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Article ; Online: A secondary isotope effect study of equine serum butyrylcholinesterase-catalyzed hydrolysis of acetylthiocholine.

Wiley, Kenneth L / Tormos, Jose R / Quinn, Daniel M

2010 Volume 187, Issue 1-3, Page(s) 124–127

Abstract: beta-Secondary deuterium isotope effects have been measured for equine serum butyrylcholinesterase-catalyzed hydrolysis of acetyl-L(3)-thiocholine (L=H or (2)H). The dependencies of initial rates on isotopic substrate concentrations show close adherence ... ...

Abstract	beta-Secondary deuterium isotope effects have been measured for equine serum butyrylcholinesterase-catalyzed hydrolysis of acetyl-L(3)-thiocholine (L=H or (2)H). The dependencies of initial rates on isotopic substrate concentrations show close adherence to Michaelis-Menten kinetics, and yield the following isotope effects: (D3)k(cat)/K(m)=0.98+/-0.02 and (D3)k(cat)=1.10+/-0.02. The modestly inverse isotope effect on k(cat)/K(m) is consistent with partial rate limitation by a step that converts the sp(2)-hybridized ester carbonyl of the E+A reactant state into a quasi-tetrahedral transition state in the acylation stage of catalysis. On the other hand, the markedly normal isotope effect on k(cat) indicates that the Michaelis complex that accumulates at substrate saturation of the active site during catalytic turnover is a tetrahedral intermediate, whose decomposition is the rate-limiting step. These results compliment a previous report [J.R. Tormos et al., J. Am. Chem. Soc. 127 (2005) 14538-14539] that showed that substrate-activated hydrolysis of acetylthiocholine (ATCh), catalyzed by recombinant human butyrylcholinesterase, is also rate limited by decomposition of an accumulating tetrahedral intermediate.
MeSH term(s)	Acetylthiocholine/metabolism ; Animals ; Biocatalysis ; Butyrylcholinesterase/blood ; Butyrylcholinesterase/chemistry ; Butyrylcholinesterase/metabolism ; Crystallography, X-Ray ; Deuterium ; Horses ; Humans ; Hydrolysis ; Kinetics
Chemical Substances	Acetylthiocholine (4468-05-7) ; Deuterium (AR09D82C7G) ; Butyrylcholinesterase (EC 3.1.1.8)
Language	English
Publishing date	2010-05-20
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218799-1
ISSN	1872-7786 ; 0009-2797
ISSN (online)	1872-7786
ISSN	0009-2797
DOI	10.1016/j.cbi.2010.05.007
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Article ; Online: Decentralized clinical trials in the trial innovation network: Value, strategies, and lessons learned.

Hanley, Daniel F / Bernard, Gordon R / Wilkins, Consuelo H / Selker, Harry P / Dwyer, Jamie P / Dean, J Michael / Benjamin, Daniel Kelly / Dunsmore, Sarah E / Waddy, Salina P / Wiley, Kenneth L / Palm, Marisha E / Mould, W Andrew / Ford, Daniel F / Burr, Jeri S / Huvane, Jacqueline / Lane, Karen / Poole, Lori / Edwards, Terri L / Kennedy, Nan /

Boone, Leslie R / Bell, Jasmine / Serdoz, Emily / Byrne, Loretta M / Harris, Paul A

Journal of clinical and translational science

2023 Volume 7, Issue 1, Page(s) e170

Abstract: New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by ... ...

Abstract	New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or "hybrid" trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology.
Language	English
Publishing date	2023-07-25
Publishing country	England
Document type	Journal Article
ISSN	2059-8661
ISSN (online)	2059-8661
DOI	10.1017/cts.2023.597
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Article ; Online: Leveraging the Expertise of the CTSA Program to Increase the Impact and Efficiency of Clinical Trials.

Harris, Paul A / Dunsmore, Sarah E / Atkinson, Jane C / Benjamin, Daniel Kelly / Bernard, Gordon R / Dean, J Michael / Dwyer, Jamie P / Ford, Daniel F / Selker, Harry P / Waddy, Salina P / Wiley, Kenneth L / Wilkins, Consuelo H / Cook, Sarah K / Burr, Jeri S / Edwards, Terri L / Huvane, Jacqueline / Kennedy, Nan / Lane, Karen / Majkowski, Ryan /

Nelson, Sarah / Palm, Marisha E / Stroud, Mary / Thompson, Dixie D / Busacca, Linda / Elkind, Mitchell S V / Kimberly, Robert P / Reilly, Muredach P / Hanley, Daniel F

JAMA network open

2023 Volume 6, Issue 10, Page(s) e2336470

Abstract: Importance: Multicenter clinical trials play a critical role in the translational processes that enable new treatments to reach all people and improve public health. However, conducting multicenter randomized clinical trials (mRCT) presents challenges. ... ...

