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SHAPEIT+Salmon: haplotype phasing and RNA-seq quantification for allele-specific eQTL mapping

SHAPEIT Salmon：用于等位基因特异性 eQTL 作图的单倍型定相和 RNA-seq 定量

基本信息

批准号：
10153860
负责人：
Se Young Kim
金额：
$ 17.22万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153860
关键词：
Address Affect Algorithms Alleles Allelic Imbalance Awareness Brain Collaborations Complex Computer software Computing Methodologies Data Detection Disease Disease susceptibility Distal Enhancers Event Gene Expression Gene Expression Regulation Generations Genes Genetic Population Study Genetic Recombination Genetic Transcription Genetic study Genome Genotype Genotype-Tissue Expression Project Goals Haplotypes Health Human Human Resources Inbred Strains Mice Inbreeding Individual Inherited Lead Maps Mental disorders Methods Mus Mutation Natural Selections Organism Phase Population Genetics Preparation Quantitative Trait Loci Regulator Genes Regulatory Element Research Research Personnel Salmon Tissues Trans-Activators Transcript Tweens Variant Work base computer framework computerized tools genetic architecture genetic variant improved insight tool transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY / ABSTRACT Allele-speciﬁc expression quantitative trait locus (eQTL) mapping has become increasingly popular, since it en- hances the traditional eQTL mapping by providing signiﬁcantly more detailed gene regulatory mechanisms un- derlying the genetic architecture of diseases. Allele-speciﬁc eQTL mapping identiﬁes cis-acting and trans-acting eQTLs that each pinpoint to cis-regulatory elements and trans-acting factors, by leveraging the fact that unlike trans-acting eQTLs, cis-acting eQTLs affect the expression of transcripts from the same haplotype as the variant itself, causing allelic imbalance in expression. However, allele-speciﬁc eQTL mapping requires a reliable long- range phasing of genome sequences and an accurate allele-speciﬁc expression quantiﬁcation from RNA-seq data consistent with the genome phasing. Most existing works have treated allele-speciﬁc expression quantiﬁcation and phasing as independent tasks, even though each can enhance the accuracy of the other. In this proposed research, we will modify and pair up the two widely-used tools, SHAPEIT for genome phasing and Salmon for RNA-seq quantiﬁcation, to obtain an accurate phasing and allele-speciﬁc expression quantiﬁcation consistent with each other for allele-speciﬁc eQTL mapping. The combined tool will inherit or enhance the accuracy and efﬁciency of the two original methods. If phased sequences are known from experimental or trio data, we will replace the EM algorithm of Salmon with an accelerated EM to address the extreme multi-mapped read problem with computational efﬁciency. If phased sequences are not available as in unrelated individuals, we will modify SHAPEIT to jointly phase the variants and allele-speciﬁc read abundances, embedding allele-speciﬁc expression quantiﬁcation within SHAPEIT and using Salmon for obtaining transcript quantiﬁcation and allele-speciﬁc read abundances. As a testbed, we will use genotype and RNA-seq data from a 50 generation intercross, cross be- tween two inbred mouse strains. Because these data are derived from two fully sequenced inbred founders, the correct phase is known. Though we use mice as a testbed, our approach is applicable to data from any diseases, tissues, and organisms, including GTEx data.

项目摘要/摘要等位基因-特定ﬁc表达的数量性状基因座(QTL)定位已越来越受到人们的重视。通过提供更详细的ﬁ基因调控机制，改进了传统的eQTL定位。颠覆了疾病的遗传结构。等位基因ﬁc eQTL定位同一ﬁEs顺式作用和反式作用 EQTL，每个都精确到顺式监管元素和反式作用因素，通过利用不同于反式作用eQTL、顺式作用eQTL影响与变异体相同单倍型的转录本的表达本身，导致等位基因表达不平衡。然而，等位基因ﬁceQTL的定位需要一个可靠的长时间- 基因组序列的范围分期和从ﬁ-SEQ数据中准确的等位基因c表达定量ﬁ 与基因组分期一致。大多数现有的工作已经治疗了等位基因ﬁc表达的量子ﬁ阳离子。和分阶段作为独立的任务，即使每一项都可以提高对方的准确性。在本建议中研究中，我们将修改并配对两个广泛使用的工具，用于基因组分期的SHAPEIT和用于 Rna-seq量子ﬁ阳离子，获得准确的定相与等位基因ﬁc表达的量子ﬁ阳离子一致进行等位基因ﬁc eQTL定位。组合工具将继承或提高精度，并 EFﬁ两种原始方法的准确性。如果从实验或三人组数据中知道了相序，我们将用加速EM替换Salmon的EM算法，以解决极端的多映射读取问题具有计算效率的ﬁ。如果阶段性序列不像无关个体那样可用，我们将修改 SHAPEIT将变异体和等位基因特异性ﬁc读取丰度相结合，嵌入等位基因特异性ﬁc表达形状内的Quantiﬁ阳离子和利用鲑鱼获得转录的Quantiﬁ阳离子和等位基因ﬁc Read 富足。作为试验床，我们将使用来自50代杂交、杂交Be-Be-Be的基因和RNA序列数据。两个近交系小鼠之间。由于这些数据来自两个完全测序的近交系创始人，已知正确的相位。虽然我们使用老鼠作为试验床，但我们的方法适用于任何疾病的数据，组织和生物体，包括GTEx数据。