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1.  A Genome- and Phenome-Wide Association Study to Identify Genetic Variants Influencing Platelet Count and Volume and their Pleiotropic Effects 
Human genetics  2013;133(1):10.1007/s00439-013-1355-7.
Platelets are enucleated cell fragments derived from megakaryocytes that play key roles in hemostasis and in the pathogenesis of atherothrombosis and cancer. Platelet traits are highly heritable and identification of genetic variants associated with platelet traits and assessing their pleiotropic effects may help to understand the role of underlying biological pathways. We conducted an electronic medical record (EMR)-based study to identify common variants that influence inter-individual variation in the number of circulating platelets (PLT) and mean platelet volume (MPV), by performing a genome-wide association study (GWAS). We characterized association of variants influencing MPV and PLT using functional, pathway and disease enrichment analysis assess pleiotropic effects of such variants by performing a phenome-wide association study (PheWAS) with a wide range of EMR-derived phenotypes. A total of 13,582 participants in the electronic MEdical Records and GEnomic (eMERGE) network had data for PLT and 6,291 participants had data for MPV. We identified 5 chromosomal regions associated with PLT and 8 associated with MPV at genome-wide significance (P<5E-8). In addition, we replicated 20 SNPs (out of 56 SNPs (α: 0.05/56=9E-4)) influencing PLT and 22 SNPs (out of 29 SNPs (α: 0.05/29=2E-3)) influencing MPV in a meta-analysis of GWAS of PLT and MPV. While our GWAS did not reveal any novel associations, our functional analyses revealed that genes in these regions influence thrombopoiesis and encode kinases, membrane proteins, proteins involved in cellular trafficking, transcription factors, proteasome complex subunits, proteins of signal transduction pathways, proteins involved in megakaryocyte development and platelet production and hemostasis. PheWAS using a single-SNP Bonferroni correction for 1368 diagnoses (0.05/1368=3.6E-5) revealed that several variants in these genes have pleiotropic associations with myocardial infarction, autoimmune and hematologic disorders. We conclude that multiple genetic loci influence interindividual variation in platelet traits and also have significant pleiotropic effects; the related genes are in multiple functional pathways including those relevant to thrombopoiesis.
PMCID: PMC3880605  PMID: 24026423
2.  Genetic Variants Associated with Serum Thyroid Stimulating Hormone (TSH) Levels in European Americans and African Americans from the eMERGE Network 
PLoS ONE  2014;9(12):e111301.
Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85×10−17, β = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08×10−6, β = −0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, β = −0.09), VEGFA (rs11755845 p = 0.01, β = −0.13), and NFIA (rs334699 p = 1.50×10−3, β = −0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations.
PMCID: PMC4249871  PMID: 25436638
3.  Characterizing Genetic Variants for Clinical Action 
Genome-wide association studies, DNA sequencing studies, and other genomic studies are finding an increasing number of genetic variants associated with clinical phenotypes that may be useful in developing diagnostic, preventive, and treatment strategies for individual patients. However, few common variants have been integrated into routine clinical practice. The reasons for this are several, but two of the most significant are limited evidence about the clinical implications of the variants and a lack of a comprehensive knowledge base that captures genetic variants, their phenotypic associations, and other pertinent phenotypic information that is openly accessible to clinical groups attempting to interpret sequencing data. As the field of medicine begins to incorporate genome-scale analysis into clinical care, approaches need to be developed for collecting and characterizing data on the clinical implications of variants, developing consensus on their actionability, and making this information available for clinical use. The National Human Genome Research Institute (NHGRI) and the Wellcome Trust thus convened a workshop to consider the processes and resources needed to: 1) identify clinically valid genetic variants; 2) decide whether they are actionable and what the action should be; and 3) provide this information for clinical use. This commentary outlines the key discussion points and recommendations from the workshop.
PMCID: PMC4158437  PMID: 24634402
genomic medicine; clinical actionability; database; electronic health records (EHR); pharmacogenomics; DNA sequencing
4.  Generalization of Variants Identified by Genome-wide Association Studies for Electrocardiographic Traits in African Americans 
Annals of human genetics  2013;77(4):321-332.
