Inclusive fitness theory and eusociality.

Arising from M. A. Nowak, C. E. Tarnita & E. O. Wilson 466, 1057-1062 (2010); Nowak et al. reply. Nowak et al. argue that inclusive fitness theory has been of little value in explaining the natural world, and that it has led to negligible progress in explaining the evolution of eusociality. However, we believe that their arguments are based upon a misunderstanding of evolutionary theory and a misrepresentation of the empirical literature. We will focus our comments on three general issues.

Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations.

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

Emergence of secretion-defective sublines of Pseudomonas aeruginosa PAO1 resulting from spontaneous mutations in the vfr global regulatory gene.

Pseudomonas aeruginosa undergoes spontaneous mutation that impairs secretion of several extracellular enzymes during extended cultivation in vitro in rich media, as well as during long-term colonization of the cystic fibrosis lung. A frequent type of strong secretion deficiency is caused by inactivation of the quorum-sensing regulatory gene lasR. Here we analyzed a spontaneously emerging subline of strain PAO1 that exhibited moderate secretion deficiency and partial loss of quorum-sensing control. Using generalized transduction, we mapped the secretion defect to the vfr gene, which is known to control positively the expression of the lasR gene and type II secretion of several proteases. We confirmed this secretion defect by sequencing and complementation of the vfr mutation. In a reconstruction experiment conducted with a 1:1 mixture of wild-type strain PAO1 and a vfr mutant of PAO1, we observed that the vfr mutant had a selective advantage over the wild type after growth in static culture for 4 days. Under these conditions, spontaneous vfr emerged in a strain PAO1 population after four growth cycles, and these mutants accounted for more than 40% of the population after seven cycles. These results suggest that partial or complete loss of quorum sensing and secretion can be beneficial to P. aeruginosa under certain environmental conditions.

Dissimilaridade de porta-enxertos da laranjeira 'folha murcha' sob dois sistemas de manejo de cobertura permanente do solo

Os porta-enxertos de citros são dependentes do sistema de manejo do solo nas entrelinhas. Este trabalho foi realizado com o objetivo de identificar a dissimilaridade de sete porta-enxertos para a laranjeira 'Folha Murcha' em dois sistemas de manejo da cobertura de um Argissolo Vermelho distrófico latossólico. O estudo foi realizado na Estação Experimental do IAPAR, em Paranavaí. O delineamento experimental foi de blocos ao acaso com quatro repetições, com gramínea mato-grosso ou batatais (Paspalum notatum Flügge) em três blocos e leguminosa amendoim forrageiro (Arachis pintoi Krap. & Greg.) em um bloco. A produção, o desenvolvimento vegetativo e os nutrientes nas folhas da laranjeira 'Folha Murcha' foram avaliados anualmente (1997 a 2002). As análises multivariadas basearam-se nas variáveis canônicas e nos componentes principais, agrupando-os pelo método Tocher. O manejo da cobertura do solo com a leguminosa amendoim forrageiro Arachis pintoi diminui a dissimilaridade dos grupos de porta-enxertos da laranjeira 'Folha Murcha'. O manejo da cobertura do solo com a gramínea Paspalum notatum aumenta a dissimilaridade dos grupos de porta-enxertos da laranjeira 'Folha Murcha' com a inclusão dos teores dos nutrientes foliares, da produção de frutos e do desenvolvimento vegetativo das plantas. A gramínea Paspalum notatum é o melhor sistema de manejo da cobertura do solo para avaliação do comportamento de porta-enxertos da laranjeira 'Folha Murcha'.

Genetic Variants of Serum Uric Acid and Gout: An Analysis of > 170,000 Individuals

