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author:("Li, shengjing")
1.  Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios 
Nature Communications  2015;6:5969.
Building a population-specific catalogue of single nucleotide variants (SNVs), indels and structural variants (SVs) with frequencies, termed a national pan-genome, is critical for further advancing clinical and public health genetics in large cohorts. Here we report a Danish pan-genome obtained from sequencing 10 trios to high depth (50 × ). We report 536k novel SNVs and 283k novel short indels from mapping approaches and develop a population-wide de novo assembly approach to identify 132k novel indels larger than 10 nucleotides with low false discovery rates. We identify a higher proportion of indels and SVs than previous efforts showing the merits of high coverage and de novo assembly approaches. In addition, we use trio information to identify de novo mutations and use a probabilistic method to provide direct estimates of 1.27e−8 and 1.5e−9 per nucleotide per generation for SNVs and indels, respectively.
The generation of a national pan-genome, a population-specific catalogue of genetic variation, may advance the impact of clinical genetics studies. Here the Besenbacher et al. carry out deep sequencing and de novo assembly of 10 parent–child trios to generate a Danish pan-genome that provides insight into structural variation, de novo mutation rates and variant calling.
doi:10.1038/ncomms6969
PMCID: PMC4309431  PMID: 25597990
2.  The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific 
Aging Cell  2013;13(3):401-407.
To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes.
doi:10.1111/acel.12186
PMCID: PMC4326891  PMID: 24341918
genetics of longevity; longevity; mitochondrial DNA; mtDNA sequencing; oxidative phosphorylation
3.  A human gut microbial gene catalog established by metagenomic sequencing 
Nature  2010;464(7285):59-65.
To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million nonredundant microbial genes, derived from 576.7 Gb sequence, from faecal samples of 124 European individuals. The gene set, ~150 times larger than the human gene complement, contains an overwhelming majority of the prevalent microbial genes of the cohort and likely includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, suggesting that the entire cohort harbours between 1000 and 1150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions encoded by the gene set.
doi:10.1038/nature08821
PMCID: PMC3779803  PMID: 20203603
4.  Analyses of pig genomes provide insight into porcine demography and evolution 
Groenen, Martien A. M. | Archibald, Alan L. | Uenishi, Hirohide | Tuggle, Christopher K. | Takeuchi, Yasuhiro | Rothschild, Max F. | Rogel-Gaillard, Claire | Park, Chankyu | Milan, Denis | Megens, Hendrik-Jan | Li, Shengting | Larkin, Denis M. | Kim, Heebal | Frantz, Laurent A. F. | Caccamo, Mario | Ahn, Hyeonju | Aken, Bronwen L. | Anselmo, Anna | Anthon, Christian | Auvil, Loretta | Badaoui, Bouabid | Beattie, Craig W. | Bendixen, Christian | Berman, Daniel | Blecha, Frank | Blomberg, Jonas | Bolund, Lars | Bosse, Mirte | Botti, Sara | Bujie, Zhan | Bystrom, Megan | Capitanu, Boris | Silva, Denise Carvalho | Chardon, Patrick | Chen, Celine | Cheng, Ryan | Choi, Sang-Haeng | Chow, William | Clark, Richard C. | Clee, Christopher | Crooijmans, Richard P. M. A. | Dawson, Harry D. | Dehais, Patrice | De Sapio, Fioravante | Dibbits, Bert | Drou, Nizar | Du, Zhi-Qiang | Eversole, Kellye | Fadista, João | Fairley, Susan | Faraut, Thomas | Faulkner, Geoffrey J. | Fowler, Katie E. | Fredholm, Merete | Fritz, Eric | Gilbert, James G. R. | Giuffra, Elisabetta | Gorodkin, Jan | Griffin, Darren K. | Harrow, Jennifer L. | Hayward, Alexander | Howe, Kerstin | Hu, Zhi-Liang | Humphray, Sean J. | Hunt, Toby | Hornshøj, Henrik | Jeon, Jin-Tae | Jern, Patric | Jones, Matthew | Jurka, Jerzy | Kanamori, Hiroyuki | Kapetanovic, Ronan | Kim, Jaebum | Kim, Jae-Hwan | Kim, Kyu-Won | Kim, Tae-Hun | Larson, Greger | Lee, Kyooyeol | Lee, Kyung-Tai | Leggett, Richard | Lewin, Harris A. | Li, Yingrui | Liu, Wansheng | Loveland, Jane E. | Lu, Yao | Lunney, Joan K. | Ma, Jian | Madsen, Ole | Mann, Katherine | Matthews, Lucy | McLaren, Stuart | Morozumi, Takeya | Murtaugh, Michael P. | Narayan, Jitendra | Nguyen, Dinh Truong | Ni, Peixiang | Oh, Song-Jung | Onteru, Suneel | Panitz, Frank | Park, Eung-Woo | Park, Hong-Seog | Pascal, Geraldine | Paudel, Yogesh | Perez-Enciso, Miguel | Ramirez-Gonzalez, Ricardo | Reecy, James M. | Zas, Sandra Rodriguez | Rohrer, Gary A. | Rund, Lauretta | Sang, Yongming | Schachtschneider, Kyle | Schraiber, Joshua G. | Schwartz, John | Scobie, Linda | Scott, Carol | Searle, Stephen | Servin, Bertrand | Southey, Bruce R. | Sperber, Goran | Stadler, Peter | Sweedler, Jonathan V. | Tafer, Hakim | Thomsen, Bo | Wali, Rashmi | Wang, Jian | Wang, Jun | White, Simon | Xu, Xun | Yerle, Martine | Zhang, Guojie | Zhang, Jianguo | Zhang, Jie | Zhao, Shuhong | Rogers, Jane | Churcher, Carol | Schook, Lawrence B.
