Publications by authors named "Anna Tyler"

32 Publications

Effects of kinship correction on inflation of genetic interaction statistics in commonly used mouse populations.

G3 (Bethesda) 2021 Apr 23. Epub 2021 Apr 23.

The Jackson Laboratory, 600 Main St. Bar Harbor, ME, 04609, USA.

It is well understood that variation in relatedness among individuals, or kinship, can lead to false genetic associations. Multiple methods have been developed to adjust for kinship while maintaining power to detect true associations. However, relatively unstudied, are the effects of kinship on genetic interaction test statistics. Here we performed a survey of kinship effects on studies of six commonly used mouse populations. We measured inflation of main effect test statistics, genetic interaction test statistics, and interaction test statistics reparametrized by the Combined Analysis of Pleiotropy and Epistasis (CAPE). We also performed linear mixed model (LMM) kinship corrections using two types of kinship matrix: an overall kinship matrix calculated from the full set of genotyped markers, and a reduced kinship matrix, which left out markers on the chromosome(s) being tested. We found that test statistic inflation varied across populations and was driven largely by linkage disequilibrium. In contrast, there was no observable inflation in the genetic interaction test statistics. CAPE statistics were inflated at a level in between that of the main effects and the interaction effects. The overall kinship matrix overcorrected the inflation of main effect statistics relative to the reduced kinship matrix. The two types of kinship matrices had similar effects on the interaction statistics and CAPE statistics, although the overall kinship matrix trended toward a more severe correction. In conclusion, we recommend using a LMM kinship correction for both main effects and genetic interactions and further recommend that the kinship matrix be calculated from a reduced set of markers in which the chromosomes being tested are omitted from the calculation. This is particularly important in populations with substantial population structure, such as recombinant inbred lines in which genomic replicates are used.
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http://dx.doi.org/10.1093/g3journal/jkab131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496251PMC
April 2021

System-Level Analysis of Alzheimer's Disease Prioritizes Candidate Genes for Neurodegeneration.

Front Genet 2021 6;12:625246. Epub 2021 Apr 6.

Department of Neurological Sciences, University of Vermont, Burlington, VT, United States.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder. Since the advent of the genome-wide association study (GWAS) we have come to understand much about the genes involved in AD heritability and pathophysiology. Large case-control meta-GWAS studies have increased our ability to prioritize weaker effect alleles, while the recent development of has provided a mechanism by which we can use machine learning to reprioritize GWAS hits in the functional context of relevant brain tissues like the hippocampus and amygdala. In parallel with these developments, groups like the Alzheimer's Disease Neuroimaging Initiative (ADNI) have compiled rich compendia of AD patient data including genotype and biomarker information, including derived volume measures for relevant structures like the hippocampus and the amygdala. In this study we wanted to identify genes involved in AD-related atrophy of these two structures, which are often critically impaired over the course of the disease. To do this we developed a combined score prioritization method which uses the cumulative distribution function of a gene's functional and positional score, to prioritize top genes that not only segregate with disease status, but also with hippocampal and amygdalar atrophy. Our method identified a mix of genes that had previously been identified in AD GWAS including , , and () and several others that have not been identified in AD genetic studies, but play integral roles in AD-effected functional pathways including , , and . Our findings support the viability of our novel combined score as a method for prioritizing region- and even cell-specific AD risk genes.
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http://dx.doi.org/10.3389/fgene.2021.625246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056044PMC
April 2021

The Combined Analysis of Pleiotropy and Epistasis (CAPE).

Methods Mol Biol 2021 ;2212:55-67

The Jackson Laboratory, Bar Harbor, ME, USA.

Epistasis, or gene-gene interaction, contributes substantially to trait variation in organisms ranging from yeast to humans, and modeling epistasis directly is critical to understanding the genotype-phenotype map. However, inference of genetic interactions is challenging compared to inference of individual allele effects due to low statistical power. Furthermore, genetic interactions can appear inconsistent across different quantitative traits, presenting a challenge for the interpretation of detected interactions. Here we present a method called the Combined Analysis of Pleiotropy and Epistasis (CAPE) that combines information across multiple quantitative traits to infer directed epistatic interactions. By combining information across multiple traits, CAPE not only increases power to detect genetic interactions but also interprets these interactions across traits to identify a single interaction that is consistent across all observed data. This method generates informative, interpretable interaction networks that explain how variants interact with each other to influence groups of related traits. This method could potentially be used to link genetic variants to gene expression, physiological endophenotypes, and higher-level disease traits.
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http://dx.doi.org/10.1007/978-1-0716-0947-7_5DOI Listing
April 2021

Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19.

JAMA 2021 04;325(15):1535-1544

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Importance: Control of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines.

Objective: To evaluate the immunogenicity of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses.

Design, Setting, And Participants: Twenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S.

Interventions: Participants were randomized to receive 1 or 2 intramuscular injections with 5 × 1010 viral particles or 1 × 1011 viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group).

Main Outcomes And Measures: Humoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses.

Results: Twenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced.

Conclusion And Relevance: In this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine.

Trial Registration: ClinicalTrials.gov Identifier: NCT04436276.
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http://dx.doi.org/10.1001/jama.2021.3645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953339PMC
April 2021

Identification of novel loci controlling inflammatory bowel disease susceptibility utilizing the genetic diversity of wild-derived mice.

Genes Immun 2020 11 26;21(5):311-325. Epub 2020 Aug 26.

Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, 05405, USA.

Inflammatory bowel disease (IBD) is a complex disorder that imposes a growing health burden. Multiple genetic associations have been identified in IBD, but the mechanisms underlying many of these associations are poorly understood. Animal models are needed to bridge this gap, but conventional laboratory mouse strains lack the genetic diversity of human populations. To more accurately model human genetic diversity, we utilized a panel of chromosome (Chr) substitution strains, carrying chromosomes from the wild-derived and genetically divergent PWD/PhJ (PWD) strain on the commonly used C57BL/6J (B6) background, as well as their parental B6 and PWD strains. Two models of IBD were used, TNBS- and DSS-induced colitis. Compared with B6 mice, PWD mice were highly susceptible to TNBS-induced colitis, but resistant to DSS-induced colitis. Using consomic mice, we identified several PWD-derived loci that exhibited profound effects on IBD susceptibility. The most pronounced of these were loci on Chr1 and Chr2, which yielded high susceptibility in both IBD models, each acting at distinct phases of the disease. Leveraging transcriptomic data from B6 and PWD immune cells, together with a machine learning approach incorporating human IBD genetic associations, we identified lead candidate genes, including Itga4, Pip4k2a, Lcn10, Lgmn, and Gpr65.
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http://dx.doi.org/10.1038/s41435-020-00110-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657953PMC
November 2020

Safety and immunogenicity of a Zika purified inactivated virus vaccine given via standard, accelerated, or shortened schedules: a single-centre, double-blind, sequential-group, randomised, placebo-controlled, phase 1 trial.

