11 research outputs found
Recommended from our members
Genetic fixity in the human major histocompatibility complex and block size diversity in the class I region including HLA-E
BACKGROUND: The definition of human MHC class I haplotypes through association of HLA-A, HLA-Cw and HLA-B has been used to analyze ethnicity, population migrations and disease association. RESULTS: Here, we present HLA-E allele haplotype association and population linkage disequilibrium (LD) analysis within the ~1.3 Mb bounded by HLA-B/Cw and HLA-A to increase the resolution of identified class I haplotypes. Through local breakdown of LD, we inferred ancestral recombination points both upstream and downstream of HLA-E contributing to alternative block structures within previously identified haplotypes. Through single nucleotide polymorphism (SNP) analysis of the MHC region, we also confirmed the essential genetic fixity, previously inferred by MHC allele analysis, of three conserved extended haplotypes (CEHs), and we demonstrated that commercially-available SNP analysis can be used in the MHC to help define CEHs and CEH fragments. CONCLUSION: We conclude that to generate high-resolution maps for relating MHC haplotypes to disease susceptibility, both SNP and MHC allele analysis must be conducted as complementary techniques
Recommended from our members
A genetic explanation for the rising incidence of type 1 diabetes, a polygenic disease
We had earlier hypothesized, if parents originated from previously isolated populations that had selected against different critical susceptibility genes for a polygenic disease, their offspring could have a greater risk of that disease than either parent. We therefore studied parents of patients with type 1 diabetes (T1D). We found that parents who transmitted HLA-DR3 to HLA-DR3/DR4 patients had different HLA-A allele frequencies on the
non-transmitted HLA haplotype than HLA-DR4-transmitters. HLA-DR3-positive parents also had different insulin (
INS) gene allele frequencies than HLA-DR4-positive parents. Parent pairs of patients had greater self-reported ethnicity disparity than parent pairs in control families. Although there was an excess of HLA-DR3/DR4 heterozygotes among type 1 diabetes patients, there were significantly fewer HLA-DR3/DR4 heterozygous parents of patients than expected. These findings are consistent with HLA-DR and
INS VNTR alleles marking both disease susceptibility and separate Caucasian parental subpopulations. Our hypothesis thus explains some seemingly disconnected puzzling phenomena, including (1) the rising world-wide incidence of T1D, (2) the excess of HLA-DR3/DR4 heterozygotes among patients, (3) the changing frequency of HLA-DR3/DR4 heterozygotes and of susceptibility alleles in general in patients over the past several decades, and (4) the association of
INS alleles with specific HLA-DR alleles in patients with T1D
Recommended from our members
The social relevance of philosophy
What is the social relevance of philosophy? Any answer to this question must involve at least three elements. First, we need to understand how philosophy has brought about social change in the past. Second, to dig into the question more deeply, we need to see how the definition of philosophy can be opened up. Thirdly, we need to critically examine and challenge some of the assumptions that might be hidden in the question. Once we have done all this, we can try to answer the question
MHP cell line and CEH allele-level typing in the core MHC region and <i>HLA-DPB1</i>.
<p>Shown are MHC alleles for the eight MHP cell lines and, underneath each, for the population CEH(s) that share HLA-DR-DQ specificities with them. Although a known CEH shares HLA-DR-DQ specificities with APD, that CEH does not share significant class II sequence similarity to APD, and is not displayed. Genes are in chromosomal order from telomere to centromere, except <i>CFB</i> and <i>C2</i> are switched because complotype was historically defined in the order shown. HLA gene alleles are shown at the highest definition known up to 4-digit resolution. Alleles containing “/” indicate microvariation.</p>a<p>Abbreviations: UNK  =  Unknown (insufficient data).</p>b<p>This CEH has two possible <i>HLA-C</i> alleles: <i>*04:01</i> and <i>*04:09N</i><a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004637#pgen.1004637-Romero1" target="_blank">[14]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004637#pgen.1004637-Pinto1" target="_blank">[16]</a>.</p><p>MHP cell line and CEH allele-level typing in the core MHC region and <i>HLA-DPB1</i>.</p
CEH sequence fixity and crossover frequencies from <i>HLA-DQA2</i> to <i>DAXX</i>.
<p>Chromosomal location is shown to scale on the abscissa and starts at the mid-point between <i>HLA-DRB1 and HLA-DQB1</i> (A–C) or at <i>HLA-DQB1</i> (D–O). The locations of several HLA class II and extended class II genes are marked by arrows below Figures 3A–C and 3O. The 11 regions analyzed for normalized crossover frequency (NCF) are enumerated in Figure 3D. The numbers of haplotypes analyzed for each CEH are given in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004637#pgen-1004637-t001" target="_blank">Table 1</a>. Sequence fixities (A) and NCFs (D–F) are shown for the CEHs B7,DR15 (black open circles), (D); B8,DR3 (green closed circles), (E); and B18,DR3 (red squares), (F). Sequence fixities (B) and NCFs (G–J) are shown for the CEHs C4,B44,DR7 (green closed circles), (G); C16,B44,DR7 (purple open circles), (H); B57,DR7 (red squares), (I); and B44,DR4,DQ7 (blue diamonds), (J). Asterisks (*) in Figures 3B, 3G and 3H indicate that sequence fixities and NCFs could not be determined centromeric to the last data points for the two B44,DR7 CEHs. Sequence fixities (C) and NCFs (K–O) for various DR4,DQ8 CEHs are shown. These include the CEHs B44,SC30/SC31 (black diamonds), (K); B62,SC33 (green closed circles), (L); B38,SC21 (purple open circles), (M); B60,SC31 (red squares), (N); and B62,SB42 (blue triangles), (O). NCFs are normalized to the remaining conserved sequences and to 1 Mb relative to the distance over which crossovers were observed, and values are displayed for 11 sub-regions (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004637#pgen.1004637.s005" target="_blank">Table S2</a>).</p
A map of the MHC class II and extended class II regions of chromosome 6p21.
<p>Sequenced sub-regions are marked by colored blocks (top). Distances (kb) are to scale from the human reference sequence. Gene locations from <i>HLA-DRA</i> on the telomeric (T) end to <i>DAXX</i> on the centromeric (C) end are shown.</p
Amplicon DOB7.5 SNPs determined from resequencing.
<p>Amplicon DOB7.5 SNPs determined from resequencing.</p
Shared and divergent sequences in related CEHs.
<p>A) A region of nearly identical sequence for the B8,DR3 and B18,DR3 CEHs was previously reported <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004637#pgen.1004637-Traherne1" target="_blank">[19]</a> and is represented by the broken line rectangle, and ends just centromeric to <i>MTC30P1</i>, approximately 50 kb centromeric to <i>HLA-DQB1</i><a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004637#pgen.1004637-Stewart1" target="_blank">[18]</a>. B) Shared sequence for the B7,DR15 and B18,DR15 CEHs is shown in the broken line rectangle. Sequence identity for these two CEHs ends centromerically between introns 8 and 6 of <i>TAP2</i>. C) Shared and divergent sequences for four DR4,DQ8 CEHs are shown in the broken line rectangle. <i>HLA-B*15:01</i> and <i>HLA-B*40:01</i> are alleles of the B62 and B60 specificities, respectively.</p