Genome-wide detection of human intronic AG-gain variants located between splicing branchpoints and canonical splice acceptor sites.
Genome-wide detection of human intronic AG-gain variants located between splicing branchpoints and canonical splice acceptor sites.
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DOI：
10.1073/pnas.2314225120
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发表时间：
2023-11-14
影响因子：
11.1
通讯作者：
Casanova, Jean- Laurent
中科院分区：
文献类型：
--
作者：
Zhang, Peng;Chaldebas, Matthieu;Ogishi, Masato;Al Qureshah, Fahd;Ponsin, Khoren;Feng, Yi;Rinchai, Darawan;Milisavljevic, Baptiste;Han, Ji Eun;Moncada-Velez, Marcela;Keles, Sevgi;Schroeder, Bernd;Stenson, Peter D.;Cooper, David N.;Cobat, Aurelie;Boisson, Bertrand;Zhang, Qian;Boisson-Dupuis, Stephanie;Abel, Laurent;Casanova, Jean- Laurent
对潜在人类疾病的候选变异的搜索通常集中在编码区和必需的剪接位点上，大多忽略了非编码内含子变异。由于我们先前开发的BPHunter，我们精确地描绘了所有人类内含子的从分支点到受体位点（BP-ACC）的内含子片段，其中AG-增益变体可能干扰组成性剪接并导致错误剪接产物。在这里，我们开发了AGAIN作为一种全基因组方法，以系统，有效和精确地定位该区域的内含子AG增益变体。AGAIN回顾性地捕获了报告的致病性AG-增益变体用于全面分析，AGAIN前瞻性地检测了成功验证的新AG-增益变体。AGAIN将允许选择具有生物学意义的有希望的内含子变体，潜在的罕见/常见和生殖系/体细胞遗传疾病。将AG引入蛋白质编码基因的分支点（BP）和典型剪接受体位点（ACC）之间的内含子区域的人类遗传变体可以破坏前体mRNA剪接。使用我们的全基因组BP数据库，我们描绘了所有人类内含子的BP-ACC片段，并发现[BP+8，ACC-4]高风险区域中AG/YAG极度缺失。我们开发了AGAIN作为全基因组计算方法，以系统和精确地查明BP-ACC区域内的内含子AG增益变体。AGAIN从人类基因突变数据库中鉴定了350种AG-增益变体，所有这些变体都会改变剪接并导致疾病。其中，74%产生了新的受体位点，而31%导致了完整的外显子跳跃。AGAIN还预测了这两种结果产生的蛋白质水平产物。我们再次对患有严重感染性疾病但没有已知遗传病因的患者的外显子组/基因组数据库进行了分析，并在患有分枝杆菌疾病的患者中鉴定了抗分枝杆菌基因SPPL 2A中的私人纯合内含子AG-增益变体。AGAIN还预测保留编码框内终止密码子的六个内含子核苷酸，将AG增益转变为停止增益。然后实验证实该等位基因通过破坏剪接导致功能丧失。我们进一步表明，高风险区域内的AG-增益变体导致错误剪接的产物，而区域外的则没有，通过基因STAT 1和IRF 7的两个案例研究。最后，我们对14个配对的exome-RNAseq样本进行了再次评估，发现高风险区域中82%的AG获得变体显示出错误剪接的证据。AGAIN可从https://hgidsoft.rockefeller.edu/AGAIN和https://github.com/casanova-lab/AGAIN公开获取。
The search for candidate variants underlying human disease typically focuses on coding regions and essential splice sites, mostly ignoring noncoding intronic variants. Thanks to our previously developed BPHunter, we precisely delineated the intronic segments from branchpoints to acceptor sites (BP-ACC) of all human introns, in which the AG-gain variants could interfere with constitutive splicing and result in misspliced products. Here, we developed AGAIN as a genome-wide method to systematically, efficiently, and precisely pinpoint intronic AG-gain variants in this region. AGAIN retrospectively captured reported pathogenic AG-gain variants for comprehensive analyses, and AGAIN prospectively detected new AG-gain variants that were successfully validated. AGAIN would permit the selection of promising intronic variants with biological significance, underlying rare/common and germline/somatic genetic diseases. Human genetic variants that introduce an AG into the intronic region between the branchpoint (BP) and the canonical splice acceptor site (ACC) of protein-coding genes can disrupt pre-mRNA splicing. Using our genome-wide BP database, we delineated the BP-ACC segments of all human introns and found extreme depletion of AG/YAG in the [BP+8, ACC-4] high-risk region. We developed AGAIN as a genome-wide computational approach to systematically and precisely pinpoint intronic AG-gain variants within the BP-ACC regions. AGAIN identified 350 AG-gain variants from the Human Gene Mutation Database, all of which alter splicing and cause disease. Among them, 74% created new acceptor sites, whereas 31% resulted in complete exon skipping. AGAIN also predicts the protein-level products resulting from these two consequences. We performed AGAIN on our exome/genomes database of patients with severe infectious diseases but without known genetic etiology and identified a private homozygous intronic AG-gain variant in the antimycobacterial gene SPPL2A in a patient with mycobacterial disease. AGAIN also predicts a retention of six intronic nucleotides that encode an in-frame stop codon, turning AG-gain into stop-gain. This allele was then confirmed experimentally to lead to loss of function by disrupting splicing. We further showed that AG-gain variants inside the high-risk region led to misspliced products, while those outside the region did not, by two case studies in genes STAT1 and IRF7. We finally evaluated AGAIN on our 14 paired exome-RNAseq samples and found that 82% of AG-gain variants in high-risk regions showed evidence of missplicing. AGAIN is publicly available from https://hgidsoft.rockefeller.edu/AGAIN and https://github.com/casanova-lab/AGAIN.
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DOI：
10.1084/jem.20121069
发表时间：
2013-01-14
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Schneppenheim J;Dressel R;Hüttl S;Lüllmann-Rauch R;Engelke M;Dittmann K;Wienands J;Eskelinen EL;Hermans-Borgmeyer I;Fluhrer R;Saftig P;Schröder B
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10.1084/jem.20220094
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2022-10-03
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影响因子：
14.9
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Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
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Flicek P
遗传性 PD-1 缺陷是儿童结核病和自身免疫性疾病的基础。
影响因子：
82.9
作者：
Ogishi M;Yang R;Aytekin C;Langlais D;Bourgey M;Khan T;Ali FA;Rahman M;Delmonte OM;Chrabieh M;Zhang P;Gruber C;Pelham SJ;Spaan AN;Rosain J;Lei WT;Drutman S;Hellmann MD;Callahan MK;Adamow M;Wong P;Wolchok JD;Rao G;Ma CS;Nakajima Y;Yaguchi T;Chamoto K;Williams SC;Emile JF;Rozenberg F;Glickman MS;Rapaport F;Kerner G;Allington G;Tezcan I;Cagdas D;Hosnut FO;Dogu F;Ikinciogullari A;Rao VK;Kainulainen L;Béziat V;Bustamante J;Vilarinho S;Lifton RP;Boisson B;Abel L;Bogunovic D;Marr N;Notarangelo LD;Tangye SG;Honjo T;Gros P;Boisson-Dupuis S;Casanova JL
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DOI：
10.1126/science.abm4245
发表时间：
2022-01-07
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Tholen J;Razew M;Weis F;Galej WP
通讯作者：
Galej WP