Lancet Infect Dis 2020 09 6;20(9):1061-1070. Epub 2020 May 6.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Electronic address:

Background: The development of an effective vaccine against Zika virus remains a public health priority. A Zika purified inactivated virus (ZPIV) vaccine candidate has been shown to protect animals against Zika virus challenge and to be well tolerated and immunogenic in humans up to 8 weeks of follow-up. We aimed to assess the safety and immunogenicity of ZPIV in humans up to 52 weeks of follow-up when given via standard or accelerated vaccination schedules.

Methods: We did a single-centre, double-blind, randomised controlled, phase 1 trial in healthy adults aged 18-50 years with no known history of flavivirus vaccination or infection at Beth Israel Deaconess Medical Center in Boston, MA, USA. Participants were sequentially enrolled into one of three groups: ZPIV given at weeks 0 and 4 (standard regimen), weeks 0 and 2 (accelerated regimen), or week 0 alone (single-dose regimen). Within each group, participants were randomly assigned using a computer-generated randomisation schedule to receive an intramuscular injection of 5 μg ZPIV or saline placebo, in a ratio of 5:1. The sponsor, clinical staff, investigators, participants, and laboratory personnel were masked to treatment assignment. The primary endpoint was safety up to day 364 after final dose administration, and secondary endpoints were proportion of participants with positive humoral immune responses (50% microneutralisation titre [MN] ≥100) and geometric mean MN at observed peak response (ie, the highest neutralising antibody level observed for an individual participant across all timepoints) and week 28. All participants who received at least one dose of ZPIV or placebo were included in the safety population; the analysis of immunogenicity at observed peak included all participants who received at least one dose of ZPIV or placebo and had any adverse events or immunogenicity data after dosing. The week 28 immunogenicity analysis population consisted of all participants who received ZPIV or placebo and had immunogenicity data available at week 28. This trial is registered with ClinicalTrials.gov, NCT02937233.

Findings: Between Dec 8, 2016, and May 17, 2017, 12 participants were enrolled into each group and then randomly assigned to vaccine (n=10) or placebo (n=2). There were no serious or grade 3 treatment-related adverse events. The most common reactions among the 30 participants who received the vaccine were injection-site pain (24 [80%]), fatigue (16 [53%]), and headache (14 [46%]). A positive response at observed peak titre was detected in all participants who received ZPIV via the standard regimen, in eight (80%) of ten participants who received ZPIV via the accelerated regimen, and in none of the ten participants who received ZPIV via the single-dose regimen. The geometric mean of all individual participants' observed peak values was 1153·9 (95% CI 455·2-2925·2) in the standard regimen group, 517·7 (142·9-1875·6) in the accelerated regimen group, and 6·3 (3·7-10·8) in the single-dose regimen group. At week 28, a positive response was observed in one (13%) of eight participants who received ZPIV via the standard regimen and in no participant who received ZPIV via the accelerated (n=7) or single-dose (n=10) regimens. The geomteric mean titre (GMT) at this timepoint was 13·9 (95% CI 3·5-55·1) in the standard regimen group and 6·9 (4·0-11·9) in the accelerated regimen group; antibody titres were undetectable at 28 weeks in participants who received ZPIV via the single-dose regimen. For all vaccine schedules, GMTs peaked 2 weeks after the final vaccination and declined to less than 100 by study week 16. There was no difference in observed peak GMTs between the standard 4-week and the accelerated 2-week boosting regimens (p=0·4494).

Interpretation: ZPIV was safe and well tolerated in humans up to 52 weeks of follow-up. ZPIV immunogenicity required two doses and was not durable. Additional studies of ZPIV to optimise dosing schedules are ongoing.

Funding: The Henry M Jackson Foundation for the Advancement of Military Medicine.
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http://dx.doi.org/10.1016/S1473-3099(20)30085-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472641PMC
September 2020

Comparison of shortened mosaic HIV-1 vaccine schedules: a randomised, double-blind, placebo-controlled phase 1 trial (IPCAVD010/HPX1002) and a preclinical study in rhesus monkeys (NHP 17-22).

Lancet HIV 2020 06 17;7(6):e410-e421. Epub 2020 Feb 17.

Janssen Vaccines & Prevention BV, Leiden, Netherlands.

Background: Current efficacy studies of a mosaic HIV-1 prophylactic vaccine require four vaccination visits over one year, which is a complex regimen that could prove challenging for vaccine delivery at the community level, both for recipients and clinics. In this study, we evaluated the safety, tolerability, and immunogenicity of shorter, simpler regimens of trivalent Ad26.Mos.HIV expressing mosaic HIV-1 Env/Gag/Pol antigens combined with aluminium phosphate-adjuvanted clade C gp140 protein.

