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PubMed2003

The cre1 and cre3 nematode resistance genes are located at homeologous loci in the wheat genome.

Differential responses in host-nematode pathotype interactions occur in wheat lines carrying different cereal cyst nematode resistance (Cre) genes. Cre1, located on chromosome 2B, confers resistance to most European nematodes and the sole Australian pathotype, while Cre3, present on chromosome 2D, is highly resistant to the Australian pathotype and susceptible to a number of European pathotypes. Genes encoding nucleotide binding site-leucine rich repeat (NBS-LRR) proteins that cosegregate with the Cre3 locus cross hybridize to homologues whose restriction fragment length polymorphism (RFLP) patterns distinguish near-isogenic Cre1 nematode-resistant wheat lines. Genetic mapping showed that the NBS-LRR gene members that distinguished the Cre1 near-isogenic lines were located on chromosome 2BL at a locus, designated Xcsl107, that cosegregates with the Cre1 locus. A haplotype of NBS-LRR genes from the Xcsl107 locus provides a diagnostic marker for the presence of Cre1 nematode resistance in a wide collection of wheat lines and segregating families. Genetic analysis of NBS-LRR haplotypes that cosegregate with Cre1 and Cre3 resistance, together with flanking cDNA markers and other markers from homoeologous group 2 chromosomes, revealed a conserved gene order that suggests Cre1 and Cre3 are homeoloci.

Animals↗
PubMed2000

Direct PCR of Cryptococcus neoformans MATalpha and MATa pheromones to determine mating type, ploidy, and variety: a tool for epidemiological and molecular pathogenesis studies.

Cryptococcus neoformans MATalpha and MATa pheromones were amplified by direct PCR. Nucleotide sequence analyses revealed unique restriction enzyme sites. Sixty strains were used to devise a restriction fragment length polymorphism typing scheme that yielded three variety-specific patterns. Additionally, pheromone-specific PCR allowed easier identification of diploid C. neoformans strains than flow cytometry.

Cryptococcosis↗
PubMed2005

Evolution of a length polymorphism in the human PER3 gene, a component of the circadian system.

Period homologue 3 (PER3) is a component of the mammalian circa-dian system, although its precise role is unknown. A biallelic variable number tandem repeat (VNTR) polymorphism exists in human PER3, consisting of 4 or 5 repeats of a 54-bp sequence in a region encoding a putative phosphorylation domain. This polymorphism has previously been reported to associate with diurnal preference ("morningness" and "eveningness") and delayed sleep-phase syndrome. We have investigated the global allele frequencies of this variant in ethnically distinct indigenous populations. All populations were polymorphic, with the shorter (4-repeat) allele ranging in frequency from 0.19 (Papua New Guinea) to 0.89 (Mongolia). To investigate if allele frequency has been influenced by natural selection, the authors 1) tested for a correlation with latitude and mean annual insolation (incident sunlight energy), using classical markers to correct for historical population differentiation; and they 2) compared allele-frequency difference between European American, African American, and East Asian populations, as measured using F(ST), to an empirical null distribution of F(ST)values based on a genome-wide dataset of single nucleotide polymorphisms (SNPs) of presumed neutral loci that were previously typed by The SNP Consortium. The variation in allele frequencies between indigenous populations did not show a pattern that would indicate selective pressure on PER3resulting from day-length variation or mean annual insolation, and the allele-frequency difference between European Americans, African Americans, and East Asians was not an outlier when compared to the distribution for presumed neutral SNPs. We therefore find no evidence for differential or balancing selection in the contemporary pattern of global PER3allele frequencies.

Circadian Rhythm↗
PubMed2006

Stepwise haplotype analysis: are LD patterns repeatable?