Abstract	Importance: Multicenter clinical trials play a critical role in the translational processes that enable new treatments to reach all people and improve public health. However, conducting multicenter randomized clinical trials (mRCT) presents challenges. The Trial Innovation Network (TIN), established in 2016 to partner with the Clinical and Translational Science Award (CTSA) Consortium of academic medical institutions in the implementation of mRCTs, consists of 3 Trial Innovation Centers (TICs) and 1 Recruitment Innovation Center (RIC). This unique partnership has aimed to address critical roadblocks that impede the design and conduct of mRCTs, in expectation of accelerating the translation of novel interventions to clinical practice. The TIN's challenges and achievements are described in this article, along with examples of innovative resources and processes that may serve as useful models for other clinical trial networks providing operational and recruitment support. Observations: The TIN has successfully integrated more than 60 CTSA institution program hubs into a functional network for mRCT implementation and optimization. A unique support system for investigators has been created that includes the development and deployment of novel tools, operational and recruitment services, consultation models, and rapid communication pathways designed to reduce delays in trial start-up, enhance recruitment, improve engagement of diverse research participants and communities, and streamline processes that improve the quality, efficiency, and conduct of mRCTs. These resources and processes span the clinical trial spectrum and enable the TICs and RIC to serve as coordinating centers, data centers, and recruitment specialists to assist trials across the National Institutes of Health and other agencies. The TIN's impact has been demonstrated through its response to both historical operational challenges and emerging public health emergencies, including the national opioid public health crisis and the COVID-19 pandemic. Conclusions and relevance: The TIN has worked to reduce barriers to implementing mRCTs and to improve mRCT processes and operations by providing needed clinical trial infrastructure and resources to CTSA investigators. These resources have been instrumental in more quickly and efficiently translating research discoveries into beneficial patient treatments.
MeSH term(s)	United States ; Humans ; COVID-19 ; Pandemics ; Translational Science, Biomedical ; Awards and Prizes ; Communication
Language	English
Publishing date	2023-10-02
Publishing country	United States
Document type	Multicenter Study ; Journal Article ; Research Support, N.I.H., Extramural
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2023.36470
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Article ; Online: Ethnic differences in DNA methyltransferases expression in patients with systemic lupus erythematosus.

Wiley, Kenneth L / Treadwell, Edward / Manigaba, Kayihura / Word, Beverly / Lyn-Cook, Beverly D

Journal of clinical immunology

2012 Volume 33, Issue 2, Page(s) 342–348

Abstract: Purpose: Systemic lupus erythematous (SLE) is a systemic autoimmune inflammatory disease with both genetic and epigenetic etiologies. Evidence suggests that deregulation of specific genes through epigenetic mechanisms may be a contributing factor to SLE ...

Abstract	Purpose: Systemic lupus erythematous (SLE) is a systemic autoimmune inflammatory disease with both genetic and epigenetic etiologies. Evidence suggests that deregulation of specific genes through epigenetic mechanisms may be a contributing factor to SLE pathology. There is increasing evidence that DNA methyltransferase activity may be involved. This study demonstrated modulation in expression of DNA methyltransferases (DNMTs) according to ethnicity in patients diagnosed with SLE. Furthermore, differential expression in one of the DNMTs was found in a subset of lupus patients on dehydroepiandrosterone (DHEA) therapy. Methods: Real-time PCR analyses of DNMT1, DNMT3A and DNMT3B in peripheral blood mononuclear cells from a cohort of African American and European American lupus and non-lupus women were conducted. Also, global DNA methylation was assessed using the MethylFlash(TM) methylated quantification colorimetric assay. Results: Significant increase in DNMT3A (p < 0.001) was shown in lupus patients when compared to age-matched healthy controls. This increase was associated with a higher SLEDI index. More striking was that expression levels for African American (AA) women were higher than European American women in the lupus populations. A subset of AA women on DHEA therapy showed a significant decrease (p < 0.05) in DNMT3A expression in comparison to lupus patients not on the therapy. DHEA is an androgenic steroid found in low levels in the serum of lupus patients. Supplementation of this hormone has been shown to be beneficial to some lupus patients. DHEA was not shown to effect DNMT1 or DNMT3B expression. Increased expression was also noted in DNMT3B (p < 0.05) in lupus patients compared to age-matched healthy controls. However, no significant difference was noted in DNMT1 (p = 0.2148) expression between lupus patients and healthy controls. Although increases were detected in de novo methyltransferases, a global decrease (p < 0.001) in 5-methycytosine was observed in lupus patients when compared to age-matched healthy controls. Conclusion: These findings suggest that epigenetic changes may play a critical role in the manifestations of the disease observed among ethnic groups, particularly African American women who often have a higher incidence of lupus. DHEA therapy effects on DNMT3A expression in AA women warrant further investigation in a larger population.
MeSH term(s)	Black or African American/genetics ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA Methyltransferase 3A ; Dehydroepiandrosterone/therapeutic use ; Epigenesis, Genetic ; Female ; Gene Expression ; Humans ; Lupus Erythematosus, Systemic/ethnology ; Lupus Erythematosus, Systemic/genetics ; Lupus Erythematosus, Systemic/therapy ; White People/genetics ; DNA Methyltransferase 3B
Chemical Substances	DNMT3A protein, human ; Dehydroepiandrosterone (459AG36T1B) ; DNA (Cytosine-5-)-Methyltransferase 1 (EC 2.1.1.37) ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNA Methyltransferase 3A (EC 2.1.1.37) ; DNMT1 protein, human (EC 2.1.1.37)
Language	English
Publishing date	2012-10-09
Publishing country	Netherlands
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	779361-3
ISSN	1573-2592 ; 0271-9142
ISSN (online)	1573-2592
ISSN	0271-9142
DOI	10.1007/s10875-012-9803-z
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Article: Digital Food Records in Community-Based Interventions: Mixed-Methods Pilot Study.