Electrocardiographic (ECG) measurements vary by ancestry. Genome-wide association studies (GWAS) have identified loci that contribute to ECG measurements; however most are performed in Europeans collected from population-based cohorts or surveys. The strongest associations reported are in NOS1AP with QT interval and SCN10A with PR and QRS durations. The extent to which these associations can be generalized to African Americans has yet to be determined. Using electronic medical records, PR and QT intervals, QRS duration, and heart rate were determined in 455 African Americans as part of the Vanderbilt Genome-Electronic Records Project and Northwestern University NUgene Project. We tested for an association between these ECG traits and >930K SNPs. We identified a total 36 novel associations with PR interval, QRS duration, QT interval, and heart rate at p< 1.0 ×10−6. Using published GWAS data, we compared our results with those previously identified in other populations. Five associations originally identified in other populations generalized with respect to statistical significance and direction of effect. A total of 43 associations have a consistent direction of effect with European and/or Asian populations. This work provides a catalogue of generalized versus non-generalized associations, a necessary step in prioritizing GWAS-identified regions for further fine-mapping in diverse populations.
PMCID: PMC3743946  PMID: 23534349
Electrocardiography; African Americans; GWAS; Generalization; Electronic Medical Records
5.  SadA, a novel adhesion receptor in Dictyostelium 
The Journal of Cell Biology  2002;159(6):1109-1119.
Little is known about cell–substrate adhesion and how motile and adhesive forces work together in moving cells. The ability to rapidly screen a large number of insertional mutants prompted us to perform a genetic screen in Dictyostelium to isolate adhesion-deficient mutants. The resulting substrate adhesion–deficient (sad) mutants grew in plastic dishes without attaching to the substrate. The cells were often larger than their wild-type parents and displayed a rough surface with many apparent blebs. One of these mutants, sadA−, completely lacked substrate adhesion in growth medium. The sadA− mutant also showed slightly impaired cytokinesis, an aberrant F-actin organization, and a phagocytosis defect. Deletion of the sadA gene by homologous recombination recreated the original mutant phenotype. Expression of sadA–GFP in sadA-null cells restored the wild-type phenotype. In sadA–GFP-rescued mutant cells, sadA–GFP localized to the cell surface, appropriate for an adhesion molecule. SadA contains nine putative transmembrane domains and three conserved EGF-like repeats in a predicted extracellular domain. The EGF repeats are similar to corresponding regions in proteins known to be involved in adhesion, such as tenascins and integrins. Our data combined suggest that sadA is the first substrate adhesion receptor to be identified in Dictyostelium.
PMCID: PMC2173991  PMID: 12499361
Dictyostelium; cell–substrate adhesion; EGF-like repeats; phagocytosis; cytokinesis
6.  A fluorescent resonant energy transfer–based biosensor reveals transient and regional myosin light chain kinase activation in lamella and cleavage furrows 
The Journal of Cell Biology  2002;156(3):543-553.
Approaches with high spatial and temporal resolution are required to understand the regulation of nonmuscle myosin II in vivo. Using fluorescence resonance energy transfer we have produced a novel biosensor allowing simultaneous determination of myosin light chain kinase (MLCK) localization and its [Ca2+]4/calmodulin-binding state in living cells. We observe transient recruitment of diffuse MLCK to stress fibers and its in situ activation before contraction. MLCK is highly active in the lamella of migrating cells, but not at the retracting tail. This unexpected result highlights a potential role for MLCK-mediated myosin contractility in the lamella as a driving force for migration. During cytokinesis, MLCK was enriched at the spindle equator during late metaphase, and was maximally activated just before cleavage furrow constriction. As furrow contraction was completed, active MLCK was redistributed to the poles of the daughter cells. These results show MLCK is a myosin regulator in the lamella and contractile ring, and pinpoints sites where myosin function may be mediated by other kinases.
PMCID: PMC2173328  PMID: 11815633
myosin light chain kinase; myosin light chains; phosphorylation; cell division; FRET
7.  Genome- and Phenome-Wide Analysis of Cardiac Conduction Identifies Markers of Arrhythmia Risk 
Circulation  2013;127(13):1377-1385.
Electrocardiographic QRS duration, a measure of cardiac intraventricular conduction, varies ~2-fold in individuals without cardiac disease. Slow conduction may promote reentrant arrhythmias.
