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PubMed2005

Risk of brain tumors in children and susceptibility to organophosphorus insecticides: the potential role of paraoxonase (PON1).

Prior research suggests that childhood brain tumors (CBTs) may be associated with exposure to pesticides. Organophosphorus insecticides (OPs) target the developing nervous system, and until recently, the most common residential insecticides were chlorpyrifos and diazinon, two OPs metabolized in the body through the cytochrome P450/paraoxonase 1 (PON1) pathway. To investigate whether two common PON1 polymorphisms, C-108T and Q192R, are associated with CBT occurrence, we conducted a population-based study of 66 cases and 236 controls using DNA from neonatal screening archive specimens in Washington State, linked to interview data. The risk of CBT was nonsignificantly increased in relation to the inefficient PON1 promoter allele [per PON1(-108T) allele, relative to PON1(-108CC): odds ratio (OR) = 1.4; 95% confidence interval (CI), 1.0-2.2; p-value for trend = 0.07]. Notably, this association was strongest and statistically significant among children whose mothers reported chemical treatment of the home for pests during pregnancy or childhood (per PON1(-108T) allele: among exposed, OR = 2.6; 95% CI, 1.2-5.5; among unexposed, OR = 0.9; 95% CI, 0.5-1.6) and for primitive neuroectodermal tumors (per PON1(-108T) allele: OR = 2.4; 95% CI, 1.1-5.4). The Q192R polymorphism, which alters the structure of PON1 and influences enzyme activity in a substrate-dependent manner, was not associated with CBT risk, nor was the PON1(C-108T/Q192R) haplotype. These results are consistent with an inverse association between PON1 levels and CBT occurrence, perhaps because of PON1's ability to detoxify OPs common in children's environments. Larger studies that measure plasma PON1 levels and incorporate more accurate estimates of pesticide exposure will be required to confirm these observations.

Aryldialkylphosphatase↗
PubMed2002

Clinical phenotype and linkage analysis of the congenital fibrosis of the extraocular muscles in an Indian family.

PURPOSE: To describe the clinical phenotype and linkage analysis of the congenital fibrosis of the extraocular muscles (CFEOM) in an Indian family. METHODS: Individuals were examined and their peripheral blood samples were withdrawn for genetic analysis. The disorder was tested for linkage to two known autosomal dominant CFEOM loci on chromosome 12p11.2-q12 (CFEOM1) and chromosome 16q24 (CFEOM3) using microsatellite markers. RESULTS: Nine individuals including seven affecteds participated in the study. All seven affecteds had a classic form of CFEOM which included congenital bilateral ptosis, hypotropia, and chin elevation. The disorder segregated as an autosomal dominant trait in this family. The maximum simulated lod score in this family was 2.02. Linkage to CFEOM3 was excluded (Z<-2.00), whereas analysis of chromosome 12 markers was positive. The maximum observed two-point lod score was 1.8 (given the size and structure of the family) at theta=0 with marker D12S345. Markers D12S61, D12S1631, D12S87, D12S345, D12S59, D12S1048, and D12S1668 cosegregated with the disease locus in all affecteds. Haplotype analysis showed that the candidate region spanned the centromere. CONCLUSIONS: The present data showed a classic CFEOM phenotype in an Indian family. The family's phenotype is consistent with linkage to CFEOM1 locus on chromosome 12p11.2-q12.

Blepharoptosis↗
PubMed2003

Large discrepancies in differentiation of allozymes, nuclear and mitochondrial DNA loci in recently founded Pacific populations of the pearl oyster Pinctada margaritifera.

This study presents a comparative analysis of population structure applied to the pearl oyster (Pinctada margaritifera) from the Central Pacific islands using three classes of molecular markers: two mitochondrial genes (mtDNA), five anonymous nuclear loci (anDNA), and eight polymorphic allozymes. Very low levels of haplotype diversity and nucleotidic divergence detected for mtDNA validate the hypothesis of a recent (re)colonization of Polynesian lagoons after their exondation during the last glaciations. Some nuclear loci, however, showed highly significant FST values, indicating a reduced amount of larval exchange between archipelagos at present. A large interlocus variance of FST was nevertheless observed. We discuss whether this pattern is inherent to the stochasticity of the drift process since recolonization, or if it could result from balancing selection acting on certain loci. This study illustrates once more the need to combine the analysis of several kinds of loci when unrelated phenomena are likely to leave their footprints on genetic structure.

