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.

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.

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.

Metrics

  • 4,285
    views
  • 514
    downloads
  • 63
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Developmental Biology
    Mehmet Mahsum Kaplan, Erika Hudacova ... Ondrej Machon
    Research Article

    Hair follicle development is initiated by reciprocal molecular interactions between the placode-forming epithelium and the underlying mesenchyme. Cell fate transformation in dermal fibroblasts generates a cell niche for placode induction by activation of signaling pathways WNT, EDA, and FGF in the epithelium. These successive paracrine epithelial signals initiate dermal condensation in the underlying mesenchyme. Although epithelial signaling from the placode to mesenchyme is better described, little is known about primary mesenchymal signals resulting in placode induction. Using genetic approach in mice, we show that Meis2 expression in cells derived from the neural crest is critical for whisker formation and also for branching of trigeminal nerves. While whisker formation is independent of the trigeminal sensory innervation, MEIS2 in mesenchymal dermal cells orchestrates the initial steps of epithelial placode formation and subsequent dermal condensation. MEIS2 regulates the expression of transcription factor Foxd1, which is typical of pre-dermal condensation. However, deletion of Foxd1 does not affect whisker development. Overall, our data suggest an early role of mesenchymal MEIS2 during whisker formation and provide evidence that whiskers can normally develop in the absence of sensory innervation or Foxd1 expression.

    1. Developmental Biology
    Bin Zhu, Rui Wei ... Pei Liang
    Research Article

    Wing dimorphism is a common phenomenon that plays key roles in the environmental adaptation of aphid; however, the signal transduction in response to environmental cues and the regulation mechanism related to this event remain unknown. Adenosine (A) to inosine (I) RNA editing is a post-transcriptional modification that extends transcriptome variety without altering the genome, playing essential roles in numerous biological and physiological processes. Here, we present a chromosome-level genome assembly of the rose-grain aphid Metopolophium dirhodum by using PacBio long HiFi reads and Hi-C technology. The final genome assembly for M. dirhodum is 447.8 Mb, with 98.50% of the assembled sequences anchored to nine chromosomes. The contig and scaffold N50 values are 7.82 and 37.54 Mb, respectively. A total of 18,003 protein-coding genes were predicted, of which 92.05% were functionally annotated. In addition, 11,678 A-to-I RNA-editing sites were systematically identified based on this assembled M. dirhodum genome, and two synonymous A-to-I RNA-editing sites on CYP18A1 were closely associated with transgenerational wing dimorphism induced by crowding. One of these A-to-I RNA-editing sites may prevent the binding of miR-3036-5p to CYP18A1, thus elevating CYP18A1 expression, decreasing 20E titer, and finally regulating the wing dimorphism of offspring. Meanwhile, crowding can also inhibit miR-3036-5p expression and further increase CYP18A1 abundance, resulting in winged offspring. These findings support that A-to-I RNA editing is a dynamic mechanism in the regulation of transgenerational wing dimorphism in aphids and would advance our understanding of the roles of RNA editing in environmental adaptability and phenotypic plasticity.