Fowler, Lauren A / Yingling, Leah R / Brooks, Alyssa T / Wallen, Gwenyth R / Peters-Lawrence, Marlene / McClurkin, Michael / Wiley, Kenneth L / Mitchell, Valerie M / Johnson, Twanda D / Curry, Kendrick E / Johnson, Allan A / Graham, Avis P / Graham, Lennox A / Powell-Wiley, Tiffany M

JMIR mHealth and uHealth

2018 Volume 6, Issue 7, Page(s) e160

Abstract: Background: A pressing need exists to understand and optimize the use of dietary assessment tools that can be used in community-based participatory research (CBPR) interventions. A digital food record, which uses a mobile device to capture the dietary ... ...

Abstract	Background: A pressing need exists to understand and optimize the use of dietary assessment tools that can be used in community-based participatory research (CBPR) interventions. A digital food record, which uses a mobile device to capture the dietary intake through text and photography inputs, is a particularly promising mobile assessment method. However, little is understood about the acceptability and feasibility of digital food records in CBPR and how to best tailor dietary assessment tools to the needs of a community. Objective: The objective of our study was to evaluate the acceptability and feasibility of digital food records among church-based populations in resource-limited wards of Washington, DC, USA, using a mixed-methods approach. Methods: This community-based pilot study was conducted as part of the Washington, DC Cardiovascular Health and Needs Assessment. Participants (n=17) received a mobile device (iPod Touch) to photodocument their dietary intake for a 3-day digital food record using a mobile app, FitNinja (Vibrent Health). The acceptability of the digital food record was explored through the thematic analysis of verbatim transcripts from a moderated focus group (n=8). In addition, the feasibility was evaluated by the percentage of participants complying with instructions (ie, capturing both before and after meal photos for at least 2 meals/day for 3 days). Results: Qualitative themes identified were related to (1) the feasibility and acceptability of the mobile device and app, including issues in recording the dietary information and difficulty with photodocumentation; (2) suggestions for additional support and training experiences; and (3) comparisons with other mobile apps. Overall, the participants accepted the digital food record by demonstrating satisfaction with the tool and intent to continue the use (eg, participants recorded an average of 5.2, SD 7, consecutive days). Furthermore, of the 17 participants, 15 photodocumented at least 1 meal during the study period and 3 fully complied with the digital food record instructions. Conclusions: This study demonstrated digital food records as an acceptable tool in CBPR and identified contributors and barriers to the feasibility of digital food records for future research. Engaging community members in the implementation of novel assessment methods allows for the tailoring of technology to the needs of the community and optimizing community-based interventions. Trial registration: ClinicalTrials.gov NCT01927783; https://www.clinicaltrials.gov/ct2/show/NCT01927783 (Archived by WebCite at http://www.webcitation.org/70WzaFWb6).
Language	English
Publishing date	2018-07-17
Publishing country	Canada
Document type	Journal Article
ZDB-ID	2719220-9
ISSN	2291-5222
ISSN	2291-5222
DOI	10.2196/mhealth.9729
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Article: Community Engagement to Optimize the Use of Web-Based and Wearable Technology in a Cardiovascular Health and Needs Assessment Study: A Mixed Methods Approach.

