ABCMdb

ABCC11 p.Ala473Cys

Predicted by SNAP2:	C: N (72%), D: N (53%), E: N (53%), F: N (57%), G: N (61%), H: N (82%), I: N (93%), K: N (82%), L: N (61%), M: N (66%), N: N (61%), P: N (87%), Q: N (66%), R: N (66%), S: N (93%), T: N (66%), V: N (93%), W: N (57%), Y: N (57%),
Predicted by PROVEAN:	C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: N, V: N, W: D, Y: D,

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[hide] Signatures of recent positive selection at the ATP... Hum Mol Genet. 2007 Jun 1;16(11):1367-80. Epub 2007 Apr 5. Wang Z, Wang J, Tantoso E, Wang B, Tai AY, Ooi LL, Chong SS, Lee CG
Signatures of recent positive selection at the ATP-binding cassette drug transporter superfamily gene loci.
Hum Mol Genet. 2007 Jun 1;16(11):1367-80. Epub 2007 Apr 5., [PMID:17412754]

Abstract [show]
Members of the ATP-binding cassette (ABC) superfamily of transporters have been implicated as major players in drug response. Single nucleotide polymorphisms (SNPs) in the ABC transporter genes may account for variation in drug response between individuals. Given the abundance of SNPs within the human genome, identification of functionally important SNPs is difficult. Here, we utilized signatures of recent positive selection (RPS) to identify SNPs in ABC genes that have potential functional significance by using the long-range-haplotype test to search for signatures of RPS at 18 ABC genes involved in drug transport. From the genotype data of these 18 ABC genes in four populations extracted from the HapMap database, at least one SNP in each of these genes displayed genomic signatures of RPS in at least one population. However, only 13 SNPs in 10 ABC genes from three populations retained statistical significance after Type I error reduction. The functional significance of six of these RPS SNPs, including those that failed multiple testing correction (MTC), has been reported previously. We experimentally confirmed a functional effect for two SNPs, including one that failed to show evidence of RPS after MTC. These observations suggest that Type I error reduction may inadvertently increase Type II error. Although the remaining positively selected SNPs have yet to be functionally validated, our study illustrates the feasibility of using this strategy to identify SNPs within 'adaptive' genes that may confer functional effect, prior to testing their roles in individual/population drug response variation or in complex disease susceptibility.

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No. Sentence Comment
66 Hence, a total of 32 SNPs were found to display RPS, most of them being selected only in a single population except for SNPs e35/T5562C in ABCA2, e21/G2677T/A in ABCB1, e9/C504T in ABCB4 and i1/T1541G and i14/A473C in ABCC11, which showed RPS in two populations (Table 2). Login to comment
71 Interestingly, the major T and A alleles of SNPs i1/T1541G and i14/A473C, respectively, in ABCC11 that showed RPS in both the YRI and CEU (Table 2) were found to be fixed in the CHB and JPT (Supplementary Material, Table S2). Login to comment
96 Ala rs497692 G - - LRH - 0.55 0.95 1.25 ABCC1 50 FR/G-260C 50 FR - rs504348 G - - LRH - - - - ABCC2 E1/C-24T Exon 1 - rs717620 T - - LRH - 20.54 2 1.14 21.46 E10/G1249A Exon 10 Val/Ile rs2273697 A - - LRH - 20.20 2 1.67 -1.32 I19/C-2133T Intron 19 - rs2002042 T - - - LRH 20.80 1.02 2 1.36 I23/G-752A Intron 23 - rs7898096 A - - - MTC - - 2 1.36 E25/G3542T Exon 25 Arg/Leu rs8187692 T - - - MTC 0.22 - 2 2.64 I26/T154C Intron 26 - rs3758395 C LRH - - - 2 1.24 20.57 20.36 I29/A154G Intron 29 - rs3740065 G LRH - - - 2.09 - 0.24 ABCC3 I1/C-3695G Intron 1 - rs719717 C MTC - - - 1.81 0.36 0.52 I30/A-1022C Intron 30 - rs3785911 C MTC - - - 0.96 0.71 0.29 ABCC4 I4/C4542Tc Intron 4 - rs17189481 T - - LRH - - - - ABCC5 I17/T20G Intron 17 - rs4148584 G LRH - - - 2 1.59 20.59 0.83 ABCC6 I30/A-31G Intron 30 - rs212097 A - - LRH - 0.76 0.17 1.02 ABCC7 I10/G377T Intron 10 - rs10487371 T - - - MTC - - 2 3.43 ABCC8 I16/A2575G Intron 16 - rs2237984 G MTC - - - 2.07 1.44 0.27 ABCC9 I27/C-1020G Intron 27 - rs704176 C - - - MTC 0.39 0.09 2.51 I37/C533G Intron 37 - rs829060 C - - - MTC 20.63 20.16 2 2.68 ABCC10 I1/G7A Intron 1 - rs9394952 A MTC - - - 0.90 1.24 1.19 ABCC11 I1/T1541G Intron 1 - rs13332304 T - - LRH LRH - - - I14/A473C Intron14 - rs7206909 A - - LRH LRH - 0.91 1.15 E19/C2436T Exon 19 Phe/Phe rs11866251 C - - MTC - - 1.37 1.15 I23/T-570C Intron 23 - rs11861031 T - - - LRH - 0.54 1.05 ABCC12 I2/C759A Intron 2 - rs8049005 C - - LRH - - 1.19 - ABCC13 50 FR/A-59G 50 FR - rs2822520 G LRH - - - 2 0.36 22.14 20.18 I1/A953C Intron 1 - rs2822522 C LRH - - - 2 1.21 20.90 21.04 ABCG2 E5/C421A Exon 5 Gln/Lys rs2231142 A MTC - - - 2 1.34 20.08 - a LRH represents SNPs that passed the modified long-range-haplotype test only if not corrected for multiple testing; MTC represents SNPs that passed both the modified LRH test and subsequent multiple test correction. Login to comment
68 Hence, a total of 32 SNPs were found to display RPS, most of them being selected only in a single population except for SNPs e35/T5562C in ABCA2, e21/G2677T/A in ABCB1, e9/C504T in ABCB4 and i1/T1541G and i14/A473C in ABCC11, which showed RPS in two populations (Table 2). Login to comment
73 Interestingly, the major T and A alleles of SNPs i1/T1541G and i14/A473C, respectively, in ABCC11 that showed RPS in both the YRI and CEU (Table 2) were found to be fixed in the CHB and JPT (Supplementary Material, Table S2). Login to comment