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PubMed2004

Characterization of a single nucleotide polymorphism in the ZNF9 gene and analysis of association with myotonic dystrophy type II (DM2) in the Italian population.

Myotonic dystrophy type 2 (DM2) is a dominant inherited disorder clinically similar to myotonic dystrophy type 1 (DM1) with a peculiar pattern of multisystemic phenotypic features. The mutation responsible for DM1 is a CTG repeat in the 3' UTR of the dystrophia myotonica protein kinase gene (DMPK) on chromosome 19q13.3, while DM2 is caused by an unstable CCTG expansion in intron 1 of the zinc finger protein 9 gene (ZNF9) on chromosome 3q21.3. Southern blotting analysis is the conventional test used to determinate the size of the repeats in the molecular diagnosis of DM2. However, the large number of CCTG repeats and their somatic instability complicates this diagnostic protocol. In order to improve the DM2 test, we have recently characterised a single nucleotide polymorphism located in the first intron of the ZNF9 gene. This SNP consists in a C to A nucleotide change, which creates or disrupts and ApaI enzyme restriction site, easily detectable by PCR amplification followed by restriction analysis. We genotyped this SNP in 30 unrelated DM2 patients and 70 unrelated Italians healthy individuals. Our results show that this polymorphism is in linkage disequilibrium with the DM2 mutation.

Case-Control Studies↗

PubMed2006

Interleukin-10 polymorphisms in Spanish IgA deficiency patients: a case-control and family study.

BACKGROUND: IgA deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. Genetic and environmental factors are suspected to be involved in the development of the disease. Interleukin-10 (IL-10) is a cytokine with stimulatory activity on immunoglobulin production and it may be an important regulator in IgAD pathogenesis. The IL-10 gene contains several single nucleotide polymorphisms (SNPs) and two polymorphic microsatellites located in the 5'-flanking region. Our aim was to ascertain if any of these polymorphic markers are associated or linked to IgAD in Spanish patients. METHODS: We genotyped 278 patients with IgAD and 573 ethnically matched controls for the microsatellites IL-10R and IL-10G and for three single nucleotide polymorphisms at positions -1082, -819 and -592 in the proximal promoter of the gene. We also included in this study the parents of 194 patients in order to study the IL-10 haplotypes transmitted and not transmitted to the affected offspring. RESULTS: The only allele where a significant difference was observed in the comparison between IgA deficiency patients and controls was the IL-10G12 allele (OR = 1.58 and p = 0.021). However, this p value could not withstand a Bonferroni correction. None of the IL-10R or promoter SNP alleles was found at a different frequency when patients were compared with controls. CONCLUSION: Our data do not show any significant difference in IL-10 polymorphism frequencies between control and IgAD patient samples. Their haplotype distribution among patients and controls was also equivalent and therefore these microsatellites and SNPs do not seem to influence IgAD susceptibility.

Case-Control Studies↗

PubMed2004

High-resolution single-nucleotide polymorphism array and clustering analysis of loss of heterozygosity in human lung cancer cell lines.

Chromosomal loss of heterozygosity (LOH) is a common mechanism for the inactivation of tumor suppressor genes in human epithelial cancers. Hybridization to single-nucleotide polymorphism (SNP) arrays is an efficient method to detect genome-wide cancer LOH. Here, we survey LOH patterns in a panel of 33 human lung cancer cell lines using SNP array hybridization containing 1500 SNPs. We compared the LOH patterns generated by SNP array hybridization to those previously obtained by 399 microsatellite markers and find a high degree of concordance between the two methods. A novel informatics platform, dChipSNP, was used to perform hierarchical tumor clustering based on genome-wide LOH patterns. We demonstrate that this method can separate non-small-cell and small-cell lung cancer samples based on their shared LOH. Furthermore, we analysed seven human lung cancer cell lines using a novel 10 000 SNP array and demonstrate that this is an efficient and reliable method of high-density allelotyping. Using this array, we identified small regions of LOH that were not detected by lower density SNP arrays or by standard microsatellite marker panels.

