Search PubMed⌕ Search

Biomedical subjects

J X She

Publications and source records attributed to J X She.

63 records · Page 4Linked to original sources
PubMed1994

Additive susceptibility to insulin-dependent diabetes conferred by HLA-DQB1 and insulin genes.

Several genomic polymorphisms at the insulin (INS) gene and its flanking regions were analyzed in 197 unrelated Caucasian patients affected by insulin-dependent diabetes (IDDM) and 159 ethnically matched, normal controls ascertained from the South-Eastern United States. We found that the frequency of homozygotes for the common variant at the insulin gene was significantly increased in the diabetic population (RR = 2.0, p < 0.005). However, the polymorphisms in the 5' and 3' regions flanking the INS were not significantly associated with IDDM. These results suggest that the IDDM susceptibility locus on chromosome 11p is located within the region extending from the 5' VNTR to the 3' end of the INS gene. We determined the HLA-DQB1 genotypes by denaturing gradient gel electrophoresis (DGGE) and/or sequence-specific primers (SSP) techniques to assess the possible interactions between INS and HLA. DQB1*0302 had the strongest predisposing effect on IDDM susceptibility (RR = 9.3) and DQB1*0602 the strongest protective effect (RR = 0.02). However, a significant predisposing effect of DQB1*0201 could be demonstrated only after removal of the effects of DQB1*0302 and DQB1*0602. Analyses of the genotypes revealed that all genotypes containing 0602 were protective and that the heterozygous genotype 0201/0302 and homozygous genotype 0302/0302 confer the highest risk (RR = 20.9 and 12.9 respectively). However, heterozygous genotypes 0302/X (X excludes 0201, 0302 and 0602) have a significantly lower predisposing risk. Similarly, there is heterogeneity in risk between predisposing 0201/0201 homozygous individuals and protective 0201/X individuals. When subjects were stratified by HLA genotypes, the relative risks conferred by INS did not vary, thus suggesting that the susceptibility effects conferred by HLA and INS are additive rather than interactive.

Base Sequence↗
PubMed1993

Sequence divergence of B2m alleles of wild Mus musculus and Mus spretus implies positive selection.

Mouse beta 2-microglobulin (beta 2m) is polymorphic. Sequences of five allelic wild mouse B2m genes have been determined from the large exons of genomic DNA using the polymerase chain reaction. Relative to the standard B2m(a) allele, the products of four alleles of Mus musculus origin (w2, w3, w4, and w5), differ by only one or two amino acids. w5 has a single nucleotide change, Asp85-->Val, and is identical to the c allele. w3 has two changes, Val(-13)-->Ile and Lys44-->Glu. w2 differs at Arg81-->Thr and w4 at His34-->Gln, and they share the Asp85-->Val change with B2mc and B2mw5. w5 and c cells are lysed by S19.8, a monoclonal antibody specific for beta 2mb (Ala85), in a complement-mediated cytotoxicity assay, whereas w4 cells are not. Thus, distant changes appear to introduce subtle conformational effects on beta 2m structure. Five independent isolates of Mus spretus (w1) differ the most from B2m(a), with 12 amino acid changes and only one silent substitution. Replacements predicted from the nucleotide sequence occur in loops of the molecule facing away from the class I heavy chain and not in regions where beta 2m associates with class I alpha 3 domains. Concordantly, the w1-5 allelic forms of beta 2m associate well with H-2 heavy chains. The many amino acid changes in the spretus sequence and the paucity of silent substitutions suggest that B2m has been subject to positive selection.

Amino Acid Sequence↗
PubMed1993

Characterizations of candidate genes for IDD susceptibility from the diabetes-prone NOD mouse strain.

The nucleotide sequences of the NOD and C57BL/6J alleles of Glut-2, Sod-2, and Il-2 were determined by RT-PCR sequencing. Each of these loci is located in intervals that strongly correlated with susceptibility to diabetes in an (NOD/Uf x C57BL/6J)F1 x NOD/Uf backcross. No significant variations in the alleles of Glut-2 at 16 cM on Chromosome (Chr) 3 or Sod-2 at 8 cM on Chr 17 were detected. However, the Il-2 allele in NOD at 20 cM on Chr 3 was found to differ from that in C57BL/6J by a complex mutation involving the contraction of a simple sequence repeat (SSR). Il-2 in NOD differs from the allele in C57BL/6J via a complex mutation involving a deletion of four CAG codons from the SSR together with a length-compensatory four-codon duplication of a segment 5' from the SSR. Two nonsynonymous mutations in the coding region 5' to the SSR were also detected. Only these two allelic forms of Il-2 were detected in a survey of 13 standard inbred lines and 4 wild mouse strains. We propose to designate these alleles as Il-2a (for alleles such as C57BL/6J that contain 12 CAG repeats) and Il-2b (for alleles such as NOD), which occurred in a variety of standard inbred strains and in all four wild Mus musculus domesticus tested. The distribution of these Il-2 alleles among inbred strains correlated with the detection of Chr 3 as an interval effecting diabetes susceptibility in three separate genetic crosses.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1993

Independent variation and positive selection in env V1 and V2 domains within maternal-infant strains of human immunodeficiency virus type 1 in vivo.

