Computing power of quantitative trait locus association mapping for haploid loci

<p>Abstract</p> <p>Background</p> <p>Statistical power calculations are a critical part of any study design for gene mapping. Most calculations assume that the locus of interest is biallelic. However, there are common situations in human genetics such as X-linked loci in males where the locus is haploid. The purpose of this work is to mathematically derive the biometric model for haploid loci, and to compute power for QTL mapping when the loci are haploid.</p> <p>Results</p> <p>We have derived the biometric model for power calculations for haploid loci and have developed software to perform these calculations. We have verified our calculations with independent mathematical methods.</p> <p>Conclusion</p> <p>Our results fill a need in power calculations for QTL mapping studies. Furthermore, failure to appropriately model haploid loci may cause underestimation of power.</p

ATLASGAL - properties of compact H II regions and their natal clumps

We present a complete sample of molecular clumps containing compact and ultracompact HII (UC HII) regions between ℓ = 10° and 60° and |b| < 1°, identified by combining the APEX Telescope Large Area Survey ofthe Galaxy submm and CORNISH radio continuum surveys with visual examination ofarchival infrared data. Our sample is complete to optically thin, compact and UC HII regions driven by a zero-age main-sequence star of spectral type B0 or earlier embedded within a 1000M clump. In total we identify 213 compact and UC HII regions, associated with 170 clumps. Unambiguous kinematic distances are derived for these clumps and used to estimate their masses and physical sizes, as well as the Lyman continuum fluxes and sizes of their embedded HII regions. We find a clear lower envelope for the surface density of molecular clumps hosting massive star formation of 0.05 g cm, which is consistent with a similar sample of clumps associated with 6.7 GHz masers. The mass of the most massive embedded starsis closely correlated with the mass of their natal clump. Young B stars appearto be significantly more luminous in the ultraviolet than predicted by current stellar atmosphere models. The properties of clumps associated with compact and UC HII regions are very similar to those associated with 6.7 GHz methanol masers and we speculate that there is little evolution in the structure of the molecular clumps between these two phases. Finally, we identifya significant peak in the surface density of compact and UC HII-regions associated with the W49A star-forming complex, noting that this complex is truly one of the most massive and intense regions of star formation in the Galaxy. © 2013 The Authors, Published by Oxford University Press on behalf of the Royal Astronomical Society

Antagonistic genetic correlations for milking traits within the genome of dairy cattle

Genome-wide association studies can be applied to identify useful SNPs associated with complex traits. Furthermore, regional genomic mapping can be used to estimate regional variance and clarify the genomic relationships within and outside regions but has not previously been applied to milk traits in cattle. We applied both single SNP analysis and regional genomic mapping to investigate SNPs or regions associated with milk yield traits in dairy cattle. The de-regressed breeding values of three traits, total yield (kg) of milk (MLK), fat (FAT), and protein (PRT) in 305 days, from 2,590 Holstein sires in Japan were analyzed. All sires were genotyped with 40,646 single-nucleotide polymorphism (SNP) markers. A genome-wide significant region (P < 0.01) common to all three traits was identified by regional genomic mapping on chromosome (BTA) 14. In contrast, single SNP analysis identified significant SNPs only for MLK and FAT (P < 0.01), but not PRT in the same region. Regional genomic mapping revealed an additional significant region (P < 0.01) for FAT on BTA5 that was not identified by single SNP analysis. The additive whole-genomic effects estimated in the regional genomic mapping analysis for the three traits were positively correlated with one another (0.830-0.924). However, the regional genomic effects obtained by using a window size of 20 SNPs for FAT on BTA14 were negatively correlated (P < 0.01) with the regional genomic effect for MLK (-0.940) and PRT (-0.878). The BTA14 regional effect for FAT also showed significant negative correlations (P < 0.01) with the whole genomic effects for MLK (-0.153), FAT (-0.172), and PRT (-0.181). These negative genomic correlations between loci are consistent with the negative linkage disequilibrium expected for traits under directional selection. Such antagonistic correlations may hamper the fixation of the FAT increasing alleles on BTA14. In summary, regional genomic mapping found more regions associated with milk production traits than did single SNP analysis. In addition, the existence of non-zero covariances between regional and whole genomic effects may influence the detection of regional effects, and antagonistic correlations could hamper the fixation of major genes under intensive selection

