Differential allelic representation (DAR) identifies candidate eQTLs and improves transcriptome analysis.
Differential allelic representation (DAR) identifies candidate eQTLs and improves transcriptome analysis.
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差异等位基因表达 (DAR) 识别候选 eQTL 并改进转录组分析。
DOI：
10.1101/2023.03.02.530865
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Lardelli,Michael
中科院分区：
文献类型：
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作者：
Baer,Lachlan;Barthelson,Karissa;Postlethwait,John;Adelson,David;Pederson,Stephen;Lardelli,Michael
在突变型和野生型基因型之间的比较中，转录组分析可以揭示突变的直接影响以及生物系统的稳态响应。最近的研究已经强调，当在非等基因背景中研究隐性突变的纯合性的影响时，位于同一染色体上突变附近的基因在那些被鉴定为差异表达（DE）的基因中经常出现过度表达。一种假说认为，DE基因染色体连锁的突变可能不反映功能的突变反应，但相反，从一个不平等的突变或野生型基因型样品组之间的表达数量性状基因座（eQTL）的分布。这是有问题的，因为eQTL表达差异很难与由于对突变的功能反应而DE的基因区分开。在这里，我们表明，染色体共定位差异表达基因（CC-DEG）也观察到杂合子中的显性突变的分析。我们定义了一种方法和一个度量来量化，在RNA测序数据中，进行差异表达分析的那些样品组之间的局部差异等位基因表示（DAR）。我们展示了DAR度量如何预测易于eQTL驱动的差异表达的区域，以及它如何通过基因排除或基于权重的方法来改善功能富集分析。有利的是，这种鉴定可能的eQTL的改进的能力还揭示了可能与突变表型功能相关的CC-DEG的实例。这支持了一个长期存在的预测，即选择有利的连锁不平衡影响染色体进化。通过比较斑马鱼（Danio rerio）和青鳉（Oryzias latipes）的基因组，一种具有保守的祖先核型的硬骨鱼，我们发现在斑马鱼谱系的进化过程中CC-DEG染色体聚集的可能例子。我们的DAR分析方法只需要RNA测序数据，便于其在新的和现有的数据集上的应用。
In comparisons between mutant and wild-type genotypes, transcriptome analysis can reveal the direct impacts of a mutation, together with the homeostatic responses of the biological system. Recent studies have highlighted that, when the effects of homozygosity for recessive mutations are studied in non-isogenic backgrounds, genes located proximal to the mutation on the same chromosome often appear over-represented among those genes identified as differentially expressed (DE). One hypothesis suggests that DE genes chromosomally linked to a mutation may not reflect functional responses to the mutation but, instead, result from an unequal distribution of expression quantitative trait loci (eQTLs) between sample groups of mutant or wild-type genotypes. This is problematic because eQTL expression differences are difficult to distinguish from genes that are DE due to functional responses to a mutation. Here we show that chromosomally co-located differentially expressed genes (CC-DEGs) are also observed in analyses of dominant mutations in heterozygotes. We define a method and a metric to quantify, in RNA-sequencing data, localised differential allelic representation (DAR) between those sample groups subjected to differential expression analysis. We show how the DAR metric can predict regions prone to eQTL-driven differential expression, and how it can improve functional enrichment analyses through gene exclusion or weighting-based approaches. Advantageously, this improved ability to identify probable eQTLs also reveals examples of CC-DEGs that are likely to be functionally related to a mutant phenotype. This supports a long-standing prediction that selection for advantageous linkage disequilibrium influences chromosome evolution. By comparing the genomes of zebrafish (Danio rerio) and medaka (Oryzias latipes), a teleost with a conserved ancestral karyotype, we find possible examples of chromosomal aggregation of CC-DEGs during evolution of the zebrafish lineage. Our method for DAR analysis requires only RNA-sequencing data, facilitating its application across new and existing datasets.