Interlocus non-random association of multiallelic polymorphisms spanning the coagulation factor VIII gene on human chromosome distalmost Xq28
E. MEDINA-ACOSTA
Núcleo de Diagnóstico e Investigação Molecular, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, Rio de Janeiro, Brazil
Search for more papers by this authorE. MEDINA-ACOSTA
Núcleo de Diagnóstico e Investigação Molecular, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, Rio de Janeiro, Brazil
Search for more papers by this authorAbstract
Summary. The most common severe hereditary bleeding disorder phenotype in humans, the coagulation factor VIII (F8) deficiency haemophilia A (HEMA), maps on Xq28 band, a region that comprises 11.7% of genes and 14.2% of phenotypes on X chromosome. Information about the distribution and extent of gametic disequilibrium (GD) covering the F8 gene is scarce, despite its relevance for linkage and association studies. The aim of this study was to determine the patterns, by frequency and strength, of non-random multiallelic interallelic associations between two-locus combinations of seven microsatellite loci (REN90833, F8Int25.2, F8Int22, F8Int13.2, HEMA154311.3, TMLHEInt5 and HEMA154507.3, in that physical order) spanning 0.813 Mb on distalmost Xq28. We measured sign-based interallelic D′ coefficients in 106 men and in 100 women drawn from a single unrelated Brazilian population. Significance and patterns of GD using haploid and phased diploid sample probabilities were close to conformity. Only 9.18% of the variance of D′ could be accounted for by changes in length, indicating that GD is not a monotonically decreasing function of length. We defined two regions of overlapping long-range GD extending 698 735 base pairs (bp) (REN90833/TMLHEInt5 block) and 689 900 bp (F8Int13.2/HEMA154507.3 block) The extent of GD overlap is 575 637 bp (F8Int13.2/TMLHEInt5 interstice). Extended haplotype homozygosity analysis centred at the F8 intronic loci revealed that the most frequent core haplotypes decay the least in the flanking GD. The F8 intronic loci attend distinct non-random association forces; F8Int13.2 serves at maintenance of the long-range overlapping pattern of GD, whereas F8Int25.2 and F8Int22 serve at lessening it in force or effect.
Supporting Information
Figure S1. Frequency distribution of significant positive (A, C) and negative (B, D) associations between pairs of alleles, as measured by Dij′ (+) and Dij′ (−) coefficients, along Xq28. n is the total number of two-locus haplotypes in significant sign-based disequilibrium observed in males (A, B) and female phased diplotypes (C, D).
Figure S2. Graphical display of a 400 Kb window in HapMap GD data comprised in the 0.813 Mb (interval position on X chromosome: 153 694 353-154 507 428 bp from Xp-tel) Xq28 region under study for CSH-CEU reference population, showing two regions of known high GD (inverted red triangles) flanking an untyped 182 821 bp gap (no triangles present; physical position 154 215 439-154 398 260 bp). HapMap GD data are confined to neighbouring two-locus allelic non-random associations, and therefore do not strictly embody the definition of blocks used in this article.
Table S1. Population parameters for the seven X-STR loci typed for this study (females; n = 100).
Table S2. (A) The haplotypes of 106 male X-chromosomes under study. (B) The phase of 200 female X-chromosomes (unambiguous diplotypes) under study.
Table S3. Loci, physical position, primer sequences, 5’ end modifications, and observed allele range, comprising the heptaplex fluorescent PCR assay for indirect tracking of HEMA.
Table S4. Gametic disequilibrium parameters in neighbouring two-locus combinations.
Table S5. Fisher exact test P values for gametic disequilibrium between two-locus combinations for 15 autosomal STR loci from an extended sample population of the Northern Region of the State of Rio de Janeiro (n = 609).
Table S6. Population parameters for 15 autosomal STR loci from an extended sample population of the Northern Region of the State of Rio de Janeiro (n = 609).
Table S7. Significance of overall gametic disequilibrium and intensity of significant sign-based gametic disequilibrium after dichotomization of allele frequencies for male haplotypes and female phased diplotypes.
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| HAE_2161_sm_fS1.pdf32.7 KB | Supporting info item |
| HAE_2161_sm_fS2.pdf23.5 KB | Supporting info item |
| HAE_2161_sm_tS1.pdf52.5 KB | Supporting info item |
| HAE_2161_sm_tS2A.pdf57.2 KB | Supporting info item |
| HAE_2161_sm_tS2B.pdf48.3 KB | Supporting info item |
| HAE_2161_sm_tS3.pdf52.6 KB | Supporting info item |
| HAE_2161_sm_tS4.pdf50.4 KB | Supporting info item |
| HAE_2161_sm_tS5.pdf46.8 KB | Supporting info item |
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