Methods: We did this randomised, double-blind, placebo-controlled phase 1 trial (IPCAVD010/HPX1002) at Beth Israel Deaconess Medical Center in Boston, MA, USA. We included healthy, HIV-uninfected participants (aged 18-50 years) who were considered at low risk for HIV infection and had not received any vaccines in the 14 days before study commencement. We randomly assigned participants via a computer-generated randomisation schedule and interactive web response system to one of three study groups (1:1:1) testing different regimens of trivalent Ad26.Mos.HIV (5 × 10 viral particles per 0·5 mL) combined with 250 μg adjuvanted clade C gp140 protein. They were then assigned to treatment or placebo subgroups (5:1) within each of the three main groups. Participants and investigators were masked to treatment allocation until the end of the follow-up period. Group 1 received Ad26.Mos.HIV alone at weeks 0 and 12 and Ad26.Mos.HIV plus adjuvanted gp140 at weeks 24 and 48. Group 2 received Ad26.Mos.HIV plus adjuvanted gp140 at weeks 0, 12, and 24. Group 3 received Ad26.Mos.HIV alone at week 0 and Ad26.Mos.HIV plus adjuvanted gp140 at weeks 8 and 24. Participants in the control group received 0·5 mL of 0·9% saline. All study interventions were administered intramuscularly. The primary endpoints were Env-specific binding antibody responses at weeks 28, 52, and 72 and safety and tolerability of the vaccine regimens for 28 days after the injection. All participants who received at least one vaccine dose or placebo were included in the safety analysis; immunogenicity was analysed using the per-protocol population. The IPCAVD010/HPX1002 trial is registered with ClinicalTrials.gov, NCT02685020. We also did a parallel preclinical study in rhesus monkeys to test the protective efficacy of the shortened group 3 regimen.

Findings: Between March 7, 2016, and Aug 19, 2016, we randomly assigned 36 participants to receive at least one dose of study vaccine or placebo, ten to each vaccine group and two to the corresponding placebo group. 30 (83%) participants completed the full study, and six (17%) discontinued it prematurely because of loss to follow-up, withdrawal of consent, investigator decision, and an unrelated death from a motor vehicle accident. The two shortened regimens elicited comparable antibody titres against autologous clade C Env at peak immunity to the longer, 12-month regimen: geometric mean titre (GMT) 41 007 (95% CI 17 959-93 636) for group 2 and 49 243 (29 346-82 630) for group 3 at week 28 compared with 44 590 (19 345-102 781) for group 1 at week 52). Antibody responses remained increased (GMT >5000) in groups 2 and 3 at week 52 but were highest in group 1 at week 72. Antibody-dependent cellular phagocytosis, Env-specific IgG3, tier 1A neutralising activity, and broad cellular immune responses were detected in all groups. All vaccine regimens were well tolerated. Mild-to-moderate pain or tenderness at the injection site was the most commonly reported solicited local adverse event, reported by 28 vaccine recipients (93%) and two placebo recipients (33%). Grade 3 solicited systemic adverse events were reported by eight (27%) vaccine recipients and no placebo recipients; the most commonly reported grade 3 systemic symptoms were fatigue, myalgia, and chills. The shortened group 3 regimen induced comparable peak immune responses in 30 rhesus monkeys as in humans and resulted in an 83% (95% CI 38·7-95, p=0·004 log-rank test) reduction in per-exposure acquisition risk after six intrarectal challenges with SHIV-SF162P3 at week 54, more than 6 months after final vaccination.

Interpretation: Short, 6-month regimens of a mosaic HIV-1 prophylactic vaccine elicited robust HIV-specific immune responses that were similar to responses elicited by a longer, 12-month schedule. Preclinical data showed partial protective efficacy of one of the short vaccine regimens in rhesus monkeys. Further clinical studies are required to test the suitability of the shortened vaccine regimens in humans. Such shortened regimens would be valuable to increase vaccine delivery at the community level, particularly in resource-limited settings.

Funding: Ragon Institute (Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University; Cambridge, MA, USA) and Janssen Vaccines & Prevention (Leiden, Netherlands).
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http://dx.doi.org/10.1016/S2352-3018(20)30001-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297076PMC
June 2020

Genetic Interactions Affect Lung Function in Patients with Systemic Sclerosis.

G3 (Bethesda) 2020 01 7;10(1):151-163. Epub 2020 Jan 7.

The Jackson Laboratory, 600 Main St. Bar Harbor, ME,

Scleroderma, or systemic sclerosis (SSc), is an autoimmune disease characterized by progressive fibrosis of the skin and internal organs. The most common cause of death in people with SSc is lung disease, but the pathogenesis of lung disease in SSc is insufficiently understood to devise specific treatment strategies. Developing targeted treatments requires not only the identification of molecular processes involved in SSc-associated lung disease, but also understanding of how these processes interact to drive pathology. One potentially powerful approach is to identify alleles that interact genetically to influence lung outcomes in patients with SSc. Analysis of interactions, rather than individual allele effects, has the potential to delineate molecular interactions that are important in SSc-related lung pathology. However, detecting genetic interactions, or epistasis, in human cohorts is challenging. Large numbers of variants with low minor allele frequencies, paired with heterogeneous disease presentation, reduce power to detect epistasis. Here we present an analysis that increases power to detect epistasis in human genome-wide association studies (GWAS). We tested for genetic interactions influencing lung function and autoantibody status in a cohort of 416 SSc patients. Using Matrix Epistasis to filter SNPs followed by the Combined Analysis of Pleiotropy and Epistasis (CAPE), we identified a network of interacting alleles influencing lung function in patients with SSc. In particular, we identified a three-gene network comprising , , and , which in combination influenced multiple pulmonary pathology measures. The associations of these genes with lung outcomes in SSc are novel and high-confidence. Furthermore, gene coexpression analysis suggested that the interactions we identified are tissue-specific, thus differentiating SSc-related pathogenic processes in lung from those in skin.
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http://dx.doi.org/10.1534/g3.119.400775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945038PMC
January 2020

Network-Based Functional Prediction Augments Genetic Association To Predict Candidate Genes for Histamine Hypersensitivity in Mice.

G3 (Bethesda) 2019 12 3;9(12):4223-4233. Epub 2019 Dec 3.

Department of Neurological Sciences,

Genetic mapping is a primary tool of genetics in model organisms; however, many quantitative trait loci (QTL) contain tens or hundreds of positional candidate genes. Prioritizing these genes for validation is often and biased by previous findings. Here we present a technique for prioritizing positional candidates based on computationally inferred gene function. Our method uses machine learning with functional genomic networks, whose links encode functional associations among genes, to identify network-based signatures of functional association to a trait of interest. We demonstrate the method by functionally ranking positional candidates in a large locus on mouse Chr 6 (45.9 Mb to 127.8 Mb) associated with histamine hypersensitivity (Histh). Histh is characterized by systemic vascular leakage and edema in response to histamine challenge, which can lead to multiple organ failure and death. Although Histh risk is strongly influenced by genetics, little is known about its underlying molecular or genetic causes, due to genetic and physiological complexity of the trait. To dissect this complexity, we ranked genes in the locus by predicting functional association with multiple Histh-related processes. We integrated these predictions with new single nucleotide polymorphism (SNP) association data derived from a survey of 23 inbred mouse strains and congenic mapping data. The top-ranked genes included , , , and , all of which had strong functional associations and were proximal to SNPs segregating with Histh. These results demonstrate the power of network-based computational methods to nominate highly plausible quantitative trait genes even in challenging cases involving large QTL and extreme trait complexity.
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http://dx.doi.org/10.1534/g3.119.400740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893195PMC
December 2019

Fullerene toxicity in the benthos with implications for freshwater ecosystem services.

