Single nucleotide polymorphisms and microsatellites in the canine glutathione S-transferase pi 1 (GSTP1) gene promoter

Abstract

BackgroundGenetic polymorphisms within the glutathione S-transferase P1 (GSTP1) gene affect the elimination of toxic xenobiotics by the GSTP1 enzyme. In dogs, exposure to environmental chemicals that may be GSTP1 substrates is associated with cancer. The objectives of this study were to investigate the genetic variability in the GSTP1 promoter in a diverse population of 278 purebred dogs, compare the incidence of any variants found between breeds, and predict their effects on gene expression. To provide information on ancestral alleles, a number of wolves, coyotes, and foxes were also sequenced.ResultsFifteen single nucleotide polymorphisms (SNPs) and two microsatellites were discovered. Three of these loci were only polymorphic in dogs while three other SNPs were unique to wolves and coyotes. The major allele at c.-46 is T in dogs but is C in the wild canids. The c.-185 delT variant was unique to dogs. The microsatellite located in the 5′ untranslated region (5′UTR) was a highly polymorphic GCC tandem repeat, consisting of simple and compound alleles that varied in size from 10 to 22-repeat units. The most common alleles consisted of 11, 16, and 17-repeats. The 11-repeat allele was found in 10% of dogs but not in the other canids. Unequal recombination and replication slippage between similar and distinct alleles may be the mechanism for the multiple microsatellites observed. Twenty-eight haplotypes were constructed in the dog, and an additional 8 were observed in wolves and coyotes. While the most common haplotype acrossbreeds was the wild-type *1A(17), other prevalent haplotypes included *3A(11) in Greyhounds, *6A(16) in Labrador Retrievers, *9A(16) in Golden Retrievers, and *8A(19) in Standard Poodles. Boxers and Siberian Huskies exhibited minimal haplotypic diversity. Compared to the simple 16*1 allele, the compound 16*2 allele (found in 12% of dogs) may interfere with transcription factor binding and/or the stability of the GSTP1 transcript.ConclusionsDogs and other canids exhibit extensive variation in the GSTP1 promoter. Genetic polymorphisms within distinct haplotypes prevalent in certain breeds can affect GSTP1 expression and carcinogen detoxification, and thus may be useful as genetic markers for cancer in dogs.Electronic supplementary materialThe online version of this article (10.1186/s40575-017-0050-8) contains supplementary material, which is available to authorized users.

Polymorphism of glutathione S‐transferase P1 of dogs with mammary tumours

“…They discovered that the minor allele frequencies (MAF) of these GSTP1 polymorphisms were higher than in our data (Table 2) and are 0.496, 0.138, 0.257, 0.356, respectively. We did not find SNP at position −37 C > T (according to Sacco et al 32 the MAF is only 0.002). However, we discovered in the 5′‐UTR another SNPs −61, −52, −48, −42 and −30 and deletions −46_−44, −46_−29 and −24_−22, which are not described in the Ensembl database from the National Center for Biotechnology Information (NCBI).…”

“…The SNPs 5 0 -UTR À61, À52, À48, À46, À43, À42, À30, À27, À21 and deletions 5 0 -UTR À46_À44, À46_À29 and À24_À22 lead to replacement at similar positions of 5 0 -UTR mRNA. Sacco et al 32 described similar SNPs 5 0 -UTR À46, À43, À27 and À21 of GSTP1 in healthy dogs. As far as we know, this is the only one publication on polymorphisms in this canine gene.…”

Genetic and environmental risk for lymphoma in boxer dogs

“…The specific effects of this microsatellite region on GSTP1 expression deserve characterization, particularly in comparison to the common 16*1 variant found in nonboxers in this population (MAF.306) and in another study of 278 dogs of various breeds (MAF.302). 44 Multiple GST variants were significantly less common in boxers compared to a heterogeneous group of nonboxers, which is expected given the low levels of heterozygosity in boxers. 45 Two functionally characterized GST variants were not overrepresented in boxers: a GSTT1 3 0 UTR haplotype that decreases expression by 50%, 36 GST variants screened in our study.…”

“…The 1 variant that was more prevalent in boxers was a 17‐unit microsatellite repeat in the GSTP1 promoter (allele frequency 0.980 vs 0.367 in nonboxers; adjusted P < .002). The next most common variant in nonboxers was a 16‐unit repeat (16*1), 44 with an allele frequency of .306. The 17‐unit variant was predicted to decrease the number of WT1‐KTS transcription factor binding from 25 sites (for 16*1) to 18 sites (for 17‐units).…”

“…An exception was a high prevalence 17‐unit microsatellite repeat in the GSTP1 promoter. This allele is predicted to decrease transcription factor binding sites for WT1‐KTS, 44 but this effect has not been evaluated experimentally. The specific effects of this microsatellite region on GSTP1 expression deserve characterization, particularly in comparison to the common 16*1 variant found in nonboxers in this population (MAF.306) and in another study of 278 dogs of various breeds (MAF.302) 44 …”