Genome-wide Association Studies of Novel Resilience Traits Identify Important Immune QTL Regions and Candidate Genes in Duroc Pigs

doi:10.1016/j.jia.2024.04.017

Advanced Online Publication | Current Issue | Archive | Adv Search

Mianyan Li^1,3, Lei Pu², David E. MacHugh^{3, 4}, Jingjing Tian¹, Xiaoqing Wang¹, Qingyao Zhao⁵, Lijun Shi¹, Hongmei Gao¹, Ying Yu⁵, Lixian Wang^1*, Fuping Zhao^1*

¹ State Key Laboratory of Animal Biotech Breeding, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China

² Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Breeding, College of Animal Science and Animal Medicine, Tianjin Agricultural University, Tianjin, 300384, P. R. China

³ Animal Genomics Laboratory, UCD School of Agriculture and Food Science, University College Dublin, Belfield, Dublin, D04 V1W8, Ireland

⁴ UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, D04 V1W8, Ireland.

⁵ College of Animal Science and Technology, China Agricultural University, Beijing, 100193, P. R. China

Abstract
References

Download: PDF in ScienceDirect
Export: BibTeX | EndNote (RIS)

摘要猪群的恢复力特性使其能更好地应对传染病和次优的生产环境。在试验期内，通过仪器自动采集猪的日增重、采食量和摄食行为数据，以评价猪的恢复力性状。本研究采用普通最小二乘（ordinary least squares, OLS）的均方误差根（mean square error roots, RMSE）和分位数回归（quantile regression, QR）的负残差，利用90 ~ 180日龄的商品杜洛克猪日采食量和饲喂时间，构建4种新的恢复力性状。基于单性状和双性状混合模型的全基因组关联研究（genome-wide associate analysis study, GWAS）对550头猪进行了研究，利用48,603个单核苷酸多态性（single nucleotide polymorphisms, SNP）来确定与生长猪恢复力性状相关的基因组区域。我们进一步针对GWAS信号进行基因注释、PigGTEx多组织eQTL共定位汇总统计以及利用公开数据鉴定增强子和启动子。估计得出这些恢复力性状的基因组遗传力在0.09 ~ 0.41之间。遗传相关性和表型相关性分别为0.16 ~ 0.95和0.05 ~ 0.36。27个SNP被鉴定出与这些恢复力性状显著相关。它们分布在9条染色体上（SSC1、SSC2、SSC6、SSC7、SSC8、SSC12、SSC14、SSC16和SSC17）。经注释，共鉴定出39个数量性状基因座（quantitative trait locus, QTL）和49个候选基因。其中存在与功能相关的候选基因，包括OTUD4、TIFA和CARD14，它们参与宿主免疫反应、疾病易感性和信号转导。在15个组织的GWAS和eQTL分析中发现了8个独特的SNP存在因果关系。值得注意的是，一个SNP（rs80794541）与七种组织 / 细胞类型（包括巨噬细胞类型）中同时鉴定的eQTL相关。此外，在5种猪组织中，4个显著SNP（rs81467127、rs81356029、rs80794541和rs81305085）与引物增强子、活性元件和启动子的功能相关。利用猪成纤维细胞HiC数据，发现SSC2上的SNP（rs81356029）调控CARNS1和SSH3，SSC7上的SNP（rs80794541）调控H2AC6。在这项研究中，我们在杜洛克猪群体中产生了4种新的恢复力性状，并确定了与这些恢复力性状显著相关的SNP。GWAS信号与参与免疫性状的候选基因有关，也与关键的调控元件有关。我们的发现将有助于阐明遗传机制，并为进一步研究家猪的恢复力提供信息。