Animals↗
PubMed2004

Genetic and haplotype diversity among wild-derived mouse inbred strains.

With the completion of the mouse genome sequence, it is possible to define the amount, type, and organization of the genetic variation in this species. Recent reports have provided an overview of the structure of genetic variation among classical laboratory mice. On the other hand, little is known about the structure of genetic variation among wild-derived strains with the exception of the presence of higher levels of diversity. We have estimated the sequence diversity due to substitutions and insertions/deletions among 20 inbred strains of Mus musculus, chosen to enable interpretation of the molecular variation within a clear evolutionary framework. Here, we show that the level of sequence diversity present among these strains is one to two orders of magnitude higher than the level of sequence diversity observed in the human population, and only a minor fraction of the sequence differences observed is found among classical laboratory strains. Our analyses also demonstrate that deletions are significantly more frequent than insertions. We estimate that 50% of the total variation identified in M. musculus may be recovered in intrasubspecific crosses. Alleles at variants positions can be classified into 164 strain distribution patterns, a number exceeding those reported and predicted in panels of classical inbred strains. The number of strains, the analysis of multiple loci scattered across the genome, and the mosaic nature of the genome in hybrid and classical strains contribute to the observed diversity of strain distribution patterns. However, phylogenetic analyses demonstrate that ancient polymorphisms that segregate across species and subspecies play a major role in the generation of strain distribution patterns.

Animals↗
PubMed2003

[Correlation between major histocompatibility complex (MHC)-class II and type 1 diabetes].

The autoimmune disease type 1 diabetes (T1D) results from a T lymphocyte-dependent, selective destruction of the insulin-producing pancreatic beta-cells and subsequent irreversible insulin deficiency. The disease is caused by a combination of genetic and environmental factors. Numerous genetic, structural and biological studies have provided a convincing case that in human T1D and in its murine model, the non obese diabetes (NOD) mouse, the major histocompatibility complex (MHC) class II molecules, HLA-DQB1 and -DRB1 and their murine orthologues, IA and IE, are the major genetic determinants. The two loci act as a complex superlocus, with both haplotype- and genotype-specific effects. In humans the HLA class II molecule-association with the disease is constituted by a two-sided gradient from positively associated-high risk to negatively associated-low risk molecules. Very low risk corresponds to dominant protection from the disease. The protein structure of DQ/IA and DR/IE molecules have been established. Molecular modeling work revealed that there are marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules show conserved similarities that differ with the shared structural patterns observed between the protective molecules. The available data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall these observations suggest shared pathways in human and murine T1D.

Diabetes Mellitus, Type 1↗
PubMed2002

Haplotype and linkage disequilibrium architecture for human cancer-associated genes.

To facilitate association-based linkage studies we have studied the linkage disequilibrium (LD) and haplotype architecture around five genes of interest for cancer risk: ATM, BRCA1, BRCA2, RAD51, and TP53. Single nucleotide polymorphisms (SNPs) were identified and used to construct haplotypes that span 93-200 kb per locus with an average SNP density of 12 kb. These markers were genotyped in four ethnically defined populations that contained 48 each of African Americans, Asian Americans, Hispanic Americans, and European Americans. Haplotypes were inferred using an expectation maximization (EM) algorithm, and the data were analyzed using D', R(2), Fisher's exact P-values, and the four-gamete test for recombination. LD levels varied widely between loci from continuously high LD across 200 kb to a virtual absence of LD across a similar length of genome. LD structure also varied at each gene and between populations studied. This variation indicates that the success of linkage-based studies will require a precise description of LD at each locus and in each population to be studied. One striking consistency between genes was that at each locus a modest number of haplotypes present in each population accounted for a high fraction of the total number of chromosomes. We conclude that each locus has its own genomic profile with regard to LD, and despite this there is the widespread trend of relatively low haplotype diversity. As a result, a low marker density should be adequate to identify haplotypes that represent the common variation at a locus, thereby decreasing costs and increasing efficacy of association studies.

Alleles↗
PubMed2004

Mitochondrial DNA phylogeography of western lowland gorillas (Gorilla gorilla gorilla).

