2002 Fiscal Year Final Research Report Summary
| Project/Area Number |
13671864
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatric surgery
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| Research Institution | University of Tsukuba |
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Principal Investigator |
HORI Tetsuo Institution of Clinical Medicine, Department of Pediatric Surgery, University of Tsukuba, Associate Professor, 臨床医学系, 助教授 (80173615)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Congenital anal atresia / anorectal anomaly / polygenic disease / linkage mapping / pig, animal model / Anorectal malformations |
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| Research Abstract |
METHODS : A pig pedigree with a high incidence of AA has been established by selective breeding using three probands from the Landrace and Large White breeds. It has been maintained by intra-familial crossing for more than fifteen years. A backcross pedigree has now been generated by mating four AA females to an unaffected male from the Chinese Meishan breed. F_1 animals were both intercrossed and backcrossed to affected AA animals. A genome scan was carried out using the F_0, F_1 and affected backcross progeny. Ninety-two microsatellite loci were analyzed using fluorescently labelled primers and an ABI377 sequencer. Linkage analysis was done with the CRI-MAP 2.4 software.
RESULTS : Crossing affected parents increased the incidence of abnormalities from 30% to 61.9%. All 39 F_1 pigs were unaffected. In the F_1 intercross, only 3/205 (1.5%) were affected while 42/523 (8.0%) backcross progeny were affected. The marked difference in the incidence of affected progeny in the F_1 intercross a
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nd in the backcross indicates the presence of multiple genes causing AA. The genome scan revealed suggestive evidence for the presence of a susceptibility locus on pig chromosome 15 (lod score 2.7 for a pig microsatellite marker SW2072).
CONCLUSIONS : The results clearly show that AA has a oligogenic or polygenic background. The genome scan revealed one suggestive locus causing AA on pig chromosome 15. A useful approach will also be to include markers closely linked to candidate genes for anal atresia such as genes in the Sonic Hedgehog (Shh) signalling pathway. For instance, mice that are homozygous for a targeted disruption of Gli2 encoding an Shh-responsive transcription factor show imperforate anus and recto-urethral fistula. Interestingly, GLI2 maps to human chromosome 2q14 and comparative map data suggest that the porcine homolog is likely to be located on 15q13, the region showing suggestive linkage to AA. We are currently investigating the chromosomal localization of GLI2 in pigs to tests if it is a positional candidate gene and if so it will be further evaluated in relation to the development of AA in pigs. Less
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