Abstract Resilience traits in pig populations allow animals to deal better with infectious disease and suboptimal production environments. The data on daily weight, feed intake and feed behaviors in pigs are collected in test period by automated feeding stations, which facilitate to evaluate the resilience traits. In this study, we adopted the mean square error roots (RMSE) of ordinary least squares (OLS) and the negative residuals of quantile regression (QR) to generate four different novel resilience traits using daily records of feed intake and feed duration between 90 and 180 days of age in a population of commercial Duroc pigs. The genome-wide association studies (GWAS) based on single- and two- trait mixed models were carried out on 550 pigs using 48,603 single nucleotide polymorphisms (SNPs) to identify genomic regions associated with resilience traits in growing pigs. We further focused on the GWAS signals to conduct gene annotation, colocalization with multi-tissue eQTL summary statistics of PigGTEx project and identification of enhancers and promoters using the publicly available data. The genomic heritabilities of four novel resilience traits ranged from 0.09 to 0.41. The pairwise genetic and phenotypic correlations ranged from 0.16 to 0.95 and from 0.05 to 0.36, respectively. Twenty-seven SNPs were identified to be significantly associated with these resilience traits. They were distributed on nine chromosomes (SSC1, SSC2, SSC6, SSC7, SSC8, SSC12, SSC14, SSC16, and SSC17). After annotation, 39 QTLs and 49 candidate genes were identified. Several of these are functionally relevant candidate genes including OTUD4, TIFA and CARD14, which are involved in the host immune response, disease susceptibility and signal transduction. Eight unique SNPs were found to be causal in both GWAS and eQTL analyses across 15 tissues. Notably, one SNP (rs80794541) was associated with eQTLs identified concurrently across seven tissues/cell types, including the macrophage cell type. Furthermore, four significant SNPs (rs81467127, rs81356029, rs80794541, and rs81305085) were linked to the function of the primed enhancer, active element, and poised promoter in five pig tissues. Using the porcine fibroblast HiC dataset, SNP (rs81356029) on SSC2 regulates the CARNS1 and SSH3, while SNP (rs80794541) on SSC7 regulates the H2AC6. In this study, we generated four novel resilience traits and identified SNPs significantly associated with these resilience traits in a Duroc pig population. GWAS signals were associated with candidate genes involving in the immune traits, and were linked to the crucial regulatory elements as well. Our findings will contribute to elucidating the genetic mechanism that can enhance genome-enabled breeding and inform further research on resilience in domestic pigs.

Keywords: candidate gene feed intake genome-wide association study pig, resilience

Online: 13 May 2024

Fund: We greatly thank the editor and all anonymous reviewers for their useful comments and suggestions on an earlier version of the manuscript. This work was funded by the National Key Research and Development Program of China (2021YFD1301102), Natural Science Foundations of China (No. 32172702) and Agricultural Science and Technology Innovation Program (ASTIP-IAS02). M.L. is supported by the China Scholarship Council for one year study at University College Dublin.

About author: Mianyan Li, Tel: +353-879266107, E-mail: mianyanli@outlook.com; #Correspondence Lixian Wang, E-mail: iaswlx@263.net; Fuping Zhao, E-mail: zhaofuping@caas.cn * indicates corresponding authors

	Service
	E-mail this article
	Add to citation manager
	E-mail Alert
	RSS
	Articles by authors

Cite this article:

Mianyan Li, Lei Pu, David E. MacHugh, Jingjing Tian, Xiaoqing Wang, Qingyao Zhao, Lijun Shi, Hongmei Gao, Ying Yu, Lixian Wang, Fuping Zhao. 2024. Genome-wide Association Studies of Novel Resilience Traits Identify Important Immune QTL Regions and Candidate Genes in Duroc Pigs. Journal of Integrative Agriculture, Doi:10.1016/j.jia.2024.04.017

Argente M J, Garcia M L, Zbynovska K, Petruska P, Capcarova M, Blasco A. 2019. Correlated response to selection for litter size environmental variability in rabbits' resilience. ANIMAL, 13, 2348-2355.

Benjamini Y, Hochberg Y. 1995. Controlling the False Discovery Rate - a Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society Series B-Statistical Methodology, 57, 289-300.

Berghof T V L, Bovenhuis H, Mulder H A. 2019. Body Weight Deviations as Indicator for Resilience in Layer Chickens. Frontiers in Genetics, 10, 1216.

Bishop S C. 2012. A consideration of resistance and tolerance for ruminant nematode infections. Frontiers in Genetics, 3, 168.

Bisset S A, Morris C A. 1996. Feasibility and implications of breeding sheep for resilience to nematode challenge. International Journal for Parasitology, 26, 857-868.

Chang C C, Chow C C, Tellier L C, Vattikuti S, Purcell S M, Lee J J. 2015. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience, 4, 7.

Chen Y, Tibbs-Cortes L E, Ashley C, Putz A M, Lim K S, Dyck M K, Fortin F, Plastow G S, Dekkers J C M, Harding J C S, PigGen C. 2020. The genetic basis of natural antibody titers of young healthy pigs and relationships with disease resilience. BMC Genomics, 21, 648.

Cheng J, Fernando R, Cheng H, Kachman S D, Lim K, Harding J C S, Dyck M K, Fortin F, Plastow G S, Canada P, Dekkers J C M. 2022. Genome-wide association study of disease resilience traits from a natural polymicrobial disease challenge model in pigs identifies the importance of the major histocompatibility complex region. G3 (Bethesda), 12, jkab441.

