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.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

The conservation status of the world’s reptiles

Effective and targeted conservation action requires detailed information about species, their distribution, systematics and ecology as well as the distribution of threat processes which affect them. Knowledge of reptilian diversity remains surprisingly disparate, and innovative means of gaining rapid insight into the status of reptiles are needed in order to highlight urgent conservation cases and inform environmental policy with appropriate biodiversity information in a timely manner. We present the first ever global analysis of extinction risk in reptiles, based on a random representative sample of 1500 species (16% of all currently known species). To our knowledge, our results provide the first analysis of the global conservation status and distribution patterns of reptiles and the threats affecting them, highlighting conservation priorities and knowledge gaps which need to be addressed urgently to ensure the continued survival of the world’s reptiles. Nearly one in five reptilian species are threatened with extinction, with another one in five species classed as Data Deficient. The proportion of threatened reptile species is highest in freshwater environments, tropical regions and on oceanic islands, while data deficiency was highest in tropical areas, such as Central Africa and Southeast Asia, and among fossorial reptiles. Our results emphasise the need for research attention to be focussed on tropical areas which are experiencing the most dramatic rates of habitat loss, on fossorial reptiles for which there is a chronic lack of data, and on certain taxa such as snakes for which extinction risk may currently be underestimated due to lack of population information. Conservation actions specifically need to mitigate the effects of human-induced habitat loss and harvesting, which are the predominant threats to reptiles.

Connecting people and ideas from around the world: global innovation platforms for next-generation ecology and beyond

We present a case for using Global Community Innovation Platforms (GCIPs), an approach to improve innovation and knowledge exchange in international scientific communities through a common and open online infrastructure. We highlight the value of GCIPs by focusing on recent efforts targeting the ecological sciences, where GCIPs are of high relevance given the urgent need for interdisciplinary, geographical, and cross-sector collaboration to cope with growing challenges to the environment as well as the scientific community itself. Amidst the emergence of new international institutions, organizations, and meetings, GCIPs provide a stable international infrastructure for rapid and long-term coordination that can be accessed by any individual. This accessibility can be especially important for researchers early in their careers. Recent examples of early-career GCIPs complement an array of existing options for early-career scientists to improve skill sets, increase academic and social impact, and broaden career opportunities. We provide a number of examples of existing early-career initiatives that incorporate elements from the GCIPs approach, and highlight an in-depth case study from the ecological sciences: the International Network of Next-Generation Ecologists (INNGE), initiated in 2010 with support from the International Association for Ecology and 20 member institutions from six continents.

The genetic associations of acute anterior uveitis and their overlap with the genetics of ankylosing spondylitis

Acute anterior uveitis (AAU) involves inflammation of the iris and ciliary body of the eye. It occurs both in isolation and as a complication of ankylosing spondylitis (AS). It is strongly associated with HLA-B*27, but previous studies have suggested that further genetic factors may confer additional risk. We sought to investigate this using the Illumina Exomechip microarray, to compare 1504 cases with AS and AAU, 1805 with AS but no AAU and 21 133 healthy controls. We also used a heterogeneity test to test the differences in effect size between AS with AAU and AS without AAU. In the analysis comparing AS+AAU+ cases versus controls, HLA-B*27 and HLA-A*02:01 were significantly associated with the presence of AAU (P<10−300 and P=6 × 10−8, respectively). Secondary independent association with PSORS1C3 (P=4.7 × 10−5) and TAP2 (P=1.1 × 10−5) were observed in the major histocompatibility complex. There was a new suggestive association with a low-frequency variant at zinc-finger protein 154 in the AS without AAU versus control analysis (zinc-finger protein 154 (ZNF154), P=2.2 × 10−6). Heterogeneity testing showed that rs30187 in ERAP1 has a larger effect on AAU compared with that in AS alone. These findings also suggest that variants in ERAP1 have a differential impact on the risk of AAU when compared with AS, and hence the genetic risk for AAU differs from AS.

