    Guan Jiuqiang    tao Wang    Gu Yiren    Lei Chen    Zhang Kai    Jideng Ma    Liu Yingkai    Zhong Zhijun    Nie Jing    Zhou Shuling    Mu Zhiping    Wang Xiaoyan    Qu Jingjing    Jing Long    Wang Huiyu    Huang Shujia    Yi Na    Wang Zhe    Xi Dongxing    Wang Juan    Guangliang Yin    Li Wang    Ning Li    Jiang Zhi    Qiulei Lang    肖华胜    Anan Jiang    Zhu Li    Jiang Yanzhi    Guoqing Tang    Mai Miaomiao    Shuai Surong    Kui Li    Jinyong WANG    Xiuqing Zhang    李英睿    Chen Haosi    高晓莲    Plastow G.    Stephan Beck    杨焕明     Jian Wang    Jun Wang    Xuewei Li    李瑞强   

Nature Communications

2012

Domestic yaks (Bos grunniens) provide meat and other necessities for Tibetans living at high altitude on the Qinghai-Tibetan Plateau and in adjacent regions. Comparison between yak and the closely related low-altitude cattle (Bos taurus) is informative in studying animal adaptation to high altitude. Here, we present the draft genome sequence of a female domestic yak generated using Illumina-based technology at 65-fold coverage. Genomic comparisons between yak and cattle identify an expansion in yak of gene families related to sensory perception and energy metabolism, as well as an enrichment of protein domains involved in sensing the extracellular environment and hypoxic stress. Positively selected and rapidly evolving genes in the yak lineage are also found to be significantly enriched in functional categories and pathways related to hypoxia and nutrition metabolism. These findings may have important implications for understanding adaptation to high altitude in other animal species and for hypoxia-related diseases in humans. © 2012 Nature America, Inc. All rights reserved.

Qiang Qiu    Guo jie Zhang    Ma Tao    Qian Wubin    叶志强    Cao Changchang    Hu Quanjun    Kim Jaebum    Larkin Denis M.    Auvil Loretta    Boris Capitanu    Jian Ma    Harris Lewin    Qian Xiaoju    Lang Yongshan    Zhou Ran    Wang Lizhong    Wang Kun    Xia Jinquan    Liao Shengguang    Shengkai Pan    Lu Xu    Haolong Hou    Wang Yan    Zang Xuetao    Ye Yin    Hui Ma    Jian Zhang    Wang Zhaofeng    Yingmei Zhang    Zhang Dawei    Takahiro Yonezawa    Masami Hasegawa    Yang Zhong    Liu Wenbin    Yan Zhang    Zhiyong Huang    Zhang Shengxiang    Ruijun Long    杨焕明     Lenstra Johannes A.    David Cooper    Yi Wu    王军    Peng Shi    Jian Wang    刘建全    Wang   

Nature Genetics

2012

Disseminated superficial actinic porokeratosis (DSAP) is an autosomal dominantly inherited epidermal keratinization disorder whose etiology remains unclear. We performed exome sequencing in one unaffected and two affected individuals from a DSAP family. The mevalonate kinase gene (MVK) emerged as the only candidate gene located in previously defined linkage regions after filtering against existing SNP databases, eight HapMap exomes and 1000 Genomes Project data and taking into consideration the functional implications of the mutations. Sanger sequencing in 57 individuals with familial DSAP and 25 individuals with sporadic DSAP identified MVK mutations in 33% and 16% of these individuals (cases), respectively. All 14 MVK mutations identified in our study were absent in 676 individuals without DSAP. Our functional studies in cultured primary keratinocytes suggest that MVK has a role in regulating calcium-induced keratinocyte differentiation and could protect keratinocytes from apoptosis induced by type A ultraviolet radiation. Our results should help advance the understanding of DSAP pathogenesis. © 2012 Nature America, Inc. All rights reserved.

Zhang Sheng-Quan    Jiang Tao    Li Min    Zhang Xin    Yunqing Ren    Wei Sheng-Cai    Liangdan Sun    Hui Cheng    Yang Li    Xianyong Yin    Zhengmao Hu    Wang Zhen-Ying    Liu Yuan    Guo Bi-Rong    Huayang Tang    Xianfa Tang    Yantao Ding    Wang Jianbo    Ping Li    Wu Bao-Yu    Wang Wen    Yuan Xiang-Feng    Hou Jun-Sheng    Ha Wei-Wei    Wang Wen-Ju    Zhai Yu-Juan    Wang Jing    Qian Fang-Fang    Fusheng Zhou    Gang Chen    Xianbo Zuo    Xiaodong Zheng    Yujun Sheng    Jinping Gao    Liang Bo    Pan Li    Zhu Jun    Fengli Xiao    Peiguang Wang    Yong Cui    Li Hui    Liu Sheng-Xiu    Min Gao    Xing Fan    Shen Song-Ke    Zeng Ming    Sun Guang-Qing    Xu Yu    Hu Jingchu    He Ting-Ting    李英睿    杨焕明     Weng Jian    Yu Zhong-Yi    Zhang Hui-Feng    Hu Xin    Yang Ke    Wang    Zhao Shi-Xiang    Youwen Zhou    Jianjun Liu    Weidong Du    张莉    Kun Xia    Sen Yang    Jun Wang    Xuejun Zhang   

