RNA-Seq in 296 phased trios provides a high-resolution map of genomic imprinting

BMC Biology

GoNL Consortium¹  BIOS Consortium¹  Ramin Monajemi²  Harmen H. M. Draisma²  Bastiaan T. Heijmans²  Szymon M. Kiełbasa²  Mark A. van de Wiel³  Bharati Jadhav⁴  Andrew J. Sharp⁴  Daniel Ho⁴  Lude Franke⁵  Peter A. C. ‘t Hoen⁶  Joyce van Meurs⁷  Rick Jansen⁸  Kristina K. Gagalova⁹ 

[1] ;Department of Biomedical Data Sciences, Leiden University Medical Center;Department of Epidemiology and Biostatistics, VU University Medical Center;Department of Genetics and Genomic Sciences, Hess Center for Science and Medicine, Mount Sinai School of Medicine;Department of Genetics, University Medical Center Groningen;Department of Human Genetics, Leiden University Medical Center;Department of Internal Medicine, Erasmus MC;Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam;GenomeScan B.V.;

关键词: Imprinting;    Allele-specific expression;    Bayesian analysis;    Parent-of-origin;    Phased genotypes;   

DOI  :  10.1186/s12915-019-0674-0

来源: DOAJ

【 摘 要 】

Abstract Background Identification of imprinted genes, demonstrating a consistent preference towards the paternal or maternal allelic expression, is important for the understanding of gene expression regulation during embryonic development and of the molecular basis of developmental disorders with a parent-of-origin effect. Combining allelic analysis of RNA-Seq data with phased genotypes in family trios provides a powerful method to detect parent-of-origin biases in gene expression. Results We report findings in 296 family trios from two large studies: 165 lymphoblastoid cell lines from the 1000 Genomes Project and 131 blood samples from the Genome of the Netherlands (GoNL) participants. Based on parental haplotypes, we identified > 2.8 million transcribed heterozygous SNVs phased for parental origin and developed a robust statistical framework for measuring allelic expression. We identified a total of 45 imprinted genes and one imprinted unannotated transcript, including multiple imprinted transcripts showing incomplete parental expression bias that was located adjacent to strongly imprinted genes. For example, PXDC1, a gene which lies adjacent to the paternally expressed gene FAM50B, shows a 2:1 paternal expression bias. Other imprinted genes had promoter regions that coincide with sites of parentally biased DNA methylation identified in the blood from uniparental disomy (UPD) samples, thus providing independent validation of our results. Using the stranded nature of the RNA-Seq data in lymphoblastoid cell lines, we identified multiple loci with overlapping sense/antisense transcripts, of which one is expressed paternally and the other maternally. Using a sliding window approach, we searched for imprinted expression across the entire genome, identifying a novel imprinted putative lncRNA in 13q21.2. Overall, we identified 7 transcripts showing parental bias in gene expression which were not reported in 4 other recent RNA-Seq studies of imprinting. Conclusions Our methods and data provide a robust and high-resolution map of imprinted gene expression in the human genome.

【 授权许可】

Unknown