HGM2002 Poster Abstracts: 11. Genome Diversity
POSTER NO: 531
Molecular-genetic analysis of VNTR and STR systems of the human phenylalanine hydroxylase gene in Volga-Ural region
V.L. Akhmetova, T.V. Viktorova, E.K. Khusnutdinova
Human phenylalanine hydroxylase (PAH) is specifically expressed in the liver to convert L-phenylalanine to L-tyrosine. Mutations in the human PAH gene cause phenylketonuria, a common autosomal recessive metabolic disorder that in untreated patients often results in varying degrees of mental retardation. The PAH gene contains multiallelic polymorphisms: STR - a series of short tandem (tetranucleotide, (TCTA)n) repeats in the third intron and VNTR - the 30bp AT-rich tandem repeats system located 3kb downstream of the final exon of the PAH gene. We have identified short tandem repeats (STR) of the PAH gene in PKU (n=112) and non-PKU (n=98) chromosomes. Eight different STR alleles were obtained: 228, 232, 236, 240, 244, 248, 252 and 256bp. There was a statistically significant difference in the distribution of these alleles among normal and mutant chromosomes (c2=68,76, p=0,000). This difference was due primarily to a higher frequency of the 240bp allele among mutant chromosomes (59%), but also to the higher frequency of the 244bp allele among normal chromosomes (29%). The 232, 248 and 252bp alleles were revealed more frequently in normal chromosomes (13, 12 and 13% respectively) than in mutant chromosomes (2, 2 and 3% respectively). The others alleles arranged uniform in mutant and normal chromosomes. Seven different VNTR alleles were obtained in PKU (n=112) and non-PKU (n=98) chromosomes: 320, 380, 440, 500, 530, 560 and 650bp. The significant differences from the VNTR-allelic frequency distribution were found between mutant and normal chromosomes (c2=34,31, P=0,000). The 380bp allele was revealed more frequently in mutant chromosomes (72%) than in normal chromosomes (34%). The frequencies of the 500bp and 530bp allele were 7, 19% in PKU and 16, 31% in non-PKU chromosomes. The 320bp alleles found in one chromosome of normal individual for the first time. The level of informativity of STR and VNTR systems were 69% and 61,5% in Bashkortostan. We have found that combined STR and VNTR polymorphic systems significantly increase the informativeness of prenatal diagnostics and carrier screening procedures in most PKU families from Bashkortostan. We have identified a distribution of frequencies of the VNTR and STR alleles within PAH gene in eight Volga-Ural populations for characterization of their genetics structure. The significant differences from the STR and VNTR-allelic frequency distribution were found between all Volga-Ural populations. The 244bp STR allele was most frequent in all investigated populations studied (from 0,32 in Bashkirs and Mordvinians to 0,47 in Maries). The frequency of the 240bp allele ranged from 0,2 in Chuvashes and Udmurts to 0,33 in Komies. The 220bp alleles found in one individual from the Mordvinians, had not been described previously. The highest value of the observed heterozygosity of STR loci was typical for the Tatars (90%), while the lowest one was detected in the Mordvinians (70,2%). The 380bp allele was most frequent in all investigated populations studied (from 0,39 in Udmurts to 0,47 in Komies). The frequency of the 530bp allele ranged from 0,2 in Maries to 0,40 in Chuvashes. The uncommon 440bp and 470bp alleles found in one individual from the population of Bashkirs and in some individuals from populations of Bashkirs, Tatars, Komies and Udmurts, respectively. An average level of the observed heterozygosity of VNTR loci in Volga-Ural populations was 71,3%. The high index value of the observed heterozygosity of VNTR and STR systems along with the established differentiation of all investigated populations in respect to the frequency distribution of this alleles permitted the conclusion that the given polymorphic loci can serve as a highly informative marker for examination of the genetic structure of the Volga-Ural populations.
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