Scientists identify genes that give mice longer legs

Research may have implications for small populations experiencing rapid climate change

Dr. Frank Chan Research Group leader at the Friedrich Miescher Laboratory. Picture: Jörg Abendroth / Max Planck Institute for Developmental Biology

The Longshanks Experiment uncovered many genes that increase tibia length in mice. © Max Planck Society / David Deen.

The Longshanks Experiment uncovered many genes that increase tibia length in mice. © Max Planck Society / David Deen.

Tübingen, Germany. 08 June 2019. An international team of scientists from Germany, Canada and Austria has reported results of five years of tracking genetic changes in a remarkable mouse evolutionary experiment. Dubbed the "Longshanks experiment", researchers led by Campbell Rolian at the University of Calgary, Canada, have taken the common laboratory mouse and created mice with longer shin bones by selective breeding for 20 generations. Now, Max Planck scientists at the Friedrich Miescher Laboratory in Tübingen have teamed up with Campbell Rolian to track which genetic changes give mice longer legs. By recording the change in leg length and associated changes in their genomes over 20 generations and modelling these changes using evolutionary theory, this research shows how populations may respond to rapid selective forces like climate change. The results have now been published in eLife, a scientific journal.

Humans have been making use of artificial selection for thousands of years. Much of what we eat, for example, from beef to poultry to cereals, comes from a collection of organisms with genomes that have been completely reshaped by the actions of generations of farmers and breeders. Yet, despite decades of research in evolutionary biology, it remains difficult to predict what will happen to an organism's genes when selective pressure is applied.

Traits that at first seem simple often arise from layers upon layers of complexity. It can take hundreds if not thousands of tiny changes to many genes, plus just the right alterations to a few key ones, to have a desired effect on a single trait. Also, if you consider that often the genomes of the starting population are unknown and that many traits are under simultaneous selection in wild populations, it becomes clear why many questions remain unanswered.

An international team of scientists, led by Frank Chan from the Friedrich Miescher Laboratory in Tübingen, Germany, Campbell Rolian from the University of Calgary, Canada and Nick Barton from the Institute of Science and Technology (IST), Austria have analyzed an on-going laboratory experiment dubbed "the Longshanks experiment" to explore how an animal's genome changes under strong selection. For the past five years, two independent populations of mice have been selectively bred to have longer legs. In each generation, the mice were measured and those with the longest tibia – a bone in the shin – relative to their body mass were allowed to breed. Genetic data were also recorded.

Now, Castro, Yancoskie, et al. have analyzed the genetic data up to the first 17 generations in the Longshanks experiment to find out what kind of genes may be relevant to the 13% increase in leg length seen in the mice so far.

This analysis uncovered many genes, possibly thousands, all acting in concert to increase tibia length. But the gene with the largest effect by far is a key developmental gene called Nkx3-2. In people, mutations in this gene cause a disease called spondylo-megaepiphyseal-metaphyseal dysplasia, which can lead to long limbs and a short trunk.

"What was remarkable about this Nkx3-2 gene is that not only are the mice carrying a leg-specific mutation not sick, they survived and bred so well under our selection for longer legs that the gene switch mutation went from a rare one-in-five copy to almost taking over the entire population of mice in five short years. You may as well say that they have won the genetic lottery," said Chan.

Even in highly controlled experiments that record a great deal of information about the organisms involved, predicting how the genome will change and which genes will be involved is not a straightforward question. Finding out how the genome may change in response to selection is important because it can help scientists build better models for breeding farm animals or crops, and better predict the consequences of climate change. As a result, experiments such as these may have broad applications in conservation, genomic medicine and agriculture.

Note to journalists:
The study described here was funded by the Max Planck Society, NSERC Discovery Grant 4181932 and the University of Calgary, Faculty of Veterinary Medicine.The original publication is published in eLife (eLife 2019;8:e42014 DOI: 10.7554/eLife.42014).

Dr. Frank Chan
Research Group Leader at the Friedrich Miescher Laboratory
Max Planck Campus Tübingen, Germany
Phone: 07071 601-888

Max Planck Campus Tübingen
Dr. Daniel Fleiter
Phone: 07071 601-777

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About the Max Planck Campus Tübingen:
The Max Planck Campus Tübingen is home to the Max Planck Institutes for Developmental Biology, Biological Cybernetics and Intelligent Systems (Tübingen site) and the Friedrich Miescher Laboratory. More than 1200 people from more than 50 nations work and conduct research on the campus. Its institutes are part of the 86 research institutions of the Max Planck Society for the Advancement of Science.