Nature  2012;491(7424):393-398.
For 10,000 years pigs and humans have shared a close and complex relationship. From domestication to modern breeding practices, humans have shaped the genomes of domestic pigs. Here we present the assembly and analysis of the genome sequence of a female domestic Duroc pig (Sus scrofa) and a comparison with the genomes of wild and domestic pigs from Europe and Asia. Wild pigs emerged in South East Asia and subsequently spread across Eurasia. Our results reveal a deep phylogenetic split between European and Asian wild boars ~1 million years ago, and a selective sweep analysis indicates selection on genes involved in RNA processing and regulation. Genes associated with immune response and olfaction exhibit fast evolution. Pigs have the largest repertoire of functional olfactory receptor genes, reflecting the importance of smell in this scavenging animal. The pig genome sequence provides an important resource for further improvements of this important livestock species, and our identification of many putative disease-causing variants extends the potential of the pig as a biomedical model.
doi:10.1038/nature11622
PMCID: PMC3566564  PMID: 23151582
5.  Comparison of Gene Expression and Genome-Wide DNA Methylation Profiling between Phenotypically Normal Cloned Pigs and Conventionally Bred Controls 
PLoS ONE  2011;6(10):e25901.
Animal breeding via Somatic Cell Nuclear Transfer (SCNT) has enormous potential in agriculture and biomedicine. However, concerns about whether SCNT animals are as healthy or epigenetically normal as conventionally bred ones are raised as the efficiency of cloning by SCNT is much lower than natural breeding or In-vitro fertilization (IVF). Thus, we have conducted a genome-wide gene expression and DNA methylation profiling between phenotypically normal cloned pigs and control pigs in two tissues (muscle and liver), using Affymetrix Porcine expression array as well as modified methylation-specific digital karyotyping (MMSDK) and Solexa sequencing technology. Typical tissue-specific differences with respect to both gene expression and DNA methylation were observed in muscle and liver from cloned as well as control pigs. Gene expression profiles were highly similar between cloned pigs and controls, though a small set of genes showed altered expression. Cloned pigs presented a more different pattern of DNA methylation in unique sequences in both tissues. Especially a small set of genomic sites had different DNA methylation status with a trend towards slightly increased methylation levels in cloned pigs. Molecular network analysis of the genes that contained such differential methylation loci revealed a significant network related to tissue development. In conclusion, our study showed that phenotypically normal cloned pigs were highly similar with normal breeding pigs in their gene expression, but moderate alteration in DNA methylation aspects still exists, especially in certain unique genomic regions.
doi:10.1371/journal.pone.0025901
PMCID: PMC3191147  PMID: 22022462
6.  Tumor heterogeneity in neoplasms of breast, colon, and skin 
BMC Research Notes  2010;3:321.
Background
Different cell subpopulations in a single tumor may show diverse capacities for growth, differentiation, metastasis formation, and sensitivity to treatments. Thus, heterogeneity is an important feature of tumors. However, due to limitations in experimental and analytical techniques, tumor heterogeneity has rarely been studied in detail.
Presentation of the hypothesis
Different tumor types have different heterogeneity patterns, thus heterogeneity could be a characteristic feature of a particular tumor type.
Testing the hypothesis
We applied our previously published mathematical heterogeneity model to decipher tumor heterogeneity through the analysis of genetic copy number aberrations revealed by array CGH data for tumors of three different tissues: breast, colon, and skin. The model estimates the number of subpopulations present in each tumor. The analysis confirms that different tumor types have different heterogeneity patterns. Computationally derived genomic copy number profiles from each subpopulation have also been analyzed and discussed with reference to the multiple hypothetical relationships between subpopulations in origin-related samples.