Biomarkers, Tumor↗

PubMed2000

Polymorphism in the gene coding for the immunodominant antigen gp43 from the pathogenic fungus Paracoccidioides brasiliensis.

The gp43 glycoprotein is an immune-dominant antigen in patients with paracoccidioidomycosis (PCM). It is protective against murine PCM and is a putative virulence factor. The gp43 gene of Paracoccidioides brasiliensis B-339 is located in a 1,329-bp DNA fragment that includes two exons, a 78-bp intron, and a leader peptide-coding region of 105 bp. Polymorphism in gp43 has been suggested by the occurrence, in the same isolate or among different fungal samples, of isoforms with distinct isoelectric points. In the present study we aligned and compared with a consensus sequence the gp43 precursor genes of 17 P. brasiliensis isolates after sequencing two PCR products from each fungal sample. The genotypic types detected showed 1 to 4 or 14 to 15 informative substitution sites, preferentially localized between 578 and 1166 bp. Some nucleotide differences within individual isolates (noninformative sites) resulted in a second isoelectric point for the deduced protein. The most polymorphic sequences were also phylogenetically distant from the others and encoded basic gp43 isoforms. The three isolates in this group were from patients with chronic PCM, and their DNA restriction patterns were distinct in Southern blots. The nucleotides encoding the inner core of the murine T-cell-protective epitope of gp43 were conserved, offering hope for the development of a universal vaccine.

Animals↗

PubMed1996

Sequence polymorphisms of potential functional relevance in the beta-globin gene locus.

The purpose of this review is to give a general up-date of the most recent developments concerning polymorphisms within the beta-globin gene cluster. The first polymorphisms to be identified were mostly restriction fragment length polymorphisms. They were important markers both for their use as diagnostic tools and for anthropological investigations. Although they have been associated with specific patterns of globin gene expression in the hemoglobinopathies, none have been demonstrated to have any intrinsic functional significance. More recently, additional single nucleotide variations and microsatellite-like polymorphic simple sequence repeats have been identified which are frequently located in trans-acting protein binding segments and hence might affect regulatory processes.

Anemia, Sickle Cell↗

PubMed1998

Optimized PCR labeling in mutational and microsatellite analysis.

To optimize the labeling and visualization of PCR products we tested different variables, including deoxynucleotide concentration and ratio, dilution of labeled product, number of PCR cycles, and use of one-step or nested labeling protocols. Labeling was achieved using a fixed amount of labeled dATP, whose relative specific activity was varied by adding increasing amounts of cold dATP. Optimal PCR-labeling intensity was reached at dATP concentrations between 0.9 and 7.0 micromol/L, with a peak at 1.8 micromol/L. This concentration corresponded to an optimal ratio between the increase in specific activity and the decrease in DNA yield. Nucleotide imbalances >1:2 were not advantageous. Mutational analysis by single-strand conformational polymorphism (SSCP) was used to validate PCR-labeling protocols. The limiting nucleotide concentrations did not affect SSCP. Clear SSCP patterns were obtained using DNA templates of different sizes derived from several genes. SSCP patterns obtained using one-step or nested PCR-labeling protocols were equivalent and were visualized after overnight exposure, using [alpha35S]dATP as the label. Dilutions of labeled products ranging between 1:10 and 1:2.5 influenced SSCP patterns, and the lowest dilution tested produced better-defined and more-intense signals. Optimized SSCP conditions allowed the detection of novel and previously characterized nucleotide variants. Clear microsatellite typing was also obtained using optimized protocols and [alpha35S]dATP as the label.

Colorectal Neoplasms, Hereditary Nonpolyposis↗

PubMed2005

Polymorphism, linkage mapping and expression pattern of the porcine skeletal muscle glycogen synthase (GYS1) gene.