Actin Dynamics in Muscle Cells

In every cell, actin is a key component involved in migration, cytokinesis, endocytosis and generation of contraction. In non-muscle cells, actin filaments are very dynamic and regulated by an array of proteins that interact with actin filaments and/or monomeric actin. Interestingly, in non-muscle cells the barbed ends of the filaments are the predominant assembly place, whereas in muscle cells actin dynamics was reported to predominate at the pointed ends of thin filaments. The actin-based thin filament pointed (slow growing) ends extend towards the middle of the sarcomere's M-line where they interact with the thick filaments to generate contraction. The actin filaments in muscle cells are organized into a nearly crystalline array and are believed to be significantly less dynamic than the ones in other cell types. However, the exact mechanisms of the sarcomere assembly and turnover are largely unknown. Interestingly, although sarcomeric actin structures are believed to be relatively non-dynamic, many proteins promoting actin dynamics are expressed also in muscle cells (e.g ADF/cofilin, cyclase-associated protein and twinfilin). Thus, it is possible that the muscle-specific isoforms of these proteins promote actin dynamics differently from their non-muscle counterparts, or that actin filaments in muscle cells are more dynamic than previously thought. To study protein dynamics in live muscle cells, I used primary cell cultures of rat cardiomyocytes. My studies revealed that a subset of actin filaments in cardiomyocyte sarcomeres displays rapid turnover. Importantly, I discovered that the turnover of actin filaments depends on contractility of the cardiomyocytes and that the contractility-induced actin dynamics plays an important role in sarcomere maturation. Together with previous studies those findings suggest that sarcomeres undergo two types of actin dynamics: (1) contractility-dependent turnover of whole filaments and (2) regulatory pointed end monomer exchange to maintain correct thin filament length. Studies involving an actin polymerization inhibitor suggest that the dynamic actin filament pool identified here is composed of filaments that do not contribute to contractility. Additionally, I provided evidence that ADF/cofilins, together with myosin-induced contractility, are required to disassemble non-productive filaments in developing cardiomyocytes. In addition, during these studies we learned that isoforms of actin monomer binding protein twinfilin, Twf-1 and Twf-2a localise to myofibrils in cardiomyocytes and may thus contribute to actin dynamics in myofibrils. Finally, in collaboration with Roberto Dominguez s laboratory we characterized a new actin nucleator in muscle cells - leiomodin (Lmod). Lmod localises towards actin filament pointed ends and its depletion by siRNA leads to severe sarcomere abnormalities in cardiomyocytes. The actin filament nucleation activity of Lmod is enhanced by interactions with tropomyosin. We also revealed that Lmod expression correlates with the maturation of myofibrils, and that it associates with sarcomeres only at relatively late stages of myofibrillogenesis. Thus, Lmod is unlikely to play an important role in myofibril formation, but rather might be involved in the second step of the filament arrangement and/or maintenance through its ability to promote tropomyosin-induced actin filament nucleation occurring at the filament pointed ends. The results of these studies provide valuable new information about the molecular mechanisms underlying muscle sarcomere assembly and turnover. These data offer important clues to understanding certain physiological and pathological behaviours of muscle cells. Better understanding of the processes occurring in muscles might help to find strategies for determining, diagnosis, prognosis and therapy in heart and skeletal muscles diseases.

Definition of the halogen bond (IUPAC Recommendations 2013)

This recommendation proposes a definition for the term ``halogen bond'', which designates a specific subset of the inter- and intramolecular interactions involving a halogen atom in a molecular entity.

Advancing biodiversity research in developing countries: the need for changing paradigms

The world is in the midst of a biodiversity crisis, threatening essential goods and services on which humanity depends. While there is an urgent need globally for biodiversity research, growing obstacles are severely limiting biodiversity research throughout the developing world, particularly in Southeast Asia. Facilities, funding, and expertise are often limited throughout this region, reducing the capacity for local biodiversity research. Although western scientists generally have more expertise and capacity, international research has sometimes been exploitative ``parachute science,'' creating a culture of suspicion and mistrust. These issues, combined with misplaced fears of biopiracy, have resulted in severe roadblocks to biodiversity research in the very countries that need it the most. Here, we present an overview of challenges to biodiversity research and case studies that provide productive models for advancing biodiversity research in developing countries. Key to success is integration of research and education, a model that fosters sustained collaboration by focusing on the process of conducting biodiversity research as well as research results. This model simultaneously expands biodiversity research capacity while building trust across national borders. It is critical that developing countries enact policies that protect their biodiversity capital without shutting down international and local biodiversity research that is essential to achieve the long-term sustainability of biodiversity, promoting food security and economic development.

An estimate of the number of tropical tree species

The high species richness of tropical forests has long been recognized, yet there remains substantial uncertainty regarding the actual number of tropical tree species. Using a pantropical tree inventory database from closed canopy forests, consisting of 657,630 trees belonging to 11,371 species, we use a fitted value of Fisher's alpha and an approximate pantropical stem total to estimate the minimum number of tropical forest tree species to fall between similar to 40,000 and similar to 53,000, i.e., at the high end of previous estimates. Contrary to common assumption, the Indo-Pacific region was found to be as species-rich as the Neotropics, with both regions having a minimum of similar to 19,000-25,000 tree species. Continental Africa is relatively depauperate with a minimum of similar to 4,500-6,000 tree species. Very few species are shared among the African, American, and the Indo-Pacific regions. We provide a methodological framework for estimating species richness in trees that may help refine species richness estimates of tree-dependent taxa.