Multiple targets for immune recognition and cellular tropism are localized to the V1 and V2 hypervariable regions in the amino portion of human immunodeficiency virus type 1 (HIV-1) gp120env. We have assessed genetic diversity in env V1 and V2 hypervariable domains in vivo within epidemiologically related strains of HIV-1. Our strategy was to analyze longitudinal samples from two seropositive mothers and multiple children infected by perinatal transmission. Although the V1 and V2 domains are closely linked in the HIV-1 genome, nucleotide sequences in V1 and in V2 evolved independently in maternal-infant viruses in vivo. A high proportion of the nucleotide substitutions would introduce amino acid diversity in V1 and in V2. A significant excess of nonsynonymous over synonymous substitutions was identified in HIV-1 env V1 and V2 peptides in the mothers and in two older children but was not generally apparent in HIV-1 sequences in infants. An excess of nonsynonymous over synonymous substitutions indicated that there is positive selection for independent genetic variation in the V1 and V2 domains in vivo. It is likely that there are host responses to complex determinants in the V1 or V2 hypervariable domain of HIV-1 gp120.

Amino Acid Sequence↗
PubMed1991

Biochemical characterization of 39-kDa class I histocompatibility antigen in plasma. A secretable membrane protein derived from transmembrane domain deletion.

Three human class I major histocompatibility antigens (HLA) with molecular masses of 44, 39, and 36 kDa were identified in plasma by immunoprecipitation and immunoblotting. Further biochemical characterization showed that these antigens in plasma could be fractionated by Sephacryl S-300 column chromatography into two different pools. The 44-kDa intact HLA heavy chains are detected only in pool I and have an apparent molecular weight of 200,000 as determined by calibrated gel filtration column chromatography. The 39- and 36-kDa HLA heavy chains are present only in pool II and have an apparent molecular weight of 50,000. HLA in pool I can be extracted by Triton X-114 detergent, but 39- and 36-kDa plasma HLA in pool II are water soluble and not extractable by Triton X-114. Amino acid sequences of NH2 termini for 44- and 39-kDa plasma HLA are identical to that of cellular HLA. In contrast, the NH2-terminal amino acid sequence for 36-kDa plasma HLA has not been reported previously for any other proteins. Since the loss of both transmembrane domain and cytoplasmic tail at the carboxyl terminus of HLA will generate a 36-kDa protein, the findings suggest that the 39-kDa HLA might be the product of alternatively spliced mRNA with deletion of the exon coding for transmembrane domain. By using polymerase chain reaction and DNA sequencing, the presence of alternatively spliced mRNA with deletion of the transmembrane domain exon was identified in mononuclear leukocytes of peripheral blood. This alternatively spliced HLA mRNA was not detectable in mononuclear leukocytes of an individual who had no 39-kDa plasma HLA. This finding indicates that the alternatively spliced mRNA in mononuclear leukocytes is responsible for the synthesis of a secretable class I HLA.

Base Sequence↗
PubMed1991

Amplification of major histocompatibility complex class II gene diversity by intraexonic recombination.

The roles of mutational and recombinational processes in the diversification of the exon encoding the antigen binding site in the murine major histocompatibility complex class II gene Ab were assessed by phylogenetic analysis of allelic nucleotide sequences. A total of 46 alleles of Ab exon 2 from 12 Mus species or subspecies and 2 Rattus species were sequenced after amplification by the polymerase chain reaction. Reliable allelic genealogies could not be determined by phylogenetic analyses, due to extensive homoplasy in the data set. This homoplasy results from the shuffling of polymorphisms between alleles by recombinational processes, indicating that polymorphisms in the antigen binding site encoded by Ab are generated by a combination of two processes. First, the accumulation of point mutations has produced highly divergent polymorphic sequence motifs in five regions of Ab exon 2, each encoding a portion of the binding site. Some of these motifs have persisted as polymorphisms in rodents since before the divergence of mouse and rat (greater than 10 million years ago). The second process mediating Ab diversification involves the shuffling of these polymorphic sequence motifs into numerous allelic combinations by repeated intraexonic recombination. Site-specific hyperrecombinational mechanisms are not involved in this process within the exon. We postulate that these mechanisms continuously generate new Ab alleles with highly divergent binding sites from which alleles with advantageous antigen-binding properties are selectively maintained by some form of balancing selection.

Alleles↗