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Study Sees Transcriptional Differences in Mouse, Human Tissues

NEW YORK (GenomeWeb) – A new study based on RNA sequence and other data for up to 15 tissue types is teasing apart transcriptional patterns that distinguish humans and mice.

Researchers from the US and Spain used new and existing deep RNA sequence data on 15 tissue types to compare and contrast transcription patterns in mice and humans. Their findings, slated to appear online this week in the Proceedings of the National Academy of Sciences, revealed substantial differences in RNA expression profiles and transcriptional diversity between human and mouse tissues despite documented similarities and conservation at the genetic level.

"Although commonalities are evident in the expression of tissue-specific genes between the two species, the expression for many sets of genes was found to be more similar in different tissues within the same species than between species," co-senior authors Joseph Ecker, at the Salk Institute for Biological Studies, Stanford University's Michael Snyder, and their colleagues wrote.

The mouse has long been used as a model for studying human traits and diseases. And many of the studies published so far have stressed the genetic, cellular, and physiological similarities between the two mammalian species, authors of the new analysis noted. Likewise, at least a few studies have pointed to gene expression parallels in similar tissue types from humans and mice.

Nevertheless, Ecker, Snyder, and colleagues reasoned that there was still more to learn about the transcriptional similarities and differences that mark various mouse and human tissues.

For their analyses, the investigators considered 13 human tissues and as many tissues from mice that were sequenced for the Encyclopedia of DNA Elements (ENCODE) study. To that, they added RNA sequencing data on 11 more human tissues considered through the Roadmap Epigenomics Consortium.

All told, the team took into account some 93 different RNA sequence datasets, along with additional information on non-coding transcripts produced for the Genotype-Tissue Expression (GTex) project.

The researchers found that gene expression profiles in different mouse tissues tended to cluster more closely with one another than with corresponding human tissues and vice versa, though they did see some tissue-related gene expression similarities across species.

Even so, tissue-specific transcripts — which were particularly common in testes, brain, heart muscle, skeletal muscle, and liver tissues — typically turned up at elevated levels compared to the expression of genes that were active across many or all of the tissue types.

Indeed, the elevated expression of tissue-specific genes relative to housekeeping genes may partly account for the tissue-related expression patterns detected in mouse and human tissues in the past, the study's authors explained, since "[o]ther  studies restricted their analyses to the same tissues expressing high numbers of tissue-specific genes."

On the other hand, when they focused on the sort of genes contributing to intra-organism expression clusters, the researchers identified more than 4,700 genes that are consistently expressed differently in mouse and human tissues — results supported by their subsequent chromatin immunoprecipitation-based analysis of histone marks associated with active promotors near those genes.

Those included 2,569 genes with enhanced expression in human tissues and almost 2,200 genes with more pronounced expression in tissues from mouse.

There were differences detected amongst the non-coding RNAs present in mouse and human tissues, too. Using the data at hand, the team was able to track long intergenic non-coding RNAs and single exon transcripts in these tissues, uncovering nearly 70,400 non-coding transcripts in human tissues and more than 116,500 in mouse tissues.

Many of those non-coding transcripts turned up in just one or a few samples, with smaller subsets of non-coding transcripts turning up as the researchers considered more and more replicates of the same tissue type. On the other hand, non-coding transcripts that were most reproducible within human or mouse tissues were also somewhat more likely to have orthologs in the other species.

"Overall, our study demonstrates the extensive divergence in the expression of both non-coding genes as well as conserved, protein-coding genes that likely mediates the extensive differences between humans and mice," the study's authors concluded.