非综合征型唇腭裂非编码区变异功能研究策略
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摘要
非综合征型唇腭裂是一种常见的先天畸形,其发病机制复杂,常包含遗传和环境两方面的因素。随着全基因组关联研究的广泛开展,针对非综合征型唇腭裂的遗传学研究取得了较为丰硕的成果,发现了大量候选突变位点。但这些突变大多位于易感基因的非编码区域,且仅拥有统计学上的意义,需要后续的功能研究来验证这些突变的真实致病性。目前唇腭裂编码区变异的研究方法已较为成熟,但由于致病机制的差异,该法对研究非编码区变异将不完全适用。因此,本文将从大数据利用、软件功能预测及体内外功能实验三方面对非编码区变异后续功能研究进行介绍,为将来更多唇腭裂非编码区突变研究提供参考。
引文
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[2] Birnbaum S, Ludwig KU, Reutter H, et al. Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24[J]. Nat Genet,2009,41(4):473-477.
[3] Beaty TH, Taub MA, Scott AF, et al. Confirming genes influenc-ing risk to cleft lip withwithout cleft palate in a case-parent trio study[J]. Hum Genet,2013,132(7):771-781.
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[5] Leslie EJ, Liu H, Carlson JC, et al. A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3[J/OL]. Am J Hum Genet,2016,98(4):744-754[2018-09-11]. http://dx.doi.org/10.1016/j.ajhg.2016.02.014.
[6] Leslie EJ, Carlson JC, Shaffer JR, et al. A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13[J]. Hum Mol Genet,2016,25(13):2862-2872.
[7] Beaty TH, Murray JC, Marazita ML, et al. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4[J]. Nat Genet,2010,42(6):525-529.
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[9] Wolf ZT, Brand HA, Shaffer JR, et al. Genome-wide association studies in dogs and humans identify ADAMTS20 as a risk variant for cleft lip and palate[J/OL]. PLoS Genet,2015,11(3):e1005059[2018-09-11]. http://dx.doi.org/10.1371/journal.pgen.1005059.
[10] Leslie EJ, Carlson JC, Shaffer JR, et al. Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate[J/OL]. Hum Genet,2017,136(3):275-286[2018-09-11]. http://dx.doi.org/10.1007/s00439-016-1754-7.
[11] Grant SF, Wang K, Zhang H, et al. A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24[J]. J Pediatr,2009,155(6):909-913.
[12] Camargo M, Rivera D, Moreno L, et al. GWAS reveals new recessive loci associated with non-syndromic facial clefting[J]. Eur J Med Genet,2012,55(10):510-514.
[13] Ludwig KU, Mangold E, Herms S, et al. Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci[J]. Nat Genet,2012,44(9):968-971.
[14] Mangold E, Ludwig KU, Birnbaum S, et al. Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate[J]. Nat Genet,2010,42(1):24-26.
[15] Sun Y, Huang Y, Yin A, et al. Genome-wide association study identifies a new susceptibility locus for cleft lip with or without a cleft palate[J/OL]. Nat Commun,2015,6:6414[2018-09-11]. http://dx.doi.org/10.1038/ncomms7414.
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[17] Eshete MA, Liu H, Li M, et al. Loss-of-Function GRHL3 Varia-nts Detected in African Patients with Isolated Cleft Palate[J/OL]. J Dent Res,2018,97(1):41-48[2018-09-11]. http://dx.doi.org/10.1177/0022034517729819.
[18] Mues G, Tardivel A, Willen L, et al. Functional analysis of Ectodysplasin-A mutations causing selective tooth agenesis[J]. Eur J Hum Genet,2010,18(1):19-25.
[19] Shen W, Wang Y, Liu Y, et al. Functional Study of Ectodyspla-sin-AMutations Causing Non-Syndromic Tooth Agenesis[J/OL]. PLoS One,2016,11(5):e0154884[2018-09-11]. http://dx.doi.org/10.1371/journal.pone.0154884.
[20] Sauna ZE, Kimchi-Sarfaty C. Understanding the contribution of synonymous mutations to human disease[J]. Nat Rev Genet,2011,12(10):683-691.
[21] Makrythanasis P, Antonarakis SE. Pathogenic variants in non-protein-coding sequences[J]. Clin Genet,2013,84(5):422-428.
[22] Zhu Y, Tazearslan C, Suh Y. Challenges and progress in interpretation of non-coding genetic variants associated with human disease[J/OL]. Exp Biol Med (Maywood),2017,242(13):1325-1334[2018-09-11]. http://dx.doi.org/10.1177/1535370217713750.
[23] Li MJ, Yan B, Sham PC, et al. Exploring the function of genetic variants in the non-coding genomic regions: approaches for identifying human regulatory variants affecting gene expression[J]. Brief Bioinform,2015,16(3):393-412.
[24] ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome[J]. Nature,2012,489(7414):57-74.