Nature Genetics

2012

Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes. © 2012 Macmillan Publishers Limited. All rights reserved.

王军    Junjie Qin    李英睿    Zhiming Cai    Li Shenghui    Zhu Jianfeng    Zhang Fan    Suisha Liang    Wenwei Zhang    Guan Yuanlin    Shen Dongqian    Peng Yangqing    Zhang Dongya    Jie Zhuye    Wu Wenxian    Qin Youwen    Xue Wenbin    Junhua Li    Han Lingchuan    Lu Donghui    Wu Peixian    Dai Yali    Xiaojuan Sun    Zesong Li    Aifa Tang    Shilong Zhong    Li Xiaoping    Chen Weineng    Xu Ran    Wang Mingbang    Qiang Feng    Gong Meihua    Jing Yu    Zhang Yanyan    Zhang Ming    Torben froestrup Hansen    Sanchez Gaston    Jeroen Raes    Gwen Falony    Okuda Shujiro    Mathieu Almeida    Lechatelier Emmanuelle    Pierre Renault    Nicolas Pons    Jean michel Batto    Zhang Zhaoxi    Chen Hua    Ruifu Yang    郑伟谋    Songgang Li    杨焕明     Stanislav dusko Ehrlich    Rasmus wedel Nielsen    Oluf borbye orbye Pedersen    Karsten Kristiansen    Jian Wang   

Nature

2012

The Pacific oyster Crassostrea gigas belongs to one of the most species-rich but genomically poorly explored phyla, the Mollusca. Here we report the sequencing and assembly of the oyster genome using short reads and a fosmid-pooling strategy, along with transcriptomes of development and stress response and the proteome of the shell. The oyster genome is highly polymorphic and rich in repetitive sequences, with some transposable elements still actively shaping variation. Transcriptome studies reveal an extensive set of genes responding to environmental stress. The expansion of genes coding for heat shock protein 70 and inhibitors of apoptosis is probably central to the oyster's adaptation to sessile life in the highly stressful intertidal zone. Our analyses also show that shell formation in molluscs is more complex than currently understood and involves extensive participation of cells and their exosomes. The oyster genome sequence fills a void in our understanding of the Lophotrochozoa. © 2012 Macmillan Publishers Limited. All rights reserved.

王军    Guofan Zhang    Xiaodong Fang    Ximing Guo    Lì Lì    Ruibang Luo    Xu Fei    杨鹏程    Linlin Zhang    Wang Xiaotong    Qi Haigang    Zhiqiang Xiong    Huayong Que    Yinlong Xie    Holland Peter W. H.    Paps Jordi    Yabing Zhu    Wu Fucun    Yuanxin Chen    Wang Jiafeng    Peng Chunfang    Jie Meng    Lan Yang    Jun Liu    Bo Wen    Zhang Na    Zhiyong Huang    Qihui Zhu    Yue Feng    Andrew Mount    Hedgecock Dennis    Zhe Xu    Liu Yunjie    Domazet-Lošo Tomislav    Du Yishuai    Xiaoqing Sun    Zhang Shoudu    Binghang Liu    Cheng Peizhou    Xuanting Jiang    Juan Li    Dingding Fan    Wang Wei    Fu Wenjing    Wang Tong    bo Wang    Zhang Jibiao    Zhiyu Peng    Li Yingxiang    Li Na    Jinpeng Wang    Maoshan Chen    Yan He    Tan Fengji    Xiaorui Song    Zheng Qiumei    Huang Ronglian    Yang Hailong    Du Xuedi    Chen Li    杨美    Gaffney Patrick M.    Wang Shan    Luo Longhai    She Zhicai    Ming Yao    Huang Wen    Shu Zhang    Huang Baoyu    Zhang Yong    Qu Tao    Peixiang Ni    Miao Guoying    Junyi Wang    Qiang Wang    Christian eugen wilhem Steinberg    Haiyan Wang    Ning Li    Qian Lumin    Guo jie Zhang    李英睿    杨焕明     Xiao Liu    Ye Yin    Jian Wang   

Nature

2012