The glycogen synthase gene (GYS1), which encodes the rate-limiting enzyme for glycogen synthesis of skeletal muscle, is a promising candidate gene for traits related to skeletal muscle in pigs. In this study, a G/A single nucleotide polymorphism in GYS1 intron 7 detected as a FokI PCR-restriction fragment length polymorphism (PCR-RFLP) showed allele frequency differences among five Chinese indigenous pig breeds and three western commercial pig breeds. Linkage analysis assigned the gene GYS1 to marker interval SW1302-SW1473 on SSC6 in a three-generation Meishan X Large White reference family. The results of association analysis and interval mapping suggested that the FokI PCR-RFLP polymorphism might be linked with the quantitative trait loci affecting carcass traits detected on SSC6 in the F2 intercross pedigree. The reverse transcriptase-polymerase chain reaction revealed that the porcine GYS1 gene was expressed in spleen, lung, liver, kidney, small intestine, skeletal muscle, heart and stomach, with the highest expression in skeletal muscle.

Animals↗

PubMed1996

Nucleotide variation at the Gpdh locus in the genus Drosophila.

The Gpdh locus was sequenced in a broad range of Drosophila species. In contrast to the extreme evolutionary constraint seen at the amino acid level, the synonymous sites evolve at rates comparable to those of other genes. Gpdh nucleotide sequences were used to infer a phylogenetic tree, and the relationships among the species of the obscura group were examined in detail. A survey of nucleotide polymorphism within D. pseudoobscura revealed no amino acid variation in this species. Applying a modified McDonald-Kreitman test, the amino acid divergence between species in the obscura group does not appear to be excessive, implying that drift is adequate to explain the patterns of amino acid change at this locus. In addition, the level of polymorphism at the Gpdh locus in D. pseudoobscura is comparable to that found at other loci, as determined by a Hudson-Kreitman-Aguadé test. Thus, the pattern of nucleotide variation within and between species at the Gpdh locus is consistent with a neutral model.

Algorithms↗

PubMed2003

Evidence for multiple hybrid groups in Trypanosoma cruzi.

A role for parasite genetic variability in the spectrum of Chagas disease is emerging but not yet evident, in part due to an incomplete understanding of the population structure of Trypanosoma cruzi. To investigate further the observed genotypic variation at the sequence and chromosomal levels in strains of standard and field-isolated T. cruzi we have undertaken a comparative analysis of 10 regions of the genome from two isolates representing T. cruzi I (Dm28c and Silvio X10) and two from T. cruzi II (CL Brener and Esmeraldo). Amplified regions contained intergenic (non-coding) sequences from tandemly repeated genes. Multiple nucleotide polymorphisms correlated with the T. cruzi I/T. cruzi II classification. Two intergenic regions had useful polymorphisms for the design of classification probes to test on genomic DNA from other known isolates. Two adjacent nucleotide polymorphisms in HSP 60 correlated with the T. cruzi I and T. cruzi II distinction. 1F8 nucleotide polymorphisms revealed multiple subdivisions of T. cruzi II: subgroups IIa and IIc displayed the T. cruzi I pattern; subgroups IId and IIe possessed both the I and II patterns. Furthermore, isolates from subgroups IId and IIe contained the 1F8 polymorphic markers on different chromosome bands supporting a genetic exchange event that resulted in chromosomes V and IX of T. cruzi strain CL Brener. Based on these analyses, T. cruzi I and subgroup IIb appear to be pure lines, while subgroups IIa/IIc and IId/IIe are hybrid lines. These data demonstrate for the first time that IIa/IIc are hybrid, consistent with the hypothesis that genetic recombination has occurred more than once within the T. cruzi lines.

Animals↗

PubMed1995

Contrasting histories of avian and mammalian Mhc genes revealed by class II B sequences from songbirds.