The geographical distribution of genetic variation within western lowland gorillas (Gorilla gorilla gorilla) was examined to clarify the population genetic structure and recent evolutionary history of this group. DNA was amplified from shed hair collected from sites across the range of the three traditionally recognized gorilla subspecies: western lowland (G. g. gorilla), eastern lowland (G. g. graueri) and mountain (G. g. beringei) gorillas. Nucleotide sequence variation was examined in the first hypervariable domain of the mitochondrial control region and was much higher in western lowland gorillas than in either of the other two subspecies. In addition to recapitulating the major evolutionary split between eastern and western lowland gorillas, phylogenetic analysis indicates a phylogeographical division within western lowland gorillas, one haplogroup comprising gorilla populations from eastern Nigeria through to southeast Cameroon and a second comprising all other western lowland gorillas. Within this second haplogroup, haplotypes appear to be partitioned geographically into three subgroups: (i) Equatorial Guinea, (ii) Central African Republic, and (iii) Gabon and adjacent Congo. There is also evidence of limited haplotype admixture in northeastern Gabon and southeast Cameroon. The phylogeographical patterns are broadly consistent with those predicted by current Pleistocene refuge hypotheses for the region and suggest that historical events have played an important role in shaping the population structure of this subspecies.

Africa South of the Sahara↗
PubMed1996

Alteration of RH gene structure and expression in human dCCee and DCW-red blood cells: phenotypic homozygosity versus genotypic heterozygosity.

This report describes a comparative study on the dCCee and DCW-red blood cells devoid of RhD and CcEe antigens, respectively. Southern blots showed that the two variants carried opposite deletions in the D and non-D (CcEe) genes. Rh haplotyping and exon polymerase chain reaction (PCR) assay indicated that the deletions did not extend beyond the 5' region upstream from exon 1 or the 3' region downstream from exon 10 of the respective genes. This was confirmed by finding intact promoters and 3' untranslated regions in both D and non-D genes in each variant. Reverse transcriptase-PCR and cDNA sequencing showed the expression of two transcripts in each cell type. In dCCee cells, one transcript was the regular Ce form and the other occurred as a D-Ce-D hybrid whose Ce sequence spanned exons 2 through 9. In DCW-cells, the two transcripts were derived from reversely arranged hybrid genes, ie, the CW-D gene was formed by fusion of CW exon 1 with D exons 2 through 10, whereas the reverse product was formed by fusion of D exons 1 through 9 with non-D exon 10. These results indicated that DNA deletion and recombination had occurred in either cis or trans configuration and involved both RH loci in the dCCee or DCW-genome. Identification of such compound alterations correlates the genotypes with phenotypes and explains the lost Rh antigenic expression. A reinvestigation of gene organization also led to the reassignment of several 5' and 3' splice sites. Together, this study not only shows the complexity of Rh phenotypic diversity, but also points to the importance of concurrent analysis of genomic structure and transcript expression in deciphering the underlying genetic mechanisms.

Base Sequence↗
PubMedDate not supplied

Integer programming approaches to haplotype inference by pure parsimony.

In 2003, Gusfield introduced the Haplotype Inference by Pure Parsimony (HIPP) problem and presented an integer program (IP) that quickly solved many simulated instances of the problem. Although it solved well on small instances, Gusfield's IP can be of exponential size in the worst case. Several authors have presented polynomial-sized IPs for the problem. In this paper, we further the work on IP approaches to HIPP. We extend the existing polynomial-sized IPs by introducing several classes of valid cuts for the IP. We also present a new polynomial-sized IP formulation that is a hybrid between two existing IP formulations and inherits many of the strengths of both. Many problems that are too complex for the exponential-sized formulations can still be solved in our new formulation in a reasonable amount of time. We provide a detailed empirical comparison of these IP formulations on both simulated and real genotype sequences. Our formulation can also be extended in a variety of ways to allow errors in the input or model the structure of the population under consideration.

Algorithms↗
PubMed2000

An autosomal dominant posterior polar cataract locus maps to human chromosome 20p12-q12.