Yingling, Leah R / Brooks, Alyssa T / Wallen, Gwenyth R / Peters-Lawrence, Marlene / McClurkin, Michael / Cooper-McCann, Rebecca / Wiley, Kenneth L / Mitchell, Valerie / Saygbe, Johnetta N / Johnson, Twanda D / Curry, Rev Kendrick E / Johnson, Allan A / Graham, Avis P / Graham, Lennox A / Powell-Wiley, Tiffany M

JMIR mHealth and uHealth

2016 Volume 4, Issue 2, Page(s) e38

Language	English
Publishing date	2016-04-25
Publishing country	Canada
Document type	Journal Article
ZDB-ID	2719220-9
ISSN	2291-5222
ISSN	2291-5222
DOI	10.2196/mhealth.4489
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Article ; Online: Accumulation of tetrahedral intermediates in cholinesterase catalysis: a secondary isotope effect study.

Tormos, Jose R / Wiley, Kenneth L / Wang, Yi / Fournier, Didier / Masson, Patrick / Nachon, Florian / Quinn, Daniel M

Journal of the American Chemical Society

2010 Volume 132, Issue 50, Page(s) 17751–17759

Abstract: In a previous communication, kinetic β-deuterium secondary isotope effects were reported that support a mechanism for substrate-activated turnover of acetylthiocholine by human butyrylcholinesterase (BuChE) wherein the accumulating reactant state is a ... ...

Abstract	In a previous communication, kinetic β-deuterium secondary isotope effects were reported that support a mechanism for substrate-activated turnover of acetylthiocholine by human butyrylcholinesterase (BuChE) wherein the accumulating reactant state is a tetrahedral intermediate ( Tormos , J. R. et al. J. Am. Chem. Soc. 2005 , 127 , 14538 - 14539 ). In this contribution additional isotope effect experiments are described with acetyl-labeled acetylthiocholines (CL(3)COSCH(2)CH(2)N(+)Me(3); L = H or D) that also support accumulation of the tetrahedral intermediate in Drosophila melanogaster acetylcholinesterase (DmAChE) catalysis. In contrast to the aforementioned BuChE-catalyzed reaction, for this reaction the dependence of initial rates on substrate concentration is marked by pronounced substrate inhibition at high substrate concentrations. Moreover, kinetic β-deuterium secondary isotope effects for turnover of acetylthiocholine depended on substrate concentration, and gave the following: (D3)k(cat)/K(m) = 0.95 ± 0.03, (D3)k(cat) = 1.12 ± 0.02 and (D3)βk(cat) = 0.97 ± 0.04. The inverse isotope effect on k(cat)/K(m) is consistent with conversion of the sp(2)-hybridized substrate carbonyl in the E + A reactant state into a quasi-tetrahedral transition state in the acylation stage of catalysis, whereas the markedly normal isotope effect on k(cat) is consistent with hybridization change from sp(3) toward sp(2) as the reactant state for deacylation is converted into the subsequent transition state. Transition states for Drosophila melanogaster AChE-catalyzed hydrolysis of acetylthiocholine were further characterized by measuring solvent isotope effects and determining proton inventories. These experiments indicated that the transition state for rate-determining decomposition of the tetrahedral intermediate is stabilized by multiple protonic interactions. Finally, a simple model is proposed for the contribution that tetrahedral intermediate stabilization provides to the catalytic power of acetylcholinesterase.
MeSH term(s)	Animals ; Catalysis ; Catalytic Domain ; Cholinesterases/chemistry ; Cholinesterases/genetics ; Deuterium/chemistry ; Drosophila/enzymology ; Isotopes/chemistry ; Kinetics ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics
Chemical Substances	Isotopes ; Recombinant Proteins ; Deuterium (AR09D82C7G) ; Cholinesterases (EC 3.1.1.8)
Language	English
Publishing date	2010-11-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/ja104496q
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Article ; Online: Adherence with physical activity monitoring wearable devices in a community-based population: observations from the Washington, D.C., Cardiovascular Health and Needs Assessment.

Yingling, Leah R / Mitchell, Valerie / Ayers, Colby R / Peters-Lawrence, Marlene / Wallen, Gwenyth R / Brooks, Alyssa T / Troendle, James F / Adu-Brimpong, Joel / Thomas, Samantha / Henry, JaWanna / Saygbe, Johnetta N / Sampson, Dana M / Johnson, Allan A / Graham, Avis P / Graham, Lennox A / Wiley, Kenneth L / Powell-Wiley, Tiffany

Translational behavioral medicine

2017 Volume 7, Issue 4, Page(s) 719–730

Abstract: Wearable mobile health (mHealth) technologies offer approaches for targeting physical activity (PA) in resource-limited, community-based interventions. We sought to explore user characteristics of PA tracking, wearable technology among a community-based ... ...