Background/Purpose: Gout is a common and excruciatingly painful inflammatory arthritis caused by hyperuricemia. In addition to various lifestyle risk factors, a substantial genetic predisposition to gout has long been recognized. The Global Urate Genetics Consortium (GUGC) has aimed to comprehensively investigate the genetics of serum uric acid and gout using data from _ 140,000 individuals of European-ancestry, 8,340 individuals of Indian ancestry, 5,820 African-Americans, and 15,286 Japanese. Methods: We performed discovery GWAS meta-analyses of serum urate levels (n_110,347 individuals) followed by replication analyses (n_32,813 different individuals). Our gout analysis involved 3,151 cases and 68,350 controls, including 1,036 incident gout cases that met the American College of Rheumatology Criteria. We also examined the association of gout with fractional excretion of uric acid (n_6,799). A weighted genetic urate score was constructed based on the number of risk alleles across urate-associated loci, and their association with the risk of gout was evaluated. Furthermore, we examined implicated transcript expression in cis (expression quantitative trait loci databases) for potential insights into the gene underlying the association signal. Finally, in order to further identify urate-associated genomic regions, we performed functional network analyses that incorporated prior knowledge on molecular interactions in which the gene products of implicated genes operate. Results: We identified and replicated 28 genome-wide significant loci in association with serum urate (P 5_10_8), including all previously-reported loci as well as 18 novel genetic loci. Unlike the majority of previouslyidentified loci, none of the novel loci appeared to be obvious candidates for urate transport. Rather, they were mapped to genes that encode for purine production, transcription, or growth factors with broad downstream responses. Besides SLC2A9 and ABCG2, no additional regions contained SNPs that differed significantly (P _ 5_10_8) between sexes. Urateincreasing alleles were associated with an increased risk of gout for all loci. The urate genetic risk score (ranging from 10 to 45) was significantly associated with an increased odds of prevalent gout (OR per unit increase, 1.11; 95% CI, 1.09-1.14) and incident gout (OR, 1.10; 95% CI, 1.08-1.13). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. Detailed characterization of the loci revealed associations with transcript expression and the fractional excretion of urate. Network analyses implicated the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. Conclusion: The novel genetic candidates identified in this urate/gout consortium study, the largest to date, highlight the importance of metabolic control of urate production and urate excretion. The modulation by signaling processes that influence metabolic pathways such as glycolysis and the pentose phosphate pathway appear to be central mechanisms underpinned by the novel GWAS candidates. These findings may have implications for further research into urate-lowering drugs to treat and prevent gout.

Choice of outcome measures in postprandial trials

Comment on: Heinrich H, Goetze O, Menne D, Iten PX, Fruehauf H, Vavricka SR, Schwizer W, Fried M, Fox M. Effect on gastric function and symptoms of drinking wine, black tea, or schnapps with a Swiss cheese fondue: randomised controlled crossover trial. BMJ. 2010 Dec 14;341:c6731. doi: 10.1136/bmj.c6731. PMID 21156747.

Anàlisi multivariada craniomètrica de les poblacions catalano-balears del passat

S'ha portat a terme una analisi estadística de les dades craniometriques de les principals poblacions catalano-balears del passat, des de J'Edat del Bronze fins a l'Edat Mitjana, i posteriorment s'han integrat les poblacions en un context peninsular més ampli. S'han analitzalles relacions entre poblacions per mitja d'un analisi d'agrupament (cluster), emprant els algoritmes UPGMA i del "veí més proper" i la distancia euclídea al quadrat. Així mateix, s'ha realitzat un re-mostreig (bootstrap) per comprovar la robustes de les agrupacions obtingudes i un test de Mantel per comprovar el grau de concordan~a entre les poblacions femenines i masculines. Els resultats mostren que, a nivell peninsular, els Bascos són la població més diferenciada de la resta des d'un punt de vista morfologic, la qual cosa pot estar relacionada amb una major antiguitat d'aquesta població, potser present des de temps pre-neolítics. La segona font de variació peninsular la constitueixen dues poblacions amb possibles influencies foranies d'origen africa: jueus i musulmans. La resta de poblacions, incloent-hi les de Mallorca, són notablement homogenies a pesar de la seva heterogene'itat cultural, temporal i geogràtfica. Finalment, es conclou que no hi ha cap analisi estadística que objectivament recolzi I'existencia deIs tipus racials tradicionalmcnt descrits a la Península Iberica, i que responen a una visió tipologica i estatica de la diversitat humana.

Les restes humanes del jaciment epipaleolític de la Balma de Guilanyà (Navés, Solsonès)

Les restes humanes deIs períodes epipaleolític i mesolític estan pobrament representades a la Península Iberica, tot i que existeixen dos jaciments mesolítics excepcional s a Muge, Portugal (Moita do Sebastiao i Cabe~o da Arruda), amb uns 67 individus, i un altre de recentment excavat a Oliva (El Collado, Valencia), on s'han trobat uns 15 individus. EIs primers estan datats entre 7.240 i 6.300 a.P. (Ferreira 1994: 664-674), mentre que el darrer té una datació de 7.640-7.570 a.P (Aparicio 1989). Ambdós jaciments es troben en zones properes a estuaris de rius o a la costa, la qual cosa permetia 1'explotació intensiva de recursos marins molt variats. Aquest tipus d' economia condicionava un tipus de vida força sedentaria i a més a més, va permetre un increment en la densitat de població, que hauria tingut lloc probablement entre el 8.000-7.000 a.e. (Ferreira 1994: 664-674). A Catalunya, s'han excavat fins ara pocs jaciments importants d'aquests periodes (Martín y Vaquer 1995: 35-73), tots d'ells en zones d'interior i corresponents presumiblement a grups petits de caçadors-recol·lectors, força diferents dels posteriors assentaments humans més grans com Muge i Oliva. De tots aquests jaciments, només a la Balma de Guilanya (Naves, Solsones) s'han trobat restes humanes que es puguin atribuir sense cap mena de dubte als nivells epipaleolítics.

