Extensive variation between tissues in allele specific expression in an outbred mammal

Abstract

BackgroundAllele specific gene expression (ASE), with the paternal allele more expressed than the maternal allele or vice versa, appears to be a common phenomenon in humans and mice. In other species the extent of ASE is unknown, and even in humans and mice there are several outstanding questions. These include; to what extent is ASE tissue specific? how often does the direction of allele expression imbalance reverse between tissues? how often is only one of the two alleles expressed? is there a genome wide bias towards expression of the paternal or maternal allele; and finally do genes that are nearby on a chromosome share the same direction of ASE? Here we use gene expression data (RNASeq) from 18 tissues from a single cow to investigate each of these questions in turn, and then validate some of these findings in two tissues from 20 cows.ResultsBetween 40 and 100 million sequence reads were generated per tissue across three replicate samples for each of the eighteen tissues from the single cow (the discovery dataset). A bovine gene expression atlas was created (the first from RNASeq data), and differentially expressed genes in each tissue were identified. To analyse ASE, we had access to unambiguously phased genotypes for all heterozygous variants in the cow’s whole genome sequence, where these variants were homozygous in the whole genome sequence of her sire, and as a result we were able to map reads to parental genomes, to determine SNP and genes showing ASE in each tissue. In total 25,251 heterozygous SNP within 7985 genes were tested for ASE in at least one tissue. ASE was pervasive, 89 % of genes tested had significant ASE in at least one tissue. This large proportion of genes displaying ASE was confirmed in the two tissues in a validation dataset.For individual tissues the proportion of genes showing significant ASE varied from as low as 8–16 % of those tested in thymus to as high as 71–82 % of those tested in lung. There were a number of cases where the direction of allele expression imbalance reversed between tissues. For example the gene SPTY2D1 showed almost complete paternal allele expression in kidney and thymus, and almost complete maternal allele expression in the brain caudal lobe and brain cerebellum. Mono allelic expression (MAE) was common, with 1349 of 4856 genes (28 %) tested with more than one heterozygous SNP showing MAE. Across all tissues, 54.17 % of all genes with ASE favoured the paternal allele. Genes that are closely linked on the chromosome were more likely to show higher expression of the same allele (paternal or maternal) than expected by chance. We identified several long runs of neighbouring genes that showed either paternal or maternal ASE, one example was five adjacent genes (GIMAP8, GIMAP7 copy1, GIMAP4, GIMAP7 copy 2 and GIMAP5) that showed almost exclusive paternal expression in brain caudal lobe.ConclusionsInvestigating the extent of ASE across 18 bovine tissues in one cow and two tissues in 20 cows demonstrated 1) ASE is pervasive in cattle, 2) the ASE is often MAE but ra...

Genetics of complex traits: prediction of phenotype, identification of causal polymorphisms and genetic architecture

“…ASE occurs at heterozygous variants where one allele is more highly expressed in the mRNA than the other. Recently, Crowley et al [35] and Chamberlain et al [23] reported that 89% of mice and cattle genes, respectively, show ASE in at least one tissue. Therefore, it seems likely that cis eQTL are very common.…”

Allele-specific expression at the androgen receptor alpha gene in a hybrid unisexual fish, the Amazon molly (Poecilia formosa)

“…A previous study on triploid Medaka ( Oryzias latipes ) reported that the maternally inherited allele was never silenced or suppressed, while one paternal allele was completely suppressed in the liver [23]. In cattle, tissue-specific complete suppression of either the maternally or paternally derived allele has been found [22]. In our present study, the maternal allele ( P .…”

“…formosa provides a rare opportunity to study allele-specific expression (ASE) [16] and cis -regulatory evolution in a unisexual vertebrate species with clonally inherited hybrid genomes. In humans, e.g., up to 60% of the genes show significant ASE differences or allelic bias within and between individuals, populations [17–21], and tissues [22]. About 18% of all examined genes showed uneven expression between alleles in the liver of the triploid Japanese rice fish Oryzias latipes in a large-scale analysis using RNA-seq [23].…”

Genetic variability of the activity of bidirectional promoters: a pilot study in bovine muscle

“…In addition, on average the expression levels in muscle of gene pairs sharing a BiP were more correlated compared with pairs of neighbouring genes in a unidirectional or convergent configuration ( Z- score test, P -value <0.05%). Using normalized gene expression counts previously measured in 18 bovine tissues and for three different cows, 43 , 44 we calculated the Pearson correlation coefficient between the expression levels of the 120 gene pairs sharing a BiP, the 163 gene pairs in an unidirectional configuration and the 218 gene pairs in a convergent configuration. We then compared the average expression correlation between these three types of gene pairs and found no significant differences between gene pairs in unidirectional and convergent configurations, but identified significant differences between gene pairs sharing a BiP and the other two types of gene pairs ( Z- score test, P -value <0.05%), The higher correlation between expression levels of genes sharing BiPs has previously been described and is a common feature of bidirectional promoters 39 …”