PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827) and PSMA3 (rs2348071) genetic diversity in Latvians, Lithuanians and Taiwanese

Abstract

PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827) and PSMA3 (rs2348071) genetic diversity was investigated in 1438 unrelated subjects from Latvia, Lithuania and Taiwan. In general, polymorphism of each individual locus showed tendencies similar to determined previously in HapMap populations. Main differences concern Taiwanese and include presence of rs2277460 rare allele A not found before in Asians and absence of rs2295827 rare alleles homozygotes TT observed in all other human populations. Observed patterns of SNPs and haplotype diversity were compatible with expectation of neutral model of evolution. Linkage disequilibrium between the rs2295826 and rs2295827 was detected to be complete in Latvians and Lithuanians (D´ = 1; r(2) = 1) and slightly disrupted in Taiwanese (D´ = 0.978; r(2) = 0.901). Population differentiation (FST statistics) was estimated from pairwise population comparisons of loci variability, five locus haplotypes and PSMA6 and PSMC6 two locus haplotypes. Latvians were significantly different from all Asians at each of 5 SNPs and from Lithuanians at the rs1048990 and PSMC6 loci. Lithuanian and Asian populations exhibited similarities at the PSMC6 loci and were different at the PSMA6 and PSMA3 SNPs. Considering five locus haplotypes all European populations were significantly different from Asian; Lithuanian population was different from both Latvian and CEU. Allele specific patterns of transcription factor binding sites and splicing signals were predicted in silico and addressed to eventual functionality of nucleotide substitutions and their potential to be involved in human genome evolution and geographical adaptation. Current study represents a novel step toward a systematic analysis of the proteasomal gene genetic diversity in human populations.

Keywords: Genetic diversity; HWE, Hardy–Weinberg equilibrium; HapMap HCB, Han Chinese; HapMap JPT, Japanese; HapMap-CEU, NorthWestern Europeans; Human population; LD, linkage disequilibrium; LT, Lithuanian population; LV, Latvian population; PSMA3; PSMA6; PSMC6; Proteasome; SNP; SNP, single nucleotide polymorphism; T2DM, type 2 diabetes mellitus; TF, transcription factor; TFBS, transcription factor binding site; TW, Taiwanese population; UPS, ubiquitin–proteasome system.

Fig. 1

Median joining network of PSMA6/PSMC6/PSMA3 haplotypes. The network was generated using the Reduced Median algorithm of the Phylogenetic network software Fluxus 4.611 (http://www.fluxus-engineering.com). Panel A: LV — Latvians, LT — Lithuanians, CEU — NorthWestern Europeans; Panel B: TW — Taiwanese, HCB — Han Chinese, JPT — Japanese. Haplotypes are numbered as in Table 3. Mutations at the rs2277460, rs1048990, rs2295826&rs2295827 and rs2348071 are indicated as stars of interrupted outline, grey, black and white colours respectively. Length of the branches is equal to time of generation and dissemination of progeny haplotype.

Fig. 2

Consequences of the rs2277460 (Panel A) and rs1048990 (Panel B) nucleotide substitutions on functional potential of corresponding genomic regions of the PSMA6 gene. Promoter and exon are coloured in white, 5′-UTR is coloured in grey; sequences of coding and noncoding genes' regions are presented by capital and small letters respectively. Positive and negative DNA strands are indicated by capital letters P and N respectively. The transcription factors family and matrix names are separated by symbol of division and given according to MatInspector, Release 7.4 online tool at www.genomatix.de/: BARB/BARBIE.01 — barbiturate-inducible element; P53F/P53.07 — tumour suppressor p53; DMRT/DMRT3.01 — double sex and mab-3 related TF 3. Splicing enhancers are indicated by solid up-directed horizontal braces; splicing silencers are indicated by interrupted down-directed horizontal braces; splicing enhancer and silencers motifs are abbreviated according to Human Splicing Finder Version 2.4 at http://www.umd.be/HSF. Other abbreviations: ESR — exonic splicing regulatory sequence. Asterix (*) indicates situation when several splicing signals of the same type could occupy the sequence and overlap each other.

Fig. 3

Consequences of the rs2295826 (Panel A) and rs2295827 (Panel B) nucleotide substitutions on functional potential of corresponding genomic regions of the PSMC6 gene. Sequence features and other marks are given as described in Fig. 2. CREB/E4BP4.01–E4BP4, bZIP domain, transcription repressor; MYT1/MYT1.02–MyT1 zinc finger TF involved in primary neurogenesis; PARF/TEF.01–thyrotrophic embryonic factor; CART/CART1.01–Cart-1 cartilage homeoprotein 1; BRN5/BRN5.04–POU class 6 homeobox 1 (POU6F1); LHXF/ISL2.01–ISL LIM homeobox 2; HOXF/NANOG.01–Homeobox TF Nanog. “Pot. Branch Point” means potential branch point.

Fig. 4

Consequences of the rs2348071 nucleotide substitutions on functional potential of corresponding genomic regions of the PSMA3 gene. Sequence features and other marks are given as described in Fig. 2. HBOX/GSH1.01–Homeobox TF Gsh-1; Cart/PHOX2.01–Phox2a (ARIX) and Phox2b of cartilage homeoproteins family; MEF2/SL1.01–member of the RSRF related to serum response factors. Other abbreviations are the same as in Fig. 2, Fig. 3.