Share This Article:

Novel Methods in the Study of the Breast Cancer Genome: Towards a Better Understanding of the Disease of Breast Cancer

Abstract Full-Text HTML Download Download as PDF (Size:655KB) PP. 797-809
DOI: 10.4236/jct.2012.325101    3,877 Downloads   6,399 Views  


Rapidly developing sequencing technologies and bioinformatic approacheshave provided us with an unprecedented instrument allowing for an unbiased and exhaustive characterization of the cancer genome in genetic, epigenetic and transcriptomic dimensions. This review introduces recent excitingfindings and new methodologies in genomic breast cancer research. With this development, cancer genome research will illuminate new delicate interactionsbetween molecular networks and thereby unravelthe underlying biological mechanisms for cancer initiation and progression. It also holds promise for providing a molecular clock for the estimation of the temporal processes of tumorigenesis. These methods in combination with single cell sequencing will make it possible to construct a family tree elucidating the evolutionary lineage relationships between cell populations at single-cell resolution. The anticipatedrapid progress in genomic breast cancer research should lead to anenhanced understanding of breast cancer biology andguide us towardsnovel ways to ultimatelyprevent and cure breast cancer.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

J. Li, X. Lin, N. Brünner, H. Yang and L. Bolund, "Novel Methods in the Study of the Breast Cancer Genome: Towards a Better Understanding of the Disease of Breast Cancer," Journal of Cancer Therapy, Vol. 3 No. 5A, 2012, pp. 797-809. doi: 10.4236/jct.2012.325101.


[1] J. Ferlay, H. R. Shin, F. Bray, et al., “Estimates of Worldwide Burden of Cancer in 2008: Globocan 2008,” International Journal of Cancer, Vol. 127, No. 12, 2010, pp. 2893-2917.
[2] M. R. Stratton, P. J. Campbell and P. A. Futreal, “The Cancer Genome,” Nature, Vol. 458, No. 7239, 2009, pp. 719-724. doi:10.1038/nature07943
[3] S. A. Forbes, N. Bindal, S. Bamford, et al., “Cosmic: Mining Complete Cancer Genomes in the Catalogue of Somatic Mutations in Cancer,” Nucleic Acids Research, Vol. 39, No. Database Issue, 2011, pp. D945-D950.
[4] M. Song, K. M. Lee and D. Kang, “Breast Cancer Prevention Based on Gene-Environment Interaction,” Molecular Carcinogenesis, Vol. 50, No. 4, 2011, pp. 280-290. doi:10.1002/mc.20639
[5] A. Petherick, “Environment and Genetics: Making Sense of the Noise,” Nature, Vol. 485, No. 7400, 2012, pp. S64-S65. doi:10.1038/485S64a
[6] N. Mavaddat, A. C. Antoniou, D. F. Easton, et al., “Genetic Susceptibility to Breast Cancer,” Molecular Oncology, Vol. 4, No. 3, 2010, pp. 174-191. doi:10.1016/j.molonc.2010.04.011
[7] L. M. Butcher and S. Beck, “Future Impact of Integrated High-Throughput Methylome Analyses on Human Health and Disease,” Journal of Genetics and Genomics, Vol. 35, No. 7, 2008, pp. 391-401. doi:10.1016/S1673-8527(08)60057-0
[8] J. Jovanovic, J. A. Ronneberg, J. Tost, et al., “The Epigenetics of Breast Cancer,” Molecular Oncology, Vol. 4, No. 3, 2010, pp. 242-254. doi:10.1016/j.molonc.2010.04.002
[9] Y. Huang, S. Nayak, R. Jankowitz, et al., “Epigenetics in Breast Cancer: What’s New?” Breast Cancer Research, Vol. 13, No. 6, 2011, p. 225. doi:10.1186/bcr2925
[10] M. Margulies, M. Egholm, W. E. Altman, et al., “Genome Sequencing in Microfabricated High-Density Picolitre Reactors,” Nature, Vol. 437, No. 7057, 2005, pp. 376-380.
