For the PKU Special IssueThe R408W phenylketonuria mutation in Europe has arisen by recurrent mutation in the human phenylalanine hydroxylase (PAH) locus and is associated with two major PAH haplotypes. R408W-2.3 exhibits a west-to-east cline of relative frequency reaching its maximum in the Balto-Slavic region, while R408W-1.8 exhibits an east-to-west cline peaking in Connacht, the most westerly province of Ireland. Spatial autocorrelation analysis has demonstrated that the R408W-2.3 cline, like that of R408W-1.8, is consistent with a pattern likely to have been established by human dispersal. Genetic diversity within wild-type and R408W chromosomes in Europe was assessed through variable number tandem repeat (VNTR) nucleotide sequence variation and tetranucleotide short tandem repeat (STR) allelic associations. Wild-type VNTR-8 chromosomes exhibited two major cassette sequence organizations: (a1) 5 -b3-b2-c1 and (a1) 5 -b5-b2-c1. R408W-1.8 was predominantly associated with (a1) 5 -b5-b2-c1. Both wild-type VNTR-3 and R408W-2.3 chromosomes exhibited a single invariant cassette sequence organization, a2-b2-c1. STR allele distributions associated with the cassette variants were consistent with greater diversity in the wild-type VNTR-8 lineage and were suggestive of different levels of diversity between R408W-1.8 and R408W-2.3. The finding of greater genetic diversity within the wild-type VNTR-8 lineage compared to VNTR-3 suggests that VNTR-8 may be older within the European population. However, in the absence of a more extensive STR data-set, no such conclusions are possible for the respective R408W mutant lineages. Hum Mutat 21:387-393,
Наведено результати молекулярно-генетичного аналізу мутацій та мінігаплотипів гена фенілаланінгідроксилази серед хворих на фенілкетонурію, членів їхніх родин та здорових індивідів (усього 445 осіб). Показано, що частота мажорної мутації R408W складає 57,3 %. Ідентифіковано вісім алельних варіантів STR-поліморфізму та 24 варіанти STR/VNTR мінігаплотипів. Показано достовірну нерівновагу у зчепленні між мутацією R408W та алелем 238 п. н. STR-поліморфізму.
The summarized results of 25-year studies of department of human genomics of IMBG NASU are presented. The investigations were focused on identification of molecular genetic nature of human genome coding and non-coding region mutations (genetic polymorphisms) and rearrangements, their spectrum, and origin in Ukrainian population. The role of genome heterogeneity in some severe monogenic and complex disorder pathogenesis has been shown. The data concerning correlation between certain determinator gene mutations and phenotypical manifestation of most common in Ukraine monogenic diseases have been demonstrated. Moreover, the role of modifying genes in specific clinical phenotype variations has been shown. Origin of particular mutant alleles and main mechanisms of their frequency maintenance in Ukrainian population have been investigated. The data about association of some polymorphic variants with infertility, cardiovascular diseases (ischemic stroke) as well as mass infectious diseases (hepatitis C, AIDS) outcome and standard therapy efficiency have been presented. The first results and prospects for candidate genes of neurodegenerative disorders and intellectual disability search using whole genome CNVs screening are shown.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.