A variety of techniques exist to describe and depict patterns of pairwise linkage disequilibrium (LD). In the current paper, a new log-linear framework is proposed for the summarisation of local interactions among single nucleotide polymorphisms (SNPs). Our approach provides a straightforward means of capturing the diversity of higher-order LD relationships for small numbers of loci by investigating inter-marker interactions. Our method was applied to a dataset of 76 SNP markers spanning a genomic interval of length 2.8 megabases. The analysis of three short sub-regions is described in detail here. Model and graphical representations of contiguous markers in medium to high LD are presented. In the regions studied, evidence for sub-structure was detected, supporting the view that the genomic reality is complex. Interestingly, a critical evaluation of the method by bootstrapping showed that while some LD relationships were captured in a highly repeatable fashion, the majority were not. Large numbers of small interactions, both direct and indirect, mean that many models can adequately summarise the data at hand. Our results suggest that repeatability should be further investigated in the application of LD-based approaches.

Haplotypes↗
PubMed2005

The importance of immune gene variability (MHC) in evolutionary ecology and conservation.

Genetic studies have typically inferred the effects of human impact by documenting patterns of genetic differentiation and levels of genetic diversity among potentially isolated populations using selective neutral markers such as mitochondrial control region sequences, microsatellites or single nucleotide polymorphism (SNPs). However, evolutionary relevant and adaptive processes within and between populations can only be reflected by coding genes. In vertebrates, growing evidence suggests that genetic diversity is particularly important at the level of the major histocompatibility complex (MHC). MHC variants influence many important biological traits, including immune recognition, susceptibility to infectious and autoimmune diseases, individual odours, mating preferences, kin recognition, cooperation and pregnancy outcome. These diverse functions and characteristics place genes of the MHC among the best candidates for studies of mechanisms and significance of molecular adaptation in vertebrates. MHC variability is believed to be maintained by pathogen-driven selection, mediated either through heterozygote advantage or frequency-dependent selection. Up to now, most of our knowledge has derived from studies in humans or from model organisms under experimental, laboratory conditions. Empirical support for selective mechanisms in free-ranging animal populations in their natural environment is rare. In this review, I first introduce general information about the structure and function of MHC genes, as well as current hypotheses and concepts concerning the role of selection in the maintenance of MHC polymorphism. The evolutionary forces acting on the genetic diversity in coding and non-coding markers are compared. Then, I summarise empirical support for the functional importance of MHC variability in parasite resistance with emphasis on the evidence derived from free-ranging animal populations investigated in their natural habitat. Finally, I discuss the importance of adaptive genetic variability with respect to human impact and conservation, and implications for future studies.

Journal Article↗
PubMed1998

Aromatic hydrocarbon receptor polymorphism: development of new methods to correlate genotype with phenotype.

Differential CYP1A1 inducibility, reflecting variations in aromatic hydrocarbon receptor (AHR) affinity among inbred mouse strains, is an important determinant of environmental toxicity. We took advantage of the Ahr polymorphism in C57BL/6 and DBA/2 mice to develop an oligonucleotide-hybridization screening approach for the rapid identification of DNA sequence differences between Ahr alleles. Oligonucleotides containing single-base changes at polymorphic sites were immobilized on a solid support and hybridized with C57BL/6 or DBA/2 AHR cDNA radiolabeled probes. The observed hybridization patterns demonstrate that this approach can be used to detect nucleotide differences in the Ahr coding region with very high accuracy. In parallel experiments, we used a yeast two-hybrid system to assess phenotypic differences in AHR function. AHR activation, as measured by beta-galactosidase reporter activity in Saccharomyces cerevisiae strain SFY526, was determined following treatment with varying doses of the AHR ligand beta-naphthoflavone (BNF). We found that the C57BL/6 AHR has about a 15-fold higher affinity for BNF than the DBA/2 AHR, in much better agreement with results reported for whole-animal studies than the values observed by in vitro ligand-binding assays. Using C57BL/6 and DBA/2 AHR chimeric proteins, we also confirmed the previously reported observation that an A375V change is principally responsible for the high- to low-affinity AHR phenotype. There has been no straightforward method to reliably and reproducibly phenotype large numbers of humans for CYP1A1 inducibility or AHR affinity. Screening human AHR cDNAs by oligonucleotide-hybridization and yeast two-hybrid methodologies will be invaluable for the rapid and unequivocal determination of changes in DNA sequence and receptor-ligand affinities associated with human AHR polymorphisms.