Methods and Results
We performed a genome-wide association study (GWAS) to identify genomic markers of QRS duration in 5,272 individuals without cardiac disease selected from electronic medical record (EMR) algorithms at five sites in the Electronic Medical Records and Genomics (eMERGE) network. The most significant loci were evaluated within the CHARGE consortium QRS GWAS meta-analysis. Twenty-three single nucleotide polymorphisms in 5 loci, previously described by CHARGE, were replicated in the eMERGE samples; 18 SNPs were in the chromosome 3 SCN5A and SCN10A loci, where the most significant SNPs were rs1805126 in SCN5A with p=1.2×10−8 (eMERGE) and p=2.5×10−20 (CHARGE) and rs6795970 in SCN10A with p=6×10−6 (eMERGE) and p=5×10−27 (CHARGE). The other loci were in NFIA, near CDKN1A, and near C6orf204. We then performed phenome-wide association studies (PheWAS) on variants in these five loci in 13,859 European Americans to search for diagnoses associated with these markers. PheWAS identified atrial fibrillation and cardiac arrhythmias as the most common associated diagnoses with SCN10A and SCN5A variants. SCN10A variants were also associated with subsequent development of atrial fibrillation and arrhythmia in the original 5,272 “heart-healthy” study population.
We conclude that DNA biobanks coupled to EMRs provide a platform not only for GWAS but may also allow broad interrogation of the longitudinal incidence of disease associated with genetic variants. The PheWAS approach implicated sodium channel variants modulating QRS duration in subjects without cardiac disease as predictors of subsequent arrhythmias.
PMCID: PMC3713791  PMID: 23463857
cardiac conduction; QRS duration; atrial fibrillation; genome-wide association study; phenome-wide association study; electronic medical records
8.  Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data 
Nature biotechnology  2013;31(12):1102-1110.
Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10−6 (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.
PMCID: PMC3969265  PMID: 24270849
9.  Admixture Mapping and Subsequent Fine-Mapping Suggests a Biologically Relevant and Novel Association on Chromosome 11 for Type 2 Diabetes in African Americans 
PLoS ONE  2014;9(3):e86931.
Type 2 diabetes (T2D) is a complex metabolic disease that disproportionately affects African Americans. Genome-wide association studies (GWAS) have identified several loci that contribute to T2D in European Americans, but few studies have been performed in admixed populations. We first performed a GWAS of 1,563 African Americans from the Vanderbilt Genome-Electronic Records Project and Northwestern University NUgene Project as part of the electronic Medical Records and Genomics (eMERGE) network. We successfully replicate an association in TCF7L2, previously identified by GWAS in this African American dataset. We were unable to identify novel associations at p<5.0×10−8 by GWAS. Using admixture mapping as an alternative method for discovery, we performed a genome-wide admixture scan that suggests multiple candidate genes associated with T2D. One finding, TCIRG1, is a T-cell immune regulator expressed in the pancreas and liver that has not been previously implicated for T2D. We performed subsequent fine-mapping to further assess the association between TCIRG1 and T2D in >5,000 African Americans. We identified 13 independent associations between TCIRG1, CHKA, and ALDH3B1 genes on chromosome 11 and T2D. Our results suggest a novel region on chromosome 11 identified by admixture mapping is associated with T2D in African Americans.
PMCID: PMC3940426  PMID: 24595071
10.  Spliceosomal genes in the D. discoideum genome: a comparison with those in H. sapiens, D. melanogaster, A. thaliana and S. cerevisiae 
Protein & cell  2011;2(5):395-409.
Little is known about pre-mRNA splicing in Dictyostelium discoideum although its genome has been completely sequenced. Our analysis suggests that pre-mRNA splicing plays an important role in D. discoideum gene expression as two thirds of its genes contain at least one intron. Ongoing curation of the genome to date has revealed 40 genes in D. discoideum with clear evidence of alternative splicing, supporting the existence of alternative splicing in this unicellular organism. We identified 160 candidate U2-type spliceosomal proteins and related factors in D. discoideum based on 264 known human genes involved in splicing. Spliceosomal small ribonucleoproteins (snRNPs), PRP19 complex proteins and late-acting proteins are highly conserved in D. discoideum and throughout the metazoa. In non-snRNP and hnRNP families, D. discoideum orthologs are closer to those in A. thaliana, D. melanogaster and H. sapiens than to their counterparts in S. cerevisiae. Several splicing regulators, including SR proteins and CUG-binding proteins, were found in D. discoideum, but not in yeast. Our comprehensive catalog of spliceosomal proteins provides useful information for future studies of splicing in D. discoideum where the efficient genetic and biochemical manipulation will also further our general understanding of pre-mRNA splicing.
