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S Gaudieri

Publications and source records attributed to S Gaudieri.

35 records · Page 2Linked to original sources
PubMed1999

Characterisation of the human central MHC gene, BAT1: genomic structure and expression.

The BAT1 gene (D6S81E) encodes a member of the DEAD-box family of RNA-binding proteins, and lies in the central MHC. This region contains genes which affect susceptibility to immunopathological diseases. A 14-kb section of the human MHC containing the BAT1 gene and a further 5-kb telomeric of BAT1 was sequenced using DNA from individuals homozygous for HLA-A1, B8, DR3 and HLA- A1, B57, DR7. Analysis of our sequences and the previously reported human cDNA sequence showed that the expressed sequence of the 8.1 and 57.1 haplotypes is identical with only minor substitutions in the introns. Phylogenetic analysis suggests BAT1 may be a translation initiation factor. Screening of cells and tissues for BAT1 mRNA suggests an abundant member of a family of proteins expressed in multiple cell types, notably macrophages and hepatocytes. Expression was independent of MHC haplotype, consistent with the lack of sequence polymorphism.

Blotting, Northern↗
PubMed1999

Different evolutionary histories in two subgenomic regions of the major histocompatibility complex.

Two subgenomic regions within the major histocompatibility complex, the alpha and beta blocks, contain members of the multicopy gene families HLA class I, human endogenous retroviral sequence (HERV-16; previously known as P5 and PERB3), hemochromatosis candidate genes (HCG) (II, IV, VIII, IX), 3.8-1, and MIC (PERB11). In this study we show that the two blocks consist of imperfect duplicated segments, which contain linked members of the different gene families. The duplication and truncation sites of the segments are associated with retroelements. The retroelement sites appear to generate the imperfect duplications, insertions/deletions, and rearrangements, most likely via homologous recombination. Although the two blocks share several characteristics, they differ in the number and orientation of the duplicated segments. On the 62.1 haplotype, the alpha block consists of at least 10 duplicated segments that predominantly contain pseudogenes and gene fragments of the HLA class I and MIC (PERB11) gene families. In contrast, the beta block has two major duplications containing the genes HLA-B and HLA-C, and MICA (PERB11.1) and MICB (PERB11.2). Given the common origin between the blocks, we reconstructed the duplication history of the segments to understand the processes involved in producing the different organization in the two blocks. We then found that the beta block contains four distinct duplications from two separate events, whereas the alpha block is characterized by multisegment duplications. We will discuss these results in relation to the genetic content of the two blocks.

Chromosome Inversion↗
PubMed1998

Sequencing of 42kb of the APO E-C2 gene cluster reveals a new gene: PEREC1.

Through the sequencing of a 42kb cosmid clone we describe a new gene, designated PEREC1, located approximately 1.5kb centromeric of the human apolipoprotein (APO) E-C2 cluster. The combination of dotplot analysis, predicted coding potential and interrogation of the Expressed Sequence Tag (EST) database determined the genomic organisation of PEREC1. Sequence alignment with multiple overlapping ESTs confirmed the predicted splice sites. The predicted cDNA and amino acid sequences of PEREC1 have extensive similarity to the Caenorhabditis elegans protein, C18E9.6. Conserved structural and functional motifs have been defined by combining nucleotide and amino acid analyses to identify third base degeneracy and therefore selection at the protein level. The Poliovirus Receptor Related Protein2 gene (PRR2), previously mapped to chromosome 19q13.2 by Fluorescent In-Situ Hybridisation, has also been located approximately 17kb centromeric of APO E.

Alzheimer Disease↗
PubMed1997

Genomic characterization of the region between HLA-B and TNF: implications for the evolution of multicopy gene families.