The mycobacterial iron-dependent regulator IdeR induces ferritin (bfrB) by alleviating Lsr2 repression

Emerging evidence indicates that precise regulation of iron (Fe) metabolism and maintenance of Fe homeostasis in Mycobacterium tuberculosis (Mtb) are essential for its survival and proliferation in the host. IdeR is a central transcriptional regulator of Mtb genes involved in Fe metabolism. While it is well understood how IdeR functions as a repressor, how it induces transcription of a subset of its targets is still unclear. We investigated the molecular mechanism of IdeR-mediated positive regulation of bfrB, the gene encoding the major Fe-storage protein of Mtb. We found that bfrB induction by Fe required direct interaction of IdeR with a DNA sequence containing four tandem IdeR-binding boxes located upstream of the bfrB promoter. Results of in vivo and in vitro transcription assays identified a direct repressor of bfrB, the histone-like protein Lsr2. IdeR counteracted Lsr2-mediated repression in vitro, suggesting that IdeR induces bfrB transcription by antagonizing the repressor activity of Lsr2. Together, these results elucidate the main mechanism of bfrB positive regulation by IdeR and identify Lsr2 as a new factor contributing to Fe homeostasis in mycobacteria.

Prevalencia del carcinoma escamoso ocular y sus precursores en un hato lechero nicaraguense, relacionado con raza, edad y pigmentación

En el presente trabajo se estudió la prevalencia del Carcinoma escamoso ocular bovino y la relación que tiene esta enfermedad con la pigmentación ocular, la raza y la edad en la Empresa Genética “Roberto Alvarado” (Chiltepe). Para esto se estudiaron 4108 animales de los grupos raciales Holstein Friesian (Canadiense), Holstein Friesian (Criollo), Holstein x Pardo, 75% Holstein y Pardo Suizo. Se determinó que la prevalencia total del cáncer en la población analizada es de 2.6%. Además que existe presencia de lesión únicamente cuando existe pigmentación. Se concluyó que hay claras diferencias entre los grupos raciales estudiados siendo el más afectado el Holstein Friesian(Canadiense), y que hay una tendencia a incrementarse la presencia del cáncer a medida la edad.

Evaluación productiva y reproductiva de la raza holstein friesian canadiense bajo explotación intensiva en el trópico seco de Nicaragua

El presente trabajo se realizó en base a los registros productivos y reproductivos del hato Holstein. Friesian Canadiense existente en el distrito tres de la Empresa Genética "Roberto Alvarado" (Chiltepe); ubicada en el Departamento de Managua, Nicaragua, a una latitud 12º 14' y una longitud de 86º 25' y a una elevación promedio de 49 msnm, con una temperatura promedio anual de 28.43°C, humedad relativa promedio anual 68.38% y una precipitación promedio anual de 87.72 mm. distribuida en dos épocas: Época lluviosa (Mayo - Octubre ) y época seca (Noviembre - Abril). A partir de la información proporcionada se evaluó el efecto de distintos factores ambientales : número de partos (NUMPA), época de parto (EPOCA) y año de parto (AP); sobre las variables productivas y reproductivas: producción de leche total (PLT), duración de la lactancia (DL), producción de leche diaria (PLD), intervalo entre partos (IEP) y producción de leche por día de intervalo entre partos (PLDIEP), las cuales resultaron todas altamente significativas (P < 0.01), considerando para la variable PLT el efecto de la covariable DL con Numpa. También se caracterizó el comportamiento productivo y reproductivo del hato, basado en el cálculo de los promedios de mínimos cuadrados de las características productivas y reproductivas en los diferentes niveles de cada uno de los factores estudiados, resultando promedios generales de: PLT 3,207.53 ± 54.37 Kg., DL 321.98 ± 3.89 días, PLD 10.67 ± 0.17 Kg., IEP 468;63 ± 4.29 días y PLDIEP 7.51 ± 0.14 Kg. Además se estimaron las correlaciones lineales fenotípicas entre las variables y los factores NUMPA y EPAR , resultando entre ellos los valores más altos para: EPAR -NUMPA (r= + 0.96), DL - IEP (r= + 0.80), PLD - PLDIEP (r= + 0.80), PLT - PLDIEP (r= + 0.76) y valores absolutos para r más bajos entre NUMPA - PLDIEP (r= + 0.18), NUMPA - PLT (r= -0.19), NUMPA - PLD (r= + 0.23) y EPAR - PLT (r= - 0.21).