To explore the evolutionary dynamics of genes in the major histocompatibility complex (Mhc) in nonmammalian vertebrates, we have amplified complete sequences of the polymorphic second (beta1) and third (beta2) exons of class II beta chain genes of songbirds. The pattern of nucleotide substitution in the antigen-binding site of sequences cloned from three behaviorally and phylogenetically divergent songbirds [scrub jays Aphelocoma coerulescens), red-winged blackbirds (Agelaius phoeniceus), and house finches (Carpodacus mexicanus) reveals that class II B genes of songbirds are subject to the same types of diversifying forces as those observed at mammalian class II loci. By contrast, the tree of avian class II B genes reveals that orthologous relationships have not been retained as in placental mammals and that, unlike class II genes in mammals, genes in songbirds and chickens have had very recent common ancestors within their respective groups. Thus, whereas the selective forces diversifying class II B genes of birds are likely similar to those in mammals, their long-term evolutionary dynamics appear to be characterized by much higher rates of concerted evolution.

Amino Acid Sequence↗

PubMed2005

Proceedings of the SMBE Tri-National Young Investigators' Workshop 2005. Molecular genetics of natural populations.

Significant progress in evolutionary genetics has been made by studying, on the one hand, patterns of DNA sequence polymorphism and, on the other, genetic architecture of complex adaptive traits. However, connections between nucleotide variants under selection and adaptively relevant phenotypes are missing. Such connections can be established using precise gene replacement. We review the recent successful introduction of this technique to the analysis of two evolutionarily interesting loci--Odysseus and desaturase2. Both genes have subtle phenotypes that nevertheless could be identified using gene replacement, demonstrating that effects of naturally occurring alleles can be measured in the laboratory. This is an important first step in connecting statistical signatures of selection with adaptation in nature. More candidate genes involved in adaptation, for example, through cloning of genes responsible for reproductive isolation, now need to be identified. Molecular genetic manipulation, DNA polymorphism analysis, and field studies then have to be integrated to provide fresh insights into the mechanisms of evolutionary change.

Alleles↗

PubMed2000

High DNA sequence variability at the alpha 1 Na/K-ATPase locus of Artemia franciscana (brine shrimp): polymorphism in a gene for salt-resistance in a salt-resistant organism.

We previously reported that the Na/K-ATPase alpha 1 subunit coding gene showed signs of being a very polymorphic locus in Artemia franciscana. This species is adapted to highly saline waters, and the Na/K-ATPase alpha 1 isoform presumably plays a key role in this adaptation. Therefore, we were interested in further study of the alpha 1 Na/K-ATPase polymorphisms to examine whether they might be due to an adaptation to salt resistance driven by natural selection. Using coding sequences from 10 genomic clones and 3 cDNAs, we observed that most substitutions are in synonymous positions (88.8%). The 12 nonsynonymous substitutions code for conservative amino acid replacements with an apparent scattered distribution across functional domains of the protein. Interspecific comparison between these sequences and two genomic clones from Artemia parthenogenetica containing 1,122 bp of the alpha 1 Na/K-ATPase locus coding sequence showed independence of the synonymous/nonsynonymous ratio in the comparison within A. franciscana and between A. franciscana and A. parthenogenetica, which fits the neutral model of evolution. Since there were no previous studies on DNA polymorphism for other A. franciscana genes, we also studied variability at the Actin 302 locus for comparison. Both loci were amplified by reverse transcription-polymerase chain reaction, and 20 sequences were obtained for each. This study shows that the amplified region of the alpha 1 Na/K-ATPase gene is 3.5 times as polymorphic as the Actin 302 gene and 2.9 times as heterozygotic. Interestingly, under a model of neutral evolution, the data observed would be expected with a probability of approximately 0.05, suggesting an excess of intraspecific variation of alpha 1 Na/K-ATPase with respect to Actin 302. Restriction fragment length polymorphism studies show similar patterns of polymorphism along the approximately 41-kb span of the alpha 1 Na/K-ATPase locus. Most of the nucleotide differences are linked in a few haplotypes, although recombination events are also inferred from the data. We propose a possible explanation for the high polymorphic levels at the alpha 1 Na/K-ATPase locus which invokes positive selection acting tightly to the locus in transiently isolated or semi-isolated subpopulations.

