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Iowa State University Animal Industry Report 2004 Swine A detailed gene map of pig chromosome 4, where the first quantitative trait locus in livestock was mapped A.S. Leaflet R1951 Christopher K. Tuggle, Professor of Animal Science Yuandan Zhang, Postdoctoral Research Associate, Max F. Rothschild, Distinguished Professor of Animal Science Maria Moller, Frida Berg, Leif Andersson Swedish University of Agricultural Sciences Uppsala, Sweden, Juliette Riquet, Denis Milan Laboratoire de Genetique Cellulaire INRA-Toulouse, France, Daniel Pomp Department of Animal Science University of Nebraska-Lincoln Alan Archibald, Susan Anderson Roslin Institute Edinburgh, Scotland Summary and Implications The first quantitative trait locus (QTL) in pigs, FAT1, was found on chromosome 4 using a wild-boar intercross. Further mapping has refined the FAT1 QTL to a region conserved on both human chromosome 1 and 8. We have now improved the comparative map of the entire SSC4 by mapping 105 loci to pig chromosome 4 (SSC4) and defined the specific human chromosome region with conservation to FAT1, using a combination of physical and linkage mapping. These types of analysis have resulted in maps with very good agreement. Comparative analysis revealed that the gene order is very well conserved across SSC4 compared to both human chromosome 1 (HSA1) and to HSA8. This refined SSC4 map and the comparative analysis will be a great aid in the search for the candidate genes for the FAT1 locus. Introduction Comparative genome analysis is a very powerful tool in the days of the post-genomic era where a wealth of information has been generated for many eukaryotic genomes. Although significant effort and resources have been dedicated to farm animals their genome maps are far from reaching the high resolution available for the human and mouse genome maps. Analysis of the genomes of farm animals such as the search for genes underlying complex traits; quantitative trait loci (QTLs) or economical trait loci (ETLs) can therefore greatly benefit from the possibility of extracting information from homologous regions of other genomes. The molecular identification of genes underlying QTLs is a challenging task and there have not been many success stories presented yet. A recent compilation of genes identified from QTL studies summarized 29 genes so far; 28 those were identified in human/mouse/rat and only one in a livestock animal. Porcine chromosome 4 (SSC4) harbor QTLs affecting growth, carcass traits and fat deposition. The first QTL on SSC4, denoted FAT1, was identified in a European wild boar – Large White intercross. SSC4 has previously been shown to share homology with human chromosomes 1 (HSA1) and 8 (HSA8). SSC4 is divided into two chromosomal blocks where the entire p arm and the q arm proximal to 4q15-16 are homologous to HSA8 and the remaining major part of 4q shares homology with HSA1. We wanted firstly to establish a dense comparative map covering the entire SSC4 but also to define the HSA1-HSA8 breakpoint accurately. This has been achieved with a combined approach of EST mapping on a radiation hybrid (RH) panel covering the entire chromosome, and by linkage and RH mapping of new markers developed around the breakpoint and across the FAT1 QTL region. Materials and Methods Primers for physical mapping were designed from pig gene sequence (EST) obtained from the Midwest Consortium for Pig Reproduction Genomics project headed by C. Tuggle. These primers amplify specific gene loci so that the presence of the gene of interest can be mapped relative to other gene locations using available data (see URL). Genetic linkage mapping was performed in Sweden using the wild-boar-Yorkshire cross available there. All data was analyzed and a comprehensive physical and linkage map was created. Results and Discussion Genetic Map development The markers developed were screened for polymorphisms among our 10 founder animals (2 wild boars and 8 Large White) and polymorphism was detected. Altogether, 11 genes were added to our previously published linkage map of SSC4. The linkage map comprising altogether 34 markers spans 135.9 cM (Figure 1). Iowa State University Animal Industry Report 2004 Physical mapping As part of an EST-based comparative mapping project with the aim to add 700 genes to the RH map (http://pigest.genome.iastate.edu/), we selected HSA1 