Search

The human intestine houses a dense microbial ecosystem in which the struggle for nutrients creates a continual and dynamic selective force. Host-produced mucus glycans provide a ubiquitous source of carbon and energy for microbial species. Not surprisingly, many gut resident bacteria have become highly adapted to efficiently consume numerous distinct structures present in host glycans. We propose that sophistication in mucus consumption is a trait most likely to be found in gut residents that have co-evolved with hosts, microbes that have adapted to the complexity associated with the host glycan landscape.

Objective To examine genetic associations of polymorphisms in the dopamine receptor D2 ( DRD2 ) and D3 ( DRD3 ) genes with risk of Parkinson's disease (PD). Methods The study included 1325 newly diagnosed patients with PD and 1735 controls from a consortium of five North American case–control studies. We collected risk factor information by in-person or telephone interview. Six DRD2 and two DRD3 polymorphisms were genotyped using a common laboratory. Odds ratios were estimated using logistic regression. Results Among non-Hispanic whites, homozygous carriers of Taq1A DRD2 (rs1800497) polymorphism had an increased risk of PD compared to homozygous wildtype carriers (OR = 1.5, 95% CI 1.0–2.3). In contrast, the direction of association for Taq1A polymorphism was opposite for African–Americans, showing an inverse association with PD risk (OR = 0.10, 95% CI 0.2–0.7). Among white Hispanics who carried two alleles, the Ser9Gly DRD3 (rs6280) polymorphism was associated with a decreased risk of PD (OR = 0.4, 95% CI 0.2–0.8). The inverse association of smoking with PD risk was not modified by any of the DRD2 or DRD3 polymorphisms. Conclusions DRD2 polymorphisms are unlikely to be true disease-causing variants; however, three DRD2 polymorphisms (including Taq1A) may be in linkage disequilibrium with possible disease associated variants in the DRD2-ANKK1-NCAM1-TTC12 gene cluster.

Objective In MPTP animal models of Parkinson’s disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine-PD association.

Adaptive Girdle Loss in Sticklebacks How do molecular changes give rise to phenotypic adaptation exemplified by the repeated reduction in the pelvic girdle observed in separate populations of sticklebacks? Now Chan et al. (p. 302 , published online 10 December) have identified the specific DNA changes that control this major skeletal adaptation. The key locus controlling pelvic phenotypes mapped to a noncoding regulatory region upstream of the Pituitary homeobox transcription factor 1 gene, which drives a tissue-specific pelvic enhancer. Multiple populations showed independent deletions in this region and enhancer function was inactivated. Reintroduction of the enhancer restored pelvic development in a pelvic-reduced stickleback.

Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

Objective Murine genetic models suggest that function of the 12/15-LOX enzyme promotes atherosclerosis. We tested the hypothesis that exonic and/or promoter single nucleotide polymorphisms (SNPs) in the human 12/15-LOX gene ( ALOX15 ) alter the risk of symptomatic coronary artery disease (CAD). Methods and results We resequenced ALOX15 and then genotyped a common promoter and a less common novel coding SNP (T560M) in 1809 subjects with CAD and 1734 controls from Kaiser Permanente including a subset of participants of the Coronary Artery Risk Development in Young Adults study. We found no association between the promoter SNP and the risk of CAD. However, heterozygote carriers of the 560M allele had an increased risk of CAD (adjusted OR, 1.62; P =0.02) compared to non-carriers. In vitro studies demonstrated a 20-fold reduction in the catalytic activity of 560M when compared to 560T. We then genotyped T560M in 12,974 participants of the Atherosclerosis Risk in Communities study and similarly found that heterozygote carriers had an increased risk of CAD compared to non-carriers (adjusted HR, 1.31; P =0.06). In both population studies, homozygote carriers were rare and associated with a non-significant decreased risk of CAD compared to non-carriers (adjusted OR, 0.55; P =0.63 and HR, 0.93; P =0.9). Conclusions A coding SNP in ALOX15 (T560M) results in a near null variant of human 12/15-LOX. Assuming a co-dominant mode of inheritance, this variant does not protect against CAD. Assuming a recessive mode of inheritance, the effect of this mutation remains unclear, but is unlikely to provide a protective effect to the degree suggested by mouse knockout studies.

Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study. A nominally significant association was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model, 1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.