Common Polymorphisms Influencing Serum Uric Acid Levels Contribute to Susceptibility to Gout, but Not to Coronary Artery Disease

BACKGROUND:Recently, a large meta-analysis including over 28,000 participants identified nine different loci with association to serum uric acid (UA) levels. Since elevated serum UA levels potentially cause gout and are a possible risk factor for coronary artery disease (CAD) and myocardial infarction (MI), we performed two large case-control association analyses with participants from the German MI Family Study. In the first study, we assessed the association of the qualitative trait gout and ten single nucleotide polymorphisms (SNP) markers that showed association to UA serum levels. In the second study, the same genetic polymorphisms were analyzed for association with CAD. METHODS AND FINDINGS:A total of 683 patients suffering from gout and 1,563 healthy controls from the German MI Family Study were genotyped. Nine SNPs were identified from a recently performed genome-wide meta-analysis on serum UA levels (rs12129861, rs780094, rs734553, rs2231142, rs742132, rs1183201, rs12356193, rs17300741 and rs505802). Additionally, the marker rs6855911 was included which has been associated with gout in our cohort in a previous study. SNPs rs734553 and rs6855911, located in SLC2A9, and SNP rs2231142, known to be a missense polymorphism in ABCG2, were associated with gout (p=5.6*10(-7), p=1.1*10(-7), and p=1.3*10(-3), respectively). Other SNPs in the genes PDZK1, GCKR, LRRC16A, SLC17A1-SLC17A3, SLC16A9, SLC22A11 and SLC22A12 failed the significance level. None of the ten markers were associated with risk to CAD in our study sample of 1,473 CAD cases and 1,241 CAD-free controls. CONCLUSION:SNP markers in SLC2A9 and ABCG2 genes were found to be strongly associated with the phenotype gout. However, not all SNP markers influencing serum UA levels were also directly associated with the clinical manifestation of gout in our study sample. In addition, none of these SNPs showed association with the risk to CAD in the German MI Family Study

The impact of genetic relationship information on genomic breeding values in German Holstein cattle

<p>Abstract</p> <p>Background</p> <p>The impact of additive-genetic relationships captured by single nucleotide polymorphisms (SNPs) on the accuracy of genomic breeding values (GEBVs) has been demonstrated, but recent studies on data obtained from Holstein populations have ignored this fact. However, this impact and the accuracy of GEBVs due to linkage disequilibrium (LD), which is fairly persistent over generations, must be known to implement future breeding programs.</p> <p>Materials and methods</p> <p>The data set used to investigate these questions consisted of 3,863 German Holstein bulls genotyped for 54,001 SNPs, their pedigree and daughter yield deviations for milk yield, fat yield, protein yield and somatic cell score. A cross-validation methodology was applied, where the maximum additive-genetic relationship (<it>a</it>_<it>max</it>) between bulls in training and validation was controlled. GEBVs were estimated by a Bayesian model averaging approach (BayesB) and an animal model using the genomic relationship matrix (G-BLUP). The accuracy of GEBVs due to LD was estimated by a regression approach using accuracy of GEBVs and accuracy of pedigree-based BLUP-EBVs.</p> <p>Results</p> <p>Accuracy of GEBVs obtained by both BayesB and G-BLUP decreased with decreasing <it>a</it>_{<it>max </it>}for all traits analyzed. The decay of accuracy tended to be larger for G-BLUP and with smaller training size. Differences between BayesB and G-BLUP became evident for the accuracy due to LD, where BayesB clearly outperformed G-BLUP with increasing training size.</p> <p>Conclusions</p> <p>GEBV accuracy of current selection candidates varies due to different additive-genetic relationships relative to the training data. Accuracy of future candidates can be lower than reported in previous studies because information from close relatives will not be available when selection on GEBVs is applied. A Bayesian model averaging approach exploits LD information considerably better than G-BLUP and thus is the most promising method. Cross-validations should account for family structure in the data to allow for long-lasting genomic based breeding plans in animal and plant breeding.</p

Association of Common Polymorphisms in GLUT9 Gene with Gout but Not with Coronary Artery Disease in a Large Case-Control Study

