Lab mice

Credit: Aaron Logan

Scientists have long known that mice are not perfect models for studying conditions in humans, but new research reveals why certain processes and systems in

mice are so different from those in humans.

As part of the mouse ENCODE project, researchers discovered that a significant number of mouse genes do not behave like their human counterparts.

This suggests scientists will need to rethink at least some roles of the lab mouse as a model organism.

“There are a substantial number of mouse genes that are regulated in ways different from similar genes in humans,” said Bing Ren, PhD, of the University of California, San Diego.

“The differences are not random. They are clustered along certain pathways, such as in genes regulating the immune system.”

The findings, part of a series of related papers being published in Nature, Science, and other journals (see below), are derived from the ongoing mouse ENCODE (Encyclopedia of DNA Elements) project.

This multi-institution effort was launched in 2007 to build a comprehensive list of functional elements of the mouse genome. It complements the earlier human ENCODE project, which published its functional catalogue in 2012.

“Both the original human and mouse genome projects gave us the sequence of genetic letters that comprise each organism but no idea how they worked or worked together to create and sustain life,” Dr Ren said.

“The human ENCODE project was designed to answer some of those questions. The mouse ENCODE project is its complement. It’s intended to provide scientists with comprehensive annotation of what mouse genes do, information that may ultimately be used for human therapeutic purposes.”

Only half of human genomic DNA aligns to mouse genomic DNA. But protein-coding genes, which provide the actionable instructions to build a living organism, are more strongly conserved across the two species.

Mice and humans share approximately 70% of the same protein-coding gene sequences, though these genes constitute just 1.5% of their respective genomes.

Dr Ren said scientists had assumed that significant conservation would occur at the deeper level of gene regulation as well, that similar genes in humans and mice would be expressed in similar ways.

Using the same high throughput technologies applied in the human ENCODE project, he and his colleagues analyzed 100 different mouse cell types and tissues.

They found that, while much conservation did exist, the expression profiles of some distinct biological pathways in mouse samples diverged considerably from human samples.

Put another way, core genomic programs were largely conserved between the species, but genes and their underlying regulatory programs had changed significantly over time. Each species had evolved to find different ways to do some of the same things.

The findings are not entirely unexpected. Dr Ren said previous studies had documented rapidly evolving transcription factors in a handful of cell types and model organisms, but the ability to more systematically discern how humans and mice differ in genomic function marks an important milestone.

“One benefit is that, while mice have proved to be substantially different than humans in some ways, we now have a better idea of where exactly they are different, where we will need to take into account those differences, perhaps finding or developing a better model, and where the mouse continues to be a very good model indeed,” Dr Ren concluded.

Visit the following links for the mouse ENCODE papers published yesterday in Nature and Science:

A comparative encyclopedia of DNA elements in the mouse genome

Conservation of trans-acting circuitry during mammalian regulatory evolution

Principles of regulatory information conservation between mouse and human

Topologically associating domains are stable units of replication-timing regulation

Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution

Related studies are set to appear in PNAS, Genome Research, Genome Biology, Nature Communications, and Blood.

Comparison of mice and men may lead to better use of mouse models