Implications of the hypothesis
Our observations imply that tumor heterogeneity could be seen as an independent parameter for determining the characteristics of tumors. In the context of more comprehensive usage of array CGH or genome sequencing in a clinical setting our study provides a new way to realize the full potential of tumor genetic analysis.
doi:10.1186/1756-0500-3-321
PMCID: PMC3002363  PMID: 21108813
7.  An improved method for genome wide DNA methylation profiling correlated to transcription and genomic instability in two breast cancer cell lines 
BMC Genomics  2009;10:223.
Background
DNA methylation is a widely studied epigenetic mechanism known to correlate with gene repression and genomic stability. Development of sensitive methods for global detection of DNA methylation events is of particular importance.
Results
We here describe a technique, called modified methylation-specific digital karyotyping (MMSDK) based on methylation-specific digital karyotyping (MSDK) with a novel sequencing approach. Briefly, after a tandem digestion of genomic DNA with a methylation-sensitive mapping enzyme and a fragmenting enzyme, short sequence tags are obtained. These tags are amplified, followed by direct, massively parallel sequencing (Solexa 1G Genome Analyzer). This method allows high-throughput and low-cost genome-wide DNA methylation mapping. We applied this method to investigate global DNA methylation profiles for widely used breast cancer cell lines, MCF-7 and MDA-MB-231, which are representatives for luminal-like and mesenchymal-like cancer types, respectively. By comparison, a highly similar overall DNA methylation pattern was revealed for the two cell lines. However a cohort of individual genomic loci with significantly different DNA methylation status between two cell lines was identified. Furthermore, we revealed a genome-wide significant correlation between gene expression and the methylation status of gene promoters with CpG islands (CGIs) in the two cancer cell lines, and a correlation of gene expression and the methylation status of promoters without CGIs in MCF-7 cells.
Conclusion
The MMSDK method will be a valuable tool to increase the current knowledge of genome wide DNA methylation profiles.
doi:10.1186/1471-2164-10-223
PMCID: PMC2696471  PMID: 19439076
8.  Estimation of tumor heterogeneity using CGH array data 
BMC Bioinformatics  2009;10:12.
Background
Array-based comparative genomic hybridization (CGH) is a commonly-used approach to detect DNA copy number variation in whole genome-wide screens. Several statistical methods have been proposed to define genomic segments with different copy numbers in cancer tumors. However, most tumors are heterogeneous and show variation in DNA copy numbers across tumor cells. The challenge is to reveal the copy number profiles of the subpopulations in a tumor and to estimate the percentage of each subpopulation.
Results
We describe a relation between experimental data and exact DNA copy number and develop a statistical method to reveal the heterogeneity of tumors containing a mixture of different-stage cells. Furthermore, we validate the method on simulated data and apply the method to 29 pairs of breast primary tumors and their matched lymph node metastases.
Conclusion
We demonstrate a new method for CGH array analysis that allows a tumor sample to be classified according to its heterogeneity. The method gives an interpretable series of copy number profiles, one for each major subpopulation in a tumor. The profiles facilitate identification of copy number alterations in cancer development.
doi:10.1186/1471-2105-10-12
PMCID: PMC2640360  PMID: 19134174
9.  Snap: an integrated SNP annotation platform 
Nucleic Acids Research  2006;35(Database issue):D707-D710.
Snap (Single Nucleotide Polymorphism Annotation Platform) is a server designed to comprehensively analyze single genes and relationships between genes basing on SNPs in the human genome. The aim of the platform is to facilitate the study of SNP finding and analysis within the framework of medical research. Using a user-friendly web interface, genes can be searched by name, description, position, SNP ID or clone name. Several public databases are integrated, including gene information from Ensembl, protein features from Uniprot/SWISS-PROT, Pfam and DAS-CBS. Gene relationships are fetched from BIND, MINT, KEGG and are integrated with ortholog data from TreeFam to extend the current interaction networks. Integrated tools for primer-design and mis-splicing analysis have been developed to facilitate experimental analysis of individual genes with focus on their variation. Snap is available at and at .
doi:10.1093/nar/gkl969
PMCID: PMC1751554  PMID: 17135198
10.  WEGO: a web tool for plotting GO annotations 
Nucleic Acids Research  2006;34(Web Server issue):W293-W297.
