Genetic Association of Fetal-hemoglobin Levels in Individuals with Sickle Cell Disease in Tanzania Maps to Conserved Regulatory Elements within the MYB Core Enhancer.

Common genetic variants residing near upstream regulatory elements for MYB, the gene encoding transcription factor cMYB, promote the persistence of fetal hemoglobin (HbF) into adulthood. While they have no consequences in healthy individuals, high HbF levels have major clinical benefits in patients with sickle cell disease (SCD) or β thalassemia. Here, we present our detailed investigation of HBS1L-MYB intergenic polymorphism block 2 (HMIP-2), the central component of the complex quantitative-trait locus upstream of MYB, in 1,022 individuals with SCD in Tanzania. We have looked at 1022 individuals with HbSS or HbS/β(0) in Tanzania. In order to achieve a detailed analysis of HMIP-2, we performed targeted genotyping for a total of 10 SNPs and extracted additional 528 SNPs information from a genome wide scan involving the same population. Using MACH, we utilized the existing YRI data from 1000 genomes to impute 54 SNPs situated within HIMP-2. Seven HbF-increasing, low-frequency variants (β > 0.3, p < 10(-5), f ≤ 0.05) were located in two partially-independent sub-loci, HMIP-2A and HMIP-2B. The spectrum of haplotypes carrying such alleles was diverse when compared to European and West African reference populations: we detected one such haplotype at sub-locus HMIP-2A, two at HMIP-2B, and a fourth including high-HbF alleles at both sub-loci ('Eurasian' haplotype clade). In the region of HMIP-2A a putative functional variant (a 3-bp indel) has been described previously, but no such candidate causative variant exists at HMIP-2B. Extending our dataset through imputation with 1000 Genomes, whole-genome-sequence data, we have mapped peak association at HMIP-2B to an 11-kb region around rs9494145 and rs9483788, flanked by two conserved regulatory elements for MYB. Studies in populations from the African continent provide distinct opportunities for mapping disease-modifying genetic loci, especially for conditions that are highly prevalent there, such as SCD. Population-genetic characteristics of our cohort, such as ethnic diversity and the predominance of shorter, African-type haplotypes, can add to the power of such studies

Synthetic associations in the context of genome-wide association scan signals

Genome-wide association studies (GWAS) have successfully identified a large number of genetic variants associated with complex traits, but these only explain a small proportion of the total heritability. It has been recently proposed that rare variants can create ‘synthetic association' signals in GWAS, by occurring more often in association with one of the alleles of a common tag single nucleotide polymorphism. While the ultimate evaluation of this hypothesis will require the completion of large-scale sequencing studies, it is informative to place it in the broader context of what is known about the genetic architecture of complex disease. In this review, we draw from empirical and theoretical data to summarize evidence showing that synthetic associations do not underlie many reported GWAS associations

Radio Astronomy

Contains reports on seven research projects and research objectives.National Science Foundation (Grant AST77-06052)Joint Services Electronics Program (Contract DAAG29-78-C-0020)National Aeronautics and Space Administration (Contract NAS5-21980)U.S. Department of Commerce - National Oceanic and Atmospheric Administration (Grant 04-8-M01-1)National Aeronautics and Space Administration (Contract NAS5-22929)National Aeronautics and Space Administration (Contract NAS5-25091)National Science Foundation (Grant AST77-12960)National Science Foundation (Grant AST77-26896

Changes in plasma levels of N-arachidonoyl ethanolamine and N-palmitoylethanolamine following bariatric surgery in morbidly obese females with impaired glucose homeostasis

Aim: We examined endocannabinoids (ECs) in relation to bariatric surgery and the association between plasma ECs and markers of insulin resistance. Methods: A study of 20 participants undergoing bariatric surgery. Fasting and 2-hour plasma glucose, lipids, insulin, and C-peptide were recorded preoperatively and 6 months postoperatively with plasma ECs (AEA, 2-AG) and endocannabinoid-related lipids (PEA, OEA). Results: Gender-specific analysis showed differences in AEA, OEA, and PEA preoperatively with reductions in AEA and PEA in females postoperatively. Preoperatively, AEA was correlated with 2-hour glucose (r = 0.55, P = 0.01), HOMA-IR (r = 0.61, P = 0.009), and HOMA %S (r = -0.71, P = 0.002). OEA was correlated with weight (r = 0.49, P = 0.03), waist circumference (r = 0.52, P = 0.02), fasting insulin (r = 0.49, P = 0.04), and HOMA-IR (r = 0.48, P = 0.05). PEA was correlated with fasting insulin (r = 0.49, P = 0.04). 2-AG had a negative correlation with fasting glucose (r = -0.59, P = 0.04). Conclusion: Gender differences exist in circulating ECs in obese subjects. Females show changes in AEA and PEA after bariatric surgery. Specific correlations exist between different ECs and markers of obesity and insulin and glucose homeostasis

Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 people with pulmonary TB and in 5,607 healthy controls. In the combined analysis of these subjects and the follow-up cohort (15,087 TB patients and controls altogether), we found an association between TB and variants located in introns of the ASAP1 gene on chromosome 8q24 (P = 2.6 × 10−11 for rs4733781; P = 1.0 × 10−10 for rs10956514). Dendritic cells (DCs) showed high ASAP1 expression that was reduced after Mycobacterium tuberculosis infection, and rs10956514 was associated with the level of reduction of ASAP1 expression. The ASAP1 protein is involved in actin and membrane remodeling and has been associated with podosomes. The ASAP1-depleted DCs showed impaired matrix degradation and migration. Therefore, genetically determined excessive reduction of ASAP1 expression in M. tuberculosis–infected DCs may lead to their impaired migration, suggesting a potential mechanism of predisposition to TB

Radio Astronomy

Contains summary of research and reports on nine research projects.National Science Foundation (Grant AST81-21416)National Science Foundation (Grant AST82-14296)National Aeronautics and Space Administration (Grant S-10781-C)National Aeronautics and Space Administration (Grant NAGW-373)National Science Foundation (Grant AST79-19553)M.I.T. Sloan Fund for Basic ResearchNational Oceanic and Atmospheric Administration (Grant 04-8-M01-1)National Aeronautics and Space Administration (Grant NAG5-10)National Aeronautics and Space Administration (Contract NAS5-22929)Defense Advanced Research Projects Agency (Contract MDA 903-82-K-0521)Center for Advanced Television Studie

Radio Astronomy

Contains reports on research objectives and eight research projects.National Science Foundation (Grant AST79-25075)National Science Foundation (Grant AST79-20984)National Science Foundation (Grant AST79-19553)U.S. Navy - Office of Naval Research (Contract N00014-80-C-0348)National Aeronautics and Space Administration (Grant NAG2-50)M.I.T. Sloan Fund for Basic ResearchJoint Services Electronics Program (Contract DAAG29-78-C-0020)Joint Services Electronics Program (Contract DAAG29-80-C-0104)National Aeronautics and Space Administration (Grant NAG5-10)National Aeronautics and Space Administration (Contract NAS5-25091)National Aeronautics and Space Administration (Contract NAS5-22929)U.S. Department of Commerce - National Oceanic and Atmospheric Administration (Grant 04-8-MOl-1

Radio Astronomy

Contains reports on eleven research projects.National Science Foundation (Grant AST79-25075)National Science Foundation (Grant AST79-20984)National Science Foundation (Grant AST79-19553)U.S. Navy - Office of Naval Research (Contract N00014-80-C-0348)National Aeronautics and Space Administration (Grant NAG2-50)MIT Sloan Fund for Basic ResearchJoint Services Electronics Program(Contract DAAG80-C-0104)Lockheed Aircraft Corporation (Contract LS90B4860F)National Aeronautics and Space Administration (Grant NAG5-10)National Aeronautics and Space Administration (Contract NAS5-22929)U.S. Department of Commerce, National Oceanic and Atmospheric Administration (Grant 04-8-MO1-1)California Institute of Technology Jet Propulsion Laboratory (Contract LZ-727891)California Institute of Technology Jet Propulsion Laboratory Subcontract 956059California Institute of Technology Jet Propulsion Laboratory Task Order RD-15

Integrated information increases with fitness in the evolution of animats

One of the hallmarks of biological organisms is their ability to integrate disparate information sources to optimize their behavior in complex environments. How this capability can be quantified and related to the functional complexity of an organism remains a challenging problem, in particular since organismal functional complexity is not well-defined. We present here several candidate measures that quantify information and integration, and study their dependence on fitness as an artificial agent ("animat") evolves over thousands of generations to solve a navigation task in a simple, simulated environment. We compare the ability of these measures to predict high fitness with more conventional information-theoretic processing measures. As the animat adapts by increasing its "fit" to the world, information integration and processing increase commensurately along the evolutionary line of descent. We suggest that the correlation of fitness with information integration and with processing measures implies that high fitness requires both information processing as well as integration, but that information integration may be a better measure when the task requires memory. A correlation of measures of information integration (but also information processing) and fitness strongly suggests that these measures reflect the functional complexity of the animat, and that such measures can be used to quantify functional complexity even in the absence of fitness data.Comment: 27 pages, 8 figures, one supplementary figure. Three supplementary video files available on request. Version commensurate with published text in PLoS Comput. Bio

Radio Astronomy

Contains reports on sixteen research projects.National Science Foundation (Grant AST81-21416)National Science Foundation (Grant AST80-22864)National Aeronautics and Space Administration (Contract S-10665-C)National Aeronautics and Space Administration (Contract NAGW373)National Science Foundation (Grant AST79-19553)National Oceanic and Atmospheric Administration (Grant 04-8-M01-1)National Aeronautics and Space Administration (Grant NAG5-10)National Aeronautics and Space Administration (Contract NAS5-22929)Defense Advanced Research Projects Agency (Contract MDA 903-82-K-0521)Intelsat (Contract Intel-188)Joint Services Electronics Program (Contract DAAG29-80-C-0104)Lockheed Missiles and Space Company (Contract LS90B4860F