Animals↗
PubMed1985

Expression of chorionic gonadotropin alpha- and beta-genes in normal and neoplastic human tissues: relationship to deoxyribonucleic acid structure.

We have investigated whether the expression of hCG genes can be attributed to changes in the structure of the alpha- and beta hCG genes, such as rearrangements, duplications, or methylation patterns. Various tissues and cell lines were studied: two term placentae, three trophoblastic tumor cell lines, two tumor cell lines ectopically producing alpha-subunit, normal cells not producing hCG or subunits, and a nonproducing malignancy. Gene structure was explored by restriction enzyme analysis and Southern blotting of DNA, using as probes 32P-labeled plasmids containing alpha- and beta hCG cDNAs. Similarly, methylation was evaluated using the restriction enzymes Msp I, Hpa II, and Hha I, each sensitive to a different pattern of cytosine methylation. No structural changes were observed in alpha- and beta hCG genes, although certain polymorphisms were observed. Analysis of methylation patterns revealed variation of the methylated cytosines; however, no clear correlation was seen between overall methylation or a specific pattern of methylation of these genes and their expression. Although specific methylated nucleotides of regulatory importance may not have been detected by our methods, we can still conclude that neither DNA structural alterations nor patterns of cytosine methylation appear to be major determinants of hCG expression.

Cell Line↗
PubMed2006

Sequence diversity, natural selection and linkage disequilibrium in the human T cell receptor alpha/delta locus.

T cell receptors (TR), through their interaction with the major histocompatibility complex, play a central role in immune responsiveness and potentially immune-related disorders. We resequenced all 57 variable (V) genes in the human T cell receptor alpha and delta (TRA/TRD) locus in 40 individuals of Northern European, Mexican, African-American and Chinese descent. Two hundred and eighty-four single nucleotide polymorphisms (SNPs) were identified. The distribution of SNPs between V genes was heterogeneous, with an average of five SNPs per gene and a range of zero to 15. We describe the patterns of linkage disequilibrium for these newly discovered SNPs and compare these patterns with other emerging large-scale datasets (e.g. Perlegen and HapMap projects) to place our findings into a framework for future analysis of genotype-phenotype associations across this locus. Furthermore, we explore signatures of natural selection across V genes. We find evidence of strong directional selection at this locus as evidenced by unusually high values of Fst.

Computer Simulation↗
PubMed1998

Characterisation of Trypanosoma cruzi populations by DNA polymorphism of the cruzipain gene detected by single-stranded DNA conformation polymorphism (SSCP) and direct sequencing.

Fifty fresh isolates of Trypanosoma cruzi from Triatoma dimidiata vectors and 31 from patients with Chagas' disease were analysed for DNA polymorphisms within the 432-bp core region of the cruzipain gene which encodes the active site of cathepsin L-like cystein proteinase. The cruzipain gene showed signs of polymorphism consisting of four different DNA sequences in Central and South American isolates of T. cruzi. The PCR fragments of Guatemalan isolates could be divided into three groups, Groups 1, 2 and 3, based on different patterns of single-stranded DNA conformation polymorphism. All of the strains isolated from Brazil, Chile, and Paraguay, except for the CL strain, showed a Group 4 pattern. Two to four isolates from each group were analysed by cloning and sequencing. A silent mutation occurred between Groups 1 and 2, and five nucleotides and two aa substitutions were detected between Groups 1 and 3. The DNA sequence of Group 4 contained five nucleotides and one aa substitution from Group 1. All of the DNA sequences corresponded well with the single-stranded DNA conformation polymorphism. The Group 1 isolates, the majority in the Guatemalan population (70/81, 86.4%), were isolated from both triatomines and humans, but Group 3 were isolated only from humans. Moreover, the Group 2 isolates were detected only in triatomine vectors (9/50; 18%), but never in humans (0/32, P<0.05) suggesting that this group has an independent life-cycle in sylvatic animals and is maintained by reservoir hosts other than humans.

Amino Acid Sequence↗
PubMed2001

Microsporum gypseum isolated from a feline case of dermatophytosis.

