ARS | Publication request: RADIATION HYBRID MAPPING OF 18 POSITIONAL AND PHYSIOLOGICAL CANDIDATE GENES FOR ARTHROGRYPOSIS MULTIPLEX CONGENITA ON PORCINE CHROMOSOME 5

Submitted to: Animal Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 16, 2006
Publication Date: May 5, 2006
Citation: Genini, S., Nguyen, T.T., Malek, M., Talbot, R., Gebert, S., Rohrer, G.A., Nonneman, D.J., Stranzinger, G., Vogeli, P. 2006. Radiation hybrid mapping of 18 positional and physiological candidate genes for arthrogryposis multiplex congenita on porcine chromosome 5. Animal Genetics. 37:239-244.

Interpretive Summary: A region on pig chromosome 5 has been shown to contain the gene that causes Arthrogryposis Multiplex Congenita (AMC) in pigs. Piglets born with this syndrome contain multiple defects to the legs and spinal column and are not viable. To identify genetic markers that can help eliminate this genetic disease, we placed 18 genes onto pig chromosome 5 to determine how this chromosome resembles human chromosome 12 and a small segment of human chromosome 22. Functional candidate genes to study were selected from an experiment comparing the genes expressed in an affected pig versus genes expressed in a normal pig. Five genes mapped to the interval believed to contain the causative gene for AMC (CPNE8, PRICKLE1, Q6ZUQ4, TUBA8 and USP18). Genetic differences in one of these genes (TUBA8) were strongly associated with the genetic defect in the studied research population. In conclusion, we determined that the order of genes on pig chromosome 5 is quite different than the order of genes on human chromosomes 12 and 22. The genetic markers in TUBA8 that were associated with AMC in the research population need to be studied in other populations to determine if they will be accurate predictors for selection in general pig populations.

Technical Abstract: We report the chromosomal assignment of 18 porcine homologues to human genes using the INRA-Minnesota swine radiation hybrid panel (ImpRH). These are interesting positional and functional candidate genes for the porcine disease Arthrogryposis Multiplex Congenita (AMC), located on SSC5. Q6ZUQ4, NR4A1 and C3F, located in the expected human AMC region, were chosen based on the results of a study using a pig 13K oligo microarray and confirmation of their differential gene expression by real-time PCR with a TaqMan assay. A total of 308 genes (131 upregulated and 177 downregulated) were differentially expressed in brain, spinal cord and muscle of a diseased piglet compared to a normal piglet in a dye swap experiment. The remaining genes CACNA1C, CPNE8, C12ORF4, COL2A1, DDX11, GDF11, MDS028, MGC5576, PHB2, PRICKLE1, SCN8A, KCNA1, TUBA8 and USP18 were selected from pig-human comparative database analysis. CPNE8, PRICKLE1, Q6ZUQ4, TUBA8and USP18 were mapped to the suited interval for pig AMC, between microsatellites SW152 and SW904. Furthermore, three SNPs in the partial gene sequence of TUBA8 co-segregated with the AMC phenotype in 230 pigs without recombinants, providing a powerful marker test to discover AMC-carriers. In addition, we provide evidence that a small chromosomal region of HSA22q11.2, containing the homologue of the porcine SW152 and the genes TUBA8, USP18 and Q6ZUQ4, evolutionarily corresponds to SSC5q12-q22, between the human regions HSA12p13 and HSA12q12. To conclude, we identified six breakpoint blocks and provide further comparative data for the elucidation of the extensive gene order rearrangements between HSA12, HSA22 and SSC5 in the proximity of the AMC region.