[11] D. R. Bentley, S. Balasubramanian, H. P. Swerdlow, et al., “Accurate Whole Human Genome Sequencing Using Reversible Terminator Chemistry,” Nature, Vol. 456, No. 7218, 2008, pp. 53-59. doi:10.1038/nature07517
[12] J. Shendure, G. J. Porreca, N. B. Reppas, et al., “Accurate Multiplex Polony Sequencing of an Evolved Bacterial Genome,” Science, Vol. 309, No. 5741, 2005, pp. 1728-1732. doi:10.1126/science.1117389
[13] R. Drmanac, A. B. Sparks, M. J. Callow, et al., “Human Genome Sequencing Using Unchained Base Reads on Self-Assembling DNA Nanoarrays,” Science, Vol. 327, No. 5961, 2010, pp. 78-81. doi:10.1126/science.1181498
[14] J. M. Rothberg, W. Hinz, T. M. Rearick, et al., “An Integrated Semiconductor Device Enabling Non-Optical Genome Sequencing,” Nature, Vol. 475, No. 7356, 2011, pp. 348-352. doi:10.1038/nature10242
[15] H. Stranneheim and J. Lundeberg, “Stepping Stones in DNA Sequencing,” Biotechnology Journal, Vol. No., 2012.
[16] L. Chin and J. W. Gray, “Translating Insights from the Cancer Genome into Clinical Practice,” Nature, Vol. 452, No. 7187, 2008, pp. 553-563. doi:10.1038/nature06914
[17] A. Mortazavi, B. A. Williams, K. McCue, et al., “Mapping and Quantifying Mammalian Transcriptomes by Rna-Seq,” Nature Methods, Vol. 5, No. 7, 2008, pp. 621-628. doi:10.1038/nmeth.1226
[18] F. Ozsolak and P. M. Milos, “Rna Sequencing: Advances, Challenges and Opportunities,” Nature Reviews Genetics, Vol. 12, No. 2, 2011, pp. 87-98. doi:10.1038/nrg2934
[19] C. Lu, S. S. Tej, S. Luo, et al., “Elucidation of the Small Rna Component of the Transcriptome,” Science, Vol. 309, No. 5740, 2005, pp. 1567-1569. doi:10.1126/science.1114112
[20] K. P. McCormick, M. R. Willmann and B. C. Meyers, “Experimental Design, Preprocessing, Normalization and Differential Expression Analysis of Small Rna Sequencing Experiments,” Silence, Vol. 2, No. 1, 2011, p. 2. doi:10.1186/1758-907X-2-2
[21] L. Ding, M. J. Ellis, S. Li, et al., “Genome Remodelling in a Basal-Like Breast Cancer Metastasis and Xenograft,” Nature, Vol. 464, No. 7291, 2010, pp. 999-1005. doi:10.1038/nature08989
[22] S. P. Shah, R. D. Morin, J. Khattra, et al., “Mutational Evolution in a Lobular Breast Tumour Profiled at Single Nucleotide Resolution,” Nature, Vol. 461, No. 7265, 2009, pp. 809-813. doi:10.1038/nature08489
[23] P. J. Stephens, D. J. McBride, M. L. Lin, et al., “Complex Landscapes of Somatic Rearrangement in Human Breast Cancer Genomes,” Nature, Vol. 462, No. 7276, 2009, pp. 1005-1010. doi:10.1038/nature08645
[24] T. J. Hudson, W. Anderson, A. Artez, et al., “International Network of Cancer Genome Projects,” Nature, Vol. 464, No. 7291, 2010, pp. 993-998. doi:10.1038/nature08987
[25] G. J. Porreca, K. Zhang, J. B. Li, et al., “Multiplex Amplification of Large Sets of Human Exons,” Nature Methods, Vol. 4, No. 11, 2007, pp. 931-936. doi:10.1038/nmeth1110
[26] G. Robertson, M. Hirst, M. Bainbridge, et al., “Genome-Wide Profiles of Stat1 DNA Association Using Chromatin Immunoprecipitation and Massively Parallel Sequencing,” Nature Methods, Vol. 4, No. 8, 2007, pp. 651-657. doi:10.1038/nmeth1068
[27] J. Li, F. Gao, N. Li, et al., “An Improved Method for Genome Wide DNA Methylation Profiling Correlated to Transcription and Genomic Instability in Two Breast Cancer Cell Lines,” BMC Genomics, Vol. 10, No., 2009, pp. 223.
