An Atlas of Genomic Imprinting in Mouse and Human Using RNA-seq data

Nature Genetics has a new paper cataloging genomic imprinting in mouse (and human) across multiple tissues.

Diploid organisms have two copies/alleles of every autosomal gene, where allele is from mother and the other is from father. Genomic imprinting is an epigenetic process that preferentially expresses an allele of a gene depending on whether the allele is inherited from mother or father.

A classic example of genomic imprinting IGF2 gene located in human chromosome 11 and IGF2 allele from father is expressed during early development, while the IGF2 allele from mother is completely silent.  In a classic series of papers in 1991, DeChiara et al.Barlow et al; Bartolomei et al., IGF2 together with IGFR2, and H19 loci were the first three loci characterized as genomically imprinted. In the last twenty years,  the number of genes known to be genomically imprinted has grown to about a few hundred genes.

It is fair to say, our understanding of imprinted genes has been mainly come from  classic genetics/mol. bio experiments. Initial hopes of using RNA-seq technology to characterize new imprinted genes suffered a set back due to technical and reference biases (This paper is from the same team that found technical issues in using RNA-seq for identifying imprinted genes). A number of papers later published using RNA-seq in multiple model organisms, in select tissues, found little or no evidence for genes imprinted.

A New Atlas of Genomic Imprinting in Mouse and Human using RNA-seq data

The paper has used massive amount of RNA-seq data from a variety of tissues and developmental stages to view the landscape of genomic imprinting in mouse and human. In mouse, the team used the F1 hybrids from two divergent mouse strains, B6 and CAST and quantified allele-specific expression in over 70 samples from over 30 tissues. In human, the team quantified allele-specific expression in 1,687 RNA-seq samples from 45 tissues in 178 individuals  from Gene-Tissue Expression Project (GTEx.v3).

Identifying Genomic Imprinting Genes by RNA-seq

The basic approach to find imprinted genes using RNA-seq technoogy rely on robust estimation of allele-specific gene expression (ASE). A gene is said to have allele-specific expression, if one allele (either maternal or paternal allele) is preferentially expressed (one allele is high and the other is low).  RNA-seq data can help find which allele is expressed, how much each allele is expressed and quantify ASE if the alleles carry one or more genetic variations.  ASE can be caused by either change in local regulatory sequences or it can be epigenetic process like genomic imprinting.  Have not had a chance to dig deeper into the computational aspects of quantifying ASE in both mouse and human, but it will be a worthwhile exercise.  Here is the gist of their approach to estimate ASE and genomic imprinting in mouse and human.

Genomic Imprinting in Reciprocal F1 Mice

Genomic Imprinting in Reciprocal F1 Mice (Image: Suppl. Fig 1)

Identifying Genomic Imprinting in Mouse

In case of mouse (and other model organisms), it is relatively easier to characterize genomic imprinting, as one can produce F1 hybrids from two direction of crosses and keep track of maternal and paternal alleles. One would simply need to check if there is strong ASE and the allele that is preferentially expressed is the same, either maternal or paternal, in both the direction of crosses.

Identifying Genomic Imprinting in Human

Predicting genomic imprinting in human

Predicting genomic imprinting in human (Image: Fig 2a)

Unlike mouse, identifying genes that undergo genomic imprinting by RNA-seq data is bit tricky. The approach the paper took was to use the phasing information together with allele-specific expression in the large unrelated individuals from GTEx project. Therefore, when there is ASE at a heterozygote loci, the phasing information also tells whether the prefered allele is maternal or paternal.

If the cause of ASE is local genetic effect, then the allele that is expressed will be the same in most individuals.  However, if the cause of ASE is genomic imprinting, both maternal and paternal allele could be preferentially expressed across the population. As a whole, there will be no preference to one allele. The authors used a large pedigree data to validate the predicted human imprinted genes.

Genomic Imprinting Atlas

One of the biggest upshots, gleaned from a quick reading, is that the systematic analysis of genomic imprinting across tissues vastly improved our understanding of imprinting across tissues.  This papers’ atlas of genomic imprinting in mouse has identified over 4000 imprinting in genes x tissues combinations. In comparison WAMIDEX, a previous effort to catalog imprinted genes in mouse,  had just about 500 imprinting measurements.  The supplementary figure 4, reproduced below, comparing the number of imprinted genes from this study to the previous effort WAMIDEX clearly tells the story. Basically, a gene that is imprinted in one tissue tend to preserve the imprinting status in other tissues as well.

Another biggest result is that the number of distinct genes that are genomically imprinted is still about few hundreds, as we knew before.  The number of novel imprinted genes identified by this study is just about 10-20 in both mouse and human.

Comparison of Genomic Imprinting Atlas in Mouse to previous effort

Comparison of Genomic Imprinting Atlas in Mouse to previous effort (Suppl Fig 4)


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