Sci Total Environ 2019 Oct 31;687:451-459. Epub 2019 May 31.

Thomas H. Gosnell School of Life Sciences, Rochester Institute of Technology, Rochester, NY, United States of America. Electronic address:

Production of engineered carbon-based nanomaterials (CNMs) is rising, with increased risk of release to the environment during production, use, and disposal. This trend highlights a need to understand potential impacts of CNMs on the natural environment. Fullerenes are an emerging class of CNMs that are insoluble in water, and form aggregates that settle quickly, suggesting higher relative vulnerability of aquatic benthic ecosystems. This study assessed eco-toxicity of fullerenes (C60, C70) and the functionalized derivative, phenyl-C61-butyric acid methyl ester (PCBM), on functionally representative benthic organisms in traditional laboratory assays, and evaluated how the potential lethal and sub-lethal effects of fullerenes may indirectly impact benthic ecosystem function, including decomposition, primary productivity and nutrient cycling in lake microcosms with natural sediments. Standard toxicity tests indicated that population growth of Lumbriculus variegatus was reduced at 25 to 150 mg C60 kg, but C70 and PCBM did not affect growth or weight of organisms in artificial sediments at 25 mg kg. Survivorship and growth were lower in natural sediments with historic contamination, but C60 did not exacerbate this effect. C60 inhibited photosynthesis by the benthic diatom Nitzschia palea, and at high exposure chlorophyll a increased, suggesting a shading response. L. variegatus had strong effects on benthic ecosystem function, especially metabolism and nitrogen cycling, but C60 ≤ 30 mg kg sediment did not influence the role of L. variegatus in driving benthic processes. These observations suggest that at moderate to high concentrations, C60 may directly impact benthic organisms. However, under natural conditions with low to moderate concentrations, C60 has little effect and does not indirectly impact the ecosystem processes maintained by such organisms. These results are a step further towards a better understanding of potential impacts of fullerenes on aquatic ecosystems, and can aid in the development of regulatory policies.
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http://dx.doi.org/10.1016/j.scitotenv.2019.05.362DOI Listing
October 2019

Cascading Ecological Impacts of Fullerenes in Freshwater Ecosystems.

Environ Toxicol Chem 2019 08;38(8):1714-1723

Golisano Institute for Sustainability, Rochester Institute of Technology, Rochester, New York, USA.

Carbonaceous nanomaterials, such as fullerenes (C60, C70) and the derivative phenyl-C61-butyric acid methyl ester (PCBM), have promising application in solar energy technologies. Although the acute ecotoxicity of C60 has been reported widely in the literature, ecotoxicity assays for different fullerene forms and broader ecosystem impact studies remain scarce. To address these knowledge gaps, acute, chronic, and life stage exposure studies with freshwater zooplankton, Daphnia magna and Daphnia pulex, were performed for each material. Experimental results indicated that C60 and PCBM are not acutely toxic at estimated environmentally relevant concentrations; however, C70 had significant acute effects. All forms of fullerene caused a gradual elevation in heart rate over time and visual darkening of the Daphnia spp. carapace. The impact of fullerenes on susceptibility to predation was then assessed experimentally by presenting D. pulex to the visual predator Lepomis macrochirus (bluegill). Predation risk was significantly increased in fullerene-exposed D. pulex. The present study underscores the need to broaden the scope of traditional ecotoxicity for emerging materials: studies are required that evaluate portfolios of related nanomaterials and that capture chronic and cascading ecosystem-level effects. Environ Toxicol Chem 2019;38:1714-1723. © 2019 SETAC.
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http://dx.doi.org/10.1002/etc.4465DOI Listing
August 2019

Is Plastic Pollution in Aquatic and Terrestrial Environments a Driver for the Transmission of Pathogens and the Evolution of Antibiotic Resistance?

Environ Sci Technol 2019 02 31;53(4):1744-1745. Epub 2019 Jan 31.

The Thomas H. Gosnell School of Life Sciences , Rochester Institute of Technology , Rochester New York United States.

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http://dx.doi.org/10.1021/acs.est.8b07287DOI Listing
February 2019

Epistatic Networks Jointly Influence Phenotypes Related to Metabolic Disease and Gene Expression in Diversity Outbred Mice.

Genetics 2017 06;206(2):621-639

The Jackson Laboratory, Bar Harbor, Maine 04609

Genetic studies of multidimensional phenotypes can potentially link genetic variation, gene expression, and physiological data to create multi-scale models of complex traits. The challenge of reducing these data to specific hypotheses has become increasingly acute with the advent of genome-scale data resources. Multi-parent populations derived from model organisms provide a resource for developing methods to understand this complexity. In this study, we simultaneously modeled body composition, serum biomarkers, and liver transcript abundances from 474 Diversity Outbred mice. This population contained both sexes and two dietary cohorts. Transcript data were reduced to functional gene modules with weighted gene coexpression network analysis (WGCNA), which were used as summary phenotypes representing enriched biological processes. These module phenotypes were jointly analyzed with body composition and serum biomarkers in a combined analysis of pleiotropy and epistasis (CAPE), which inferred networks of epistatic interactions between quantitative trait loci that affect one or more traits. This network frequently mapped interactions between alleles of different ancestries, providing evidence of both genetic synergy and redundancy between haplotypes. Furthermore, a number of loci interacted with sex and diet to yield sex-specific genetic effects and alleles that potentially protect individuals from the effects of a high-fat diet. Although the epistatic interactions explained small amounts of trait variance, the combination of directional interactions, allelic specificity, and high genomic resolution provided context to generate hypotheses for the roles of specific genes in complex traits. Our approach moves beyond the cataloging of single loci to infer genetic networks that map genetic etiology by simultaneously modeling all phenotypes.
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http://dx.doi.org/10.1534/genetics.116.198051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499176PMC
June 2017

Genetic interactions improve models of quantitative traits.