PMCID: PMC3893067  PMID: 21667333
pre-mRNA splicing; spliceosomal genes; Dictyostelium discoideum; comparative genomics; splicing regulators
12.  The Electronic Medical Records and Genomics (eMERGE) Network: Past, Present and Future 
The Electronic Medical Records and Genomics (eMERGE) Network is a National Human Genome Research Institute (NHGRI)-funded consortium engaged in the development of methods and best-practices for utilizing the Electronic Medical Record (EMR) as a tool for genomic research. Now in its sixth year, its second funding cycle and comprising nine research groups and a coordinating center, the network has played a major role in validating the concept that clinical data derived from EMRs can be used successfully for genomic research. Current work is advancing knowledge in multiple disciplines at the intersection of genomics and healthcare informatics, particularly electronic phenotyping, genome-wide association studies, genomic medicine implementation and the ethical and regulatory issues associated with genomics research and returning results to study participants. Here we describe the evolution, accomplishments, opportunities and challenges of the network since its inception as a five-group consortium focused on genotype-phenotype associations for genomic discovery to its current form as a nine-group consortium pivoting towards implementation of genomic medicine.
PMCID: PMC3795928  PMID: 23743551
electronic medical records; personalized medicine; genome-wide association studies; genetics and genomics; collaborative research
13.  High Density GWAS for LDL Cholesterol in African Americans Using Electronic Medical Records Reveals a Strong Protective Variant in APOE 
Only one LDL-C GWAS has been reported in African Americans. We performed a GWAS of LDL-C in African Americans using data extracted from electronic medical records (EMR) in the eMERGE network. African Americans were genotyped on the Illumina 1M chip. All LDL-C measurements, prescriptions, and diagnoses of concomitant disease were extracted from EMR. We created two analytic datasets; one dataset having median LDL-C calculated after the exclusion of some lab values based on co-morbidities and medication (n = 618) and another dataset having median LDL-C calculated without any exclusions (n = 1249). Rs7412 in APOE was strongly associated with LDL-C at levels of GWAS significance in both datasets (p < 5 X 10−8). In the dataset with exclusions, a decrease of 20.0 mg/dl per minor allele was observed. The effect size was attenuated (12.3 mg/dl) in the dataset without any lab values excluded. Although other signals in APOE have been detected in previous GWAS, this large and important SNP association has not been well detected in large GWAS because rs7412 was not included on many genotyping arrays. Use of median LDL-C extracted from EMR after exclusions for medications and co-morbidities increased the percentage of trait variance explained by genetic variation.
PMCID: PMC3521536  PMID: 23067351
GWAS; LDL; electronic medical records
14.  Nonmuscle myosin IIA with a GFP fused to the N-terminus of the regulatory light chain is regulated normally 
Nonmuscle myosin II plays a crucial role in a variety of cellular processes (e.g., polarity formation, cell motility, and cytokinesis). It is composed of two heavy chains, two regulatory light chains and two essential light chains. The ATPase activity of the myosin II motor domain is regulated through phosphorylation of the regulatory light chain (RLC) by myosin light chain kinase. To study myosin function and localization in cellular processes, GFP-fused RLCs are widely used; however, the exact kinetic properties of myosins with bound GFP-RLC are poorly described. More importantly, it has not been shown that a regulatory light chain fused at its N-terminus with GFP can maintain the normal phosphorylation-dependent regulation of nonmuscle myosin or serve as a substrate for myosin light chain kinase. We coexpressed N-terminal GFP-RLC with a heavy meromyosin (HMM)-like fragment of nonmuscle myosin IIA and essential light chain to characterize the phosphorylation dynamics and in vitro kinetic properties of the resulting HMM. Myosin light chain kinase phosphorylates the GFP-RLC bound to HMM IIA with the same Vmax as it does the wild type RLC bound to HMM IIA, but the Km is about two fold higher for the GFP fusion protein, meaning that it is a somewhat poorer substrate. The steady-state actin-activated MgATPase activity of the GFP-RLC HMM is very low in the absence of phosphorylation demonstrating that the GFP moiety does not prevent formation of the off state. The actin-activated MgATPase activity of phosphorylated GFP-RLC-HMM and is about half that of wild type phosphorylated HMM. The ability of phosphorylated GFP-RLC-HMM to move actin filaments in the actin gliding assay is also slightly compromised. These data indicate that despite some kinetic differences the N-terminal GFP fusion to the regulatory light chain is a reasonable model system for studying myosin function in vivo.