Actins↗

PubMed1998

A 'de novo' point mutation of the low-density lipoprotein receptor gene in an Italian subject with primary hypercholesterolemia.

Severe hypercholesterolemia was found in an 11-year-old boy with no family history of familial hypercholesterolemia. The reduced LDL-receptor activity in cultured skin fibroblasts (40% 125I-LDL degradation as compared with a control cell line) indicated the presence of an LDL-receptor defect. The analysis of the promoter region and the exons of LDL-receptor gene by single strand conformation polymorphism revealed an abnormal migration pattern in exon 1, which was due to a T --> A transversion at nucleotide 28 of the cDNA. This novel mutation causes an arginine for tryptophane substitution at position - 12 of the signal peptide (W-12R) and introduces an AviII restriction site in exon 1. Screening of the mutation by polymerase chain reaction (PCR) amplification of exon 1 and AviII digestion revealed that none of the proband's family members carried the mutation. Non-paternity was excluded after the analysis of a battery of 14 short tandem repeats located in 13 different chromosomes. These results are consistent with the hypothesis that the proband is heterozygous for a 'de novo' mutation of the LDL-receptor gene producing a non-conservative amino acid substitution. We suggest that the change in the net charge of the signal peptide, caused by the addition of a positively charged amino acid, impairs the co-translational translocation of the nascent receptor protein across the endoplasmic reticulum membrane.

Adolescent↗

PubMed2007

Sub-populations within the major European and African derived haplogroups R1b3 and E3a are differentiated by previously phylogenetically undefined Y-SNPs.

Single nucleotide polymorphisms on the Y chromosome (Y-SNPs) have been widely used in the study of human migration patterns and evolution. Potential forensic applications of Y-SNPs include their use in predicting the ethnogeographic origin of the donor of a crime scene sample, or exclusion of suspects of sexual assaults (the evidence of which often comprises male/female mixtures and may involve multiple perpetrators), paternity testing, and identification of non- and half-siblings. In this study, we used a population of 118 African- and 125 European-Americans to evaluate 12 previously phylogenetically undefined Y-SNPs for their ability to further differentiate individuals who belong to the major African (E3a)- and European (R1b3, I)-derived haplogroups. Ten of these markers define seven new sub-clades (equivalent to E3a7a, E3a8, E3a8a, E3a8a1, R1b3h, R1b3i, and R1b3i1 using the Y Chromosome Consortium nomenclature) within haplogroups E and R. Interestingly, during the course of this study we evaluated M222, a sub-R1b3 marker rarely used, and found that this sub-haplogroup in effect defines the Y-STR Irish Modal Haplotype (IMH). The new bi-allelic markers described here are expected to find application in human evolutionary studies and forensic genetics.

Black People↗

PubMed2006

Altered expression of vasoactive intestinal peptide receptors in T lymphocytes and aberrant Th1 immunity in multiple sclerosis.

Vasoactive intestinal peptide (VIP) has a unique property of regulating T(h)1 and T(h)2 immunity of CD4+ T cells. In this study, we demonstrated, for the first time, that differential expression of VIP receptors and a compensatory mechanism directly affect the responsiveness of CD4+ T cells and their T(h)1 and T(h)2 properties to VIP. The expression of VIP receptor-1 (VPAC1) and VPAC2 in CD4+ T cells changed reciprocally in the context of the activation state. In activated CD4+ T cells of healthy individuals, markedly decreased VPAC1 expression was compensated for by increased expression of VPAC2 induced by T cell activation. In contrast, there was altered expression of VPAC2 in activated CD4+ T cells derived from multiple sclerosis (MS) patients, which rendered CD4+ T cells less responsive to VIP and skewed the system to a predominantly in a T(h)1 direction. Detailed characterization with agonist peptides of VIP showed that residues Met and Ser at positions 17 and 25 of VIP were critical to its regulatory properties through interaction with VAPC2. Furthermore, altered levels of VPAC2 expression in T cells of MS patients were not associated with single-nucleotide polymorphism in the encoding region of the VPAC2 gene but with gene regulation as characterized by a distinct DNA footprinting pattern in the promoter region of the VPAC2 gene in MS as compared with controls. This study has provided new evidence for an intrinsic mechanism associated with an aberrant, pro-inflammatory state of CD4+ T cells in MS.

