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

Abstract
Data availability
Article and author information
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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

1. Castro JPL
2. Yancoskie MN
3. Marchini M
4. Belohlavy S
5. Hiramatsu L
6. Kučka M
7. Beluch WH
8. Naumann R
9. Skuplik IO
10. Cobb J
11. Barton NH
12. Rolian CP
13. Chan YF
(2019) An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice
NCBI Sequence Read Archive, SRP165718.

http://www.ncbi.nlm.nih.gov/sra?term=SRP165718
1. Castro JPL
2. Yancoskie MN
3. Marchini M
4. Belohlavy S
5. Hiramatsu L
6. Kučka M
7. Beluch WH
8. Naumann R
9. Skuplik IO
10. Cobb J
11. Barton NH
12. Rolian CP
13. Chan YF
(2019) An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice
NCBI Gene Expression Omnibus, GSE121564.

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE121564
1. Castro JPL
2. Yancoskie MN
3. Marchini M
4. Belohlavy S
5. Hiramatsu L
6. Kučka M
7. Beluch WH
8. Naumann R
9. Skuplik IO
10. Cobb J
11. Barton NH
12. Rolian CP
13. Chan YF
(2019) An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice
NCBI Gene Expression Omnibus, GSE121565.

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE121565
1. Castro JPL
2. Yancoskie MN
3. Marchini M
4. Belohlavy S
5. Hiramatsu L
6. Kučka M
7. Beluch WH
8. Naumann R
9. Skuplik IO
10. Cobb J
11. Barton NH
12. Rolian CP
13. Chan YF
(2019) An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice
NCBI Gene Expression Omnibus, GSE121566.

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE121566
1. Castro JPL
2. Yancoskie MN
3. Marchini M
4. Belohlavy S
5. Hiramatsu L
6. Kučka M
7. Beluch WH
8. Naumann R
9. Skuplik IO
10. Cobb J
11. Barton NH
12. Rolian CP
13. Chan YF
(2019) Data from: An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice
Dryad Digital Repository, doi:10.5061/dryad.0q2h6tk.

http://dx.doi.org/10.5061/dryad.0q2h6tk

The following previously published data sets were used

(2011) Mouse Genomes Project version 3 dbSNP v137 release
dbSNP v137 release.

https://www.sanger.ac.uk/science/data/mouse-genomes-project
1. Y Shen
2. F Yue
3. D F McCleary
4. Z Ye
5. L Edsall
6. S Kuan
7. U Wagner
8. J.Dixon
9. L Lee
10. V V Lobanenkov
11. B Ren
(2012) A map of the cis-regulatory sequences in the mouse genome.
Mouse E14.5 Limb.

https://genome.ucsc.edu/encode/dataMatrix/encodeDataMatrixHuman.html
(2018) Mouse knockout phenotypes
Mouse Genome Informatics.

http://www.informatics.jax.org
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2. Smith CM
3. Hayamizu TF
4. McCright IJ
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6. Law M
7. Shaw DR
8. Baldarelli RM
9. Beal JS
10. Blodgett O
11. Campbell JW
12. Corbani LE
13. Lewis JR
14. Forthofer KL
15. Frost PJ
16. Giannatto SC
17. Hutchins LN
18. Miers DB
19. Motenko H
20. Stone KR
21. Eppig JT
22. Kadin JA
23. Richardson JE
24. Ringwald M
(2017) Mouse Gene Expression Database
Mouse Gene Expression Database.

http://www.informatics.jax.org/expression.shtml
(2014) Defining the role of common variation in the genomic and biological architecture of adult human height
GWAS Anthropometric 2014 Height.

https://portals.broadinstitute.org/collaboration/giant/index.php?title=GIANT_consortium&oldid=251

Article and author information

Author details

João P L Castro

Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany

Competing interests
The authors declare that no competing interests exist.
Michelle N Yancoskie

Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany

Competing interests
The authors declare that no competing interests exist.
Marta Marchini

University of Calgary, Calgary, Canada

Competing interests
The authors declare that no competing interests exist.
Stefanie Belohlavy

IST Austria, Klosterneuburg, Austria

Competing interests
The authors declare that no competing interests exist.
Layla Hiramatsu

Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany

Competing interests
The authors declare that no competing interests exist.
Marek Kučka

Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany

Competing interests
The authors declare that no competing interests exist.
William H Beluch

Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany

Competing interests
The authors declare that no competing interests exist.
Ronald Naumann

Max Planck Institute for Cell Biology and Genetics, Dresden, Germany

Competing interests
The authors declare that no competing interests exist.
Isabella Skuplik

University of Calgary, Calgary, Canada

Competing interests
The authors declare that no competing interests exist.
John Cobb

University of Calgary, Calgary, Canada

Competing interests
The authors declare that no competing interests exist.
Nick H Barton

IST Austria, Klosterneuburg, Austria

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8548-5240
Campbell Rolian

University of Calgary, Calgary, Canada

For correspondence
cprolian@ucalgary.ca

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7242-342X
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.

"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

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.