Composite effects of polymorphisms near multiple regulatory elements create a major-effect QTL.
Composite effects of polymorphisms near multiple regulatory elements create a major-effect QTL.
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DOI：
10.1371/journal.pgen.1001275
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发表时间：
2011-01-13
期刊：
影响因子：
4.5
通讯作者：
Nuzhdin SV
中科院分区：
文献类型：
--
作者：
Bickel RD;Kopp A;Nuzhdin SV
许多在农业上、进化上和医学上重要的性状以数量的方式变化。不幸的是，由于各种生物学和技术挑战，导致这种变异的基因和序列变体在很大程度上仍然未知。果蝇含有高水平的序列变异和低连锁不平衡，使我们能够剖析一个单一的基因座内的许多致病变异的影响。在这里，我们利用这些功能，以确定和表征的序列多态性，包括主效应QTL等位基因分离的bric-a-brac基因座。我们表明，对表皮色素沉着有很大影响的天然小玩意等位基因反映了影响三个功能区域的多态性的累积影响：启动子、组织特异性增强子和Polycomb反应元件。在bric-a-brac位点的等位基因特异性表达的分析证实，这些多态性在顺式调节水平调节转录。我们的研究结果表明，一个单一的QTL可以通过多种分子机制的汇合，并在实验验证的功能元件侧翼区域的序列变异可以对转录活性和表型有显着的定量影响。这些发现对基础和医学基因组学具有重要的设计和概念意义。已经鉴定了多种表型的数量变异基因。然而，仍有许多要了解的致病遗传变异的分布在一个基因座。在这项研究中，我们调查了一个基因座，有助于自然变化的腹色素在果蝇。我们发现，该基因座的大表型效应来自于许多小效应多态性的累积作用，这些多态性集中在三个不同的功能区域：启动子，组织特异性增强子和Polycomb反应元件（一个参与染色质重塑的区域）。相同的区域影响成体表型和转录丰度，表明致病序列变异通过调节转录起作用。有趣的是，这些多态性聚集在功能验证的调控区附近，但不在其内，这表明核心功能元件周围的DNA序列可能在定量变异中起关键作用。
Many agriculturally, evolutionarily, and medically important characters vary in a quantitative fashion. Unfortunately, the genes and sequence variants accounting for this variation remain largely unknown due to a variety of biological and technical challenges. Drosophila melanogaster contains high levels of sequence variation and low linkage disequilibrium, allowing us to dissect the effects of many causative variants within a single locus. Here, we take advantage of these features to identify and characterize the sequence polymorphisms that comprise major effect QTL alleles segregating at the bric-a-brac locus. We show that natural bric-a-brac alleles with large effects on cuticular pigmentation reflect a cumulative impact of polymorphisms that affect three functional regions: a promoter, a tissue-specific enhancer, and a Polycomb response element. Analysis of allele-specific expression at the bric-a-brac locus confirms that these polymorphisms modulate transcription at the cis-regulatory level. Our results establish that a single QTL can act through a confluence of multiple molecular mechanisms and that sequence variation in regions flanking experimentally validated functional elements can have significant quantitative effects on transcriptional activity and phenotype. These findings have important design and conceptual implications for basic and medical genomics. Genes responsible for quantitative variation have been identified for a diverse range of phenotypes. However, much remains to be learned about the distribution of causative genetic variation within a locus. In this study, we investigated a locus that contributes to natural variation in abdominal pigmentation in Drosophila melanogaster. We found that the large phenotypic effect of this locus results from the cumulative action of many small-effect polymorphisms that are concentrated in three distinct functional regions: a promoter, a tissue-specific enhancer, and a Polycomb response element (a region involved in chromatin remodeling). The same regions influence the adult phenotype and transcript abundance, indicating that the causative sequence variants act by modulating transcription. Interestingly, these polymorphisms cluster near, but not within, the functionally validated regulatory regions, suggesting that DNA sequences surrounding core functional elements may play a key role in quantitative variation.
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DOI：
10.1038/nrg2847
发表时间：
2010-08
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
12.3
作者：
QianWu, Jia;Du, Jiang;Snyder, Michael
通讯作者：
Snyder, Michael
影响因子：
4.4
作者：
Main, Bradley J.;Bickel, Ryan D.;Nuzhdin, Sergey V.
通讯作者：
Nuzhdin, Sergey V.
影响因子：
30.8
作者：
Protas, ME;Hersey, C;Tabin, CJ
通讯作者：
Tabin, CJ
影响因子：
3.3
作者：
Genissel, A;Pastinen, T;Long, AD
通讯作者：
Long, AD