Scientists uncover striking differences between mouse and human gene expression across a variety of tissues.

By | November 17, 2014

WIKIPEDIA, RAMAMice are widely used to model human metabolism, disease, and drug response. But results published today (November 17) in PNAS reveal widespread differences between human and mouse gene expression, both in protein-coding and noncoding genes, suggesting that understanding these disparities could help explain fundamental differences in the two species’ physiology.

Michael Snyder of Stanford University and his colleagues compared how genes are expressed in 15 different human and mouse tissues, including brain, heart, liver, and kidney. They found that gene expression patterns clustered by species rather than tissues. For example, gene expression in a mouse liver more closely resembled the patterns observed in a mouse heart than those observed in a human liver. Using data from the ENCODE and modENCODE projects, among other sources, the analysis spanned “the most tissue-diverse RNA-seq dataset to date,” the authors wrote in their paper.

The results “go a little against the grain,” said bioinformatician Mark Gerstein of Yale University who was not involved in the study. “We might think that humans and mice are very similar [genetically], but when we compare their transcriptomes, they’re more different than we thought.”

Several previous studies involving a similar comparison of gene expression in human and mouse tissues have found the opposite: that gene expression in human and mouse livers was more similar compared to that of mouse liver and brain, for example. These tissue-specific gene expression patterns may have turned up because the tissues tested included the kidney, testes, brain, liver and muscle—all of which perform very specialized, parallel functions in both species. Snyder said that the limited number of highly specialized tissues included in these studies may have hidden species-specific patterns. “There’s a lot of similarity between organs within an organism that wasn’t appreciated before,” he said.

However, Nuno Barbosa Morais of the University of Lisbon in Portugal, authored coauthor on one of these earlier papers, noted in an e-mail that the groups used different algorithms to analyze their data, which may have contributed to the discrepancies.

Snyder and his colleagues found that more than 4,000 genes were differentially expressed in human and mouse tissues. Looking for epigenetic changes—such as histone modifications—underlying these differences, the researchers found that when genes were more highly expressed in one of the two species, two histones, H3K4me3 and H3K27ac, showed more active promoter marks than in the other. According to Snyder, this suggests that gene expression differences are biological and unlikely to be an artifact of the experiments or analysis.  

Extending their work to noncoding RNAs, the team discovered a greater variability in these transcript levels across tissues than observed for protein-coding genes. Previously, the majority of noncoding transcripts were thought to be highly tissue-specific. But knowing how many noncoding transcripts are truly tissue-specific will require larger datasets across a wider variety of tissues. The new results are “consistent with the idea that regulatory information in general, such as transcription factor binding, is highly diverged” between the two species, the authors wrote in their paper.

The new results are “significant and complementary” to previous comparisons of gene expression patterns across species and tissues, said computational biologist Chao Cheng of Dartmouth College in New Hampshire who was not involved in the work.

These data “guide us as to where a mouse model might be useful and where to be more cautious,” said Snyder. “A mouse and human have almost the same genes. But how we express those genes differs quite a bit.”

S. Lin et al. “Comparison of the transcriptional landscapes between human and mouse tissues,” PNAS, doi:10.1073/pnas.1413624111, 2014.

Correction (November 18): This article has been updated to correct an error in a previous version: the University of Lisbon is in Portugal. The Scientist regrets the error.

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Avatar of: CSilva


Posts: 1

November 18, 2014

I'm sorry, I just want to rectify an error. In the text it's writen "Nuno Barbosa Morais Of the University of Lisbon in Spain", when actually the University of Lisbon is in Portugal (a whole different country), being Lisbon Portugal's capital city. Thank you.

Avatar of: wctopp


Posts: 110

November 18, 2014

I hope they move on to do rat.  We've always known that mouse data is suspect as a predictor but vast amounts of drug research rides on rats.

Avatar of: tvence


Posts: 1052

Replied to a comment from CSilva made on November 18, 2014

November 18, 2014

Thanks for reading and catching our mistake, CSilva. It's fixed.

All the best,

Tracy Vence

News Editor, The Scientist

Avatar of: James V. Kohl

James V. Kohl

Posts: 481

November 18, 2014

(This model of RNA-mediated cell type differentiation was first presented in our 1996 Hormones and Behavior review.)

The metabolism of nutrients to species-specific pheromones that control the physiology of reproduction in species from microbes to man exemplifies how comparisons of RNA-mediated transcriptional landscapes have since established the validity of Nutrient-dependent/pheromone-controlled adaptive evolution: a model.

"Until recently, the association of the nutrient choline in humans and its metabolism to trimethylamine odor in different species of mice was the best example of how a change in diet becomes associated with the presence of mammalian conspecifics whose androgen estrogen ratio-associated odor distinguishes them sexually, and also as nutrient-dependent physically fit mates (Stensmyr & Maderspacher, 2013). The mouse model makes it clearer that glucose uptake changes cellular thermodynamic equilibrium and differential pathway regulation that results in adaptively evolved fitness in species from microbes (Kondrashov, 2012) to mammals. Species-specific health and reproductive fitness is associated with nutrient-dependent amino acid substitutions and with pheromone-controlled reproduction. Disease is associated with mutations exemplified in cancer where perturbations of the glucose-dependent thermodynamic/thermoregulatory equilibrium are equally clear (Locasale, 2012).

Theorists insist that beneficial mutations somehow lead to increasing organismal complexity manifested in epigenetically altered transcriptional landscapes. Their theories are based on what they learned about conserved molecular mechanisms from population geneticists, which serious scientists now understand is NOTHING AT ALL.

