Abstract
The intermediary metabolic enzyme alanine:glyoxylate aminotransferase (AGT) contains a Pro11Leu polymorphism that decreases its catalytic activity by a factor of three and causes a small proportion to be mistargeted from its normal intracellular location in the peroxisomes to the mitochondria. These changes are predicted to have significant effects on the synthesis and excretion of the metabolic end-product oxalate and the deposition of insoluble calcium oxalate in the kidney and urinary tract. Based on the evolution of AGT targeting in mammals, we have previously hypothesised that this polymorphism would be advantageous for individuals who have a meat-rich diet, but disadvantageous for those who do not. If true, the frequency distribution of Pro11Leu in different extant human populations should have been shaped by their dietary history so that it should be more common in populations with predominantly meat-eating ancestral diets than it is in populations in which the ancestral diets were predominantly vegetarian. In the present study, we have determined frequency of Pro11Leu in 11 different human populations with divergent ancestral dietary lifestyles. We show that the Pro11Leu allelic frequency varies widely from 27.9% in the Saami, a population with a very meat-rich ancestral diet, to 2.3% in Chinese, who are likely to have had a more mixed ancestral diet. FST analysis shows that the differences in Pro11Leu frequency between some populations (particularly Saami vs Chinese) was very high when compared with neutral loci, suggesting that its frequency might have been shaped by dietary selection pressure.
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Akey JM, Zhang G, Zhang K, Jin L, Shriver MD (2002) Interrogating a high-density SNP map for signatures of natural selection. Genome Res 12:1805–1814
Birdsey GM, Lewin J, Cunningham A, Bruford MW, Danpure CJ (2004) Differential enzyme targeting as an evolutionary adaptation to herbivory in Carnivora. Mol Biol Evol 21:632–646
Cavalli-Sforza LL, Piazza A, Menozzi P, Mountain J (1988) Reconstruction of human evolution: bringing together genetic, archeological, and linguistic data. Proc Natl Acad Sci USA 85:6002–6006
Cavalli-Sforza LL, Menozzi P, Piazza A (1994) The history and geography of human genes. Princeton University Press, Princeton
Cavalli-Sforza LL (1996) Population structure and human evolution. Proc R Soc Lond B Biol Sci 164:362–379
Cooper PJ, Danpure CJ, Wise PJ, Guttridge KM (1988) Immunocytochemical localization of human hepatic alanine:glyoxylate aminotransferase in control subjects and patients with primary hyperoxaluria type 1. J Histochem Cytochem 36:1285–1294
Danpure CJ (1997) Variable peroxisomal and mitochondrial targeting of alanine:glyoxylate aminotransferase in mammalian evolution and disease. Bioessays 19:317–326
Danpure CJ (2000) Genetic disorders and urolithiasis. In: Resnick MI (ed) Urolithiasis. Saunders, Philadelphia, pp 287–299
Danpure CJ (2001) Primary Hyperoxaluria. In: Scriver CR, Beaudet AL, Sly WS et al (eds) The molecular and metabolic bases of inherited disease. McGraw-Hill, New York, pp 3323–3367
Danpure CJ, Rumsby G (1996) Strategies for the prenatal diagnosis of primary hyperoxaluria type 1. Prenat Diagn 16:587–598
Danpure CJ, Cooper PJ, Wise PJ, Jennings PR (1989) An enzyme trafficking defect in two patients with primary hyperoxaluria type 1: peroxisomal alanine/glyoxylate aminotransferase rerouted to mitochondria. J Cell Biol 108:1345–1352
Danpure CJ, Guttridge KM, Fryer P, Jennings PR, Allsop J, Purdue PE (1990) Subcellular distribution of hepatic alanine:glyoxylate aminotransferase in various mammalian species. J Cell Sci 97:669–678
Danpure CJ, Birdsey GM, Rumsby G, Lumb MJ, Purdue PE, Allsop J (1994a) Molecular characterization and clinical use of a polymorphic tandem repeat in an intron of the human alanine:glyoxylate aminotransferase gene. Hum Genet 94:55–64
Danpure CJ, Fryer P, Jennings PR, Allsop J, Griffiths S, Cunningham A (1994b) Evolution of alanine:glyoxylate aminotransferase 1 peroxisomal and mitochondrial targeting. A survey of its subcellular distribution in the livers of various representatives of the classes Mammalia, Aves and Amphibia. Eur J Cell Biol 64:295–313
Eaton SB, Eaton SBI (2000) Paleolithic vs modern diets—selected pathophysiological implications. Eur J Nutr 39:67–70
Haglin L (1991) Nutrient intake among the Saami people today compared with an old, traditional Saami diet. Artic Med Res (Suppl) 741–746