The major histocompatibility complex (MHC) contains genes which confer susceptibility to numerous diseases and must be important in primate evolution. In some instances, genes have been mapped to the region between human histocompatibility leukocyte antigen (HLA)-B and tumor necrosis factor (TNF) but precise localization has proven difficult especially since this region is subject to insertions, deletions, and duplications. Utilizing computer similarity searches and coding prediction programs, we have identified several potential coding sequences between HLA-B and TNF. Three of these sequences, PERB11.2, PERB15, and PERB 18, are similar to members of multicopy gene families that are located in other regions of the MHC. The identification of numerous fragmented and intact retroelements (L1, Alu, LTR, and THE sequences) flanking the PERB11 and PERB15 genes suggests that these retroelements are involved in the duplication process. The evaluation of candidate genes for disease susceptibility within the MHC is complicated by their similarity to other members of multicopy gene families. The determination of sequence differences within and between species provides a strategy with which to investigate the candidate genes between HLA-B and TNF.

Amino Acid Sequence↗
PubMed1997

The major histocompatability complex (MHC) contains conserved polymorphic genomic sequences that are shuffled by recombination to form ethnic-specific haplotypes.

The major histocompatibility complex (MHC) consists of polymorphic frozen blocks (PFBs) that are linked to form megabase haplotypes. These blocks consist of polymorphic sequences and define regions where recombination appears to be inhibited. We have been able to show, using a highly polymorphic sequence centromeric of HLA-B (within the beta block), that PFBs are conserved and contain specific insertions/deletions and substitutions that are the same for individuals with the same MHC haplotype but that differ between at least most different haplotypes. A sequence comparison between ethnic-specific haplotypes shows that these sequences have remained stable and predate the formation of these haplotypes. To determine whether the same conserved block has been involved in the generation of multiple haplotypes, we compared the block typing profiles of different ethnic specific haplotypes. Block typing profiles have previously been shown to be identical in individuals with the same MHC haplotype but, generally, to differ between different haplotypes. It was found that some PFBs are common to more than one haplotype, implying a common ancestry. Subsequently, haplotypes have been generated by the shuffling and exchange of these PFBs. The regions between these PFBs appear to permit the recombination sites and therefore could be expected to exhibit either low polymorphism or a localized "hotspot."

Asian People↗
PubMed1997

The evolution of MHC diversity by segmental duplication and transposition of retroelements.

Sequence analysis of a 237 kb genomic fragment from the central region of the MHC has revealed that the HLA-B and HLA-C genes are contained within duplicated segments peri-B (53 kb) and peri-C (48 kb), respectively, and separated by an intervening sequence (IF) of 30 kb. The peri-B and peri-C segments share at least 90% sequence homology except when interrupted by insertions/deletions including Alu, L1, an endogenous retrovirus, and pseudogenes. The sequences of peri-B, IF, and peri-C were searched for the presence of Alu elements to use as markers of evolution, chromosomal rearrangements, and polymorphism. Of 29 Alu elements, 14 were identified in peri-B, 11 in peri-C, and 4 in IF. The Alu elements in peri-B and peri-C clustered phylogenetically into two clades which were classified as "preduplication" and "postduplication" clades. Four Alu J elements that are shared by peri-B and peri-C and are flanked by homologous sequences in their paralogous locations, respectively, clustered into a "preduplication" clade. By contrast, the majority of Alu elements, which are unique to either peri-B or peri-C, clustered into a postduplication clade together with the Alu consensus subfamily members ranging from platyrrhine-specific (Spqxcg) to catarrhine-specific Alu sequences (Y). The insertion of platyrrhine-specific Alu elements in postduplication locations of peri-B and peri-C implies that these two segments are the products of a duplication which occurred in primates prior to the divergence of the New World primate from the human lineage (35-44 mya). Examination of the paralogous Alu integration sites revealed that 9 of 14 postduplication Alu sequences have produced microsatellites of different length and sequence within the Alu 3'-poly A tail. The present analysis supports the hypothesis that HLA-B and HLA-C genes are products of an extended segmental duplication between 44 and 81 million years ago (mya), and that subsequent diversification of both genomic segments occurred because of the mobility and mutation of retroelements such as Alu repeats.

Amino Acid Sequence↗
PubMed1997

Allelic and interlocus comparison of the PERB11 multigene family in the MHC.