Nat Genet 2017 Mar;49(4):486-488

Jackson Laboratory, Bar Harbor, Maine, USA.

A study of genetic variation in yeast has identified key quantitative trait loci (QTLs) that suppress the effects of variation at multiple other loci. These loci prove essential to accurately modeling yeast growth in response to different environments.
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http://dx.doi.org/10.1038/ng.3829DOI Listing
March 2017

State-Dependent Differences in Functional Connectivity in Young Children With Autism Spectrum Disorder.

EBioMedicine 2015 Dec 5;2(12):1905-15. Epub 2015 Nov 5.

National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Room 1C250, Bethesda, MD 20892, USA.

Background: While there is increasing evidence of altered brain connectivity in autism, the degree and direction of these alterations in connectivity and their uniqueness to autism has not been established. The aim of the present study was to compare connectivity in children with autism to that of typically developing controls and children with developmental delay without autism.

Methods: We assessed EEG spectral power, coherence, phase lag, Pearson and partial correlations, and epileptiform activity during the awake, slow wave sleep, and REM sleep states in 137 children aged 2 to 6 years with autism (n = 87), developmental delay without autism (n = 21), or typical development (n = 29).

Findings: We found that brain connectivity, as measured by coherence, phase lag, and Pearson and partial correlations distinguished children with autism from both neurotypical and developmentally delayed children. In general, children with autism had increased coherence which was most prominent during slow wave sleep.

Interpretation: Functional connectivity is distinctly different in children with autism compared to samples with typical development and developmental delay without autism. Differences in connectivity in autism are state and region related. In this study, children with autism were characterized by a dynamically evolving pattern of altered connectivity.
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http://dx.doi.org/10.1016/j.ebiom.2015.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703709PMC
December 2015

Weak Epistasis Generally Stabilizes Phenotypes in a Mouse Intercross.

PLoS Genet 2016 Feb 1;12(2):e1005805. Epub 2016 Feb 1.

The Jackson Laboratory, Bar Harbor, Maine, United States of America.

The extent and strength of epistasis is commonly unresolved in genetic studies, and observed epistasis is often difficult to interpret in terms of biological consequences or overall genetic architecture. We investigated the prevalence and consequences of epistasis by analyzing four body composition phenotypes--body weight, body fat percentage, femoral density, and femoral circumference--in a large F2 intercross of B6-lit/lit and C3.B6-lit/lit mice. We used Combined Analysis of Pleiotropy and Epistasis (CAPE) to examine interactions for the four phenotypes simultaneously, which revealed an extensive directed network of genetic loci interacting with each other, circulating IGF1, and sex to influence these phenotypes. The majority of epistatic interactions had small effects relative to additive effects of individual loci, and tended to stabilize phenotypes towards the mean of the population rather than extremes. Interactive effects of two alleles inherited from one parental strain commonly resulted in phenotypes closer to the population mean than the additive effects from the two loci, and often much closer to the mean than either single-locus model. Alternatively, combinations of alleles inherited from different parent strains contribute to more extreme phenotypes not observed in either parental strain. This class of phenotype-stabilizing interactions has effects that are close to additive and are thus difficult to detect except in very large intercrosses. Nevertheless, we found these interactions to be useful in generating hypotheses for functional relationships between genetic loci. Our findings suggest that while epistasis is often weak and unlikely to account for a large proportion of heritable variance, even small-effect genetic interactions can facilitate hypotheses of underlying biology in well-powered studies.
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http://dx.doi.org/10.1371/journal.pgen.1005805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734753PMC
February 2016

The detection and characterization of pleiotropy: discovery, progress, and promise.

Brief Bioinform 2016 Jan 28;17(1):13-22. Epub 2015 Jul 28.

The impact of a single genetic locus on multiple phenotypes, or pleiotropy, is an important area of research. Biological systems are dynamic complex networks, and these networks exist within and between cells. In humans, the consideration of multiple phenotypes such as physiological traits, clinical outcomes and drug response, in the context of genetic variation, can provide ways of developing a more complete understanding of the complex relationships between genetic architecture and how biological systems function in health and disease. In this article, we describe recent studies exploring the relationships between genetic loci and more than one phenotype. We also cover methodological developments incorporating pleiotropy applied to model organisms as well as humans, and discuss how stepping beyond the analysis of a single phenotype leads to a deeper understanding of complex genetic architecture.
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http://dx.doi.org/10.1093/bib/bbv050DOI Listing
January 2016

Detecting and Characterizing Pleiotropy: New Methods for Uncovering the Connection Between the Complexity of Genomic Architecture and Multiple phenotypes.

Pac Symp Biocomput 2014 Jan:183-187

Department of Biochemistry and Molecular Biology, Pennsylvania State University, Pennsylvania State University, University Park, PA 16802, USA.

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http://dx.doi.org/10.1142/9789814583220_0018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108263PMC
January 2014

Dissection of complex gene expression using the combined analysis of pleiotropy and epistasis.

Pac Symp Biocomput 2014 :200-11

The Jackson Laboratory, Bar Harbor, ME, 04609, USA.

Global transcript expression experiments are commonly used to investigate the biological processes that underlie complex traits. These studies can exhibit complex patterns of pleiotropy when trans-acting genetic factors influence overlapping sets of multiple transcripts. Dissecting these patterns into biological modules with distinct genetic etiology can provide models of how genetic variants affect specific processes that contribute to a trait. Here we identify transcript modules associated with pleiotropic genetic factors and apply genetic interaction analysis to disentangle the regulatory architecture in a mouse intercross study of kidney function. The method, called the combined analysis of pleiotropy and epistasis (CAPE), has been previously used to model genetic networks for multiple physiological traits. It simultaneously models multiple phenotypes to identify direct genetic influences as well as influences mediated through genetic interactions. We first identify candidate trans expression quantitative trait loci (eQTL) and the transcripts potentially affected. We then clustered the transcripts into modules of co-expressed genes, from which we compute summary module phenotypes. Finally, we applied CAPE to map the network of interacting module QTL (modQTL) affecting the gene modules. The resulting network mapped how multiple modQTL both directly and indirectly affect modules associated with metabolic functions and biosynthetic processes. This work demonstrates how the integration of pleiotropic signals in gene expression data can be used to infer a complex hypothesis of how multiple loci interact to co-regulate transcription programs, thereby providing additional constraints to prioritize validation experiments.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900022PMC
August 2014

CAPE: an R package for combined analysis of pleiotropy and epistasis.