Cheng J, Putz A M, Harding J C S, Dyck M K, Fortin F, Plastow G S, Canada P, Dekkers J C M. 2020. Genetic analysis of disease resilience in wean-to-finish pigs from a natural disease challenge model. Journal of Animal Science, 98, skaa244.

Colditz I G, Hine B C. 2016. Resilience in farm animals: biology, management, breeding and implications for animal welfare. Animal Production Science, 56, 1961-1983.

Cunningham F, Allen J E, Allen J, Alvarez-Jarreta J, Amode M R, Armean I M, Austine-Orimoloye O, Azov A G, Barnes I, Bennett R, Berry A, Bhai J, Bignell A, Billis K, Boddu S, Brooks L, Charkhchi M, Cummins C, Da Rin Fioretto L, Davidson C, Dodiya K, Donaldson S, El Houdaigui B, El Naboulsi T, Fatima R, Giron C G, Genez T, Martinez J G, Guijarro-Clarke C, Gymer A, Hardy M, Hollis Z, Hourlier T, Hunt T, Juettemann T, Kaikala V, Kay M, Lavidas I, Le T, Lemos D, Marugán J C, Mohanan S, Mushtaq A, Naven M, Ogeh D N, Parker A, Parton A, Perry M, Piližota I, Prosovetskaia I, Sakthivel M P, Salam A I A, Schmitt B M, Schuilenburg H, Sheppard D, Pérez-Silva J G, Stark W, Steed E, Sutinen K, Sukumaran R, Sumathipala D, Suner M M, Szpak M, Thormann A, Tricomi F F, Urbina-Gómez D, Veidenberg A, Walsh T A, Walts B, Willhoft N, Winterbottom A, Wass E, Chakiachvili M, Flint B, Frankish A, Giorgetti S, Haggerty L, Hunt S E, GR I I, Loveland J E, Martin F J, Moore B, Mudge J M, Muffato M, Perry E, Ruffier M, Tate J, Thybert D, Trevanion S J, Dyer S, Harrison P W, Howe K L, Yates A D, Zerbino D R, Flicek P. 2022. Ensembl 2022. Nucleic Acids Research, 50, D988-d995.

Dervishi E, Yang T, Dyck M K, Harding J C S, Fortin F, PigGen C, Cheng J, Dekkers J C M, Plastow G. 2021. Heritability and genetic correlations of plasma metabolites of pigs with production, resilience and carcass traits under natural polymicrobial disease challenge. Scientific Reports, 11, 20628.

Ernst J, Kellis M. 2012. ChromHMM: automating chromatin-state discovery and characterization. Nature Methods, 9, 215-216.

Giambartolomei C, Vukcevic D, Schadt E E, Franke L, Hingorani A D, Wallace C, Plagnol V. 2014. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genetics, 10, e1004383.

Gorssen W, Winter C, Meyermans R, Chapard L, Hooyberghs K, Janssens S, Huisman A, Peeters K, Mulder H, Buys N. 2023. A promosing resilience parameter for breeding: the use of weight and feed trajectories in growing pigs. J Anim Sci Biotechnol, 14, 101.

Guy S Z Y, Li L, Thomson P C, Hermesch S. 2019. Quantifying the health challenges in an Australian piggery using medication records for the definition of disease resilience1. Journal of Animal Science, 97, 1076-1089.

Hammer S E, Ho C S, Ando A, Rogel-Gaillard C, Charles M, Tector M, Tector A J, Lunney J K. 2020. Importance of the Major Histocompatibility Complex (Swine Leukocyte Antigen) in Swine Health and Biomedical Research. Annual Review of Animal Biosciences, 8, 171-198.

Hine B C, Acton G A, Elks D J, Niemeyer D D O, Bell A M, Colditz I G, Ingham A B, Smith J L. 2022. Targeting improved resilience in Merino sheep - Correlations between immune competence and health and fitness traits. ANIMAL, 16, 100544.

Homma C, Hirose K, Ito T, Kamikawa M, Toma S, Nikaido S, Satoh M, Uemoto Y. 2021. Estimation of genetic parameter for feed efficiency and resilience traits in three pig breeds. ANIMAL, 15, 100384.

Hu Z L, Park C A, Wu X L, Reecy J M. 2013. Animal QTLdb: an improved database tool for livestock animal QTL/association data dissemination in the post-genome era. Nucleic Acids Research, 41, D871-879.

Israel L, Mellett M. 2018. Clinical and Genetic Heterogeneity of CARD14 Mutations in Psoriatic Skin Disease. Frontiers in Immunology, 9, 2239.