The 1- to 2-month-old female cross-breed cat presented with alopecia, erythema and many crusts were present on the tail. Microscopic examination of crusts from the tail disclosed epithelial debris, exudate, mycelium, and arthrospores. Microsporum gypseum which is rarely isolated from cats as a causative agent of dermatophytsis was cultured from the crusts on a 1/10 Sabouraud glucose agar at 27 degrees C for 1 week. The isolate of M. gypseum from the cat was examined by random amplification of polymorphic DNA (RAPD), chitin synthase 1 gene (CHS1) sequence and mating experiments. The RAPD band patterns of the clinical isolate of M. gypseum was identical to those of tester strains of Arthroderma gypseum. Nucleotide sequence analysis of the CHS1 gene fragments from the isolate and a tester strain of A. gypseum showed 100% similarity. The mating experiments on the clinical isolate of M. gypseum completely agreed with the results from RAPD and CHS1 gene sequence. The isolate from the cat was confirmed to be A. gypseum (-) mating type, which was consistent with the result of mycological examination by molecular analyses.

Animals↗
PubMed2005

Exon skipping in the KIT gene causes a Sabino spotting pattern in horses.

Sabino (SB) is a white spotting pattern in the horse characterized by white patches on the face, lower legs, or belly, and interspersed white hairs on the midsection. Based on comparable phenotypes in humans and pigs, the KIT gene was investigated as the origin of the Sabino phenotype. In this article we report the genetic basis of one type of Sabino spotting pattern in horses that we call Sabino 1, with the alleles represented by the symbols SB1 and sb1. Transcripts of KIT were characterized by reverse transcriptase polymerase chain reaction (RT-PCR) and sequencing cDNA from horses with the genotypes SB1/SB1, SB1/sb1, and sb1/sb1. Horses with the Sabino 1 trait produced a splice variant of KIT that did not possess exon 17. Genomic DNA sequencing of KIT revealed a single nucleotide polymorphism (SNP) caused by a base substitution for T with A in intron 16, 1037 bases following exon 16. The SNP associated with SB1 was designated KI16+1037A. This substitution eliminated a MnlI restriction site and allowed the use of PCR-RFLP to characterize individuals for this base change. Complete linkage was observed between this SNP and Sabino 1 in the Tennessee Walking Horse families (LOD = 9.02 for Theta = 0). Individual horses from other breeds were also tested. All five horses homozygous for this SNP were white, and all 68 horses with one copy of this SNP either exhibited the Sabino 1 phenotype or were multipatterned. Some multipatterned individuals appeared white due to the additive effect of white spotting patterns. However, 13 horses with other Sabino-type patterns did not have this SNP. Based on these results we propose the following: (1) this SNP, found within intron 16, is responsible for skipping of exon 17 and the SB1 phenotype, (2) the White and Sabino phenotypes are heterogeneous and this mechanism is not the only way to produce the pattern described as "Sabino" or "White," and (3) homozygosity for SB1 results in a complete or nearly completely white phenotype.

Animals↗
PubMed2002

Identification of Taenia asiatica in China: molecular, morphological, and epidemiological analysis of a Luzhai isolate.

Multiple analysis has characterized a recently described tapeworm of people, Taenia asiatica, in mainland China. Six adult tapeworms collected from people of the Zhuang minority residing in the southern part of China (Luzhai isolate) were comparatively analyzed with other tapeworms from people: T. asiatica (n = 2, South Korea), T. saginata (n = 1, Poland; n = 1, Korea), and T. solium (n = 1, People's Republic of China). Experimental infections with eggs from the Luzhai isolate in pigs and cattle produced cysticerci, each with a hookletless scolex and with wartlike formations on the external surface of the bladder wall. There were rostellar protrusions in the scolices of adult worms. Random amplified polymorphic DNA analysis using 3 arbitrary primers produced bands identical to those of the Korean T. asiatica. Conversely, T. saginata and T. solium exhibited different banding patterns. Phylogenetic relationships inferred from the complete nucleotide sequences of the internal transcribed spacer 2 placed the Chinese tapeworms consistently within the T. asiatica clade by 96% bootstrapping value in the maximum likelihood analysis, 96% in maximum parsimony, and 100% in neighbor joining. These collective data demonstrate that T. asiatica is sympatrically distributed with the other 2 species of Taenia in the human host in mainland China.