[28] D. Serre, B. H. Lee and A. H. Ting, “Mbd-Isolated Genome Sequencing Provides a High-Throughput and Comprehensive Survey of DNA Methylation in the Human Genome,” Nucleic Acids Research, Vol. 38, No. 2, 2010, pp. 391-399. doi:10.1093/nar/gkp992
[29] F. V. Jacinto, E. Ballestar and M. Esteller, “Methyl-DNA Immunoprecipitation (Medip): Hunting down the DNA Methylome,” Biotechniques, Vol. 44, No. 1, 2008, pp. 35, 37, 39 passim. doi:10.2144/000112708
[30] R. Lister, M. Pelizzola, R. H. Dowen, et al., “Human DNA Methylomes at Base Resolution Show Widespread Epigenomic Differences,” Nature, Vol. 462, No. 7271, 2009, pp. 315-322. doi:10.1038/nature08514
[31] Y. Li, J. Zhu, G. Tian, et al., “The DNA Methylome of Human Peripheral Blood Mononuclear Cells,” PLoS Biology, Vol. 8, No. 11, 2010, p. e1000533. doi:10.1371/journal.pbio.1000533
[32] A. Meissner, T. S. Mikkelsen, H. Gu, et al., “Genome-Scale DNA Methylation Maps of Pluripotent and Differentiated Cells,” Nature, Vol. 454, No. 7205, 2008, pp. 766-770.
[33] N. Li, M. Ye, Y. Li, et al., “Whole Genome DNA Methylation Analysis Based on High Throughput Sequencing Technology,” Methods, Vol. 52, No. 3, 2010, pp. 203-212. doi:10.1016/j.ymeth.2010.04.009
[34] P. W. Laird, “Principles and Challenges of Genome-Wide DNA Methylation Analysis,” Nature Reviews Genetics, Vol. 11, No. 3, 2010, pp. 191-203. doi:10.1038/nrg2732
[35] C. Bock, E. M. Tomazou, A. B. Brinkman, et al., “Quantitative Comparison of Genome-Wide DNA Methylation Mapping Technologies,” Nature Biotechnology, Vol. 28, No. 10, 2010, pp. 1106-1114. doi:10.1038/nbt.1681
[36] R. A. Harris, T. Wang, C. Coarfa, et al., “Comparison of Sequencing-Based Methods to Profile DNA Methylation and Identification of Monoallelic Epigenetic Modifications,” Nature Biotechnology, Vol. 28, No. 10, 2010, pp. 1097-1105. doi:10.1038/nbt.1682
[37] S. T. Bennett, C. Barnes, A. Cox, et al., “Toward the 1,000 Dollars Human Genome,” Pharmacogenomics, Vol. 6, No. 4, 2005, pp. 373-382. doi:10.1517/14622416.6.4.373
[38] T. Sorlie, C. M. Perou, R. Tibshirani, et al., “Gene Expression Patterns of Breast Carcinomas Distinguish Tumor Subclasses with Clinical Implications,” Proceedings of the National Academy of Sciences of the United States, Vol. 98, No. 19, 2001, pp. 10869-10874. doi:10.1073/pnas.191367098
[39] M. Meyerson, S. Gabriel and G. Getz, “Advances in Understanding Cancer Genomes through Second-Generation Sequencing,” Nature Reviews Genetics, Vol. 11, No. 10, 2010, pp. 685-696. doi:10.1038/nrg2841
[40] P. A. Cowin, M. Anglesio, D. Etemadmoghadam, et al., “Profiling the Cancer Genome,” Annual Review of Genomics and Human Genetics, Vol. 11, No., 2010, pp. 133-159.
