参考文献:1. Venter, JC, Adams, MD, Myers, EW, Li, PW, Mural, RJ, Sutton, GG, Smith, HO, Yandell, M, Evans, CA, Holt, RA (2001) The sequence of the human genome. Science 291: pp. 1304-1351 CrossRef 2. Feero, WG, Guttmacher, AE, Collins, FS (2010) Genomic medicine -an updated primer. N Engl J Med 362: pp. 2001-2011 CrossRef 3. Consortium, EP (2004) The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 306: pp. 636-640 CrossRef 4. Consortium, EP, Bernstein, BE, Birney, E, Dunham, I, Green, ED, Gunter, C, Snyder, M (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: pp. 57-74 CrossRef 5. Spielmann, M, Klopocki, E (2013) CNVs of noncoding cis-regulatory elements in human disease. Curr Opin Genet Dev 23: pp. 249-256 CrossRef 6. Gilissen, C, Hehir-Kwa, JY, Thung, DT, Vorst, M, Bon, BW, Willemsen, MH, Kwint, M, Janssen, IM, Hoischen, A, Schenck, A (2014) Genome sequencing identifies major causes of severe intellectual disability. Nature 511: pp. 344-347 CrossRef 7. Klopocki, E, Mundlos, S (2011) Copy-number variations, noncoding sequences, and human phenotypes. Annu Rev Genomics Hum Genet 12: pp. 53-72 CrossRef 8. Wittkopp, PJ, Kalay, G (2012) Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence. Nat Rev Genet 13: pp. 59-69 CrossRef 9. Dathe, K, Kjaer, KW, Brehm, A, Meinecke, P, Nurnberg, P, Neto, JC, Brunoni, D, Tommerup, N, Ott, CE, Klopocki, E (2009) Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2. Am J Hum Genet 84: pp. 483-492 CrossRef 10. Montavon, T, Soshnikova, N, Mascrez, B, Joye, E, Thevenet, L, Splinter, E, Laat, W, Spitz, F, Duboule, D (2011) A regulatory archipelago controls Hox genes transcription in digits. Cell 147: pp. 1132-1145 CrossRef 11. Nora, EP, Dekker, J, Heard, E (2013) Segmental folding of chromosomes: a basis for structural and regulatory chromosomal neighborhoods?. Bioessays 35: pp. 818-828 CrossRef 12. Dekker, J (2006) The three ?C-s of chromosome conformation capture: controls, controls, controls. Nat Methods 3: pp. 17-21 CrossRef 13. Werken, HJ, Landan, G, Holwerda, SJ, Hoichman, M, Klous, P, Chachik, R, Splinter, E, Valdes-Quezada, C, Oz, Y, Bouwman, BA (2012) Robust 4C-seq data analysis to screen for regulatory DNA interactions. Nat Methods 9: pp. 969-972 CrossRef 14. Lieberman-Aiden, E, Berkum, NL, Williams, L, Imakaev, M, Ragoczy, T, Telling, A, Amit, I, Lajoie, BR, Sabo, PJ, Dorschner, MO (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326: pp. 289-293 CrossRef 15. Dixon, JR, Selvaraj, S, Yue, F, Kim, A, Li, Y, Shen, Y, Hu, M, Liu, JS, Ren, B (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485: pp. 376-380 CrossRef 16. Lettice, LA, Williamson, I, Wiltshire, JH, Peluso, S, Devenney, PS, Hill, AE, Essafi, A, Hagman, J, Mort, R, Grimes, G (2012) Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly. Dev Cell 22: pp. 459-467
Despite the great advances in genomic high-throughput technologies more than 40- of all patients in human genetics still remain without a molecular diagnosis. So far the focus has been on the 1.5- of the coding genome. This suggests that a large proportion of diseases may be caused by alterations outside the coding region and/or by structural variations that are not detectable with microarray-based comparative genomic hybridization (CGH) and whole exome sequencing. Recent efforts to annotate and analyze the non-coding genome can now effectively be used by human geneticists to analyze variants from whole genome data sets for potential cis-regulatory mutations. Additionally, it could be shown that the human genome is divided into domains which undertake a three dimensional regulatory active architecture via chromatin structures. This will broaden our view of genes and their regulatory landscapes and contribute to our understanding of pathomechanisms underlying human congenital diseases.