Genetic dissection of the Drosophila melanogaster female head transcriptome reveals widespread allelic heterogeneity.
Genetic dissection of the Drosophila melanogaster female head transcriptome reveals widespread allelic heterogeneity.
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果蝇的遗传解剖是女性头部转录组的遗传解剖显示出广泛的等位基因异质性。
DOI：
10.1371/journal.pgen.1004322
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发表时间：
2014-05
期刊：
影响因子：
4.5
通讯作者：
Macdonald SJ
中科院分区：
文献类型：
--
作者：
King EG;Sanderson BJ;McNeil CL;Long AD;Macdonald SJ
现代遗传作图一直受到“遗传力缺失”问题的困扰，这是指数量性状的估计遗传力与作图的致病变异所占方差之间的不一致。缺失遗传力的一个主要潜在解释是等位基因异质性，其中每个致病基因存在多个致病变体，只有一小部分已被鉴定。大多数全基因组关联研究（GWAS）隐含地假设单个SNP可以解释致病基因座的所有变异。然而，如果等位基因异质性是普遍的，大量的遗传变异将仍然无法解释。在本文中，我们采取了单倍型为基础的映射方法和量化的等位基因分离在每个位点使用一个大的7922 eQTL的调节变化在果蝇雌性头的数量。这项研究不仅提供了一个全面的eQTL图谱的主要社区遗传资源，果蝇合成人口资源，但它也提供了一个直接的测试等位基因异质性假说。我们发现95%的顺式eQTL和78%的反式eQTL是由多个等位基因引起的，这表明果蝇eQTL中普遍存在等位基因异质性。等位基因异质性可能是导致GWAS研究中常见的遗传力缺失问题的重要原因。对于具有复杂遗传的性状，通常已证明很难确定所涉及的大多数特定致病变异。人们提出了一系列假设来解释这种所谓的“缺失遗传力”。其中一种观点等位基因异质性，即每个基因都含有多种不同的致病变异体，很少受到关注，因为大多数遗传图谱设计都很难检测到。在这里，我们利用一组来自多个创始人的黑腹果蝇品系，使我们能够直接测试在一个大的遗传位点影响基因表达的多个等位基因的存在。我们发现，绝大多数的位点海港两个以上的功能等位基因，表现出广泛的等位基因异质性的基因表达水平，并表明这种异质性是一个重要的因素，一般决定复杂的性状变异的遗传基础。
Modern genetic mapping is plagued by the “missing heritability” problem, which refers to the discordance between the estimated heritabilities of quantitative traits and the variance accounted for by mapped causative variants. One major potential explanation for the missing heritability is allelic heterogeneity, in which there are multiple causative variants at each causative gene with only a fraction having been identified. The majority of genome-wide association studies (GWAS) implicitly assume that a single SNP can explain all the variance for a causative locus. However, if allelic heterogeneity is prevalent, a substantial amount of genetic variance will remain unexplained. In this paper, we take a haplotype-based mapping approach and quantify the number of alleles segregating at each locus using a large set of 7922 eQTL contributing to regulatory variation in the Drosophila melanogaster female head. Not only does this study provide a comprehensive eQTL map for a major community genetic resource, the Drosophila Synthetic Population Resource, but it also provides a direct test of the allelic heterogeneity hypothesis. We find that 95% of cis-eQTLs and 78% of trans-eQTLs are due to multiple alleles, demonstrating that allelic heterogeneity is widespread in Drosophila eQTL. Allelic heterogeneity likely contributes significantly to the missing heritability problem common in GWAS studies. For traits with complex genetic inheritance it has generally proven very difficult to identify the majority of the specific causative variants involved. A range of hypotheses have been put forward to explain this so-called “missing heritability”. One idea—allelic heterogeneity, where genes each harbor multiple different causative variants—has received little attention, because it is difficult to detect with most genetic mapping designs. Here we make use of a panel of Drosophila melanogaster lines derived from multiple founders, allowing us to directly test for the presence of multiple alleles at a large set of genetic loci influencing gene expression. We find that the vast majority of loci harbor more than two functional alleles, demonstrating extensive allelic heterogeneity at the level of gene expression and suggesting that such heterogeneity is an important factor determining the genetic basis of complex trait variation in general.
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影响因子：
3.7
作者：
Alberts, Rudi;Terpstra, Peter;Li, Yang;Breitling, Rainer;Nap, Jan-Peter;Jansen, Ritsert C.
通讯作者：
Jansen, Ritsert C.
影响因子：
7
作者：
Huang, Guo-Jen;Shifman, Sagiv;Flint, Jonathan
通讯作者：
Flint, Jonathan
影响因子：
56.9
作者：
Buckler, Edward S.;Holland, James B.;McMullen, Michael D.
通讯作者：
McMullen, Michael D.
DOI：
10.1073/pnas.1100465108
发表时间：
2011-03-15
影响因子：
11.1
作者：
Huang, Xueqing;Paulo, Maria-Joao;van Eeuwijk, Fred A.
通讯作者：
van Eeuwijk, Fred A.
影响因子：
30.8
作者：
Baud, Amelie;Hermsen, Roel;Guryev, Victor;Stridh, Pernilla;Graham, Delyth;McBride, Martin W.;Foroud, Tatiana;Calderari, Sophie;Diez, Margarita;Ockinger, Johan;Beyeen, Amennai D.;Gillett, Alan;Abdelmagid, Nada;Guerreiro-Cacais, Andre Ortlieb;Jagodic, Maja;Tuncel, Jonatan;Norin, Ulrika;Beattie, Elisabeth;Ngan Huynh;Miller, William H.;Koller, Daniel L.;Alam, Imranul;Falak, Samreen;Osborne-Pellegrin, Mary;Martinez-Membrives, Esther;Canete, Toni;Blazquez, Gloria;Vicens-Costa, Elia;Mont-Cardona, Carme;Diaz-Moran, Sira;Tobena, Adolf;Hummel, Oliver;Zelenika, Diana;Saar, Kathrin;Patone, Giannino;Bauerfeind, Anja;Bihoreau, Marie-Therese;Heinig, Matthias;Lee, Young-Ae;Rintisch, Carola;Schulz, Herbert;Wheeler, David A.;Worley, Kim C.;Muzny, Donna M.;Gibbs, Richard A.;Lathrop, Mark;Lansu, Nico;Toonen, Pim;Ruzius, Frans Paul;de Bruijn, Ewart;Hauser, Heidi;Adams, David J.;Keane, Thomas;Atanur, Santosh S.;Aitman, Tim J.;Flicek, Paul;Malinauskas, Tomas;Jones, E. Yvonne;Ekman, Diana;Lopez-Aumatell, Regina;Dominiczak, Anna F.;Johannesson, Martina;Holmdahl, Rikard;Olsson, Tomas;Gauguier, Dominique;Hubner, Norbert;Fernandez-Teruel, Alberto;Cuppen, Edwin;Mott, Richard;Flint, Jonathan
通讯作者：
Flint, Jonathan