BACKGROUND: Serum uric acid (UA) levels have recently been shown to be genetically influenced by common polymorphisms in the GLUT9 gene in two genome-wide association analyses of Italian and British populations. Elevated serum UA levels are often found in conjunction with the metabolic syndrome. Hyperuricemia is the major risk factor for gout and has been associated with increased cardiovascular morbidity and mortality. The aim of the present study was to further elucidate the association of polymorphisms in GLUT9 with gout and coronary artery disease (CAD) or myocardial infarction (MI). To test our hypotheses, we performed two large case-control association analyses of individuals from the German MI Family Study. METHODS AND FINDINGS: First, 665 patients with gout and 665 healthy controls, which were carefully matched for age and gender, were genotyped for four single nucleotide polymorphisms (SNPs) within or near the GLUT9 gene. All four SNPs demonstrated highly significant association with gout. SNP rs6855911, located within intron 7 of GLUT9, showed the strongest signal with a protective effect of the minor allele with an allelic odds ratio of 0.62 (95% confidence interval 0.52-0.75; p = 3.2*10(-7)). Importantly, this finding was not influenced by adjustment for components of the metabolic syndrome or intake of diuretics. Secondly, 1,473 cases with severe CAD or MI and 1,241 healthy controls were tested for the same four GLUT9 SNPs. The analyses revealed, however, no significant association with CAD or with MI. Additional screening of genome-wide association data sets showed no signal for CAD or MI within the GLUT9 gene region. CONCLUSION: Thus, our results provide compelling evidence that common genetic variations within the GLUT9 gene strongly influence the risk for gout but are unlikely to have a major effect on CAD or MI in a German population

A Genome-Wide SNP Scan Reveals Novel Loci for Egg Production and Quality Traits in White Leghorn and Brown-Egg Dwarf Layers

Availability of the complete genome sequence as well as high-density SNP genotyping platforms allows genome-wide association studies (GWAS) in chickens. A high-density SNP array containing 57,636 markers was employed herein to identify associated variants underlying egg production and quality traits within two lines of chickens, i.e., White Leghorn and brown-egg dwarf layers. For each individual, age at first egg (AFE), first egg weight (FEW), and number of eggs (EN) from 21 to 56 weeks of age were recorded, and egg quality traits including egg weight (EW), eggshell weight (ESW), yolk weight (YW), eggshell thickness (EST), eggshell strength (ESS), albumen height(AH) and Haugh unit(HU) were measured at 40 and 60 weeks of age. A total of 385 White Leghorn females and 361 brown-egg dwarf dams were selected to be genotyped. The genome-wide scan revealed 8 SNPs showing genome-wise significant (P<1.51E-06, Bonferroni correction) association with egg production and quality traits under the Fisher's combined probability method. Some significant SNPs are located in known genes including GRB14 and GALNT1 that can impact development and function of ovary, but more are located in genes with unclear functions in layers, and need to be studied further. Many chromosome-wise significant SNPs were also detected in this study and some of them are located in previously reported QTL regions. Most of loci detected in this study are novel and the follow-up replication studies may be needed to further confirm the functional significance for these newly identified SNPs

Adenylyl Cyclase α and cAMP Signaling Mediate Plasmodium Sporozoite Apical Regulated Exocytosis and Hepatocyte Infection

Malaria starts with the infection of the liver of the host by Plasmodium sporozoites, the parasite form transmitted by infected mosquitoes. Sporozoites migrate through several hepatocytes by breaching their plasma membranes before finally infecting one with the formation of an internalization vacuole. Migration through host cells induces apical regulated exocytosis in sporozoites. Here we show that apical regulated exocytosis is induced by increases in cAMP in sporozoites of rodent (P. yoelii and P. berghei) and human (P. falciparum) Plasmodium species. We have generated P. berghei parasites deficient in adenylyl cyclase α (ACα), a gene containing regions with high homology to adenylyl cyclases. PbACα-deficient sporozoites do not exocytose in response to migration through host cells and present more than 50% impaired hepatocyte infectivity in vivo. These effects are specific to ACα, as re-introduction of ACα in deficient parasites resulted in complete recovery of exocytosis and infection. Our findings indicate that ACα and increases in cAMP levels are required for sporozoite apical regulated exocytosis, which is involved in sporozoite infection of hepatocytes