TWAS results are complementary to and less affected by linkage disequilibrium than GWAS

Li, Delin; Liu, Qiang; Schnable, Patrick S.

doi:10.1093/plphys/kiab161

Cited by 42 publications

(44 citation statements)

References 58 publications

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“…For example, Y1 encodes a phytoene synthetase involved in carotenoid biosynthesis 60 (Figure 7a & e). This gene is associated with endosperm color via GWASs (this study) and transcriptome wide association studies (TWAS) 75 and this study (Figure 7a). Temperate maize was specifically selected for the y1 allele, resulting in the greater accumulation of carotenoids in the endosperm compared to that of tropical maize 76 (Figure 7b).…”

Section: Discussionsupporting

confidence: 51%

A role for heritable transcriptomic variation in maize adaptation to temperate environments

Sun

Wang

et al. 2022

Preprint

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Transcription bridges genetic information and phenotypes. Here, we evaluated how changes in transcriptional regulation enable maize (Zea mays), a crop originally domesticated in the tropics, to adapt to temperate environments. We generated 572 unique RNA-seq datasets from the roots of 340 maize genotypes. Genes involved in core processes such as cell division, chromosome organization and cytoskeleton organization showed lower heritability of gene expression. While genes involved in anti-oxidation activity exhibited higher expression heritability. An expression genome-wide association study (eGWAS) identified 19,602 expression quantitative trait loci (eQTLs) associated with the expression of 11,444 genes. A GWAS for alternative splicing identified 49,897 splicing QTLs (sQTLs) for 7,614 genes. Rare allele burden within genomic intervals with trans-eQTLs correlated with extremes of expression in target genes as previously reported for cis-eQTLs. Genes harboring both cis-eQTLs and cis-sQTLs in linkage disequilibrium were disproportionately likely to encode transcription factors or were annotated as responding to one or more stresses. Independent component analysis of gene expression data identified loci regulating co-expression modules involved in phytohormone pathways, cell wall biosynthesis, lipid metabolism and stress response. Several genes involved in cell proliferation, flower development, DNA replication and gene silencing showed lower gene expression variation explained by genetic factors between temperate and tropical maize lines. A GWAS of 27 previously published phenotypes identified several candidate genes overlapping with genomic intervals showing signatures of selection during adaptation to temperate environments. Our results illustrate how maize transcriptional regulatory networks enable changes in transcriptional regulation to adapt to temperate regions.

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Section: Discussionsupporting

confidence: 51%

A role for heritable transcriptomic variation in maize adaptation to temperate environments

Sun

Wang

et al. 2022

Preprint

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“…The use of gene expression data, offering gene-level resolution and insight into regulatory variation, has the potential to help overcome these obstacles. Transcriptome-wide association studies (TWAS), which assess the association between gene expression and terminal phenotypes (Hirsch et al 2014;Lin et al 2017;Pasaniuc and Price 2017;Li et al 2021), have successfully identified associations previously found in GWAS and have highlighted new and promising associations for mature grain carotenoids and tocochromanols (Kremling et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Transcriptome-wide association and prediction for carotenoids and tocochromanols in fresh sweet corn kernels

