解析细胞类型异质性对皮质基因表达的贡献。
Deconvolving the contributions of cell-type heterogeneity on cortical gene expression.
机构信息
School of Mathematics and Statistics, The University of Sydney, Sydney, New South Wales, Australia.
The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
出版信息
PLoS Comput Biol. 2020 Aug 17;16(8):e1008120. doi: 10.1371/journal.pcbi.1008120. eCollection 2020 Aug.
Complexity of cell-type composition has created much skepticism surrounding the interpretation of bulk tissue transcriptomic studies. Recent studies have shown that deconvolution algorithms can be applied to computationally estimate cell-type proportions from gene expression data of bulk blood samples, but their performance when applied to brain tissue is unclear. Here, we have generated an immunohistochemistry (IHC) dataset for five major cell-types from brain tissue of 70 individuals, who also have bulk cortical gene expression data. With the IHC data as the benchmark, this resource enables quantitative assessment of deconvolution algorithms for brain tissue. We apply existing deconvolution algorithms to brain tissue by using marker sets derived from human brain single cell and cell-sorted RNA-seq data. We show that these algorithms can indeed produce informative estimates of constituent cell-type proportions. In fact, neuronal subpopulations can also be estimated from bulk brain tissue samples. Further, we show that including the cell-type proportion estimates as confounding factors is important for reducing false associations between Alzheimer's disease phenotypes and gene expression. Lastly, we demonstrate that using more accurate marker sets can substantially improve statistical power in detecting cell-type specific expression quantitative trait loci (eQTLs).
细胞类型组成的复杂性使得人们对批量组织转录组研究的解释产生了很大的怀疑。最近的研究表明,去卷积算法可用于从批量血液样本的基因表达数据中计算估计细胞类型的比例,但将其应用于脑组织的效果尚不清楚。在这里,我们从 70 个人的脑组织中生成了五种主要细胞类型的免疫组织化学(IHC)数据集,这些人也有批量皮质基因表达数据。利用 IHC 数据作为基准,该资源可对脑组织的去卷积算法进行定量评估。我们通过使用源自人类大脑单细胞和细胞分选 RNA-seq 数据的标记集,将现有的去卷积算法应用于脑组织。我们表明,这些算法确实可以对组成细胞类型的比例产生有信息的估计。事实上,也可以从批量脑组织样本中估计神经元亚群。此外,我们表明,将细胞类型比例估计作为混杂因素纳入其中对于减少阿尔茨海默病表型与基因表达之间的虚假关联非常重要。最后,我们证明,使用更准确的标记集可以显著提高检测细胞类型特异性表达数量性状基因座(eQTL)的统计能力。