PMCID: PMC3786345  PMID: 20711642
GFP; Nonmuscle myosin; Regulatory light chain; Enzymatic activity; In vitro motility
15.  One stop shop for everything Dictyostelium: dictyBase and the Dicty Stock Center in 2012 
dictyBase (http://, the model organism database for Dictyostelium discoideum, includes the complete genome sequence and expression data for this organism. Relevant literature is integrated into the database, and gene models and functional annotation are manually curated from experimental results and comparative multigenome analyses. dictyBase has recently expanded to include the genome sequences of three additional Dictyostelids, and has added new software tools to facilitate multigenome comparisons. The Dicty Stock Center, a strain and plasmid repository for Dictyostelium research has relocated to Northwestern University in 2009. This allowed us integrating all Dictyostelium resources to better serve the research community. In this chapter, we will describe how to navigate the website and highlight some of our newer improvements.
PMCID: PMC3762881  PMID: 23494302
Dictyostelium discoideum; database; genomic sequence; multigenome; genome browser; Blast; gene page; functional annotation; strains; phenotypes
16.  Electronic Medical Records for Genetic Research: Results of the eMERGE Consortium 
Science translational medicine  2011;3(79):79re1.
Clinical data in Electronic Medical Records (EMRs) is a potential source of longitudinal clinical data for research. The Electronic Medical Records and Genomics Network or eMERGE investigates whether data captured through routine clinical care using EMRs can identify disease phenotypes with sufficient positive and negative predictive values for use in genome wide association studies (GWAS). Using data from five different sets of EMRs, we have identified five disease phenotypes with positive predictive values of 73–98% and negative predictive values of 98–100%. A majority of EMRs captured key information (diagnoses, medications, laboratory tests) used to define phenotypes in a structured format. We identified natural language processing as an important tool to improve case identification rates. Efforts and incentives to increase the implementation of interoperable EMRs will markedly improve the availability of clinical data for genomics research.
PMCID: PMC3690272  PMID: 21508311
18.  Use of diverse electronic medical record systems to identify genetic risk for type 2 diabetes within a genome-wide association study 
Genome-wide association studies (GWAS) require high specificity and large numbers of subjects to identify genotype–phenotype correlations accurately. The aim of this study was to identify type 2 diabetes (T2D) cases and controls for a GWAS, using data captured through routine clinical care across five institutions using different electronic medical record (EMR) systems.
Materials and Methods
An algorithm was developed to identify T2D cases and controls based on a combination of diagnoses, medications, and laboratory results. The performance of the algorithm was validated at three of the five participating institutions compared against clinician review. A GWAS was subsequently performed using cases and controls identified by the algorithm, with samples pooled across all five institutions.
The algorithm achieved 98% and 100% positive predictive values for the identification of diabetic cases and controls, respectively, as compared against clinician review. By standardizing and applying the algorithm across institutions, 3353 cases and 3352 controls were identified. Subsequent GWAS using data from five institutions replicated the TCF7L2 gene variant (rs7903146) previously associated with T2D.
By applying stringent criteria to EMR data collected through routine clinical care, cases and controls for a GWAS were identified that subsequently replicated a known genetic variant. The use of standard terminologies to define data elements enabled pooling of subjects and data across five different institutions to achieve the robust numbers required for GWAS.
An algorithm using commonly available data from five different EMR can accurately identify T2D cases and controls for genetic study across multiple institutions.