We assigned the locus for a previously reported new type of autosomal dominant posterior polar cataract (CPP3) to 20p12-q12 by a genome-wide two-point linkage analysis with microsatellite markers. CPP3 is characterized by progressive, disc-shaped, posterior subcapsular opacity. The disease was seen in 10 members of a Japanese family and transmitted in an autosomal dominant fashion through four generations. We obtained a maximum lod score (Zmax) of 3.61 with a recombination fraction (theta) of 0.00 for markers D20S917, D20S885 and D20S874. Haplotype analysis gave the disease gene localization at a 15.7-cM interval between D20S851 and D20S96 loci on chromosome 20p12-q12. Since the BFSP1 that encodes the lens-specific beaded filament structural protein 1 (filensin) has been mapped around the CPP3 region, we performed sequence analysis on its entire coding region. However, no base substitution or deletion was detected in the CPP3 patients. The mapping of the CPP3 locus to 20p12-q12 not only expands our understanding of the genetic heterogeneity in autosomal dominant posterior polar cataracts but also is a clue for the positional cloning of the disease gene.

Base Sequence↗
PubMedDate not supplied

Understanding human DNA sequence variation.

Over the past century researchers have identified normal genetic variation and studied that variation in diverse human populations to determine the amounts and distributions of that variation. That information is being used to develop an understanding of the demographic histories of the different populations and the species as a whole, among other studies. With the advent of DNA-based markers in the last quarter century, these studies have accelerated. One of the challenges for the next century is to understand that variation. One component of that understanding will be population genetics. We present here examples of many of the ways these new data can be analyzed from a population perspective using results from our laboratory on multiple individual DNA-based polymorphisms, many clustered in haplotypes, studied in multiple populations representing all major geographic regions of the world. These data support an "out of Africa" hypothesis for human dispersal around the world and begin to refine the understanding of population structures and genetic relationships. We are also developing baseline information against which we can compare findings at different loci to aid in the identification of loci subject, now and in the past, to selection (directional or balancing). We do not yet have a comprehensive understanding of the extensive variation in the human genome, but some of that understanding is coming from population genetics.

Base Sequence↗
PubMed2005

Molecular complementation of IL-12Rbeta1 deficiency reveals functional differences between IL-12Rbeta1 alleles including partial IL-12Rbeta1 deficiency.

Patients with mutations in IL12RB1, the gene encoding IL-12Rbeta1, suffer from combined IL-12R/IL-23R deficiency and are unusually susceptible to nontuberculous mycobacteria and salmonellae. The functional effects of amino acid changes in IL-12Rbeta1, however, have not been determined at the molecular level. Molecular complementation studies are essential to demonstrate how structural amino acid changes affect IL-12Rbeta1 function, and whether functionally different IL-12Rbeta1 alleles can be distinguished. Thirteen different IL-12Rbeta1 alleles, including 11 amino acid substitutions and the two major haplotypes (214Q-365M-378G and 214R-365T-378R), were retrovirally transduced in IL-12Rbeta1 deficient human T cells. We provide functional evidence that L77P, R173P, C186S, R213W and Y367C are deleterious mutations leading to non-functional proteins. Conversely, S74R, R156H, H438Y, A525T and G594E are fully functional IL-12Rbeta1 variants. The C198R mutation leads to a partially functional IL-12Rbeta1, representing the first molecularly proven partial IL-12Rbeta1 deficiency. Interleukin-12 (IL-12) induced not only Interferon-gamma but also IL-10 in all responder but not in null-mutant alleles, with intermediate levels in C198R. The QMG allele was found to be a higher IL-12 responder allele compared with the RTR allele. These results have implications for understanding IL-12R/IL-23R structure-function and the role of IL-12R/IL-23R in human disease.

Alleles↗
PubMed2006

Position-dependent repression and promotion of DQB1 intron 3 splicing by GGGG motifs.