The serious scientists have learned from comparisons of transcriptional landscapes across species and comparisons of morphological AND behavioral phenotypes. See for example, Dobzhansky (1973):

...the so-called alpha chains of hemoglobin have identical sequences of amino acids in man and the chimpanzee, but they differ in a single amino acid (out of 141) in the gorilla. 

Theorists are now forced to claim that amino acid substitutions are akin to mutations. But mutations perturb the chemistry of protein folding, which is why they cannot lead to increasing organismal complexity.

For comparison, amino acid substitutions are linked from the de novo creation of olfactory receptor genes to species diversity in vertebrates and invertebrates via conserved molecular mechanisms of ecological, social, neurogenic, and socio-cognitive niche construction with examples in my 2013 review.

Avatar of: Hugh-F-61


Posts: 69

November 18, 2014

 I  wonder about the effect of time of day of sample collection on these experiments. Many genes must show daily cycles of activity, especially in brains and other organs where activity differs between waking and sleeping. Mice, active in the dark, migtht be completely out of phase with humans who sleep at night. Has this been investigated and controlled for in these experiments? Where do the human samples come from? I expect the mouse samples were taken during the human working day.

Given the difference in shape and behaviour I am not surprised that mice and humans differ in gene expression.

Avatar of: James V. Kohl

James V. Kohl

Posts: 481

Replied to a comment from Hugh-F-61 made on November 18, 2014

November 18, 2014

I think the point to be made is that the differences in shape and behavior are nutrient-dependent and pheromone-controlled in the context of the nutrient-dependent pheromone-controlled physiology of species-specific reproduction in species from microbes to man.

See, for instance: Physiology is rocking the foundations of evolutionary biology

The president of the International Union of Physiological Sciences concluded:

Perhaps the elegant mathematics and the extraordinary reputation of the scientists involved blinded us to what now seems obvious: the organism should never have been relegated to the role of mere carrier of its genes.

He appears to have been too polite to state directly that evolutionary theorists who believe in beneficial mutations are science idiots. For that, we need to hear from a physicist like Brian Cox.

Robin Ince “Am I wrong to sometimes be scared of science idiots?”

Brian Cox  “…my favoured response would be: ‘you bunch of utter nob ends’.

Excerpted from: Interview - Prof Brian Cox and Robin Ince "The two minds discuss science and comedy ahead of their Uncaged Monkeys show"


Avatar of: James V. Kohl

James V. Kohl

Posts: 481

November 18, 2014

See also: The Nose Knows

The human nose can differentiate more than a trillion odors, a study finds.

By | March 25, 2014

What the nose knows about species-specificity extends Synchronous Evolution of an Odor Biosynthesis Pathway and Behavioral Response across species via conserved molecular mechanisms.

TAAR5 is an evolutionarily conserved olfactory receptor required for a species-specific behavior. Synchronized changes in odor biosynthesis pathways and odor-evoked behaviors could ensure species-appropriate social interactions.

However, the pseudoscientific nonsense of Mutation-driven evolution must be dismissed because it has become clearer that Feedback loops link odor and pheromone signaling with reproduction in species from microbes to man in the context of what is known about physics, chemistry, and molecular biology, which limits the use of any so-called explanations from the pseudoscience of social science.

What we see extended across species has always been predicted in the context of receptor-mediated cell type differentiation via RNA-mediated amino acid substitutions, whether the receptors are TAARs or any other receptors. Receptors link nutrient uptake to gene duplication and the de novo creation of new cell types, which are clearly linked to biodiversity via the morphological and behavioral phenotypes of species from microbes to man.

Ideas about the evolution of behavior should have been critically examined before now in an effort to determine if any model organism exemplified the evolution of behavior outside the biophysical contraints of protein folding, which prevent mutations from leading to anything but diseases and disorders.

Avatar of: primativebeliever


Posts: 30

November 18, 2014

the bibles said the same thing hundreds of years ago. they is one fleah of man and one of beast anotther of birds...... this would make mediccal reseach even more flawed than Dr David Page said it was on his youtube video "why sex matters"

Avatar of: gbscientist0424


Posts: 1

November 19, 2014

The title of this article is absurd. Am I suppose to be impressed by this? Were they expecting to find out that mouse and human tissue is identical? This article is a waste time.
Avatar of: James V. Kohl

James V. Kohl

Posts: 481

Replied to a comment from gbscientist0424 made on November 19, 2014

November 19, 2014

First line:

Mice are widely used to model human metabolism, disease, and drug response.

Testing is now available that predicts how differences in metabolic networks and genetic networks interact. This leads to personalized medicine via pharmacogenomics, which helps to avoid ineffective treatments or reactions.

Testing appears to be largely based on nutrient-dependent RNA-mediated amino acid substitutions linked to cell type differentiation and the physiology of species-specific reproduction in species from microbes to man.

The mouse to human model in which a single base pair change and single amino acid substitution alter synergistic interactions in the liver and other organs, which are linked to sex differences in morphological and behavioral phenotypes, may seem to be a waste of time to some people. But the mouse to human model of cell type differentiation has defined scientific progress in terms that limit evolutionary inferrences and focus on biologically-based facts.

The facts will set a new practice standard outside the context of evolutionary theory and evolutionary medicine. Critics should be honest and admit they simply don't want anyone to pay more attention to the molecular epigenetics of biodiversity than to claims that biodiversity evolved via mutations.

We can expect some people to think personalized medicine outside the context of evolution is absurd. It would be great if scientists could simply accept the facts and welcome others to the 21st century.

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