PLoS Comput Biol 2013 Oct 24;9(10):e1003270. Epub 2013 Oct 24.

The Jackson Laboratory, Bar Harbor, Maine, United States of America.

Contemporary genetic studies are revealing the genetic complexity of many traits in humans and model organisms. Two hallmarks of this complexity are epistasis, meaning gene-gene interaction, and pleiotropy, in which one gene affects multiple phenotypes. Understanding the genetic architecture of complex traits requires addressing these phenomena, but interpreting the biological significance of epistasis and pleiotropy is often difficult. While epistasis reveals dependencies between genetic variants, it is often unclear how the activity of one variant is specifically modifying the other. Epistasis found in one phenotypic context may disappear in another context, rendering the genetic interaction ambiguous. Pleiotropy can suggest either redundant phenotype measures or gene variants that affect multiple biological processes. Here we present an R package, R/cape, which addresses these interpretation ambiguities by implementing a novel method to generate predictive and interpretable genetic networks that influence quantitative phenotypes. R/cape integrates information from multiple related phenotypes to constrain models of epistasis, thereby enhancing the detection of interactions that simultaneously describe all phenotypes. The networks inferred by R/cape are readily interpretable in terms of directed influences that indicate suppressive and enhancing effects of individual genetic variants on other variants, which in turn account for the variance in quantitative traits. We demonstrate the utility of R/cape by analyzing a mouse backcross, thereby discovering novel epistatic interactions influencing phenotypes related to obesity and diabetes. R/cape is an easy-to-use, platform-independent R package and can be applied to data from both genetic screens and a variety of segregating populations including backcrosses, intercrosses, and natural populations. The package is freely available under the GPL-3 license at http://cran.r-project.org/web/packages/cape.
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http://dx.doi.org/10.1371/journal.pcbi.1003270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808451PMC
October 2013

Speed modulation of hippocampal theta frequency correlates with spatial memory performance.

Hippocampus 2013 Dec 5;23(12):1269-79. Epub 2013 Aug 5.

Department of Neurology, Geisel School of Medicine, Hanover, New Hampshire.

Hippocampal theta rhythm is believed to play a critical role in learning and memory. In animal models of temporal lobe epilepsy (TLE), there is evidence that alterations of hippocampal theta oscillations are involved in the cognitive impairments observed in this model. However, hippocampal theta frequency and amplitude at both the local field potential (LFP) and single unit level are strongly modulated by running speed, suggesting that the integration of locomotor information into memory processes may also be critical for hippocampal processing. Here, we investigate whether hippocampal speed-theta integration influences spatial memory and whether it could account for the memory deficits observed in TLE rats. LFPs were recorded in both Control (CTR) and TLE rats as they were trained in a spatial alternation task. TLE rats required more training sessions to perform the task at CTR levels. Both theta frequency and power were significantly lower in the TLE group. In addition, speed/theta frequency correlation coefficients and regression slopes varied from session to session and were worse in TLE. Importantly, there was a strong relationship between speed/theta frequency parameters and performance. Our analyses reveal that speed/theta frequency correlation with performance cannot merely be explained by the direct influence of speed on behavior. Therefore, variations in the coordination of theta frequency with speed may participate in learning and memory processes. Impairments of this function could explain at least partially memory deficits in epilepsy.
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http://dx.doi.org/10.1002/hipo.22164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410367PMC
December 2013

Functional network changes in hippocampal CA1 after status epilepticus predict spatial memory deficits in rats.

J Neurosci 2012 Aug;32(33):11365-76

Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755-1404, USA.

Status epilepticus (SE) is a common neurological emergency, which has been associated with subsequent cognitive impairments. Neuronal death in hippocampal CA1 is thought to be an important mechanism of these impairments. However, it is also possible that functional interactions between surviving neurons are important. In this study we recorded in vivo single-unit activity in the CA1 hippocampal region of rats while they performed a spatial memory task. From these data we constructed functional networks describing pyramidal cell interactions. To build the networks, we used maximum entropy algorithms previously applied only to in vitro data. We show that several months following SE pyramidal neurons display excessive neuronal synchrony and less neuronal reactivation during rest compared with those in healthy controls. Both effects predict rat performance in a spatial memory task. These results provide a physiological mechanism for SE-induced cognitive impairment and highlight the importance of the systems-level perspective in investigating spatial cognition.
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http://dx.doi.org/10.1523/JNEUROSCI.1516-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536550PMC
August 2012

Differential daytime and night-time stomatal behavior in plants from North American deserts.

New Phytol 2012 Apr 20;194(2):464-476. Epub 2012 Feb 20.

Department of Biological Sciences, Texas Tech University, Lubbock 79409-3131, TX, USA.

Night-time stomatal conductance (g(night)) occurs in many ecosystems, but the g(night) response to environmental drivers is relatively unknown, especially in deserts. Here, we conducted a Bayesian analysis of stomatal conductance (g) (N=5013) from 16 species in the Sonoran, Chihuahuan, Mojave and Great Basin Deserts (North America). We partitioned daytime g (g(day)) and g(night) responses by describing g as a mixture of two extreme (dark vs high light) behaviors. Significant g(night) was observed across 15 species, and the g(night) and g(day) behavior differed according to species, functional type and desert. The transition between extreme behaviors was determined by light environment, with the transition behavior differing between functional types and deserts. Sonoran and Chihuahuan C(4) grasses were more sensitive to vapor pressure difference (D) at night and soil water potential (Ψ(soil)) during the day, Great Basin C(3) shrubs were highly sensitive to D and Ψ(soil) during the day, and Mojave C(3) shrubs were equally sensitive to D and Ψ(soil) during the day and night. Species were split between the exhibition of isohydric or anisohydric behavior during the day. Three species switched from anisohydric to isohydric behavior at night. Such behavior, combined with differential D, Ψ(soil) and light responses, suggests that different mechanisms underlie g(day) and g(night) regulation.
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http://dx.doi.org/10.1111/j.1469-8137.2012.04068.xDOI Listing
April 2012

Polymorphisms in the brain-derived neurotrophic factor gene influence memory and processing speed one month after brain injury.