Influencia de humedad y temperatura sobre la fertilidad de vacas holstein, en la Península de Chiltepe

Se analizó los resultados de 2,419 inseminaciones al primer servicio (782 en vaquillas y 1,637 en vacas) realizadas en la Empresa Genética Roberto Alvarado (EGRA), ubicada en la península de Chiltepe (km 24 carretera a León), durante los años 1987 y 1988. Estos resultados fueron cotejados con los datos de humedad y temperatura ambiente del día de su realización provenientes de la estación meteorológica Agusto Cesar Sandino, ubicada en el Aeropuerto Internacional de Managua. Se estudió la influencia de cuatro variables de temperatura, lo mismo que de humedad relativa: Máxima diaria, mínima diaria, promedio diario y promedio diurno. Además se estudió la combinación de temperatura y humedad: Máxima diaria con máxima diaria, mínima diaria con mínima diaria, etc. Se encontró que la fertilidad de las vaquillas parece no ser influenciada por ninguna de las variables estudiadas, a excepción de HMX Humedad Relativa Máxima del día de inseminación) cuya influencia parece ser muy débil. De acuerdo con las Pruebas de Independencia de Chi cuadrado las variables más relacionadas con la fertilidad de las vacas son HDA (Humedad Relativa Promedio del día de inseminación) y HMX. Las variables de temperatura ambiental más relacionadas con la fertilidad de las vacas son TDA (Temperatura Promedio del día de inseminación) y TDU (Temperatura Promedio diurna del día de inseminación). Un incremento de TDA o TDU parece afectar positivamente la fertilidad de las vacas con valores de TDA 24 – 29°c se obtuvieron tasas de concepción entre 34 y 35% y con valores de TDA de 29- 31.5°c se obtuvo una tasa de concepción del 47%. Todas las variables de humedad relativa parecen afectar negativamente la fertilidad de las vacas: la tasa de concepción bajó de un 46.6% con valores de HDA de 48 – 65% a un 29.7% con valores de HDA de 80 – 96%. Al estudiar el efecto combinada de temperatura y humedad se muestra una tendencia de la tasas de concepción a disminuir conforme la humedad relativa aumenta y a incrementarse 1igeramente conforme aumenta 1a temperatura, aun cuando esta última tendencia puede variar según el nivel de humedad presente. Los valores medios de temperatura combinados con valores medios y altos de humedad resultan muy adversos a la fertilidad de las vacas. La Humedad Relativa parece ser el principal factor responsable de la caída en las tasas de concepción durante algunos meses del año.

Evaluación de tres tipos de dietas (calostro: leche) en terneras holstein friesian bajo crianza artificial

El presente trabajo se realizó en la Empresa Genética Roberto Alvarado (Chiltepe), ubicada en la península de Chiltepe, en el departamento de Managua, con el objetivo de establecer la mejor forma de suministrar dietas liquidas, establecer la asociación entre los niveles de calostro con los comportamientos productivos de terneras bajo crianza artificial. Se emplearon 18 terneras de raza Holstein F., con un promedio de 40 Kg+- 8 kg de peso vivo, las que fueron distribuidas aleatoriamente en tres grupos asignándoles los siguientes tratamientos: T15 litros de leche entera/día (testigo) ; T2: 5 Litros de mezcla de calostro y leche/día (20:80) y T3: 5 Litros de mezcla de calostro y leche/día (40:60). Adicionalmente todos los tratamientos recibieron "adibitum", alimento solido a base de forraje Taiwán picado, heno de pasto estrella, agua y concentrado iniciador. El manejo de las terneras se realizó de manera similar a la utilizada en los centros de crianza de las empresas. Se efectuaron pasajes semanales individuales y se registró el consumo de concentrado. Se realizó análisis bromatológico de las dietas liquidas según metodología A.O.A.C. (1984), así como un análisis económico de las mismas. Al realizar ANDEVA para la variable GMD28, GMD49 y GMD70, se encontró para la primera que no existen diferencias (P<0.05) y para la dos últimas si existen diferencias significativas (P<0.05). El ANDECOVA (mínimo cuadrado realizado para la variable P28, utilizando la covariable PI mostró que no existen diferencias entre las dietas, y diferencias significativas (P<0.05) para la covariable. Para la variable Cons28, utilizando como variable el PI, se encontró diferencias significativas entre las dietas y no significativas para la variable concomitante. Al analizar la variable P49 usando como variable concomitante el P28, mostró diferencias estadísticamente significativas (P<0.05) tanto para las dietas como para la covariable. Para la variable P70, utilizando como covariable P49, se encontró que existen diferencias significativas para las dietas suministradas así como para la variable concomitante. Posteriormente al realizar prueba de separación de medidas con rangos múltiples utilizando test de Duncan, para las variables GMD14, GMD28, GMD49 y GMD70 se encontró el siguiente orden de mérito para las dietas: Calostro: Leche (40:60) a; Calostro: Leche (20:80)a, y Calostro: Leche (0:100) b. El análisis económico mostro que las dietas T3 y T2 tiene costos notablemente inferiores en relación al costo del T1. Estos análisis conllevan a establecer un orden decreciente del efecto de las dietas liquidas sobre la GMD y el PF según el siguiente esquema: T3 (40:60)>T2 (20:80)>T1 (0.100). Encontrando que la dieta más efectiva es la del T3.