The major histocompatibility complex (MHC) contains at least a hundred genes over 4 megabases of DNA. Within the MHC there are several new multigene families which have been recently described. PERB11 is a multigene family which occurs over the class I and central region of the MHC. Two members of the family have been shown to be functional and share domains with members of the supergene family including HLA class I, FcRn, and Zn-alpha2-glycoprotein molecules. The two functional members are contained within an area of the MHC which has been associated with increased susceptibility to autoimmune diseases such as insulin-dependent diabetes mellitus and also rapid progression to AIDS following HIV-1 infection. Intralocus and interlocus differences between PERB11.1 and PERB11.2 include: (1) several nucleotide substitutions leading to amino acid changes; (2) presence and absence of potential glycosylation sites; (3) insertions and deletions leading to a frame shift resulting in diversity at the amino acid level and an early termination signal. There are ten different alleles of PERB11.1 including one allele which contains a frame shift in the transmembrane region causing a putative truncated molecule lacking the cytoplasmic tail. The significance of this polymorphism in disease associations is under investigation. The most divergent domain is the transmembrane region when PERB11.1 and PERB11.2 are compared. The results suggest that these two molecules may have different functions.

Alleles↗
PubMed1997

Duplication and polymorphism in the MHC: Alu generated diversity and polymorphism within the PERB11 gene family.

The PERB11 gene family has at least five members within the telomeric region of the MHC. The PERB11.1 and PERB11.2 genes are approximately 40 kb and 160 kb centromeric of HLA-B, respectively. Using continuous genomic sequence encompassing PERB11.1 and PERB11.2, we have found a large (approximately 25 kb) segmental duplication extending beyond the genes themselves and other potential coding sequences. The major difference between the segments are large indels which are predominantly Alu sequences. The Alu sequences within the duplicated segments have created diversity via the internal and 3' poly A-rich region. A sequence comparison of an Alu sequence between two different human ancestral haplotypes shows a high level of polymorphism, particularly in the poly A-rich regions. This study characterises the Alu sequences within the peri-PERB11.1 and peri-PERB11.2 duplicated segments in relation to diversity and polymorphism and as evolutionary markers.

Base Sequence↗
PubMed1994

Effects of acute exercise on lymphocyte subsets and metabolic activity.

Lymphocyte subsets, their responsiveness to mitogen and their capacity for glutamine oxidation and glycolysis were assessed in seven subjects before and after an acute bout of interval exercise, the purpose being to establish whether exercise is associated with alterations in lymphocyte metabolic capacities. The subjects exercised at 112% of their maximal work capacity (as determined by pre-test) on a treadmill and performed 25 repeat tests, each of 1 min duration interrupted by 2 min rest periods. Venous blood samples were taken at rest and 3 min following completion of exercise. Acute exercise was associated with significant decreases in the percentage of T- (p < 0.01) and B-cells (p < 0.01) and an increase in the percentage of NK-cells (p < 0.05). These changes were accompanied by a significant decrease in the responsiveness of peripheral blood lymphocytes to the mitogen concanavalin A (p < 0.05). Acute exercise was also associated with profound changes in the metabolic capacities of peripheral blood lymphocytes: rates of 14CO2 production from [U-14C]glutamine (19%: p < 0.05) and lactate (27%: p < 0.05) production were increased significantly in response to interval exercise. Linear regression analysis revealed significant correlation between the exercise-mediated changes (%) in T- and NK-cells and changes (%) in both lymphocyte responsiveness to concanavalin A and metabolic capacity, particularly glutamine oxidation to CO2. One interpretation of these data is that acute exercise promotes a redistribution in lymphocyte subsets, and that it is this redistribution that is the basis of both the impairment in lymphocyte responsiveness to mitogens and the increase in lymphocyte metabolic capacity, especially glutamine oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Psychological and immunological correlates of acute overtraining.

