The landscape of genomic imprinting across diverse adult human tissues

Baran, Yael; Subramaniam, Meena; Biton, Anne; Tukiainen, Taru; Tsang, Emily K.; Rivas, Manuel A.; Pirinen, Matti; Gutiérrez‐Arcelus, María; Smith, Kevin S.; Kukurba, Kim; Zhang, Rui; Eng, Celeste; Torgerson, Dara G.; Urbanek, Cydney; Li, Jin Billy; Rodríguez‐Santana, José; Burchard, Esteban G.; Seibold, Max A.; MacArthur, Daniel G.; Montgomery, Stephen B.; Zaitlen, Noah; Lappalainen, Tuuli

doi:10.1101/gr.192278.115

Cited by 191 publications

(274 citation statements)

References 56 publications

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“…A large-scale, multi-tissue resource of ASE estimates complements eQTL mapping by providing access to individual-specific effects, which assists in the interpretation of rare variants, somatic mutations and patterns of imprinting 8,13,14 . We measured ASE at more than 135 million sites across tissues and donors, with a median of over 10,000 genes quantified per donor (Supplementary Information 11 and Supplementary Fig.…”

Section: Allele-specific Expression Across Human Tissuesmentioning

confidence: 99%

Genetic effects on gene expression across human tissues

groups

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Nhgri³

et al. 2017

Nature

3,450

2,146

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Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.

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Section: Allele-specific Expression Across Human Tissuesmentioning

confidence: 99%

Genetic effects on gene expression across human tissues

groups

Fund

Nhgri³

et al. 2017

Nature

3,450

2,146

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“…The genes DLK1 and GATM in the kidney, DIRAS3, INPP5F , and BLCAP in the brain were also among the highest expressed. While the tissue-specific expression of imprinted genes [29] have been reported previously in various species, they were mostly conducted using real time PCR which only gives relative values, while TPM from RNA-seq provides a close estimate to the absolute expression values after correcting for transcriptome size and gene length, allowing the visualization of expression differences among different genes across samples.…”

Section: Resultsmentioning

confidence: 99%

Effects of maternal nutrition on the expression of genomic imprinted genes in ovine fetuses

et al. 2018

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Genomic imprinting is an epigenetic phenomenon of differential allelic expression based on parental origin. To date, 263 imprinted genes have been identified among all investigated mammalian species. However, only 21 have been described in sheep, of which 11 are annotated in the current ovine genome. Here, we aim to i) use DNA/RNA high throughput sequencing to identify new monoallelically expressed and imprinted genes in day 135 ovine fetuses and ii) determine whether maternal diet (100%, 60%, or 140% of National Research Council Total Digestible Nutrients) influences expression of imprinted genes. We also reported strategies to solve technical challenges in the data analysis pipeline. We identified 80 monoallelically expressed, 13 new putative imprinted genes, and five known imprinted genes in sheep using the 263 genes stated above as a guide. Sanger sequencing confirmed allelic expression of seven genes, CASD1, COPG2, DIRAS3, INPP5F, PLAGL1, PPP1R9A, and SLC22A18. Among the 13 putative imprinted genes, five were localized in the known sheep imprinting domains of MEST on chromosome 4, DLK1/GTL2 on chromosome 18 and KCNQ1 on chromosome 21, and three were in a novel sheep imprinted cluster on chromosome 4, known in other species as PEG10/SGCE. The expression of DIRAS3, IGF2, PHLDA2, and SLC22A18 was altered by maternal diet, albeit without allelic expression reversal. Together, our results expanded the list of sheep imprinted genes to 34 and demonstrated that while the expression levels of four imprinted genes were changed by maternal diet, the allelic expression patterns were un-changed for all imprinted genes studied.

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“…The 14q32 region has been associated with imprinting disorders 35 and tumorigenesis. 36 In particular, this genomic area harbors three differentially methylated regions 37,38 described to coordinately regulate (1) the paternally expressed genes DLK1 and RTL1 (retrosposon-like1) and (2) the maternally expressed genes MEG3 (long intergenic non-protein coding RNA 23 or GTL2), RTL-antisense transcript, MEG8, MEG9, and several polyadenylated C/D box small nucleolar (sno)RNAs 39,40 and microRNAs 20,[40][41][42][43] ( Figure 2, Tables S6 and S7). From our analysis, we validated the known imprinting statuses of MEG3, MEG8, MEG9, DLK1, and RTL-antisense transcripts (Tables S7), but the DIO3 and RTL1 genes were not detectable in fibroblasts.…”

Section: Characterization Of Known Imprinted Genes In Singlecell Fibrmentioning

confidence: 99%

“…15 In the early 1990s, Igf2 (paternally expressed) and H19 (maternally expressed) were the first two imprinted genes to be discovered in mice. [16][17][18] To date, approximatively 150 human imprinted genes have been discovered, 19,20 but the quest to identify of the whole repertoire of imprinted genes is still ongoing. Recent studies have concluded that cell type-specific imprinted transcription is pervasive and underestimated.…”

Section: Introductionmentioning

confidence: 99%

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Detection of Imprinted Genes by Single-Cell Allele-Specific Gene Expression

Santoni

Stamoulis

Garieri

et al. 2017

The American Journal of Human Genetics

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Genomic imprinting results in parental-specific gene expression. Imprinted genes are involved in the etiology of rare syndromes and have been associated with common diseases such as diabetes and cancer. Standard RNA bulk cell sequencing applied to whole-tissue samples has been used to detect imprinted genes in human and mouse models. However, lowly expressed genes cannot be detected by using RNA bulk approaches. Here, we report an original and robust method that combines single-cell RNA-seq and whole-genome sequencing into an optimized statistical framework to analyze genomic imprinting in specific cell types and in different individuals. Using samples from the probands of 2 family trios and 3 unrelated individuals, 1,084 individual primary fibroblasts were RNA sequenced and more than 700,000 informative heterozygous single-nucleotide variations (SNVs) were genotyped. The allele-specific coverage per gene of each SNV in each single cell was used to fit a beta-binomial distribution to model the likelihood of a gene being expressed from one and the same allele. Genes presenting a significant aggregate allelic ratio (between 0.9 and 1) were retained to identify of the allelic parent of origin. Our approach allowed us to validate the imprinting status of all of the known imprinted genes expressed in fibroblasts and the discovery of nine putative imprinted genes, thereby demonstrating the advantages of single-cell over bulk RNA-seq to identify imprinted genes. The proposed single-cell methodology is a powerful tool for establishing a cell type-specific map of genomic imprinting.

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The landscape of genomic imprinting across diverse adult human tissues

Cited by 191 publications

References 56 publications

Genetic effects on gene expression across human tissues

Genetic effects on gene expression across human tissues

Effects of maternal nutrition on the expression of genomic imprinted genes in ovine fetuses

Detection of Imprinted Genes by Single-Cell Allele-Specific Gene Expression

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