and HSA8 genes to improve gene marker density across the entire SSC4. For HSA1, emphasis was placed on HSA1q21-24, as we previously showed this was the region on HSA1 closest to the FAT1 QTL. Genes were selected for RH mapping based on strength of BLAST score; agreement of human cytogenetic mapping localizations; and equal distribution across human chromosomes. A total of 103 new genes were successfully mapped onto SSC4. Comparative mapping Comparative mapping of SSC4 confirms clearly that SSC4 corresponds to two large blocks on human chromosomes 1 and 8 (Figure 2). Information of the corresponding human gene homology is presented for 101 genes/markers from the RH and linkage maps, 34 that maps to HSA8 and 67 to HSA1. The markers cover the entire length of SSC4 but an emphasis has been made to put markers within the region harbouring the FAT1 QTL, 23 markers has been added to this region (Figure 2). The comparative genome analysis also clearly reveals that there are no major rearrangements between the two synteny blocks. The gene order seems to be overall very well conserved as opposed to several other porcine chromosomes that display several large intrachromosomal rearrangements. However there is some evidence to suggest a small inversion of the gene order compared to HSA8 around the centromere on SSC4. Improved Mapping of the FAT1 QTL There appears to be several QTLs affecting, growth, fat, and carcass traits on porcine chromosome 4. Our intention of creating a dense comparative gene map between SSC4 and HSA1/8 has clearly been fulfilled by adding another 101 genes/markers to the map and an additional 5 markers where comparative information has not yet been obtained. The FAT1 QTL region which boundaries are defined by the Sw1364 – S0214 markers has had an increase of 23 genes/markers. We used two different methods to develop SSC4 chromosome maps; radiation hybrid mapping and linkage mapping. The maps are in very good agreement, however on some parts of the linkage map, the gene order could not be resolved due to no recombination events between markers. To resolve the order of the markers on the most Swine dense area they could be mapped on the latest RH panel developed for pig by colleagues in France. Acknowledgements This work was supported by USDA-NRICGP 9935205-8370. We thank Katie Barry and Darla Hartzler for excellent technical assistance in gene selection. FAT1 QTL Region Figure 1. Genetic Linkage map of Pig Chromosome 4, emphasizing the FAT1 region. This map contains 33 markers, of which 11 are newly reported in this paper. Iowa State University Animal Industry Report 2004 Swine HSA8 GPT1 SIAHBP1 14 0 SSC4 GPT1 SIAHBP1 SLA DDEF1 NSE2 MYC C8FW SQLE ZHX1 SNTB 1 ZFPM2 OXR1 ATP6V1C1 PABPC LOC157567 1 RNF1 PLEKHF2 9 UQCRB PGC LAPTM4B KIAA1750 P CBFA2T1 IMAGE:361836 LOC8369 5 TOG39053 0 MGC39325 TO 5 MGC2217 X PLAG MO 1 ATP6V1H S MCM4 UBE2V ATP1B1 SELE 2 ATP1B1 POU2F KIAA1513 1 RXRG SDHC NDUFS FCER1G PPOX USF1 2 DUSP1 APOA2 NCSTN 2 ATP1A2 KCNJ PEA1 COP 9 5PEA1 AH32 CASQ1 5 6 APCS MRPL2 4 BCA FDPS MGC13102 EFNA N KIAA0446 1 KIAA0080 KIAA0907 RUSC1 HAX1 NICE-3 SLC39A1 ILF2 SNAPAP SPRR1 SELENBP1 B KIAA1441 TMSG1 APH-1A SEMA6CSPEC 1LASS MCL1 DKFZP434K1772 2 HIST2H2A CGI-143 A LOC126964 NGF BTSHB FLJ22457 SLC16A4 AD-020 AMY1A LOC5099 RPL5 9 12 0 10 0 5 80 10 60 15 SLA DDEF1 MY NSE2 C C8FW SQLE ZHX1 SNTB TOG39053 1 5 OXR1 ZFPM2 ATP6V1C1 PABPC1 LOC157567 RNF1 LAPTM4B 9 KIAA1750 PGCP UQCRB PLEKHF2 CBFA2T1 DKFZp762O07 6 IMAGE:361836 5 LOC83690 TO MGC39325 X MGC2217 PLAG MOS 1 ATP6V1H MCM4 UBE2V 2 40 ADRB3 20 SSC15 SSC9 HSA1 25 16 0 30 14 0 12 0 35 10 0 SSC6 SERPINC PIG SELE C ATP1B1 POU2F1 KIAA1513 RXR DUSP12 G SDHC NDUFS2FCER1GAPOA2 PPOX USF1 COPANCST PEA15H326 N ATP1A2 CASQ KCNJ9 1 APCS MRPL2 KIAA0446BCAN 4 MGC13102 KIAA0907 KIAA0080 FDPSRUSC1 EFNA NICE-3 1 HAX SLC39A1 1 ILF2 SNAPAP SPRR1 SELENBP1 B KIAA1441 SEMA6C SPEC TMSG 1 LASS2 DKFZP434K1772 MCL1 1 LOC126964 APH-1A HIST2H2A CGI-143 A NGF TSHB B FLJ22457 SLC16A4 AD-020 AMY1A LOC5099 9 RPL 5 UOX PRKACB Figure 2. A comparative map of SSC4 and HSA1/HSA8 chromosomes. The porcine distances are given in Rays (measure of physical distance) and the human in Millions of base pairs from human genome sequence. Green signifies high level of confidence in the porcine position; while blue is most likely position for that gene. The red box indicates a region of possible gene order difference between pig and human.