Human genetic diversity is shaped by both demographic and biological factors and has fundamental implications for understanding the genetic basis of diseases. We studied 938 unrelated individuals from 51 populations of the Human Genome Diversity Panel at 650,000 common single-nucleotide polymorphism loci. Individual ancestry and population substructure were detectable with very high resolution. The relationship between haplotype heterozygosity and geography was consistent with the hypothesis of a serial founder effect with a single origin in sub-Saharan Africa. In addition, we observed a pattern of ancestral allele frequency distributions that reflects variation in population dynamics among geographic regions. This data set allows the most comprehensive characterization to date of human genetic variation.

Functional analysis of a genome requires accurate gene structure information and a complete gene inventory. A dual experimental strategy was used to verify and correct the initial genome sequence annotation of the reference plant Arabidopsis . Sequencing full-length cDNAs and hybridizations using RNA populations from various tissues to a set of high-density oligonucleotide arrays spanning the entire genome allowed the accurate annotation of thousands of gene structures. We identified 5817 novel transcription units, including a substantial amount of antisense gene transcription, and 40 genes within the genetically defined centromeres. This approach resulted in completion of ∼30% of the Arabidopsis ORFeome as a resource for global functional experimentation of the plant proteome.

Heterologous expression of genes for membrane proteins can provide a useful approach to analyze ligand binding and other cell surface characteristics. We analyzed the expression and processing of a barley lectin gene in mammalian cells and demonstrated that this cytotoxic plant lectin could be expressed in a functional state using a transient expression system. The mammalian cells did not recognize all the processing signals on the lectin, and, as a result, the protein was secreted into the medium. The lectin expression studies suggest that it would be feasible to use the mammalian system for the expression and identification of plant genes encoding proteins that are able to bind the Nod factor, a bacterially-produced signal molecule required for the establishment of the legume-Rhizobium symbiosis. A Nod factor-binding assay was developed, and specific sets of transfected mammalian cells were shown to exhibit Nod factor-binding activity.

Bipolar disorder (BP) is a disabling and often life-threatening disorder that affects ≈1% of the population worldwide. To identify genetic variants that increase the risk of BP, we genotyped on the Illumina HumanHap550 Beadchip 2,076 bipolar cases and 1,676 controls of European ancestry from the National Institute of Mental Health Human Genetics Initiative Repository, and the Prechter Repository and samples collected in London, Toronto, and Dundee. We imputed SNP genotypes and tested for SNP-BP association in each sample and then performed meta-analysis across samples. The strongest association P value for this 2-study meta-analysis was 2.4 × 10 −6 . We next imputed SNP genotypes and tested for SNP-BP association based on the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium for 1,868 BP cases and a reference set of 12,831 individuals. A 3-study meta-analysis of 3,683 nonoverlapping cases and 14,507 extended controls on >2.3 M genotyped and imputed SNPs resulted in 3 chromosomal regions with association P ≈ 10 −7 : 1p31.1 (no known genes), 3p21 (>25 known genes), and 5q15 ( MCTP1 ). The most strongly associated nonsynonymous SNP rs1042779 (OR = 1.19, P = 1.8 × 10 −7 ) is in the ITIH1 gene on chromosome 3, with other strongly associated nonsynonymous SNPs in GNL3 , NEK4 , and ITIH3 . Thus, these chromosomal regions harbor genes implicated in cell cycle, neurogenesis, neuroplasticity, and neurosignaling. In addition, we replicated the reported ANK3 association results for SNP rs10994336 in the nonoverlapping GSK sample (OR = 1.37, P = 0.042). Although these results are promising, analysis of additional samples will be required to confirm that variant(s) in these regions influence BP risk.

A susceptibility locus for coronary artery disease (CAD) at chromosome 9p21 has recently been reported, which may influence the age of onset of CAD. We sought to replicate these findings among white subjects and to examine whether these results are consistent with other racial/ethnic groups by genotyping three single nucleotide polymorphisms (SNPs) in the risk interval in the Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology (ADVANCE) study. One or more of these SNPs was associated with clinical CAD in whites, U.S. Hispanics and U.S. East Asians. None of the SNPs were associated with CAD in African Americans although the power to detect an odds ratio (OR) in this group equivalent to that seen in whites was only 24-30%. ORs were higher in Hispanics and East Asians and lower in African Americans, but in all groups the 95% confidence intervals overlapped with ORs observed in whites. High-risk alleles were also associated with increased coronary artery calcification in controls and the magnitude of these associations by racial/ethnic group closely mirrored the magnitude observed for clinical CAD. Unexpectedly, we noted significant genotype frequency differences between male and female cases (P = 0.003-0.05). Consequently, men tended towards a recessive and women tended towards a dominant mode of inheritance. Finally, an effect of genotype on the age of onset of CAD was detected but only in men carrying two versus one or no copy of the high-risk allele and presenting with CAD at age >50 years. Further investigations in other populations are needed to confirm or refute our findings.

