Revisiting genetic structuring in spotted gums (genus Corymbia section Maculatae) focusing on C. maculata, an early diverged, insular lineage

Species delineation in the spotted gum complex was revisited focusing on Corymbia maculata. This study expands the range of C. maculata analysed with microsatellite markers to include populations from the north of the species range. It supported earlier findings that it is a cohesive genetic entity, well resolved from northern spotted gum taxa, Corymbia citriodora and Corymbia henryi; and inferences that its insularity is due to early lineage divergence and historical isolation. The northern extent of C. maculata sampled, as defined by chloroplast and nuclear genomes predominantly of C. maculata character, was the location of Kiwarrak, south of the Manning River near Taree in New South Wales. Trees from a recognised intergrade zone at the Yarratt locality, around 26 km north of Kiwarrak, also possessed a uniquely C. maculata chloroplast haplotype, but their nuclear genomes were predominantly of northern taxa ancestry. Range expansion of northern taxa leading to southerly gene movement into populations formerly C. maculata, would account for this apparent instance of chloroplast capture. Two subpopulations were identified in C. maculata, a northern population of which the Ourimbah locality was the most southerly studied, and a southern population of which Wingello was the most northerly locality studied. Diminished levels of northern taxa ancestry, i.e. C. citriodora or C. henryi, in individuals from the southern, relative to the northern subpopulation of C. maculata, suggested that secondary contact with northern taxa contributes to its substructure.

'Mutiny on the Bounty': The genetic history of Norfolk Island reveals extreme gender-biased admixture

Background The Pacific Oceania region was one of the last regions of the world to be settled via human migration. Here we outline a settlement of this region that has given rise to a uniquely admixed population. The current Norfolk Island population has arisen from a small number of founders with mixed Caucasian and Polynesian ancestry, descendants of a famous historical event. The ‘Mutiny on the Bounty’ has been told in history books, songs and the big screen, but recently this story can be portrayed through comprehensive molecular genetics. Written history details betrayal and murder leading to the founding of Pitcairn Island by European mutineers and the Polynesian women who left Tahiti with them. Investigation of detailed genealogical records supports historical accounts. Findings Using genetics, we show distinct maternal Polynesian mitochondrial lineages in the present day population, as well as a European centric Y-chromosome phylogeny. These results comprehensively characterise the unique gender-biased admixture of this genetic isolate and further support the historical records relating to Norfolk Island. Conclusions Our results significantly refine previous population genetic studies investigating Polynesian versus Caucasian diversity in the Norfolk Island population and add information that is beneficial to future disease and gene mapping studies.

The Expanded mtDNA Phylogeny of the Franco-Cantabrian Region Upholds the Pre-Neolithic Genetic Substrate of Basques

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Population genetic structure of Carchesium polypinum (Ciliophora : Peritrichia) in four chinese lakes inferred from ISSR fingerprinting: High diversity but low differentiation

Although the peritrichous ciliate Carchesium polypinum is common in freshwater, its population genetic structure is largely unknown. We used inter-simple sequence repeat (ISSR) fingerprinting to analyze the genetic structure of 48 different isolates of the species from four lakes in Wuhan, central China. Using eight polymorphic primers, 81 discernible DNA fragments were detected, among which 76 (93.83%) were polymorphic, indicating high genetic diversity at the isolate level. Further, Nei's gene diversity (h) and Shannon's Information index (I) between the different isolates both revealed a remarkable genetic diversity, higher than previously indicated by their morphology. At the same time, substantial gene flow was found. So the main factors responsible for the high level of diversity within populations are probably due to conjugation (sexual reproduction) and wide distribution of swarmers. Analysis of molecular variance (AMOVA) showed that there was low genetic differentiation among the four populations probably due to common ancestry and flooding events. The cluster analysis and principal component analysis (PCA) suggested that genotypes isolated from the same lake displayed a higher genetic similarity than those from different lakes. Both analyses separated C. polypinum isolates into subgroups according to the geographical locations. However, there is only a weak positive correlation between the genetic distance and geographical distance, suggesting a minor effect of geographical distance on the distribution of genetic diversity between populations of C. polypinum at the local level. In conclusion, our studies clearly demonstrated that a single morphospecies may harbor high levels of genetic diversity, and that the degree of resolution offered by morphology as a marker for measuring distribution patterns of genetically distinct entities is too low.