Adolescent↗
PubMed2000

The dynamics of natural selection and vicariance in the Dominican anole: patterns of within-island molecular and morphological divergence.

The larger islands of the Lesser Antilles are ecologically and geologically complex and are inhabited by single, but morphologically variable, Anolis species. Although earlier work has indicated that a large part of the morphological variation in Anolis oculatus from Dominica can be attributed to selection, a history of recurrent volcanic activity over the last few million years suggests that vicariance may have also played a significant role. We report a study of variation in the cytochrome b gene of mitochondrial DNA across the island to address this issue. We uncovered a very high degree of polymorphism, with an overall gene diversity of 0.97 and a nucleotide diversity of 0.04. Sequences, on average, differ by 3.82% and the maximum pairwise divergence (corrected for multiple hits) is 9.29%. Most haplotypes are restricted to single localities (a pattern not changed by increasing the sample size). Phylogenetic analysis revealed the presence of two distinct lineages on the island with strong phylogeographic structure. One of these is geographically restricted to a relatively small part of the central Caribbean coast. Sublineages were also discernible within the other more widely distributed lineage, but resolution within and support for these sublineages was poor. The phylogeographic pattern is not congruent with generalized body shape and scalation, but is significantly correlated with color pattern. Even when correcting for this lineage effect with partial Matrix correspondence tests, the relationship between color pattern and vegetation is reaffirmed, suggesting that although both vicariance and selection have played a role in the morphological differentiation of this species, selection for current environmental conditions has been more important. We discuss the causes of the phylogeographic structure in light of the volcanic history of the island and highlight the exceptional instance of congruence between all morphological character systems and lineage boundaries, which occurs at the transition between the northern and southern Caribbean ecotypes.

Animals↗
PubMed1992

A termination mutation (2143delT) in the CFTR gene of German cystic fibrosis patients.

German patients with cystic fibrosis (CF) were screened for molecular lesions in exon 13 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by single strand conformation polymorphism (SSCP) and chemical cleavage of mismatch analyses. Direct sequencing of four samples that displayed the same SSCP pattern and that were susceptible to cleavage of hetero-duplexes by osmium tetroxide revealed, in all cases, a deletion of a single T residue at nucleotide position 2143 within codon 671 of the CFTR gene. As a result, leucine codon 671 is changed into a termination codon. In total, the 2143delT mutation was confirmed in 6 out of 271 German non-delta F508 CF chromosomes by artificial restriction fragment length polymorphism analysis, indicating that this frameshift mutation accounts for about 2% of German non-delta F508 mutations. The 6 pancreas insufficient patients who are compound heterozygous for 2143-delT suffer from the typical features of pulmonary and gastrointestinal CF disease. The 2143delT mutation completes the panel of the more frequent CFTR mutations that reside on the "delta F508 haplotype" and that contribute to its overpresentation among German non-delta F508 alleles that are associated with severe forms of disease.

Adolescent↗
PubMed1995

Familial hypocalciuric hypercalcemia associated with mutation in the human Ca(2+)-sensing receptor gene.

Familial hypocalciuric hypercalcemia (FHH) is generally characterized by lifelong hypercalcemia without hypercalciuria and is inherited in an autosomal dominant manner. Affected individuals show abnormal parathyroid and renal responses to changes in the extracellular calcium concentration. A Japanese FHH family was screened for mutations in the Ca(2+)-sensing receptor gene by the polymerase chain reaction and single strand conformation polymorphism. The proband with hypercalcemia showed an abnormal pattern in exon 1 of the gene, whereas her two sisters with normocalcemia showed a normal pattern. The consanguineous parents with borderline serum calcium concentrations showed both patterns. Nucleotide sequence analysis identified a G-->C point mutation at nucleotide 118 that resulted in the conversion of the normal codon for proline into a codon for alanine at amino acid 40 (numbered according to the bovine complementary DNA). The proband was homozygous for the mutation, and the parents were heterozygous. These results imply that this mutation in the human Ca(2+)-sensing receptor gene causes FHH and that the dosage of the gene defect determines disease phenotype.

