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Peeling Back the Evolutionary Layers of Molecular MechanismsResponsive to Exercise-Stress in the Skeletal Muscle of the Racing HorseH YEONGMIN Kim 1,† , T AEHEON Lee 1 , W ON C HEOUL Park 1 , J IN W OO Lee 2 , J AEMIN Kim 3 , B O -Y OUNG Lee 1 ,H YEONJU Ahn 1 , S UNJIN Moon 1 , S EOAE Cho 4 , K YOUNG -T AG Do 5 , H EUI -S OO Kim 6 , H AK -K YO Lee 7 , C HANG -K YU Lee 1 ,H ONG -S IK Kong 7 , Y OUNG -M OK Yang 8 , J ONGSUN Park 9 , H AK -M IN Kim 9 , B YUNG C HUL Kim 9 , S EUNGWOO Hwang 10 ,J ONG Bhak 11 , D AVE Burt 12 , K YOUNG -D O Park 7, *, B YUNG -W OOK Cho 5, *, and H EEBAL Kim 1,3,4, *Department of Agricultural Biotechnology, Animal Biotechnology Major, and Research Institute for Agriculture andLife Sciences, Seoul National University, Seoul 151-921, Republic of Korea 1 ; Horse Industry Research Center, KoreaRacing Authority, Gwacheon 471-711, Republic of Korea 2 ; Interdisciplinary Program in Bioinformatics, SeoulNational University, Seoul 151-742, Republic of Korea 3 ; C&K Genomics, Seoul National University Research Park,Seoul 151-919, Republic of Korea 4 ; Department of Animal Science, College of Life Sciences, Pusan NationalUniversity, Miryang 627-702, Republic of Korea 5 ; Department of Biological Sciences, College of Natural Sciences,Pusan National University, Busan 609-735, Republic of Korea 6 ; Genomic Informatics Center, Hankyong NationalUniversity, Anseong 456-749, Republic of Korea 7 ; Department of Pathology, School of Medicine, and Institute ofBiomedical Science and Technology, Konkuk University, Seoul 143-701, Republic of Korea 8 ; Genomic Department,Personal Genomics Institute, Suwon 443-270, Republic of Korea 9 ; KOBIC, KRIBB, Daejeon 305-806, Republic ofKorea 10 ; TBI, TheragenEtex, Suwon 443-270, Republic of Korea 11 and The Roslin Institute, University of Edinburgh,Midlothian EH25 9GR, UK 12*To whom correspondence should be addressed. Tel. þ82-2-880-4803 (H.K.)/þ82-55-350-5515(B.W.C.)/þ82-31-670-5332 (K.D.P.). Fax. þ82-2-883-8812 (H.K.). Email: heebal@snu.ac.kr (H.K.)/bwcho@pusan.ac.kr (B.W.C.)/doobalo@hknu.ac.kr (K.D.P.)Edited by Dr Mikita Suyama(Received 8 October 2012; accepted 12 March 2013)AbstractThe modern horse (Equus caballus) is the product of over 50 million yrs of evolution. The athleticabilities of the horse have been enhanced during the past 6000 yrs under domestication. Therefore,the horse serves as a valuable model to understand the physiology and molecular mechanisms of adaptiveresponses to exercise. The structure and function of skeletal muscle show remarkable plasticity to thephysical and metabolic challenges following exercise. Here, we reveal an evolutionary layer of responsive-ness to exercise-stress in the skeletal muscle of the racing horse. We analysed differentially expressedgenes and their co-expression networks in a large-scale RNA-sequence dataset comparing expressionbefore and after exercise. By estimating genome-wide d N /d S ratios using six mammalian genomes, andF ST and iHS using re-sequencing data derived from 20 horses, we were able to peel back the evolutionarylayers of adaptations to exercise-stress in the horse. We found that the oldest and thickest layer (d N /d S )consists of system-wide tissue and organ adaptations. We further find that, during the period of horsedomestication, the older layer (F ST ) is mainly responsible for adaptations to inflammation and energymetabolism, and the most recent layer (iHS) for neurological system process, cell adhesion, andproteolysis.Key words: horse; exercise; evolution; RNA sequencing; re-sequencing†The authors wish it to be known that, in their opinion, the firstthree authors should be regarded as joint first authors.# The Author 2013. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided theoriginal work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.DNA R ESEARCH 20, 287–298, (2013) doi:10.1093/dnares/dst010Advance Access publication on 11 April 2013