[41] T. Sjoblom, “Systematic Analyses of the Cancer Genome: Lessons Learned from Sequencing Most of the Annotated Human Protein-Coding Genes,” Current Opinion in Oncology, Vol. 20, No. 1, 2008, pp. 66-71. doi:10.1097/CCO.0b013e3282f31108
[42] T. Sjoblom, S. Jones, L. D. Wood, et al., “The Consensus Coding Sequences of Human Breast and Colorectal Cancers,” Science, Vol. 314, No. 5797, 2006, pp. 268-274. doi:10.1126/science.1133427
[43] L. D. Wood, D. W. Parsons, S. Jones, et al., “The Genomic Landscapes of Human Breast and Colorectal Cancers,” Science, Vol. 318, No. 5853, 2007, pp. 1108-1113. doi:10.1126/science.1145720
[44] J. Lin, C. M. Gan, X. Zhang, et al., “A Multidimensional Analysis of Genes Mutated in Breast and Colorectal Cancers,” Genome Research, Vol. 17, No. 9, 2007, pp. 1304-1318. doi:10.1101/gr.6431107
[45] Q. Zhao, E. F. Kirkness, O. L. Caballero, et al., “Systematic Detection of Putative Tumor Suppressor Genes through the Combined Use of Exome and Transcriptome Sequencing,” Genome Biology, Vol. 11, No. 11, 2010, pp. R114. doi:10.1186/gb-2010-11-11-r114
[46] K. Inaki, A. M. Hillmer, L. Ukil, et al., “Transcriptional Consequences of Genomic Structural Aberrations in Breast Cancer,” Genome Research, Vol. 21, No. 5, 2011, pp. 676-687. doi:10.1101/gr.113225.110
[47] Z. Sun, Y. W. Asmann, K. R. Kalari, et al., “Integrated Analysis of Gene Expression, Cpg Island Methylation, and Gene Copy Number in Breast Cancer Cells by Deep Sequencing,” PLoS One, Vol. 6, No. 2, 2011, p. e17490. doi:10.1371/journal.pone.0017490
[48] S. Anderson, A. T. Bankier, B. G. Barrell, et al., “Sequence and Organization of the Human Mitochondrial Genome,” Nature, Vol. 290, No. 5806, 1981, pp. 457-465. doi:10.1038/290457a0
[49] D. L. Croteau and V. A. Bohr, “Repair of Oxidative Damage to Nuclear and Mitochondrial DNA in Mammalian Cells,” The Journal of Biological Chemistry, Vol. 272, No. 41, 1997, pp. 25409-25412. doi:10.1074/jbc.272.41.25409
[50] D. J. Tan, R. K. Bai and L. J. Wong, “Comprehensive Scanning of Somatic Mitochondrial DNA Mutations in Breast Cancer,” Cancer Research, Vol. 62, No. 4, 2002, pp. 972-976.
[51] P. Parrella, Y. Xiao, M. Fliss, et al., “Detection of Mitochondrial DNA Mutations in Primary Breast Cancer and Fine-Needle Aspirates,” Cancer Research, Vol. 61, No. 20, 2001, pp. 7623-7626.
[52] A. Chatterjee, E. Mambo and D. Sidransky, “Mitochondrial DNA Mutations in Human Cancer,” Oncogene, Vol. 25, No. 34, 2006, pp. 4663-4674. doi:10.1038/sj.onc.1209604
[53] M. S. Fliss, H. Usadel, O. L. Caballero, et al., “Facile Detection of Mitochondrial DNA Mutations in Tumors and Bodily Fluids,” Science, Vol. 287, No. 5460, 2000, pp. 2017-2019. doi:10.1126/science.287.5460.2017
[54] C. Isaacs, L. R. Cavalli, Y. Cohen, et al., “Detection of Loh and Mitochondrial DNA Alterations in Ductal Lavage and Nipple Aspirate Fluids from Hngh-Risk Patients,” Breast Cancer Research and Treatment, Vol. 84, No. 2, 2004, pp. 99-105. doi:10.1023/B:BREA.0000018406.03679.2e
[55] N. G. Larsson, “Somatic Mitochondrial DNA Mutations in Mammalian Aging,” Annual Review of Biochemistry, Vol. 79, No., 2010, pp. 683-706.