Unified, structured vocabularies and classifications freely provided by the Gene Ontology (GO) Consortium are widely accepted in most of the large scale gene annotation projects. Consequently, many tools have been created for use with the GO ontologies. WEGO (Web Gene Ontology Annotation Plot) is a simple but useful tool for visualizing, comparing and plotting GO annotation results. Different from other commercial software for creating chart, WEGO is designed to deal with the directed acyclic graph structure of GO to facilitate histogram creation of GO annotation results. WEGO has been used widely in many important biological research projects, such as the rice genome project and the silkworm genome project. It has become one of the daily tools for downstream gene annotation analysis, especially when performing comparative genomics tasks. WEGO, along with the two other tools, namely External to GO Query and GO Archive Query, are freely available for all users at . There are two available mirror sites at and . Any suggestions are welcome at wego@genomics.org.cn.
doi:10.1093/nar/gkl031
PMCID: PMC1538768  PMID: 16845012
11.  The Genomes of Oryza sativa: A History of Duplications 
Yu, Jun | Wang, Jun | Lin, Wei | Li, Songgang | Li, Heng | Zhou, Jun | Ni, Peixiang | Dong, Wei | Hu, Songnian | Zeng, Changqing | Zhang, Jianguo | Zhang, Yong | Li, Ruiqiang | Xu, Zuyuan | Li, Shengting | Li, Xianran | Zheng, Hongkun | Cong, Lijuan | Lin, Liang | Yin, Jianning | Geng, Jianing | Li, Guangyuan | Shi, Jianping | Liu, Juan | Lv, Hong | Li, Jun | Wang, Jing | Deng, Yajun | Ran, Longhua | Shi, Xiaoli | Wang, Xiyin | Wu, Qingfa | Li, Changfeng | Ren, Xiaoyu | Wang, Jingqiang | Wang, Xiaoling | Li, Dawei | Liu, Dongyuan | Zhang, Xiaowei | Ji, Zhendong | Zhao, Wenming | Sun, Yongqiao | Zhang, Zhenpeng | Bao, Jingyue | Han, Yujun | Dong, Lingli | Ji, Jia | Chen, Peng | Wu, Shuming | Liu, Jinsong | Xiao, Ying | Bu, Dongbo | Tan, Jianlong | Yang, Li | Ye, Chen | Zhang, Jingfen | Xu, Jingyi | Zhou, Yan | Yu, Yingpu | Zhang, Bing | Zhuang, Shulin | Wei, Haibin | Liu, Bin | Lei, Meng | Yu, Hong | Li, Yuanzhe | Xu, Hao | Wei, Shulin | He, Ximiao | Fang, Lijun | Zhang, Zengjin | Zhang, Yunze | Huang, Xiangang | Su, Zhixi | Tong, Wei | Li, Jinhong | Tong, Zongzhong | Li, Shuangli | Ye, Jia | Wang, Lishun | Fang, Lin | Lei, Tingting | Chen, Chen | Chen, Huan | Xu, Zhao | Li, Haihong | Huang, Haiyan | Zhang, Feng | Xu, Huayong | Li, Na | Zhao, Caifeng | Li, Shuting | Dong, Lijun | Huang, Yanqing | Li, Long | Xi, Yan | Qi, Qiuhui | Li, Wenjie | Zhang, Bo | Hu, Wei | Zhang, Yanling | Tian, Xiangjun | Jiao, Yongzhi | Liang, Xiaohu | Jin, Jiao | Gao, Lei | Zheng, Weimou | Hao, Bailin | Liu, Siqi | Wang, Wen | Yuan, Longping | Cao, Mengliang | McDermott, Jason | Samudrala, Ram | Wang, Jian | Wong, Gane Ka-Shu | Yang, Huanming
PLoS Biology  2005;3(2):e38.
We report improved whole-genome shotgun sequences for the genomes of indica and japonica rice, both with multimegabase contiguity, or almost 1,000-fold improvement over the drafts of 2002. Tested against a nonredundant collection of 19,079 full-length cDNAs, 97.7% of the genes are aligned, without fragmentation, to the mapped super-scaffolds of one or the other genome. We introduce a gene identification procedure for plants that does not rely on similarity to known genes to remove erroneous predictions resulting from transposable elements. Using the available EST data to adjust for residual errors in the predictions, the estimated gene count is at least 38,000–40,000. Only 2%–3% of the genes are unique to any one subspecies, comparable to the amount of sequence that might still be missing. Despite this lack of variation in gene content, there is enormous variation in the intergenic regions. At least a quarter of the two sequences could not be aligned, and where they could be aligned, single nucleotide polymorphism (SNP) rates varied from as little as 3.0 SNP/kb in the coding regions to 27.6 SNP/kb in the transposable elements. A more inclusive new approach for analyzing duplication history is introduced here. It reveals an ancient whole-genome duplication, a recent segmental duplication on Chromosomes 11 and 12, and massive ongoing individual gene duplications. We find 18 distinct pairs of duplicated segments that cover 65.7% of the genome; 17 of these pairs date back to a common time before the divergence of the grasses. More important, ongoing individual gene duplications provide a never-ending source of raw material for gene genesis and are major contributors to the differences between members of the grass family.
Comparative genome sequencing of indica and japonica rice reveals that duplication of genes and genomic regions has played a major part in the evolution of grass genomes
doi:10.1371/journal.pbio.0030038
PMCID: PMC546038  PMID: 15685292

Results 1-11 (11)