Haglin L (1999) The nutrient density of present-day and traditional diets and their health aspects: the Saami and lumberjack families living in rural areas of Northern Sweden. Int J Circumpolar Health 58:30–43
Holbrook JD, Birdsey GM, Yang Z, Bruford MW, Danpure CJ (2000) Molecular adaptation of alanine:glyoxylate aminotransferase targeting in primates. Mol Biol Evol 17:387–400
Kiple KF, Ornelas KC (2000) The Cambridge world history of food. Cambridge University Press, Cambridge
Lewontin RC, Krakauer J (1973) Distribution of gene frequency as a test of the theory of the selective neutrality of polymorphisms. Genetics 74:175–195
Lumb MJ, Danpure CJ (2000) Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations. J Biol Chem 275:36415–36422
Lumb MJ, Drake AF, Danpure CJ (1999) Effect of N-terminal alpha helix formation on the dimerization and intracellular targeting of alanine:glyoxylate aminotransferase. J Biol Chem 274:20587–20596
Motley A, Lumb MJ, Oatey PB, Jennings PR, De Zoysa PA, Wanders RJ, Tabak HF, Danpure CJ (1995) Mammalian alanine:glyoxylate aminotransferase 1 is imported into peroxisomes via the PTS1 translocation pathway. Increased degeneracy and context specificity of the mammalian PTS1 motif and implications for the peroxisome-to-mitochondrion mistargeting of AGT in primary hyperoxaluria type 1. J Cell Biol 131:95–109
Noguchi T (1987) Amino acid metabolism in animal peroxisomes. In: Fahimi HD, Sies H (eds) Peroxisomes in biology and medicine. Springer, Berlin Heidelberg New York, pp 234–243
Parra EJ, Marcini A, Akey J, Martinson J, Batzer MA, Cooper R, Forrester T, Allison DB, Deka R, Ferrell RE, Shriver MD (1998) Estimating African American admixture proportions by use of population-specific alleles. Am J Hum Genet 63:1839–1851
Purdue PE, Takada Y, Danpure CJ (1990) Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1. J Cell Biol 111:2341–2351
Purdue PE, Lumb MJ, Allsop J, Danpure CJ (1991) An intronic duplication in the alanine: glyoxylate aminotransferase gene facilitates identification of mutations in compound heterozygote patients with primary hyperoxaluria type 1. Hum Genet 87:394–396
Robertson WG (1993) Urinary tract calculi. In: Nordin BE, Need AG, Morris HA (eds) Metabolic bone and stone disease. Churchill Livingstone, Edinburgh, pp 249–311
Robertson WG, Heyburn PJ, Peacock M, Hanes FA, Swaminathan R (1979a) The effect of a high animal protein intake on the risk of calcium stone formation in the urinary tract. Clin Sci 57:285–288
Robertson WG, Peacock M, Heyburn PJ, Hanes FA, Rutherford A, Clementson E, Swaminathan R, Clark PB (1979b) Should recurrent calcium oxalate stone formers become vegetarians? Br J Urol 51:427–431
Rumsby G (2000) Biochemical and genetic diagnosis of the primary hyperoxalurias: a review. Mol Urol 4:349–354
Sachidanandam R, Weissman D, Schmidt SC, Kakol JM, Stein LD, Marth G, Sherry S et al (2001) A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409:928–933
Takayama T, Fujita K, Suzuki K, Sakaguchi M, Fujie M, Nagai E, Watanabe S, Ichiyama A, Ogawa Y (2003) Control of oxalate formation from L-hydroxyproline in liver mitochondria. J Am Soc Nephrol 14:939–946
Thomas MG, Weale ME, Jones AL, Richards M, Smith A, Redhead N, Torroni A, Scozzari R, Gratrix F, Tarekegn A, Wilson JF, Capelli C, Bradman N, Goldstein DB (2002) Founding mothers of Jewish communities: geographically separated Jewish groups were independently founded by very few female ancestors. Am J Hum Genet 70:1411–1420
Weale ME, Yepiskoposyan L, Jager RF, Hovhannisyan N, Khudoyan A, Burbage-Hall O, Bradman N, Thomas MG (2001) Armenian Y chromosome haplotypes reveal strong regional structure within a single ethno-national group. Hum Genet 109:659–674
Weale ME, Weiss DA, Jager RF, Bradman N, Thomas MG (2002) Y chromosome evidence for Anglo-Saxon mass migration. Mol Biol Evol 19:1008–1021
Weir M (1996) Genetic data analysis II. Sinauer, Sunderland
Wessel P, Smith W (1998) New improved version of generic mapping tools released. EOS Trans Am Geophys U 79:579
Acknowledgements
We thank Michael Weale for advice on statistical analysis, Neil Bradman for access to some of the DNA samples, and all the anonymous donors.
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Caldwell, E.F., Mayor, L.R., Thomas, M.G. et al. Diet and the frequency of the alanine:glyoxylate aminotransferase Pro11Leu polymorphism in different human populations. Hum Genet 115, 504–509 (2004). https://doi.org/10.1007/s00439-004-1191-x
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DOI: https://doi.org/10.1007/s00439-004-1191-x