Hershberger

Tanaka

Wood

et al. 2021

Preprint

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Sweet corn is consistently one of the most highly consumed vegetables in the U.S., providing a valuable opportunity to increase nutrient intake through biofortification. Significant variation for carotenoid (provitamin A, lutein, zeaxanthin) and tocochromanol (vitamin E, antioxidants) levels is present in temperate sweet corn germplasm, yet previous genome-wide association studies (GWAS) of these traits have been limited by low statistical power and mapping resolution. Here, we employed a high-quality transcriptomic dataset collected from fresh sweet corn kernels to conduct transcriptome-wide association studies (TWAS) and transcriptome prediction studies for 39 carotenoid and tocochromanol traits. In agreement with previous GWAS findings, TWAS detected significant associations for four causal genes, β-carotene hydroxylase (crtRB1), lycopene epsilon cyclase (lcyE), γ-tocopherol methyltransferase (vte4), and homogentisate geranylgeranyltransferase (hggt1) on a transcriptome-wide level. Pathway-level analysis revealed additional associations for deoxy-xylulose synthase2 (dxs2), diphosphocytidyl methyl erythritol synthase2 (dmes2), cytidine methyl kinase1 (cmk1), and geranylgeranyl hydrogenase1 (ggh1), of which, dmes2, cmk1, and ggh1 have not previously been identified through maize association studies. Evaluation of prediction models incorporating genome-wide markers and transcriptome-wide abundances revealed a trait-dependent benefit to the inclusion of both genomic and transcriptomic data over solely genomic data, but both transcriptome- and genome-wide datasets outperformed a priori candidate gene-targeted prediction models for most traits. Altogether, this study represents an important step towards understanding the role of regulatory variation in the accumulation of vitamins in fresh sweet corn kernels.

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“…It has been increasingly realized that variation in transcript abundance provides significant clues regarding genes that underlie whole-organism phenotypic outcomes [ 41 , 42 ]. Accordingly, we created the web tool, T-CLIM, which integrates transcriptome landscapes and environmental clines in Arabidopsis .…”

Section: Resultsmentioning

confidence: 99%

“…This limitation can be partially ameliorated by TWAS analyses, as we have done here (Figs. 1 and 2 ), which are less susceptible to issues of linkage disequilibrium [ 41 , 42 ]. RiboSNitch and GWA analyses in humans are further complicated by heterozygosity; here, Arabidopsis has an advantage as it is naturally inbred, avoiding the need for disambiguation of alleles within an accession.…”

Section: Discussionmentioning

confidence: 99%

Experimental demonstration and pan-structurome prediction of climate-associated riboSNitches in Arabidopsis

et al. 2022

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Background Genome-wide association studies (GWAS) aim to correlate phenotypic changes with genotypic variation. Upon transcription, single nucleotide variants (SNVs) may alter mRNA structure, with potential impacts on transcript stability, macromolecular interactions, and translation. However, plant genomes have not been assessed for the presence of these structure-altering polymorphisms or “riboSNitches.” Results We experimentally demonstrate the presence of riboSNitches in transcripts of two Arabidopsis genes, ZINC RIBBON 3 (ZR3) and COTTON GOLGI-RELATED 3 (CGR3), which are associated with continentality and temperature variation in the natural environment. These riboSNitches are also associated with differences in the abundance of their respective transcripts, implying a role in regulating the gene's expression in adaptation to local climate conditions. We then computationally predict riboSNitches transcriptome-wide in mRNAs of 879 naturally inbred Arabidopsis accessions. We characterize correlations between SNPs/riboSNitches in these accessions and 434 climate descriptors of their local environments, suggesting a role of these variants in local adaptation. We integrate this information in CLIMtools V2.0 and provide a new web resource, T-CLIM, that reveals associations between transcript abundance variation and local environmental variation. Conclusion We functionally validate two plant riboSNitches and, for the first time, demonstrate riboSNitch conditionality dependent on temperature, coining the term “conditional riboSNitch.” We provide the first pan-genome-wide prediction of riboSNitches in plants. We expand our previous CLIMtools web resource with riboSNitch information and with 1868 additional Arabidopsis genomes and 269 additional climate conditions, which will greatly facilitate in silico studies of natural genetic variation, its phenotypic consequences, and its role in local adaptation.

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TWAS results are complementary to and less affected by linkage disequilibrium than GWAS

Cited by 42 publications

References 58 publications

A role for heritable transcriptomic variation in maize adaptation to temperate environments

A role for heritable transcriptomic variation in maize adaptation to temperate environments

Transcriptome-wide association and prediction for carotenoids and tocochromanols in fresh sweet corn kernels

Experimental demonstration and pan-structurome prediction of climate-associated riboSNitches in Arabidopsis

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