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Use of Genome Sequence Information for Meat Quality Trait QTL Mining for Causal Genes and Mutations on Pig Chromosome 17 Zhi-Liang Hu Iowa State University

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Use of Genome Sequence Information for Meat Quality Trait QTL Mining for Causal Genes and Mutations on Pig Chromosome 17 Zhi-Liang Hu Iowa State University Animal Science Publications Animal Science 7-2011 Use of Genome Sequence Information for Meat Quality Trait QTL Mining for Causal Genes and Mutations on Pig Chromosome 17 Zhi-Liang Hu Iowa State University Antonio M. Ramos Iowa State University Sean J. Humphray Wellcome Trust Sanger Institute Jane Rogers Wellcome Trust Sanger Institute James M. Reecy IFoowlalo Swta tthie Usn iaverndsit ay,dd jreiteciony@ialas wtaorkte.edus at: http://lib.dr.iastate.edu/ans_pubs Part of the Agriculture Commons, Genetics and Genomics Commons, and the Meat Science See next page for additional authors Commons The ompc lete bibliographic information for this item can be found at http://lib.dr.iastate.edu/ ans_pubs/143. For information on how to cite this item, please visit http://lib.dr.iastate.edu/ howtocite.html. This Article is brought to you for free and open access by the Animal Science at Iowa State University Digital Repository. It has been accepted for inclusion in Animal Science Publications by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Use of Genome Sequence Information for Meat Quality Trait QTL Mining for Causal Genes and Mutations on Pig Chromosome 17 Abstract The newly available pig genome sequence has provided new information to fine am p quantitative trait loci (QTL) in order to eventually identify causal variants. With targeted genomic sequencing efforts, we were able to obtain high quality BAC sequences that cover a region on pig chromosome 17 where a number of meat quality QTL have been previously discovered. Sequences from 70 BAC clones were assembled to form an 8-Mbp contig. Subsequently, we successfully mapped five previously identified QTL, three for meat color and two for lactate related traits, to the contig. With an additional 25 genetic markers that were identified by sequence comparison, we were able to carry out further linkage disequilibrium analysis to narrow down the genomic locations of these QTL, which allowed identification of the chromosomal regions that likely contain the causative variants. This research has provided one practical approach to combine genetic and molecular information for QTL mining. Keywords meat quality QTL, pig chromosome 17, integrated analysis Disciplines Agriculture | Animal Sciences | Genetics and Genomics | Meat Science Comments This article is from Frontiers in Genetics 2 (2011): Article 43, doi:10.3389/fgene.2011.00043. Posted with permission. Rights This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Authors Zhi-Liang Hu, Antonio M. Ramos, Sean J. Humphray, Jane Rogers, James M. Reecy, and Max F. Rothschild This article is available at Iowa State University Digital Repository: http://lib.dr.iastate.edu/ans_pubs/143 ORIGINAL RESEARCH ARTICLE published: 14 July 2011 doi: 10.3389/fgene.2011.00043 Use of genome sequence information for meat quality trait QTL mining for causal genes and mutations on pig chromosome 17 Zhi-Liang Hu1, Antonio M. Ramos1†, Sean J. Humphray2, Jane Rogers2, James M. Reecy1 and Max F. Rothschild1* 1 Center for Integrated Animal Genomics, Department of Animal Science, Iowa State University, Ames, IA, USA 2 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK Edited by: The newly available pig genome sequence has provided new information to fine map Johan Van Arendonk, Wageningen quantitative trait loci (QTL) in order to eventually identify causal variants. With targeted University, Netherlands genomic sequencing efforts, we were able to obtain high quality BAC sequences that Reviewed by: Shu-Hong Zhao, Huazhong cover a region on pig chromosome 17 where a number of meat quality QTL have been Agricultural University, China previously discovered. Sequences from 70 BAC clones were assembled to form an 8-Mbp Merete Fredholm, University of contig. Subsequently, we successfully mapped five previously identified QTL, three for Copenhagen, Denmark meat color and two for lactate related traits, to the contig. With an additional 25 genetic *Correspondence: markers that were identified by sequence comparison, we were able to carry out further Max F.Rothschild, Department of Animal Science, Iowa State linkage disequilibrium analysis to narrow down the genomic locations of these QTL, which University, 2255 Kildee Hall, Ames, IA allowed identification of the chromosomal regions that likely contain the causative vari- 50011, USA. ants. This research has provided one practical approach to combine genetic and molecular e-mail: [email protected] information for QTL mining. †Present address: Antonio M. Ramos, Animal Breeding Keywords: meat quality QTL, pig chromosome 17, integrated analysis and Genomics Centre, Wageningen University, Wageningen, Netherlands. INTRODUCTION the BAC sequences in