J Neurotrauma 2012 Apr 2;29(6):1111-8. Epub 2012 Mar 2.

Section of Neuropsychiatry, Department of Psychiatry, Dartmouth Medical School, Lebanon, New Hampshire 05756, USA.

Brain-derived neurotrophic factor (BDNF) plays a role in cognition, as well as neural survival and plasticity. There are several common polymorphisms in the BDNF gene, one of which (rs6265) is an extensively studied non-synonymous coding polymorphism (Val66Met) which has been linked to cognitive performance in healthy controls and some clinical populations. We hypothesized that the Met allele of rs6265 would be associated with poorer cognitive performance in individuals with mild-to-moderate traumatic brain injury, and that other polymorphisms in the BDNF gene would also affect cognition. Genotype at 9 single-nucleotide polymorphisms (SNPs) in the BDNF gene, and measures of speed of information processing, learning, and memory were assessed in 75 patients with mTBI and 38 healthy subjects. Consistent with previous reports, the Met allele of rs6265 was associated with cognition (slower processing speed) in the entire group. Two other SNPs were associated with processing speed in the mTBI group, but both are in linkage disequilibrium with rs6265, and neither remained significant after adjustment for rs6265 status. Within the mTBI group, but not the controls, 4 SNPs, but not rs6265, were associated with memory measures. These associations were not affected by adjustment for rs6265 status. Polymorphisms in BDNF influence cognitive performance shortly after mTBI. The results raise the possibility that a functional polymorphism other than rs6265 may contribute to memory function after mTBI.
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http://dx.doi.org/10.1089/neu.2011.1930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325555PMC
April 2012

SLC39A2 and FSIP1 polymorphisms as potential modifiers of arsenic-related bladder cancer.

Hum Genet 2012 Mar 25;131(3):453-61. Epub 2011 Sep 25.

Section of Biostatistics and Epidemiology, Dartmouth Medical School, Lebanon, NH 03756, USA.

Arsenic is a carcinogen that contaminates drinking water worldwide. Accumulating evidence suggests that both exposure and genetic factors may influence susceptibility to arsenic-induced malignancies. We sought to identify novel susceptibility loci for arsenic-related bladder cancer in a US population with low to moderate drinking water levels of arsenic. We first screened a subset of bladder cancer cases using a panel of approximately 10,000 non-synonymous single nucleotide polymorphisms (SNPs). Top ranking hits on the SNP array then were considered for further analysis in our population-based case-control study (n = 832 cases and 1,191 controls). SNPs in the fibrous sheath interacting protein 1 (FSIP1) gene (rs10152640) and the solute carrier family 39, member 2 (SLC39A2) in the ZIP gene family of metal transporters (rs2234636) were detected as potential hits in the initial scan and validated in the full case-control study. The adjusted odds ratio (OR) for the FSIP1 polymorphism was 2.57 [95% confidence interval (CI) 1.13, 5.85] for heterozygote variants (AG) and 12.20 (95% CI 2.51, 59.30) for homozygote variants (GG) compared to homozygote wild types (AA) in the high arsenic group (greater than the 90th percentile), and unrelated in the low arsenic group (equal to or below the 90th percentile) (P for interaction = 0.002). For the SLC39A2 polymorphism, the adjusted ORs were 2.96 (95% CI 1.23, 7.15) and 2.91 (95% CI 1.00, 8.52) for heterozygote (TC) and homozygote (CC) variants compared to homozygote wild types (TT), respectively, and close to one in the low arsenic group (P for interaction = 0.03). Our findings suggest novel variants that may influence risk of arsenic-associated bladder cancer and those who may be at greatest risk from this widespread exposure.
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http://dx.doi.org/10.1007/s00439-011-1090-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278547PMC
March 2012

Pollen performance of Raphanus sativus (Brassicaceae) declines in response to elevated [CO(2)].

Sex Plant Reprod 2010 Dec 19;23(4):325-36. Epub 2010 Jun 19.

Department of Biology, University of New Mexico, Albuquerque, NM 87131, USA.

Although increases in atmospheric [CO(2)] are known to affect plant physiology, growth and reproduction, understanding of these effects is limited because most studies of reproductive consequences focus solely on female function. Therefore, we examined the effects of CO(2) enrichment on male function in the annual Raphanus sativus. Pollen donors grown under elevated [CO(2)] initially sired a higher proportion of seeds per fruit than ambient [CO(2)]-grown plants when each was tested against two different standard competitors; however, by the end of the 5-month experiment, these pollen donors sired fewer seeds than ambient [CO(2)]-grown plants and produced a lower proportion of viable pollen grains. The results of this experiment confirm that elevated [CO(2)] can alter reproductive success. Additionally, the change in response to elevated [CO(2)] over time varied among pollen donor families; thus, changes in [CO(2)] could act as a selective force on this species.
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http://dx.doi.org/10.1007/s00497-010-0146-8DOI Listing
December 2010

Shadows of complexity: what biological networks reveal about epistasis and pleiotropy.

Bioessays 2009 Feb;31(2):220-7

Computational Genetics Laboratory, Department of Genetics, Dartmouth Medical School, Lebanon, NH 03756, USA.

Pleiotropy, in which one mutation causes multiple phenotypes, has traditionally been seen as a deviation from the conventional observation in which one gene affects one phenotype. Epistasis, or gene-gene interaction, has also been treated as an exception to the Mendelian one gene-one phenotype paradigm. This simplified perspective belies the pervasive complexity of biology and hinders progress toward a deeper understanding of biological systems. We assert that epistasis and pleiotropy are not isolated occurrences, but ubiquitous and inherent properties of biomolecular networks. These phenomena should not be treated as exceptions, but rather as fundamental components of genetic analyses. A systems level understanding of epistasis and pleiotropy is, therefore, critical to furthering our understanding of human genetics and its contribution to common human disease. Finally, graph theory offers an intuitive and powerful set of tools with which to study the network bases of these important genetic phenomena.
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http://dx.doi.org/10.1002/bies.200800022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159922PMC
February 2009

Single nucleotide polymorphisms in ANKK1 and the dopamine D2 receptor gene affect cognitive outcome shortly after traumatic brain injury: a replication and extension study.