Five men undertook two intensive interval training sessions per day for 10 days, followed by 5 days of active recovery. Subjects supplied a venous blood sample and completed a mood-state questionnaire on days 1, 6, 11 and 16 of the study. Performance capabilities were assessed on days 1, 11 and 16 using a timed treadmill test to exhaustion at 18 kmh-1 and 1% grade. These individuals became acutely overtrained as indicated by significant reductions in running performance from day 1 to day 11. The overtrained state was accompanied by severe fatigue, immune system deficits, mood disturbance, physical complaints, sleep difficulties, and reduced appetite. Mood states moved toward baseline during recovery, but feelings of fatigue and immune system deficits persisted throughout the study.

Adaptation, Physiological↗
PubMed1993

Differences in the central major histocompatibility complex between humans and chimpanzees. Implications for development of autoimmunity and acquired immune deficiency syndrome.

Chimpanzees (Pan Troglodytes) and humans are closely related and belong to the same subfamily, Homininae. The approximately 1.8% genetic difference that exists between humans and the chimpanzees must be responsible for observed differences between these two species. It has been shown that chimpanzees can be infected with HIV, but AIDS has not been reported. Furthermore, the prevalence of autoimmune diseases may be low in this species. For instance, type II diabetes occurs, but type I (autoimmune) diabetes (IDDM), to our knowledge, has not been reported. In humans, susceptibility genes for MG and IDDM have been localized to the region between TNF and HLA-B. This region may also influence the rate of progression to death after HIV infection. We have identified differences in this region between humans and the chimpanzees. As shown by PFGE, the TNF to Patr-B region in the chimpanzees is approximately 130-160 kb shorter than the equivalent in humans. Southern and sequence analyses indicate that the deletions in chimpanzees (insertions in humans) include one copy of CL (approximately 10 kb) and the X sequences (< 30 kb). Obviously, other deletions/insertions (approximately 120 kb) need to be identified. Since CL has been shown to be transcribed, the results imply the lack of the gene or, at least, a different gene copy number in the chimpanzees, and we propose that such differences may be relevant to the observed functional differences. We demonstrate here a strategy to identify critical genes responsible for disease development.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Phylogenetic analysis of primate MIC (PERB11) sequences suggests that the representation of the gene family differs in different primates: comparison of MIC (PERB11) and C4.

Duplication of segments within the MHC has led to numerous multicopy families such as class I, class II, C4 and MIC (PERB11). Different copy numbers between haplotypes and species may be explained by the extent of duplication and subsequent deletion. There are at least five copies of MIC (PERB11) in humans, but MICA (PERB11.1) appears to have been deleted from the chimpanzee. By comparing the sequences of primates (chimpanzee, gorilla, gibbon, orang-utan, pygmy chimpanzee, Patas monkey, Aethiops and baboon) we conclude that the gorilla has a copy of PERB11.1, whereas the baboon and Patas possess MICD (PERB11.4) and/or MICE (PERB11.5) rather than MICA (PERB11.1). These findings indicate that the primate MHC is more plastic than has been appreciated.

Amino Acid Sequence↗
PubMedDate not supplied

Further characterization of MHC haplotypes demonstrates conservation telomeric of HLA-A: update of the 4AOH and 10IHW cell panels.

Cell panels have been used extensively in studies of polymorphism and disease associations within the major histocompatibility complex (MHC), but the results from these panels require continuous updates with the increasing availability of novel data. We present here an updated table of the typings of the 10IHW and 4AOH panels. Local data included are HFE, HERV-K(C4) and six microsatellites telomeric of HLA-A. Typings for class I, MICA (PERB11.1), MICB (PERB11.2), XA, XB, LMP2 and 10 microsatellites reported by others have also been consolidated in this table. The tabulation shows that the length of conservation in the human MHC is even more extensive than previously thought. Human MHC ancestral haplotypes are inherited as a conserved region of genomic sequence spanning some 6-8 megabases from the HLA class II region and beyond the HLA class I region up to and including the HFE gene. Numerous examples of historical recombinations were also observed.

Cell Line↗