Objective The aim of this study was to assess systematic differences between patients with acute myocardial infarction (MI) and patients with stable angina in matrix metalloproteinase (MMP) circulating levels and genetic polymorphisms. Methods We identified adults in a large integrated health care delivery system whose initial clinical presentation of coronary disease was either an acute MI or stable exertional angina. A total of 909 patients with acute MI, 466 patients with stable angina, and 1023 healthy older control subjects were genotyped. Serum levels of pro-MMP1, MMP2, MMP3, MMP9, and MMP10 were measured in 199 randomly selected patients from each group. Results At a median of 15 weeks after initial clinical presentation, higher circulating levels of MMP2 and MMP9 were independently associated with acute MI after statistical adjustment for conventional risk factors, hs-CRP levels, and cardiac medications. By contrast, none of the polymorphisms in MMP1 , MMP2 , MMP3 , MMP9 , or MMP10 was significantly associated with either acute MI compared with angina, or with coronary disease compared with controls. Conclusions Circulating levels of MMP2 and MMP9 are independently associated with development of an acute MI rather than stable angina as the initial clinical presentation of coronary artery disease.

Genetic polymorphisms may affect the balance between coagulation and fibrinolysis and thereby affect individual vulnerability to acute myocardial infarction (MI) among patients with underlying coronary atherosclerosis.We enrolled 1375 patients with an initial clinical presentation of coronary disease. We genotyped 49 single nucleotide polymorphisms (SNPs) in 9 coagulation system genes and compared patients who had an initial acute MI with patients who presented with stable exertional angina.An SNP in CD36 (rs3211956) was significantly (P = .04) more common among patients who presented with acute MI (minor allele frequency 10.5%) than patients with stable exertional angina (minor allele frequency 8.0%). This association became marginally significant, however, after adjustment for conventional cardiac risk factors in an additive genetic model (odds ratio 1.34, CI 1.00-1.88, P = .053). An SNP in ITGB3 (Leu59Pro, rs5918) was slightly, but not significantly (P = .083), more common among patients with acute MI (minor allele frequency 14.5%) than among patients with stable exertional angina (minor allele frequency 12.0%). Two linked SNPs in THBD (Ala473Val, rs1042579; and rs3176123) were slightly, but not significantly (P = .079 and 0.052, respectively), less common among patients with acute MI (minor allele frequency 16.1%) than among patients with stable exertional angina (18.7% and 19.0%, respectively).Four SNPs in platelet glycoprotein and hemostatic genes were nominally associated with acute MI rather than stable exertional angina as the initial clinical presentation of coronary artery disease. These findings are suggestive but require independent confirmation in larger studies.

International audience; BACKGROUND: A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain. METHODS: Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies. FINDINGS: In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966. INTERPRETATION: Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease.

Rhizobium bacteria synthesize signal molecules called Nod factors that elicit responses in the legume root during nodulation. Nod factors, modified N-acylated β-(1,4)- N -acetylglucosamine, are synthesized by the nodulation ( nod ) gene products. We tested the ability of three Sinorhizobium meliloti nod gene products to modify Nod factor analogs with thio linkages instead of O-glycosidic bonds in the oligosaccharide backbone.

The genome of the flowering plant Arabidopsis thaliana has five chromosomes. Here we report the sequence of the largest, chromosome 1, in two contigs of around 14.2 and 14.6 megabases. The contigs extend from the telomeres to the centromeric borders, regions rich in transposons, retrotransposons and repetitive elements such as the 180-base-pair repeat. The chromosome represents 25% of the genome and contains about 6,850 open reading frames, 236 transfer RNAs (tRNAs) and 12 small nuclear RNAs. There are two clusters of tRNA genes at different places on the chromosome. One consists of 27 tRNA(Pro) genes and the other contains 27 tandem repeats of tRNA(Tyr)-tRNA(Tyr)-tRNA(Ser) genes. Chromosome 1 contains about 300 gene families with clustered duplications. There are also many repeat elements, representing 8% of the sequence.