Targeted nasal vaccination provides antibody-independent protection against Staphylococcus aureus.

Despite showing promise in preclinical models, anti-Staphylococcus aureus vaccines have failed in clinical trials. To date, approaches have focused on neutralizing/opsonizing antibodies; however, vaccines exclusively inducing cellular immunity have not been studied to formally test whether a cellular-only response can protect against infection. We demonstrate that nasal vaccination with targeted nanoparticles loaded with Staphylococcus aureus antigen protects against acute systemic S. aureus infection in the absence of any antigen-specific antibodies. These findings can help inform future developments in staphylococcal vaccine development and studies into the requirements for protective immunity against S. aureus.

Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

Alterações nos atributos físicos de um latossolo vermelho sob plantio direto induzidas por diferentes tipos de escarificadores e o rendimento da soja

A compactação do solo, quando em níveis elevados, é um processo de difícil reversão sob sistema de plantio direto (SPD), especialmente em solos argilosos. Geralmente, a sua ocorrência em áreas comerciais de grãos é descontínua e restrita a áreas com histórico de pressões associadas ao trânsito intenso de máquinas agrícolas. O objetivo deste trabalho foi investigar as alterações nos atributos físicos de um Latossolo Vermelho distrófico de textura argilosa (450 g kg-1) promovidas por dois tipos de escarificações sítio-específico e uma convencional (aleatória), bem como seus efeitos sobre o rendimento da soja. Para isso, selecionou-se no município de Victor Graeff, na região do planalto do RS, uma lavoura de 50,6 ha manejada sob SPD por longo prazo e, recentemente, com agricultura de precisão. O clima local é subtropical Cfa, com precipitação pluvial anual oscilando entre 1.500 e 1.750 mm, temperatura média de 20 ºC e altitude de 490 m. Com base nos mapas de rendimento de três safras anteriores, a área foi subdividida em três zonas de potencial produtivo. Na zona de baixo rendimento (ZB) foram implantados os seguintes tratamentos: (a) escarificação convencional com profundidade fixa de 0,30 m (EC); (b) escarificação sítio-específico com equipamento Fox® com profundidade fixa de 0,30 m (ESEF); (c) escarificação sítio-específico com equipamento Fox® com profundidade de atuação variável (0,10 a 0,30 m), em função da resistência máxima do solo à penetração (ESEV); e (d) controle sem escarificação (SE). A zona de alto rendimento (ZA) foi usada como referência para avaliar o efeito dos tratamentos no rendimento de grãos. Os tratamentos foram implantados em faixas paralelas de 100 x 20 m, seguindo o delineamento de blocos casualizados. Avaliaram-se, em três épocas, a densidade do solo, macroporosidade, microporosidade e porosidade total nas profundidades de 0,0-0,05, 0,05-0,10, 0,10-0,15 e 0,15-0,20 m, bem como a infiltração de água no solo. Os resultados da caracterização inicial dos atributos do solo por zona de rendimento evidenciaram maior densidade do solo e menor porosidade total, na profundidade de 0,15-0,20 m, na ZB em relação à ZA. Em todos os tratamentos com escarificação mecânica, observou-se, logo após o preparo, incremento da infiltração de água em relação ao SE, que aumentou em torno de quatro vezes nos tratamentos EC e ESEV em comparação a esse controle. No entanto, o efeito da escarificação, independentemente do tipo de escarificador, foi efêmero; transcorridos sete meses, verificou-se decréscimo na infiltração de água no solo, que não diferiu do tratamento controle. Entre os escarificadores investigados, o ESEV destacou-se pela manutenção da cobertura do solo em relação ao EC e proporcionou maior rendimento de soja. Contudo, sob condições de elevada precipitação pluvial não foi observado incremento no rendimento da soja nos tratamentos com escarificação mecânica, em relação ao tratamento controle (SE).

Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

Common variants in mendelian kidney disease genes and their association with renal function.

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

Hundreds of variants clustered in genomic loci and biological pathways affect human height.

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.