PMCID: PMC3277617  PMID: 22101970
Analytics; application of biological knowledge to clinical care; bioinformatics; biomedical informatics; clinical phenotyping; controlled terminologies and vocabularies; data mining; EHR; EMR secondary and meaningful use; genetic epidemiology; genetics; genome-wide association studies; genomics; HIT data standards; improving the education and skills training of health professionals; infection control; information retrieval; knowledge representations; linking the genotype and phenotype; medical informatics; modeling; natural-language processing; ontologies; pharmacogenomics; phenotyping; reuseability; translational research
19.  dictyBase 2013: integrating multiple Dictyostelid species 
Nucleic Acids Research  2012;41(Database issue):D676-D683.
dictyBase ( is the model organism database for the social amoeba Dictyostelium discoideum. This contribution provides an update on dictyBase that has been previously presented. During the past 3 years, dictyBase has taken significant strides toward becoming a genome portal for the whole Amoebozoa clade. In its latest release, dictyBase has scaled up to host multiple Dictyostelids, including Dictyostelium purpureum [Sucgang, Kuo, Tian, Salerno, Parikh, Feasley, Dalin, Tu, Huang, Barry et al.(2011) (Comparative genomics of the social amoebae Dictyostelium discoideum and Dictyostelium purpureum. Genome Biol., 12, R20)], Dictyostelium fasciculatum and Polysphondylium pallidum [Heidel, Lawal, Felder, Schilde, Helps, Tunggal, Rivero, John, Schleicher, Eichinger et al. (2011) (Phylogeny-wide analysis of social amoeba genomes highlights ancient origins for complex intercellular communication. Genome Res., 21, 1882–1891)]. The new release includes a new Genome Browser with RNAseq expression, interspecies Basic Local Alignment Search Tool alignments and a unified Basic Local Alignment Search Tool search for cross-species comparisons.
PMCID: PMC3531180  PMID: 23172289
20.  Uncovering a Role for the Tail of the Dictyostelium discoideum SadA Protein in Cell-Substrate Adhesion ▿ † 
Eukaryotic Cell  2011;10(5):662-671.
Previous work from our laboratory showed that the Dictyostelium discoideum SadA protein plays a central role in cell-substrate adhesion. SadA null cells exhibit a loss of adhesion, a disrupted actin cytoskeleton, and a cytokinesis defect. How SadA mediates these phenotypes is unknown. This work addresses the mechanism of SadA function, demonstrating an important role for the C-terminal cytoplasmic tail in SadA function. We found that a SadA tailless mutant was unable to rescue the sadA adhesion deficiency, and overexpression of the SadA tail domain reduced adhesion in wild-type cells. We also show that SadA is closely associated with the actin cytoskeleton. Mutagenesis studies suggested that four serine residues in the tail, S924/S925 and S940/S941, may regulate association of SadA with the actin cytoskeleton. Glutathione S-transferase pull-down assays identified at least one likely interaction partner of the SadA tail, cortexillin I, a known actin bundling protein. Thus, our data demonstrate an important role for the carboxy-terminal cytoplasmic tail in SadA function and strongly suggest that a phosphorylation event in this tail regulates an interaction with cortexillin I. Based on our data, we propose a model for the function of SadA.
PMCID: PMC3127660  PMID: 21441344
21.  Comparative genomics of the social amoebae Dictyostelium discoideum and Dictyostelium purpureum 
Genome Biology  2011;12(2):R20.
The social amoebae (Dictyostelia) are a diverse group of Amoebozoa that achieve multicellularity by aggregation and undergo morphogenesis into fruiting bodies with terminally differentiated spores and stalk cells. There are four groups of dictyostelids, with the most derived being a group that contains the model species Dictyostelium discoideum.
We have produced a draft genome sequence of another group dictyostelid, Dictyostelium purpureum, and compare it to the D. discoideum genome. The assembly (8.41 × coverage) comprises 799 scaffolds totaling 33.0 Mb, comparable to the D. discoideum genome size. Sequence comparisons suggest that these two dictyostelids shared a common ancestor approximately 400 million years ago. In spite of this divergence, most orthologs reside in small clusters of conserved synteny. Comparative analyses revealed a core set of orthologous genes that illuminate dictyostelid physiology, as well as differences in gene family content. Interesting patterns of gene conservation and divergence are also evident, suggesting function differences; some protein families, such as the histidine kinases, have undergone little functional change, whereas others, such as the polyketide synthases, have undergone extensive diversification. The abundant amino acid homopolymers encoded in both genomes are generally not found in homologous positions within proteins, so they are unlikely to derive from ancestral DNA triplet repeats. Genes involved in the social stage evolved more rapidly than others, consistent with either relaxed selection or accelerated evolution due to social conflict.