Adult↗

PubMed2001

Nucleotide sequence variation at two genes of the phenylpropanoid pathway, the FAH1 and F3H genes, in Arabidopsis thaliana.

The FAH1 and F3H genes encode ferulate-5-hydroxylase and flavanone-3-hydroxylase, which are enzymes in the pathways leading to the synthesis of sinapic acid esters and flavonoids, respectively. Nucleotide variation at these genes was surveyed by sequencing a sample of 20 worldwide Arabidopsis thaliana ecotypes and one Arabidopsis lyrata spp. petraea stock. In contrast with most previously studied genes, the percentage of singletons was rather low in both the FAH1 and the F3H gene regions. There was, therefore, no footprint of a recent species expansion in the pattern of nucleotide variation in these regions. In both FAH1 and F3H, nucleotide variation was structured into two major highly differentiated haplotypes. In both genes, there was a peak of silent polymorphism in the 5' part of the coding region without a parallel increase in silent divergence. In FAH1, the peak was centered at the beginning of the second exon. In F3H, nucleotide diversity was highest at the beginning of the gene. The observed pattern of variation in both FAH1 and F3H, although suggestive of balancing selection, was compatible with a neutral model with no recombination.

Arabidopsis↗

PubMed1995

Nucleotide diversity of mitochondrial DNAs between the swamp and the river types of domestic water buffaloes, Bubalus bubalis, based on restriction endonuclease cleavage patterns.

Cleavage patterns of mitochondrial DNAs (mtDNAs) by 15 restriction endonucleases were analyzed for 10 swamp and 13 river types of domestic water buffaloes. Digestions with nine enzymes exhibited polymorphisms giving two or three kinds of cleavage patterns. Five mtDNA types were identified, three types in the swamp buffaloes of the Philippines, Vietnam, and Indonesia (S-types) and two types in the river buffaloes of Bangladesh and Pakistan (R-types). Nucleotide diversities ranged from 0.2 to 0.6% within the S- and R-types and from 1.9 to 2.4% between the R-types and the S-types. These values indicated that R-type and S-type mtDNAs differentiated at the subspecific level of other mammalian species reported. The possibility of polyphyletic domestication in different places is discussed for the origin of two distinct types of domestic water buffaloes.

Animals↗

PubMed2005

Large-scale genomic correlations in Arabidopsis thaliana relate to chromosomal structure.

BACKGROUND: The chromosomes of the plant Arabidopsis thaliana contain various genomic elements, distributed with appreciable spatial heterogeneity. Clustering of and/or correlations between these elements presumably should reflect underlying functional or structural factors. We studied the positional density fluctuations and correlations between genes, indels, single nucleotide polymorphisms (SNPs), retrotransposons, 180 bp tandem repeats, and conserved centromeric sequences (CCSs) in Arabidopsis in order to elucidate any patterns and possible responsible factors for their genomic distributions. RESULTS: The spatial distributions of all these elements obeyed a common pattern: the density profiles of each element within chromosomes exhibited low-frequency fluctuations indicative of regional clustering, and the individual density profiles tended to correlate with each other at large measurement scales. This pattern could be attributed to the influence of major chromosomal structures, such as centromeres. At smaller scales the correlations tended to weaken -- evidence that localized cis-interactions between the different elements had a comparatively minor, if any, influence on their placement. CONCLUSION: The conventional notion that retrotransposon insertion sites are strongly influenced by cis-interactions was not supported by these observations. Moreover, we would propose that large-scale chromosomal structure has a dominant influence on the intrachromosomal distributions of genomic elements, and provides for an additional shared hierarchy of genomic organization within Arabidopsis.

Arabidopsis↗