Brain Inj 2008 Aug;22(9):705-14

Department of Psychiatry, Section of Neuropsychiatry, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.

Objective: The two objectives of this study were (1) to replicate the previous finding that a single nucleotide polymorphism (SNP) in the ANKK1 gene (SNP rs1800497 formerly known as the DRD2 TAQ1 A allele) is associated with measures of learning and response latency after traumatic brain injury (TBI) and (2) to further characterize the genetic basis of the effect by testing the strength of association and degree of linkage disequilibrium between the cognitive outcome measures and a selected ensemble of 31 polymorphisms from three adjacent genes in the region of rs1800497.

Method: A cohort of 54 patients with TBI and 21 comparison subjects were genotyped for the DRD2 TAQ1 A polymorphism (rs1800497). Ninety-three patients with TBI and 48 comparison subjects (the current cohort and an earlier independent cohort) were also genotyped for 31 additional neighbouring polymorphisms in NCAM, ANKK1 and DRD2. TBI patients were studied 1 month after injury. All subjects completed memory and attention tests, including the California Verbal Learning Test (CVLT) recognition task and the Gordon Continuous Performance Test (CPT).

Results: As in a previous study the T allele of TAQ1 A (rs1800497) was associated with poorer performance on the CVLT recognition trial in both TBI and control subjects. There was also a significant diagnosis-by-allele interaction on CPT measures of response latency, largely driven by slower performance in the TBI participants with the T allele. Analysis of 31 additional neighbouring polymorphisms from NCAM, ANKK1 and DRD2 in the TBI patients showed four haploblocks. A haploblock of three SNPs in ANKK1 (rs11604671, rs4938016 and rs1800497 (TAQ1A)) showed the greatest association with cognitive outcome measures.

Conclusions: The results confirm a previously published association between the TAQ1 A (rs1800497) T allele and cognitive outcome measures 1 month after TBI and suggest that a haploblock of polymorphisms in ANKK1, rather than the adjacent DRD2 gene, has the highest association with these measures after TBI.
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http://dx.doi.org/10.1080/02699050802263019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169811PMC
August 2008

Photosynthetic resource-use efficiency and demographic variability in desert winter annual plants.

Ecology 2008 Jun;89(6):1554-63

Ecology and Evolutionary Biology, University of Arizona, Tucson, Arizona 85721-0088, USA.

We studied a guild of desert winter annual plants that differ in long-term variation in per capita reproductive success (lb, the product of per capita survival from germination to reproduction, l, times per capita reproduction of survivors, b) to relate individual function to population and community dynamics. We hypothesized that variation in lb should be related to species' positions along a trade-off between relative growth rate (RGR) and photosynthetic water-use efficiency (WUE) because lb is a species-specific function of growing-season precipitation. We found that demographically variable species have greater RGR and greater leaf carbon isotope discrimination (Delta, a proxy inversely related to WUE). We examined leaf nitrogen and photosynthetic characteristics and found that, in this system, variation in Delta is a function of photosynthetic demand rather than stomatal regulation of water loss. The physiological characteristics that result in low Delta in some species may confer greater photosynthetic performance during the reliably moist but low temperature periods that immediately follow winter rainfall in the Sonoran Desert or alternatively during cool periods of the day or early growing season. Conversely, while species with high Delta and high RGR exhibit low leaf N, they have high biomass allocation to canopy leaf area display. Such trait associations may allow for greater performance during the infrequent conditions where high soil moisture persists into warmer conditions, resulting in high demographic variance. Alternatively, high variance could arise from specialization to warm periods of the day or season. Population dynamic buffering via stress tolerance (low RGR and Delta) correlates negatively with buffering via seed banks, as predicted by bet-hedging theory. By merging analyses of population dynamics with functional trait relationships, we develop a deeper understanding of the physiological, ecological, and evolutionary mechanisms involved in population and community dynamics.
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http://dx.doi.org/10.1890/06-2080.1DOI Listing
June 2008

Nitrogen inputs promote the spread of an invasive marsh grass.

Ecol Appl 2007 Oct;17(7):1886-98

Department of Environmental Science and Policy, University of California, One Shields Avenue, Davis, California 95616, USA.

Excess nutrient loading and large-scale invasion by nonnatives are two of the most pervasive and damaging threats to the biotic and economic integrity of our estuaries. Individually, these are potent forces, but it is important to consider their interactive impacts as well. In this study we investigated the potential limitation of a nonnative intertidal grass, Spartina alterniflora, by nitrogen (N) in estuaries of the western United States. Nitrogen fertilization experiments were conducted in three mud-flat habitats invaded by S. alterniflora in Willapa Bay, Washington, USA, that differed in sediment N. We carried out parallel experiments in San Francisco Bay, California, USA, in three habitats invaded by hybrid Spartina (S. alterniflora x S. foliosa), in previously unvegetated mud flat, and in native S. foliosa or Salicornia virginica marshes. We found similar aboveground biomass and growth rates between habitats and estuaries, but end-of-season belowground biomass was nearly five times greater in San Francisco Bay than in Willapa Bay. In Willapa Bay, aboveground biomass was significantly correlated with sediment N content. Addition of N significantly increased aboveground biomass, stem density, and the rate of spread into uninvaded habitat (as new stems per day) in virtually all habitats in both estuaries. Belowground biomass increased in Willapa Bay only, suggesting that belowground biomass is not N limited in San Francisco Bay due to species differences, N availability, or a latitudinal difference in the response of Spartina to N additions. The relative impact of added N was greater in Willapa Bay, the estuary with lower N inputs from the watershed, than in San Francisco Bay, a highly eutrophic estuary. Nitrogen fertilization also altered the competitive interaction between hybrid Spartina and Salicornia virginica in San Francisco Bay by increasing the density and biomass of the invader and decreasing the density of the native. There was no significant effect of N on the native, Spartina foliosa. Our results indicate that excess N loading to these ecosystems enhances the vulnerability of intertidal habitats to rapid invasion by nonnative Spartina sp.
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http://dx.doi.org/10.1890/06-0822.1DOI Listing
October 2007
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