A Copine family member, Cpne8 , is a candidate quantitative trait gene for prion disease incubation time in mouse

... Rabl2a (33) and Cpne8 (38). All variants were assessed using a function of HAPPY that uses progenitor strain information to identify quantitative trait nucleotides by reconstructing ancestral haplotypes [ 22 ]. The most significant candidates from this analysis were: Rabl2a (log P =6.02), Syt10 (log P =5.4) and Cpne8 (log P =5.1). A graphic display from HAPPY is shown in Fig. 1b , and details of all identified individual SNPs are shown in Electronic supplementary material, Table 3 . For Rabl2a , the most significant strain distribution pattern (Table 1 ) is seen for two SNPs, one of which is a non-synonymous amino acid change (S276G). For Syt10 , only one SNP reaches the level of significance, and this is a synonymous change in exon 1 (G46G). For Cpne8 , nine significant SNPs were detected, six of which were intronic and three were seen in the 3UTR. Table1 Most significant strain distribution patterns D15Mit241D15Mit34 Strain distribution pattern Genes log P Comment (A, C3H, C57, CBA) (AKR, BALB, DBA, LP) Rabl2a 6.02 Exon 7 S276G And 1 3UTR (A, AKR,C3H, C57, CBA, LP) (BALB, DBA) Syt10 5.40 Exon 1 G46G (A, C3H, CBA, LP) (AKR, BALB, C57, DBA) Cpne8 5.11 6 Intronic and 3 3UTR log P values are estimated by HAPPY based on polymorphisms detected in the parental strains of the HS To verify these data, we genotyped representative significant SNPs from Rabl2a , Syt10 and Cpne8 in the HS animals and analysed the data by ANOVA (Table 2 and Electronic supplementary material, Table 5 ). Surprisingly, the Rabl2a SNP was not significant ( P =0.84), but SNPs for Syt10 ( P =0.0019) and Cpne8 ( P =0.0002) were both highly significant. The original linkage data for Mmu15 came from a C57BLxRIII cross which suggest that if we are detecting an effect from the same gene in both crosses, then the functional polymorphism should be present in both crosses. We therefore sequenced the candidate SNPs in RIIIS/J and compared this to the C57BL/6J alleles. For the single Syt10 SNP (Gly46Gly), C57BL/6J and

... pattern. Using RT-PCR, we examined the Cpne8 transcript across different mouse strains for splice variants, but at the level of detection by ethidium bromide-stained agarose gel, we could not detect any alternative splicing events (data not shown). Table2 Polymorphism genotyping in HS mice Gene Polymorphism HS p -value (ANOVA) Rabl2 Exon 7 S276G P =0.8416 ( n =567) Syt10 Exon 1 G46G P =0.0019 ( n =403) Cpne8 Intron 17 A/G P =0.0002 ( n =415) Cpne8 3UTR T/C P =0.0026 ( n =406) P =0.0007 ( n =970) All

... approximately 25 to 1.2cM. Sequence analysis and subsequent testing of the SNPs identified many genes, with SNPs reaching the threshold of significance (log P >3); however, Syt10 and Cpne8 were identified as the most promising candidate genes. In studies of this nature, it is not always possible to eliminate the possibility that genes excluded by us may still be contributing to the QTL. Further, our sequencing of the region was not exhaustive, and it is possible that the most significant strain distribution pattern could be seen in other genes or intergenic regions. Although SNPs in both Syt10 and Cpne8 gave highly significant results, we discounted Syt10 because these were not polymorphic between C57BL/6 and RIIIS strains. This was based on the assumption that the quantitative trait gene and nucleotides are the same in the original C57BL RIII backcross and the HS. Although a reasonable assumption, it is possible that this may not be the case because we used C57BL/6J mice, and the original cross used

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Gene: SYT10 - synaptotagmin X - (NCBI)

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