Alternative splicing of HLA-DQB1 exon 4 is allele-dependent and results in variable expression of soluble DQbeta. We have recently shown that differential inclusion of this exon in mature transcripts is largely due to intron 3 variants in the branch point sequence (BPS) and polypyrimidine tract. To identify additional regulatory cis-elements that contribute to haplotype-specific splicing of DQB1, we systematically examined the effect of guanosine (G) repeats on intron 3 removal. We found that the GGG or GGGG repeats generally improved splicing of DQB1 intron 3, except for those that were adjacent to the 5' splice site where they had the opposite effect. The most prominent splicing enhancement was conferred by GGGG motifs arranged in tandem upstream of the BPS. Replacement of a G-rich segment just 5' of the BPS with a series of random sequences markedly repressed splicing, whereas substitutions of a segment further upstream that lacked the G-rich elements and had the same size did not result in comparable splicing inhibition. Systematic mutagenesis of both suprabranch guanosine quadruplets (G(4)) revealed a key role of central G residues in splicing enhancement, whereas cytosines in these positions had the most prominent repressive effects. Together, these results show a significant role of tandem G(4)NG(4) structures in splicing of both complete and truncated DQB1 intron 3, support position dependency of G repeats in splicing promotion and inhibition, and identify positively and negatively acting sequences that contribute to the haplotype-specific DQB1 expression.

Animals↗
PubMed2000

Splenocytes cultured in low concentrations of IL-2 generate NK cell specificities toward syngenic and allogenic targets.

Splenocytes cultured in the presence of 30-60 units/ml IL-2 for 5 days develop natural killer activity toward syngeneic and allogeneic tumor cell targets. The IL-2 activated splenocytes, themselves, are partially resistant, whereas concanavalin A-activated T blast cells are completely resistant to killing. Surprisingly, major histocompatibility complex (MHC)-I-negative target cells are also resistant to natural killer (NK)-cell-mediated killing. Cells resistant to killing were unable to block NK-cell-mediated killing of sensitive targets as judged from cold target cell inhibition experiments, and one type of target cells sensitive to killing did generally not cross-block killing of other killing-sensitive target cell types. Alloantigen exposure of splenocytes, i.e., one-way mixed lymphocyte cultures, partially prevents the development of NK-cell activity. Our data suggest that target structures which trigger killing activity of NK cells are determined by the phenotype of the target cell and are dependent on its MHC class I expression disregarding the haplotype of the cell.

Animals↗
PubMed1996

Structural analysis of the HLA-A/HLA-F subregion: precise localization of two new multigene families closely associated with the HLA class I sequences.

Positional cloning strategies for the hemochromatosis gene have previously concentrated on a target area restricted to a maximum genomic expanse of 400 kb around the HLA-A and HLA-F loci. Recently, the candidate region has been extended to 2-3 Mb on the distal side of the MHC. In this study, 10 coding sequences [hemochromatosis candidate genes (HCG) I to X] were isolated by cDNA selection using YACs covering the HLA-A/HLA-F subregion. Two of these (HCG II and HCG IV) belong to multigene families, as well as other sequences already described in this region, i.e., P5, pMC 6.7, and HLA class 1. Fingerprinting of the four YACs overlapping the region was performed and allowed partial localization of the different multigene family sequences on each YAC without defining their exact positions. Fingerprinting on cosmids isolated from the ICRF chromosome 6-specific cosmid library allowed more precise localization of the redundant sequences in all of the multigene families and revealed their apparent organization in clusters. Further examination of these intertwined sequences demonstrated that this structural organization resulted from a succession of complex phenomena, including duplications and contractions. This study presents a precise description of the structural organization of the HLA-A/HLA-F region and a determination of the sequences involved in the megabase size polymorphism observed among the A3, A24, and A31 haplotypes.

Cell Line↗
PubMed1992

Tumor induction by the LTR, v-src, LTR DNA in four B (MHC) congenic lines of chickens.

We report that the cloned DNA harboring the long terminal repeat (LTR), v-src, LTR proviral structure is tumorigenic in chickens of the Prague congenic lines. The growth rate of these tumors is by far the highest in the recombinant CC.R1 line, the B haplotype of which is composed of the B-F/L4 and B-G12 subregions originating from different naturally occurring haplotypes. Some of the tumors induced by the LTR, v-src, LTR DNA are repeatedly transplantable in syngeneic chickens, maintain unaltered provirus, and express v-src mRNA. Differences in the response to challenge with Rous sarcoma virus (RSV) and LTR, v-src, LTR DNA on a given experimental model are compared and possible involvement of an interaction between B-F/L and B-G region genes is considered. Regression of the LTR, v-src, LTR DNA-induced tumors did not prevent the formation and growth of tumors induced subsequently by RSV.

Animals↗