alignment with the known linkage map. A large number of quantitative trait loci (QTL) for economically This resulted in a ∼8-Mbp chromosomal contig that harbors 19 important traits has been identified in pigs over the past 15+ years. genes or open reading frames (ORFs), which were identified by More than 6,300 pig QTL have been deposited in the Animal comparative synteny alignment to the human genome. QTLdb (http://www.animalgenome.org/QTLdb/) as of January 1, We have previously identified five meat quality QTL on pig 2011. Despite the large number of QTL reported, the screening of chromosome 17 in a genome scan using an F2 population derived QTL for causal mutations still suffers from the fact that QTL often from a Berkshire × Yorkshire (BY) cross (Malek et al., 2001a). In span large chromosomal intervals, which makes their practical use order to increase the marker density under the QTL region on in pig breeding schemes very limited. In essence, the causal vari- SSC17, we have previously added 21 new markers to the SSC17 ant(s) for any given QTL are likely in strong linkage disequilibrium linkage map (Ramos et al., 2006). We have added more markers (LD) with other genetic markers, which makes identification diffi- in this study to facilitate the fine mapping of QTL. The objectives cult. However, this may or may not always be the case. Previously, of the current study were to use the genome sequence informa- only a limited number of causal or presumed variants for QTL tion to fine map the SSC17 QTL region, identify the chromosomal have been discovered in pigs (Milan et al., 2000; Ciobanu et al., region(s) most likely to contain the causative variant(s) respon- 2001; Van Laere et al., 2003). sible for the observed SSC17 meat quality QTL and to identify Sequencing of the pig genome has provided a new approach potential causative variants. for QTL examinations. As part of the Swine Genome Sequencing Consortium (SGSC), Iowa State University allocated funds toward targeted sequencing of pig chromosome 17. The sequencing was MATERIALS AND METHODS carried out at the Wellcome Trust Sanger Institute (Hinxton, UK) ANIMALS AND PHENOTYPE DATA and generated 70 high quality BACs ordered by overlapping tile Resource population: two Berkshire sires were crossed with nine path (Hart et al., 2007). Due to limitations using known pub- Yorkshire dams to produce nine F1 litters. From these litters, 8 sires licly available software to assemble them for their relatively large and 26 dams were selected and crossed to generate 515 F2 indi- clone sizes (>200 kbp), we have taken an ad hoc approach to viduals (Malek et al., 2001b). Growth, carcass composition and combine information from several sources including the BAC fin- meat quality data were collected in the F2 individuals. Traits and ger printed clones (FPC) tiling path, comparative human maps, procedures to collect the trait data were as described previously and overlapping BAC-end sequence blast evidence, to assemble (Malek et al., 2001b). www.frontiersin.org July 2011 | Volume 2 | Article 43 | 1 Hu et al. Dissection of pig chromosome 17 for QTL SEQUENCING OF INDIVIDUAL GENES AND ADDITION OF NEW marker was fitted at a time. The PROC MIXED procedure of SAS MARKERS TO THE LINKAGE MAP package was used to perform all analyses. Pooled DNA from BY founder animals were used to sequence Additional association analyses that combined information 15 selected genes in the chromosomal region (correspond to from more than one marker at a time were also performed. The 54–64 Mbp on pig assembly-10) of interest: Melanocortin 3 recep- combined genotype analysis was done by grouping animals that tor (MC3R), Aurora kinase A (AURKA), Cleavage stimulation shared common genotypes with different markers. A gene effect factor 3 pre-RNA, subunit 1 (CSTF1), Transcription factor AP- was declared to be significant when significant P-values were 2 gamma (TFAP2C), Bone morphogenetic protein 7 (BMP7), reached (P < 0.05) in both analysis of variance of the gene and Protein phosphatase 4, Regulatory subunit 1-like (PPP4R1L), the least-squares means analysis for all markers within the gene. RAB22A member RAS oncogene family (RAB22A), vesicle- associated membrane protein (VAMP), associated protein B and RESULTS C (VAPB), Phosphoenolpyruvate carboxykinase 1 (PCK1), Chro- SEQUENCE ASSEMBLY, CANDIDATE GENE SEARCH, AND MOLECULAR mosome 20 ORFs 108 (C20orf108), 32 (C20orf32), 43 (C20orf43), DISSECTION 106 (C20orf106), 174 (C20orf174). The entire coding regions and Sequencing of 70 selected BACs was carried out at the Wellcome the 5 and 3 UTR regions of the 15 genes were sequenced. A com- Trust Sanger Institute (Hart et al., 2007). The order of the BACs puter program, Expeditor (Hu et al., 2005) was used to design 114 was based on the minimum tiling path and best BAC-end sequence sets of primers based on the completed pig SSC17 sequence. blast overlaps (Hu et al., 2006). The finished sequence of all clones Polymorphic sites were identified by sequence comparisons to comprised 7,792,673 bp that were confirmed by Hart et al.
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