[25] Thurman RE, Rynes E, Humbert R, et al. The accessible chromatin landscape of the human genome[J/OL]. Nature,2012,489(7414):75-82[2018-09-11]. http://dx.doi.org/10.1038/nature11232.
[26] Qu H, Fang X. A brief review on the Human Encyclopedia of DNA Elements (ENCODE) project[J/OL]. Genomics Proteomics Bioinformatics,2013,11(3):135-141[2018-09-11]. http://dx.doi.org/10.1016/j.gpb.2013.05.001.
[27] Bernstein BE, Stamatoyannopoulos JA, Costello JF, et al. The NIH Roadmap Epigenomics Mapping Consortium[J]. Nat Biotechnol,2010,28(10):1045-1048.
[28] Kundaje A, Meuleman W, Ernst J, et al. Integrative analysis of 111 reference human epigenomes[J/OL]. Nature,2015,518(7539):317-330[2018-09-11]. http://dx.doi.org/10.1038/nature14248.
[29] Boyle AP, Hong EL, Hariharan M, et al. Annotation of functional variation in personal genomes using RegulomeDB[J]. Genome Res,2012,22(9):1790-1797.
[30] Ritchie GR, Dunham I, Zeggini E, et al. Functional annotation of noncoding sequence variants[J/OL]. Nat Methods,2014,11(3):294-296[2018-09-11]. http://dx.doi.org/10.1038/nmeth.2832.
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[33] Shihab HA, Rogers MF, Gough J, et al. An integrative approach to predicting the functional effects of non-coding and coding sequence variation[J]. Bioinformatics,2015,31(10):1536-1543.
[34] Pollard KS, Hubisz MJ, Rosenbloom KR, et al. Detection of nonneutral substitution rates on mammalian phylogenies[J]. Genome Res,2010,20(1):110-121.
[35] Drubay D, Gautheret D, Michiels S. A benchmark study of scoring methods for non-coding mutations[J/OL]. Bioinformatics,2018,34(10):1635-1641[2018-09-11]. http://dx.doi.org/10.1093/bioinformatics/bty008.
[36] Natarajan A, Yardimci GG, Sheffield NC, et al. Predicting cell-type-specific gene expression from regions of open chromatin[J/OL]. Genome Res,2012,22(9):1711-1722[2018-09-11]. http://dx.doi.org/10.1101/gr.135129.111.
[37] Dong X, Greven MC, Kundaje A, et al. Modeling gene expression using chromatin features in various cellular contexts[J/OL]. Genome Biol,2012,13(9):R53[2018-09-11]. http://dx.doi.org/10.1186/gb-2012-13-9-r53.
[38] Phornphutkul C, Anikster Y, Huizing M, et al. The promoter of a lysosomal membrane transporter gene, CTNS, binds Sp-1, shares sequences with the promoter of an adjacent gene, CARKL, and causes cystinosis if mutated in a critical region[J]. Am J Hum Genet,2001,69(4):712-721.
[39] Niimi T, Munakata M, Keck-Waggoner CL, et al. A polymorphism in the human UGRP1 gene promoter that regulates transcription is associated with an increased risk of asthma[J]. Am J Hum Genet,2002,70(3):718-725.
[40] Hu XZ, Lipsky RH, Zhu G, et al. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder[J]. Am J Hum Genet,2006,78(5):815-826.
[41] Theuns J, Brouwers N, Engelborghs S, et al. Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease[J]. Am J Hum Genet,2006,78(6):936-946.
[42] Tuupanen S, Turunen M, Lehtonen R, et al. The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling[J/OL]. Nat Genet,2009,41(8):885-890[2018-09-11]. http://dx.doi.org/10.1038/ng.406.
[43] Cowper-Sal lari R, Zhang X, Wright JB, et al. Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression[J/OL]. Nat Genet,2012,44(11):1191-1198[2018-09-11]. http://dx.doi.org/10.1038/ng.2416.
[44] Vernes SC, Spiteri E, Nicod J, et al. High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2,a gene mutated in speech and language disorders[J/OL]. Am J Hum Genet,2007,81(6):1232-1250[2018-09-11]. http://dx.doi.org/10.1086/522238.
[45] Simonis M, Kooren J, de Laat W. An evaluation of 3C-based methods to capture DNA interactions[J/OL]. Nat Methods,2007,4(11):895-901[2018-09-11]. http://dx.doi.org/10.1038/nmeth1114.
[46] Dekker J. The three &2018-09-11039;C&2018-09-11039; s of chromosome conformation capture: controls,controls,controls[J/OL]. Nat Methods,2006,3(1):17-21[2018-09-11]. http://dx.doi.org/10.1038/nmeth823.
[47] Zhao Z, Tavoosidana G, Sjolinder M, et al. Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions[J]. Nat Genet,2006,38(11):1341-1347.
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