Genetic variants in IGF-I, IGF-II, IGFBP-3, and adiponectin genes and colon cancer risk in African Americans and Whites.

PURPOSE: Evaluating genetic susceptibility may clarify effects of known environmental factors and also identify individuals at high risk. We evaluated the association of four insulin-related pathway gene polymorphisms in insulin-like growth factor-1 (IGF-I) (CA)( n ) repeat, insulin-like growth factor-2 (IGF-II) (rs680), insulin-like growth factor-binding protein-3 (IGFBP-3) (rs2854744), and adiponectin (APM1 rs1501299) with colon cancer risk, as well as relationships with circulating IGF-I, IGF-II, IGFBP-3, and C-peptide in a population-based study. METHODS: Participants were African Americans (231 cases and 306 controls) and Whites (297 cases, 530 controls). Consenting subjects provided blood specimens and lifestyle/diet information. Genotyping for all genes except IGF-I was performed by the 5'-exonuclease (Taqman) assay. The IGF-I (CA)(n) repeat was assayed by PCR and fragment analysis. Circulating proteins were measured by enzyme immunoassays. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated by logistic regression. RESULTS: The IGF-I (CA)( 19 ) repeat was higher in White controls (50 %) than African American controls (31 %). Whites homozygous for the IGF-I (CA)(19) repeat had a nearly twofold increase in risk of colon cancer (OR = 1.77; 95 % CI = 1.15-2.73), but not African Americans (OR = 0.73, 95 % CI 0.50-1.51). We observed an inverse association between the IGF-II Apa1 A-variant and colon cancer risk (OR = 0.49, 95 % CI 0.28-0.88) in Whites only. Carrying the IGFBP-3 variant alleles was associated with lower IGFBP-3 protein levels, a difference most pronounced in Whites (p-trend <0.05). CONCLUSIONS: These results support an association between insulin pathway-related genes and elevated colon cancer risk in Whites but not in African Americans.

Genetic susceptibility to invasive meningococcal disease: MBL2 structural polymorphisms revisited in a large case–control study and a systematic review

Invasive infection caused by Neisseria meningitidis is a worldwide public health problem. Previous reports have indicated that carriage of common ‘defective’ structural polymorphisms of the host mannose-binding lectin gene (MBL2) greatly increases an individual’s risk of developing the disease. We report the largest case–control study so far to investigate the effect of these polymorphisms in meningococcal disease (296 PCR-positive cases and 5196 population controls, all of European ancestry) and demonstrate that no change in risk is associated with the polymorphisms overall or in any age-defined subgroup. This finding contrasts with two smaller studies that reported an increase in risk. A systematic review of all studies of MBL2 polymorphisms in people of European ancestry published since 1999, including 24 693 individuals, revealed a population frequency of the combined ‘defective’MBL2 allele of 0.230 (95% confidence limits: 0.226–0.234). The past reported associations of increased risk of meningococcal disease were because of low ‘defective’ allele frequencies in their study control populations (0.13 and 0.04) that indicate systematic problems with the studies. The data from our study and all other available evidence indicate that MBL2 structural polymorphisms do not predispose children or adults to invasive meningococcal disease.

Genetic susceptibility to invasive meningococcal disease: MBL2 structural polymorphisms revisited in a large case-control study and a systematic review.

AbstractInvasive infection caused by Neisseria meningitidis is a worldwide public health problem. Previous reports have indicated that carriage of common 'defective' structural polymorphisms of the host mannose-binding lectin gene (MBL2) greatly increases an individual's risk of developing the disease. We report the largest case-control study so far to investigate the effect of these polymorphisms in meningococcal disease (296 PCR-positive cases and 5196 population controls, all of European ancestry) and demonstrate that no change in risk is associated with the polymorphisms overall or in any age-defined subgroup. This finding contrasts with two smaller studies that reported an increase in risk. A systematic review of all studies of MBL2 polymorphisms in people of European ancestry published since 1999, including 24 693 individuals, revealed a population frequency of the combined 'defective'MBL2 allele of 0.230 (95% confidence limits: 0.226-0.234). The past reported associations of increased risk of meningococcal disease were because of low 'defective' allele frequencies in their study control populations (0.13 and 0.04) that indicate systematic problems with the studies. The data from our study and all other available evidence indicate that MBL2 structural polymorphisms do not predispose children or adults to invasive meningococcal disease.