[56] S. Durinck, C. Ho, N. J. Wang, et al., “Temporal Dissection of Tumorigenesis in Primary Cancers,” Cancer Discovery, Vol. 1, No. 2, 2011, pp. 137-143. doi:10.1158/2159-8290.CD-11-0028
[57] P. J. Campbell, S. Yachida, L. J. Mudie, et al., “The Patterns and Dynamics of Genomic Instability in Metastatic Pancreatic Cancer,” Nature, Vol. 467, No. 7319, 2010, pp. 1109-1113. doi:10.1038/nature09460
[58] S. Yachida, S. Jones, I. Bozic, et al., “Distant Metastasis Occurs Late during the Genetic Evolution of Pancreatic Cancer,” Nature, Vol. 467, No. 7319, 2010, pp. 1114-1117. doi:10.1038/nature09515
[59] E. D. Pleasance, R. K. Cheetham, P. J. Stephens, et al., “A Comprehensive Catalogue of Somatic Mutations from a Human Cancer Genome,” Nature, Vol. 463, No. 7278, 2010, pp. 191-196. doi:10.1038/nature08658
[60] S. Durinck, N. Wang, W. Liao, L. Jakkula, E. Collisson, J. Pons, S.-W. Chan, E. Lam, C. Chu, K. Park, S.-W. Hong, J. Hur, N. Huh, I. Neuhaus, S. Yu, R. Grekin, T. Mauro, J. Cleaver, P.-Y. Kwok, P. Leboit, G. Getz, K. Cibulskis, J. Aster, H. Huang, E. Purdom, J. Li, L. Bolund, S. Arron, J. Gray, P. Spellman and R. Cho, “Temporal Dissection of Tumorigenesis in Primary Cancers,” Cancer Discovery, Vol. 1, No. 2, 2011, pp. OF1-OF7.
[61] M. G. Daidone, R. Silvestrini, B. Valentinis, et al., “Proliferative Activity of Primary Breast Cancer and of Synchronous Lymph Node Metastases Evaluated by [3h]-Thymidine Labelling Index,” Cell and Tissue Kinetics, Vol. 23, No. 5, 1990, pp. 401-408.
[62] D. L. Dexter and J. T. Leith, “Tumor Heterogeneity and Drug Resistance,” Journal of Clinical Oncology, Vol. 4, No. 2, 1986, pp. 244-257.
[63] M. Aubele and M. Werner, “Heterogeneity in Breast Cancer and the Problem of Relevance of Findings,” Analytical Cellular Pathology, Vol. 19, No. 2, 1999, pp. 53-58.
[64] N. Navin and J. Hicks, “Future Medical Applications of Single-Cell Sequencing in Cancer,” Genome Medicine, Vol. 3, No. 5, 2011, pp. 31. doi:10.1186/gm247
[65] F. Tang, C. Barbacioru, Y. Wang, et al., “Mrna-Seq Whole-Transcriptome Analysis of a Single Cell,” Nature Methods, Vol. 6, No. 5, 2009, pp. 377-382. doi:10.1038/nmeth.1315
[66] N. Navin, J. Kendall, J. Troge, et al., “Tumour Evolution Inferred by Single-Cell Sequencing,” Nature, Vol. 472, No. 7341, 2011, pp. 90-94. doi:10.1038/nature09807
[67] X. Xu, Y. Hou, X. Yin, et al., “Single-Cell Exome Sequencing Reveals Single-Nucleotide Mutation Characteristics of a Kidney Tumor,” Cell, Vol. 148, No. 5, 2012, pp. 886-895. doi:10.1016/j.cell.2012.02.025
[68] Y. Hou, L. Song, P. Zhu, et al., “Single-Cell Exome Sequencing and Monoclonal Evolution of a Jak2-Negative Myeloproliferative Neoplasm,” Cell, Vol. 148, No. 5, 2012, pp. 873-885. doi:10.1016/j.cell.2012.02.028
[69] V. G. Cheung and S. F. Nelson, “Whole Genome Amplification Using a Degenerate Oligonucleotide Primer Allows Hundreds of Genotypes to Be Performed on Less Than One Nanogram of Genomic DNA,” Proceedings of the National Academy of Sciences of the United States, Vol. 93, No. 25, 1996, pp. 14676-14679. doi:10.1073/pnas.93.25.14676
[70] H. Telenius, N. P. Carter, C. E. Bebb, et al., “Degenerate Oligonucleotide-Primed Pcr: General Amplification of Target DNA by a Single Degenerate Primer,” Genomics, Vol. 13, No. 3, 1992, pp. 718-725. doi:10.1016/0888-7543(92)90147-K
[71] J. M. Lage, J. H. Leamon, T. Pejovic, et al., “Whole Genome Analysis of Genetic Alterations in Small DNA Samples Using Hyperbranched Strand Displacement Amplification and Array-Cgh,” Genome Research, Vol. 13, No. 2, 2003, pp. 294-307. doi:10.1101/gr.377203
[72] F. Tang, K. Lao and M. A. Surani, “Development and Applications of Single-Cell Transcriptome Analysis,” Nature Methods, Vol. 8, No. 4 Suppl, 2011, pp. S6-11.