The findings from this new genome sequence and comparative analysis shed light on the biology and evolution of the Dictyostelia.
PMCID: PMC3188802  PMID: 21356102
22.  The eMERGE Network: A consortium of biorepositories linked to electronic medical records data for conducting genomic studies 
BMC Medical Genomics  2011;4:13.
The eMERGE (electronic MEdical Records and GEnomics) Network is an NHGRI-supported consortium of five institutions to explore the utility of DNA repositories coupled to Electronic Medical Record (EMR) systems for advancing discovery in genome science. eMERGE also includes a special emphasis on the ethical, legal and social issues related to these endeavors.
The five sites are supported by an Administrative Coordinating Center. Setting of network goals is initiated by working groups: (1) Genomics, (2) Informatics, and (3) Consent & Community Consultation, which also includes active participation by investigators outside the eMERGE funded sites, and (4) Return of Results Oversight Committee. The Steering Committee, comprised of site PIs and representatives and NHGRI staff, meet three times per year, once per year with the External Scientific Panel.
Current progress
The primary site-specific phenotypes for which samples have undergone genome-wide association study (GWAS) genotyping are cataract and HDL, dementia, electrocardiographic QRS duration, peripheral arterial disease, and type 2 diabetes. A GWAS is also being undertaken for resistant hypertension in ≈2,000 additional samples identified across the network sites, to be added to data available for samples already genotyped. Funded by ARRA supplements, secondary phenotypes have been added at all sites to leverage the genotyping data, and hypothyroidism is being analyzed as a cross-network phenotype. Results are being posted in dbGaP. Other key eMERGE activities include evaluation of the issues associated with cross-site deployment of common algorithms to identify cases and controls in EMRs, data privacy of genomic and clinically-derived data, developing approaches for large-scale meta-analysis of GWAS data across five sites, and a community consultation and consent initiative at each site.
Future activities
Plans are underway to expand the network in diversity of populations and incorporation of GWAS findings into clinical care.
By combining advanced clinical informatics, genome science, and community consultation, eMERGE represents a first step in the development of data-driven approaches to incorporate genomic information into routine healthcare delivery.
PMCID: PMC3038887  PMID: 21269473
23.  Towards BioDBcore: a community-defined information specification for biological databases 
The present article proposes the adoption of a community-defined, uniform, generic description of the core attributes of biological databases, BioDBCore. The goals of these attributes are to provide a general overview of the database landscape, to encourage consistency and interoperability between resources; and to promote the use of semantic and syntactic standards. BioDBCore will make it easier for users to evaluate the scope and relevance of available resources. This new resource will increase the collective impact of the information present in biological databases.
PMCID: PMC3017395  PMID: 21205783
24.  Towards BioDBcore: a community-defined information specification for biological databases 
Nucleic Acids Research  2010;39(Database issue):D7-D10.
The present article proposes the adoption of a community-defined, uniform, generic description of the core attributes of biological databases, BioDBCore. The goals of these attributes are to provide a general overview of the database landscape, to encourage consistency and interoperability between resources and to promote the use of semantic and syntactic standards. BioDBCore will make it easier for users to evaluate the scope and relevance of available resources. This new resource will increase the collective impact of the information present in biological databases.
PMCID: PMC3013734  PMID: 21097465
25.  dictyBase update 2011: web 2.0 functionality and the initial steps towards a genome portal for the Amoebozoa 
Nucleic Acids Research  2010;39(Database issue):D620-D624.
dictyBase (, the model organism database for Dictyostelium, aims to provide the broad biomedical research community with well integrated, high quality data and tools for Dictyostelium discoideum and related species. dictyBase houses the complete genome sequence, ESTs, and the entire body of literature relevant to Dictyostelium. This information is curated to provide accurate gene models and functional annotations, with the goal of fully annotating the genome to provide a ‘reference genome’ in the Amoebozoa clade. We highlight several new features in the present update: (i) new annotations; (ii) improved interface with web 2.0 functionality; (iii) the initial steps towards a genome portal for the Amoebozoa; (iv) ortholog display; and (v) the complete integration of the Dicty Stock Center with dictyBase.
PMCID: PMC3013695  PMID: 21087999

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