Jiang Y, Ji Q, Long X, Wang P, Tu Z, Zhang X, Zhu X, Huang K, Li J. 2022. CLCF1 Is a Novel Potential Immune-Related Target With Predictive Value for Prognosis and Immunotherapy Response in Glioma. Frontiers in Immunology, 13, 810832.

Jordan C T, Cao L, Roberson E D, Pierson K C, Yang C-F, Joyce C E, Ryan C, Duan S, Helms C A, Liu Y. 2012. PSORS2 is due to mutations in CARD14. The American Journal of Human Genetics, 90, 784-795.

Kern C, Wang Y, Xu X, Pan Z, Halstead M, Chanthavixay G, Saelao P, Waters S, Xiang R, Chamberlain A, Korf I, Delany M E, Cheng H H, Medrano J F, Van Eenennaam A L, Tuggle C K, Ernst C, Flicek P, Quon G, Ross P, Zhou H. 2021. Functional annotations of three domestic animal genomes provide vital resources for comparative and agricultural research. Nature Communications, 12, 1821.

Kramer N E, Davis E S, Wenger C D, Deoudes E M, Parker S M, Love M I, Phanstiel D H. 2022. Plotgardener: cultivating precise multi-panel figures in R. Bioinformatics, 38, 2042-2045.

Laghouaouta H, Fraile L, Suarez-Mesa R, Ros-Freixedes R, Estany J, Pena R N. 2022. A genome-wide screen for resilient responses in growing pigs. Genetics, selection, evolution : GSE, 54, 50.

Laghouaouta H, Pena R N, Ros-Freixedes R, Reixach J, Diaz M, Estany J, Armengol R, Bassols A, Fraile L. 2021. A Methodology to Quantify Resilience in Growing Pigs. Animals (Basel), 11, 2970.

Liuyu T, Yu K, Ye L, Zhang Z, Zhang M, Ren Y, Cai Z, Zhu Q, Lin D, Zhong B. 2019. Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS. Cell Research, 29, 67-79.

Martin-Gallausiaux C, Garcia-Weber D, Lashermes A, Larraufie P, Marinelli L, Teixeira V, Rolland A, Beguet-Crespel F, Brochard V, Quatremare T, Jamet A, Dore J, Gray-Owen S D, Blottiere H M, Arrieumerlou C, Lapaque N. 2022. Akkermansia muciniphila upregulates genes involved in maintaining the intestinal barrier function via ADP-heptose-dependent activation of the ALPK1/TIFA pathway. Gut Microbes, 14, 2110639.

Medzhitov R, Horng T. 2009. Transcriptional control of the inflammatory response. Nature Reviews Immunology, 9, 692-703.

Mulder H A, Rashidi H. 2017. Selection on resilience improves disease resistance and tolerance to infections. Journal of Animal Science, 95, 3346-3358.

Nathan C. 2006. Role of iNOS in human host defense. Science, 312, 1874-1875.

Poppe M, Bonekamp G, van Pelt M L, Mulder H A. 2021. Genetic analysis of resilience indicators based on milk yield records in different lactations and at different lactation stages. Journal of Dairy Science, 104, 1967-1981.

Putz A M, Harding J C S, Dyck M K, Fortin F, Plastow G S, Dekkers J C M, PigGen Canada. 2018. Novel Resilience Phenotypes Using Feed Intake Data From a Natural Disease Challenge Model in Wean-to-Finish Pigs. Frontiers in Genetics, 9, 660.

Quinlan A R, Hall I M. 2010. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics, 26, 841-842.

Sanglard L P, Fernando R L, Gray K A, Linhares D C L, Dekkers J C M, Niederwerder M C, Serão N V L. 2020. Genetic Analysis of Antibody Response to Porcine Reproductive and Respiratory Syndrome Vaccination as an Indicator Trait for Reproductive Performance in Commercial Sows. Frontiers in Genetics, 11, 1011.

Smith E, Shilatifard A. 2014. Enhancer biology and enhanceropathies. Nature Structural and Molecular Biology, 21, 210-219.

Sun Z-c, Li G-t, Zhang C-l, Wang Z-m, Lin Q-m, Zhao X-r. 2020. Contrasting resilience of soil microbial biomass, microbial diversity and ammonification enzymes under three applied soil fumigants. Journal of Integrative Agriculture, 19, 2561-2570.