[73] K. Kurimoto, Y. Yabuta, Y. Ohinata, et al., “An Improved Single-Cell Cdna Amplification Method for Efficient High-Density Oligonucleotide Microarray Analysis,” Nucleic Acids Research, Vol. 34, No. 5, 2006, p. e42. doi:10.1093/nar/gkl050
[74] D. Hanahan and R. A. Weinberg, “The Hallmarks of Cancer,” Cell, Vol. 100, No. 1, 2000, pp. 57-70. doi:10.1016/S0092-8674(00)81683-9
[75] D. Branton, D. W. Deamer, A. Marziali, et al., “The Potential and Challenges of Nanopore Sequencing,” Nature Biotechnology, Vol. 26, No. 10, 2008, pp. 1146-1153. doi:10.1038/nbt.1495
[76] E. E. Schadt, S. Turner and A. Kasarskis, “A Window into Third-Generation Sequencing,” Human Molecular Genetics, Vol. 19, No. R2, 2010, pp. R227-240. doi:10.1093/hmg/ddq416
[77] J. Clarke, H. C. Wu, L. Jayasinghe, et al., “Continuous Base Identification for Single-Molecule Nanopore DNA Sequencing,” Nature Nanotechnology, Vol. 4, No. 4, 2009, pp. 265-270. doi:10.1038/nnano.2009.12
[78] J. Qin, R. Li, J. Raes, et al., “A Human Gut Microbial Gene Catalogue Established by Metagenomic Sequencing,” Nature, Vol. 464, No. 7285, 2010, pp. 59-65. doi:10.1038/nature08821
[79] C. Human Microbiome Project, “A Framework for Human Microbiome Research,” Nature, Vol. 486, No. 7402, 2012, pp. 215-221. doi:10.1038/nature11209
[80] C. Human Microbiome Project, “Structure, Function and Diversity of the Healthy Human Microbiome,” Nature, Vol. 486, No. 7402, 2012, pp. 207-214. doi:10.1038/nature11234
[81] J. Harrow, F. Denoeud, A. Frankish, et al., “Gencode: Producing a Reference Annotation for Encode,” Genome Biology, Vol. 7, Suppl. 1, 2006, pp. S41-S49.
[82] R. M. Myers, J. Stamatoyannopoulos, M. Snyder, et al., “A User's Guide to the Encyclopedia of DNA Elements (Encode),” PLoS Biology, Vol. 9, No. 4, 2011, p. e1001046. doi:10.1371/journal.pbio.1001046
[83] S. T. Sherry, M. Ward and K. Sirotkin, “Dbsnp-Database for Single Nucleotide Polymorphisms and Other Classes of Minor Genetic Variation,” Genome Research, Vol. 9, No. 8, 1999, pp. 677-679.
[84] D. M. Altshuler, R. A. Gibbs, L. Peltonen, et al., “Integrating Common and Rare Genetic Variation in Diverse Human Populations,” Nature, Vol. 467, No. 7311, 2010, pp. 52-58. doi:10.1038/nature09298
[85] A. J. Iafrate, L. Feuk, M. N. Rivera, et al., “Detection of Large-Scale Variation in the Human Genome,” Nature Genetics, Vol. 36, No. 9, 2004, pp. 949-951. doi:10.1038/ng1416
[86] 1000 Genomes Project Consortium, “A Map of Human Genome Variation from Population-Scale Sequencing,” Nature, Vol. 467, No. 7319, 2010, pp. 1061-1073. doi:10.1038/nature09534
[87] B. E. Bernstein, J. A. Stamatoyannopoulos, J. F. Costello, et al., “The Nih Roadmap Epigenomics Mapping Consortium,” Nature Biotechnology, Vol. 28, No. 10, 2010, pp. 1045-1048. doi:10.1038/nbt1010-1045
[88] K. M. Wong, T. J. Hudson and J. D. McPherson, “Unraveling the Genetics of Cancer: Genome Sequencing and Beyond,” Annual Review of Genomics and Human Genetics, 2011.
[89] E. S. Lander, L. M. Linton, B. Birren, et al., “Initial Sequencing and Analysis of the Human Genome,” Nature, Vol. 409, No. 6822, 2001, pp. 860-921. doi:10.1038/35057062

comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.