An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice

  1. João P L Castro
  2. Michelle N Yancoskie
  3. Marta Marchini
  4. Stefanie Belohlavy
  5. Layla Hiramatsu
  6. Marek Kučka
  7. William H Beluch
  8. Ronald Naumann
  9. Isabella Skuplik
  10. John Cobb
  11. Nick H Barton
  12. Campbell Rolian  Is a corresponding author
  13. Yingguang Frank Chan  Is a corresponding author
  1. Friedrich Miescher Laboratory of the Max Planck Society, Germany
  2. University of Calgary, Canada
  3. IST Austria, Austria
  4. Max Planck Institute for Cell Biology and Genetics, Germany

Abstract

Evolutionary studies are often limited by missing data that are critical to understanding the history of selection. Selection experiments, which reproduce rapid evolution under controlled conditions, are excellent tools to study how genomes evolve under selection. Here we present a genomic dissection of the Longshanks selection experiment, in which mice were selectively bred over 20 generations for longer tibiae relative to body mass, resulting in 13% longer tibiae in two replicates. We synthesized evolutionary theory, genome sequences and molecular genetics to understand the selection response and found that it involved both polygenic adaptation and discrete loci of major effect, with the strongest loci tending to be selected in parallel between replicates. We show that selection may favor de-repression of bone growth through inactivating two limb enhancers of an inhibitor, Nkx3-2. Our integrative genomic analyses thus show that it is possible to connect individual base-pair changes to the overall selection response.

Data availability

Sequencing data have been deposited in SRA (accession number SRP165718), GEO (accession numbers GSE121564, GSE121565 and GSE121566)Non-sequence data have been deposited at Dryad (doi:10.5061/dryad.0q2h6tk).Analytical code and additional notes have been deposited in the following repository: https://github.com/evolgenomics/LongshanksAdditional raw data and code are hosted via our institute's FTP servers at http://ftp.tuebingen.mpg.de/fml/ag-chan/Longshanks/

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. João P L Castro

    Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Michelle N Yancoskie

    Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Marta Marchini

    University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Stefanie Belohlavy

    IST Austria, Klosterneuburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
  5. Layla Hiramatsu

    Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Marek Kučka

    Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. William H Beluch

    Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Ronald Naumann

    Max Planck Institute for Cell Biology and Genetics, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Isabella Skuplik

    University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. John Cobb

    University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. Nick H Barton

    IST Austria, Klosterneuburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8548-5240
  12. Campbell Rolian

    University of Calgary, Calgary, Canada
    For correspondence
    cprolian@ucalgary.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7242-342X
  13. Yingguang Frank Chan

    Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany
    For correspondence
    frank.chan@tue.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6292-9681

Funding

Natural Sciences and Engineering Research Council of Canada (4181932)

  • Campbell Rolian

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Magnus Nordborg, Austrian Academy of Sciences, Austria

Ethics

Animal experimentation: All experimental procedures described in this study have been approved by the applicable University institutional ethics committee for animal welfare at the University of Calgary (HSACC Protocols M08146 and AC13-0077); or local competent authority: Landesdirektion Sachsen, Germany, permit number 24-9168.11-9/2012-5.

Version history

  1. Received: September 14, 2018
  2. Accepted: May 19, 2019
  3. Accepted Manuscript published: June 6, 2019 (version 1)
  4. Version of Record published: July 2, 2019 (version 2)

Copyright

© 2019, Castro et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. João P L Castro
  2. Michelle N Yancoskie
  3. Marta Marchini
  4. Stefanie Belohlavy
  5. Layla Hiramatsu
  6. Marek Kučka
  7. William H Beluch
  8. Ronald Naumann
  9. Isabella Skuplik
  10. John Cobb
  11. Nick H Barton
  12. Campbell Rolian
  13. Yingguang Frank Chan
(2019)
An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice
eLife 8:e42014.
https://doi.org/10.7554/eLife.42014

Share this article

https://doi.org/10.7554/eLife.42014

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