Adult↗
PubMed2003

Comparative molecular population genetics of the Xdh locus in the cactophilic sibling species Drosophila buzzatii and D. koepferae.

The Xdh (rosy) gene is one of the best studied in the Drosophila genus from an evolutionary viewpoint. Here we analyze nucleotide variation in a 1875-bp fragment of the second exon of Xdh in Argentinian populations of the cactophilic D. buzzatii and its sibling D. koepferae. The major electrophoretic alleles of D. buzzatii not only lack diagnostic amino acids in the region studied but also differ on average from each other by four to 13 amino acid changes. Our data also suggest that D. buzzatii populations belonging to different phytogeographic regions are not genetically differentiated, whereas D. koepferae exhibits a significant pattern of population structure. The Xdh region studied is twice as polymorphic in D. buzzatii as in D. koepferae. Differences in historical population size or in recombinational environment between species could account for the differences in the level of nucleotide variation. In both species, the Xdh region exhibits a great number of singletons, which significantly departs from the frequency spectrum expected under neutrality for nonsynonymous sites and also for synonymous sites in D. buzzatii. These excesses of singletons could be the signature of a recent population expansion in D. buzzatii, whereas they may be simply explained as the result of negative selection in D. koepferae.

Amino Acid Sequence↗
PubMed2004

Conservation of genomic imprinting at the XIST, IGF2, and GTL2 loci in the bovine.

Genomic imprinting is theorized to exist in all placental mammals and some marsupials; however, extensive comparative analysis of animals aside from humans and mice remains incomplete. Here we report conservation of genomic imprinting in the bovine at the X chromosome inactivation-specific transcript (XIST), insulin-like growth factor 2 (IGF2), and gene trap locus 2 (GTL2) loci. Coding single nucleotide polymorphisms (SNPs) between Bos gaurus and Bos taurus were detected at the XIST, IGF2, and GTL2 loci, which have previously been identified as imprinted in either humans, mice, or sheep. Expression patterns of parental alleles in F1 hybrids indicated preferential paternal expression at the XIST locus solely in the chorion of females, whereas analysis of the IGF2 and GTL2 loci indicated preferential paternal and maternal expression of alleles, respectively, in both fetal and placental tissues. Comparative sequence analysis of the XIST locus and adjacent regions suggests that repression of the maternal allele in the bovine is controlled by a different mechanism than in mice, further reinforcing the importance of comparative analysis of imprinting.

Alleles↗
PubMed1998

Mutations in T cell receptor zeta chain mRNA of peripheral T cells from systemic lupus erythematosus patients.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown aetiology. Although it has been reported that T cells might be responsible for the pathogenesis of SLE, it remains unclear whether immune aberrations of SLE T cells are the primary event in this pathological process. We have recently reported that tyrosine phosphorylation and expression of the T cell receptor zeta chain (TCR zeta) was significantly decreased in SLE T cells and that two SLE patients exhibited a 36 bp, exon 7 deletion of the TCR zeta mRNA. To investigate further common mutations in TCR zeta mRNA among SLE patients, mRNA was isolated from the peripheral blood T cells of two normal controls, two systemic sclerosis (SSc) patients, and eight SLE patients. TCR zeta cDNA was amplified by RT-PCR. Five out of the eight SLE patients exhibited abnormal migration patterns of the TCR zeta cDNA in PCR single stranded conformational polymorphism analysis. PCR products were ligated into pUC18 and five clones obtained were sequenced. Analysis of the nucleotide sequences revealed that all of the five pUC18 clones from the normal controls and SSc patients had the normal nucleotide sequence, whereas all eight SLE patients had mutations in TCR zeta cDNA accompanied by predicted amino acid substitutions. Mutations found in six of these patients corresponded to those of the third immunoreceptor tyrosine-based activation motif (ITAM) domain or the GTP/GDP binding site in TCR zetaThus, these mutations in TCR zeta mRNA could be responsible for the decreased expression of the TCR zeta protein in SLE T cells.

Amino Acid Substitution↗