Background The lectin-like oxidized LDL receptor LOX-1 (encoded by OLR1) is believed to play a key role in atherogenesis and some reports suggest an association of OLR1 polymorphisms with myocardial infarction (MI). We tested whether single nucleotide polymorphisms (SNPs) in OLR1 are associated with clinically significant CAD in the Atherosclerotic Disease, VAscular FuNction, & Geneti C Epidemiology (ADVANCE) study. Methods ADVANCE is a population-based case-control study of subjects receiving care within Kaiser Permanente of Northern California including a subset of participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study. We first resequenced the promoter, exonic, and splice site regions of OLR1 and then genotyped four single nucleotide polymorphisms (SNPs), including a non-synonymous SNP (rs11053646, Lys167Asn) as well as an intronic SNP (rs3736232) previously associated with CAD. Results In 1,809 cases with clinical CAD and 1,734 controls, the minor allele of the coding SNP was nominally associated with a lower odds ratio (OR) of CAD across all ethnic groups studied (minimally adjusted OR 0.8, P = 0.007; fully adjusted OR 0.8, P = 0.01). The intronic SNP was nominally associated with an increased risk of CAD (minimally adjusted OR 1.12, p = 0.03; fully adjusted OR 1.13, P = 0.03). However, these associations were not replicated in over 13,200 individuals (including 1,470 cases) in the Atherosclerosis Risk in Communities (ARIC) study. Conclusion Our results do not support the presence of an association between selected common SNPs in OLR1 and the risk of clinical CAD.

Summary Genes underlying repeated adaptive evolution in natural populations are still largely unknown. Stickleback fish ( Gasterosteus aculeatus ) have undergone a recent dramatic evolutionary radiation, generating numerous examples of marine-freshwater species pairs and a small number of benthic-limnetic species pairs found within single lakes [1]. We have developed a new genome-wide SNP genotyping array to study patterns of genetic variation in sticklebacks over a wide geographic range, and to scan the genome for regions that contribute to repeated evolution of marine-freshwater or benthic-limnetic species pairs. Surveying 34 global populations with 1,159 informative markers revealed substantial genetic variation, with predominant patterns reflecting demographic history and geographic structure. After correcting for geographic structure and filtering for neutral markers, we detected large repeated shifts in allele frequency at some loci, identifying both known and novel loci likely contributing to marine-freshwater and benthic-limnetic divergence. Several novel loci fall close to genes implicated in epithelial barrier or immune functions, which have likely changed as sticklebacks adapt to contrasting environments. Specific alleles differentiating sympatric benthic-limnetic species pairs are shared in nearby solitary populations, suggesting an allopatric origin for adaptive variants and selection pressures unrelated to sympatry in the initial formation of these classic vertebrate species pairs.

Pectic fragments of cell wall polysaccharides, released from the walls of suspension-cultured sycamore cells by treatment with endopolygalacturonase, were tested for morphogenesis-regulating activity in a modified tobacco thin-cell-layer explant (TCL) bioassay (D. Mohnen, S. Eberhard, V. Marfa, N. Doubrava, P. Toubart, D. J. Gollin, T.A. Gruber, W. Nuri, P. Albersheim, and A. Darvill, manuscript submitted). The pectic fragments inhibited the formation of roots on TCLs grown on a root-inducing medium containing 15 micromolar indole-3-butyric acid and 0.5 micromolar kinetin. Addition of the pectic fragments to a root-inducing medium containing 7 micromolar indole-3-butyric acid and 0.15 micromolar kinetin caused roots to form on the basal end of TCLs. TCLs cultured on this medium in the absence of added pectic fragments formed roots along their entire length. The pectic fragments induced polar tissue enlargement and the formation of flowers on TCLs cultured on transition medium. The flower-inducing activity was stable to heat treatment and proteolytic digestion. Pectic fragments isolated from the walls of suspension-cultured tobacco cells were as effective as those from the walls of sycamore cells in inducing de novo flower formation in the TCLs. These results support the hypothesis that oligosaccharins from plant cell walls regulate morphogenesis.

Genome-wide SNP analyses reveal the admixed African genetic ancestry of African Americans., Background Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped in 94 Africans of diverse geographic origins included in the HGDP, as well as 136 African Americans and 38 European Americans participating in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. To focus on African ancestry, we reduced the data to include only those genotypes in each African American determined statistically to be African in origin. Results From cluster analysis, we found that all the African Americans are admixed in their African components of ancestry, with the majority contributions being from West and West-Central Africa, and only modest variation in these African-ancestry proportions among individuals. Furthermore, by principal components analysis, we found little evidence of genetic structure within the African component of ancestry in African Americans. Conclusions These results are consistent with historic mating patterns among African Americans that are largely uncorrelated to African ancestral origins, and they cast doubt on the general utility of mtDNA or Y-chromosome markers alone to delineate the full African ancestry of African Americans. Our results also indicate that the genetic architecture of African Americans is distinct from that of Africans, and that the greatest source of potential genetic stratification bias in case-control studies of African Americans derives from the proportion of European ancestry.