Genome-wide association study to identify genetic determinants of severe asthma

BACKGROUND: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. OBJECTIVE: To identify common genetic variants affecting susceptibility to severe asthma. METHODS: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480?889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. RESULTS: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10((-8)) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10((-8)) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. CONCLUSIONS: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

Using ancestry-informative markers to identify fine structure across 15 populations of European origin

The Wellcome Trust Case Control Consortium 3 anorexia nervosa genome-wide association scan includes 2907 cases from 15 different populations of European origin genotyped on the Illumina 670K chip. We compared methods for identifying population stratification, and suggest list of markers that may help to counter this problem. It is usual to identify population structure in such studies using only common variants with minor allele frequency (MAF) >5%; we find that this may result in highly informative SNPs being discarded, and suggest that instead all SNPs with MAF >1% may be used. We established informative axes of variation identified via principal component analysis and highlight important features of the genetic structure of diverse European-descent populations, some studied for the first time at this scale. Finally, we investigated the substructure within each of these 15 populations and identified SNPs that help capture hidden stratification. This work can provide information regarding the designing and interpretation of association results in the International Consortia. 

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Immunochip SNP array identifies novel genetic variants conferring susceptibility to candidaemia.

Candidaemia is the fourth most common cause of bloodstream infection, with a high mortality rate of up to 40%. Identification of host genetic factors that confer susceptibility to candidaemia may aid in designing adjunctive immunotherapeutic strategies. Here we hypothesize that variation in immune genes may predispose to candidaemia. We analyse 118,989 single-nucleotide polymorphisms (SNPs) across 186 loci known to be associated with immune-mediated diseases in the largest candidaemia cohort to date of 217 patients of European ancestry and a group of 11,920 controls. We validate the significant associations by comparison with a disease-matched control group. We observe significant association between candidaemia and SNPs in the CD58 (P = 1.97 × 10(-11); odds ratio (OR) = 4.68), LCE4A-C1orf68 (P = 1.98 × 10(-10); OR = 4.25) and TAGAP (P = 1.84 × 10(-8); OR = 2.96) loci. Individuals carrying two or more risk alleles have an increased risk for candidaemia of 19.4-fold compared with individuals carrying no risk allele. We identify three novel genetic risk factors for candidaemia, which we subsequently validate for their role in antifungal host defence.

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies.

Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant. Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

Genetic variants influencing circulating lipid levels and risk of coronary artery disease.

OBJECTIVE: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)). CONCLUSIONS: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

Genetic relatedness of Plasmodium falciparum isolates and the origin of allelic diversity at the merozoite surface protein-1 (MSP-1) locus in Brazil and Vietnam

Background: Despite the extensive polymorphism at the merozoite surface protein-1 (MSP-1) locus of Plasmodium falciparum, that encodes a major repetitive malaria vaccine candidate antigen, identical and nearly identical alleles frequently occur in sympatric parasites. Here we used microsatellite haplotyping to estimate the genetic distance between isolates carrying identical and nearly identical MSP-1 alleles. Methods: We analyzed 28 isolates from hypoendemic areas in north-western Brazil, collected between 1985 and 1998, and 23 isolates obtained in mesoendemic southern Vietnam in 1996. MSP-1 alleles were characterized by combining PCR typing with allele-specific primers and partial DNA sequencing. The following single-copy microsatellite markers were typed: Polyα, TA42 (only for Brazilian samples), TA81, TA1, TA87, TA109 (only for Brazilian samples), 2490, ARAII, PfG377, PfPK2, and TA60. Results: The low pair-wise average genetic distance between microsatellite haplotypes of isolates sharing identical MSP-1 alleles indicates that epidemic propagation of discrete parasite clones originated most identical MSP-1 alleles in parasite populations from Brazil and Vietnam. At least one epidemic clone propagating in Brazil remained relatively unchanged over more than one decade. Moreover, we found no evidence that rearrangements of MSP-1 repeats, putatively created by mitotic recombination events, generated new alleles within clonal lineages of parasites in either country. Conclusion: Identical MSP-1 alleles originated from co-ancestry in both populations, whereas nearly identical MSP-1 alleles have probably appeared independently in unrelated parasite lineages.