Teng J, Gao Y, Yin H, Bai Z, Liu S, Zeng H, Bai L, Cai Z, Zhao B, Li X, Xu Z, Lin Q, Pan Z, Yang W, Yu X, Guan D, Hou Y, Keel B N, Rohrer G A, Lindholm-Perry A K, Oliver W T, Ballester M, Crespo-Piazuelo D, Quintanilla R, Canela-Xandri O, Rawlik K, Xia C, Yao Y, Zhao Q, Yao W, Yang L, Li H, Zhang H, Liao W, Chen T, Karlskov-Mortensen P, Fredholm M, Amills M, Clop A, Giuffra E, Wu J, Cai X, Diao S, Pan X, Wei C, Li J, Cheng H, Wang S, Su G, Sahana G, Lund M S, Dekkers J C M, Kramer L, Tuggle C K, Corbett R, Groenen M A M, Madsen O, Gòdia M, Rocha D, Charles M, Li C J, Pausch H, Hu X, Frantz L, Luo Y, Lin L, Zhou Z, Zhang Z, Chen Z, Cui L, Xiang R, Shen X, Li P, Huang R, Tang G, Li M, Zhao Y, Yi G, Tang Z, Jiang J, Zhao F, Yuan X, Liu X, Chen Y, Xu X, Zhao S, Zhao P, Haley C, Zhou H, Wang Q, Pan Y, Ding X, Ma L, Li J, Navarro P, Zhang Q, Li B, Tenesa A, Li K, Liu G E, Zhang Z, Fang L. 2024. A compendium of genetic regulatory effects across pig tissues. Nature Genetics, 56, 112-123.

Tsartsianidou V, Kapsona V V, Sanchez-Molano E, Basdagianni Z, Carabano M J, Chatziplis D, Arsenos G, Triantafyllidis A, Banos G. 2021. Understanding the seasonality of performance resilience to climate volatility in Mediterranean dairy sheep. Scientific Reports, 11, 1889.

VanRaden P M. 2008. Efficient methods to compute genomic predictions. Journal of Dairy Science, 91, 4414-4423.

Walker L R, Engle T B, Vu H, Tosky E R, Nonneman D J, Smith T P L, Borza T, Burkey T E, Plastow G S, Kachman S D, Ciobanu D C. 2018. Synaptogyrin-2 influences replication of Porcine circovirus 2. PLoS Genetics, 14, e1007750.

Wang M, Zhang S, Zheng G, Huang J, Songyang Z, Zhao X, Lin X. 2018. Gain-of-Function Mutation of Card14 Leads to Spontaneous Psoriasis-like Skin Inflammation through Enhanced Keratinocyte Response to IL-17A. Immunity, 49, 66-79.e65.

Warr A, Affara N, Aken B, Beiki H, Bickhart D M, Billis K, Chow W, Eory L, Finlayson H A, Flicek P, Girón C G, Griffin D K, Hall R, Hannum G, Hourlier T, Howe K, Hume D A, Izuogu O, Kim K, Koren S, Liu H, Manchanda N, Martin F J, Nonneman D J, O'Connor R E, Phillippy A M, Rohrer G A, Rosen B D, Rund L A, Sargent C A, Schook L B, Schroeder S G, Schwartz A S, Skinner B M, Talbot R, Tseng E, Tuggle C K, Watson M, Smith T P L, Archibald A L. 2020. An improved pig reference genome sequence to enable pig genetics and genomics research. Gigascience, 9, giaa051.

Weller J I, Song J Z, Heyen D W, Lewin H A, Ron M. 1998. A new approach to the problem of multiple comparisons in the genetic dissection of complex traits. Genetics, 150, 1699-1706.

Yang J, Lee S H, Goddard M E, Visscher P M. 2011. GCTA: a tool for genome-wide complex trait analysis. American Journal of Human Genetics, 88, 76-82.

Yin L, Zhang H, Tang Z, Xu J, Yin D, Zhang Z, Yuan X, Zhu M, Zhao S, Li X, Liu X. 2021. rMVP: A Memory-efficient, Visualization-enhanced, and Parallel-accelerated Tool for Genome-wide Association Study. Genomics, Proteomics and Bioinformatics, 19, 619-628.

Zhao Y, Mudge M C, Soll J M, Rodrigues R B, Byrum A K, Schwarzkopf E A, Bradstreet T R, Gygi S P, Edelson B T, Mosammaparast N. 2018. OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-Dependent Signaling. Molecular Cell, 69, 505-516.e505.

Zhou X, Stephens M. 2012. Genome-wide efficient mixed-model analysis for association studies. Nature Genetics, 44, 821-824.

No related articles found!

No Suggested Reading articles found!

Viewed

Full text

Abstract

Cited

Shared

Discussed

Cite this article:

About JIA

Editorial board

For authors