Abstract	Wearable mobile health (mHealth) technologies offer approaches for targeting physical activity (PA) in resource-limited, community-based interventions. We sought to explore user characteristics of PA tracking, wearable technology among a community-based population within a health and needs assessment. In 2014-2015, we conducted the Washington, D.C., Cardiovascular Health and Needs Assessment in predominantly African-American churches among communities with higher obesity rates and lower household incomes. Participants received a mHealth PA monitor and wirelessly uploaded PA data weekly to church data collection hubs. Participants (n = 99) were 59 ± 12 years, 79% female, and 99% African-American, with a mean body mass index of 33 ± 7 kg/m
MeSH term(s)	Accelerometry ; Body Mass Index ; Christianity ; District of Columbia ; Exercise ; Female ; Fitness Trackers ; Health Behavior ; Humans ; Male ; Middle Aged ; Needs Assessment ; Obesity ; Patient Compliance ; Poverty ; Telemedicine ; Vulnerable Populations ; Wireless Technology
Language	English
Publishing date	2017-01-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2586893-7
ISSN	1613-9860 ; 1869-6716
ISSN (online)	1613-9860
ISSN	1869-6716
DOI	10.1007/s13142-016-0454-0
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Article: The reactant state for substrate-activated turnover of acetylthiocholine by butyrylcholinesterase is a tetrahedral intermediate.

Tormos, Jose R / Wiley, Kenneth L / Seravalli, Javier / Nachon, Florian / Masson, Patrick / Nicolet, Yvain / Quinn, Daniel M

Journal of the American Chemical Society

2005 Volume 127, Issue 42, Page(s) 14538–14539

Abstract: Secondary beta-deuterium kinetic isotope effects have been measured as a function of substrate concentration for recombinant human butyrylcholinesterase-catalyzed hydrolysis of acetyl-L3-thiocholine (L = 1H or 2H). The isotope effect on V/K is inverse, ... ...

Abstract	Secondary beta-deuterium kinetic isotope effects have been measured as a function of substrate concentration for recombinant human butyrylcholinesterase-catalyzed hydrolysis of acetyl-L3-thiocholine (L = 1H or 2H). The isotope effect on V/K is inverse, D3V/K = 0.93 +/- 0.03, which is consistent with conversion of the sp2 hybridized carbonyl carbon of the scissile ester bond of the E + A reactant state to a quasi-tetrahedral structure in the acylation transition state. In contrast, the isotope effect on Vmax under conditions of substrate activation is markedly normal, D3(betaVmax) = 1.29 +/- 0.06, an observation that is consistent with accumulation of a tetrahedral intermediate as the reactant state for catalytic turnover. Generally, tetrahedral intermediates for nonenzymatic ester hydrolyses are high-energy steady-state intermediates. Apparently, butyrylcholinesterase displays an unusual ability to stabilize such intermediates. Hence, the catalytic power of cholinesterases can largely be understood in terms of their ability to stabilize tetrahedral intermediates in the multistep reaction mechanism.
MeSH term(s)	Acetylthiocholine/chemistry ; Butyrylcholinesterase/chemistry ; Catalysis ; Deuterium/chemistry ; Kinetics
Chemical Substances	Acetylthiocholine (4468-05-7) ; Deuterium (AR09D82C7G) ; Butyrylcholinesterase (EC 3.1.1.8)
Language	English
Publishing date	2005-10-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/ja052401q
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Article: Revisiting the protein-coding gene catalog of Drosophila melanogaster using 12 fly genomes.

Lin, Michael F / Carlson, Joseph W / Crosby, Madeline A / Matthews, Beverley B / Yu, Charles / Park, Soo / Wan, Kenneth H / Schroeder, Andrew J / Gramates, L Sian / St Pierre, Susan E / Roark, Margaret / Wiley, Kenneth L / Kulathinal, Rob J / Zhang, Peili / Myrick, Kyl V / Antone, Jerry V / Celniker, Susan E / Gelbart, William M / Kellis, Manolis

Genome research

2007 Volume 17, Issue 12, Page(s) 1823–1836

Abstract: The availability of sequenced genomes from 12 Drosophila species has enabled the use of comparative genomics for the systematic discovery of functional elements conserved within this genus. We have developed quantitative metrics for the evolutionary ... ...

Abstract	The availability of sequenced genomes from 12 Drosophila species has enabled the use of comparative genomics for the systematic discovery of functional elements conserved within this genus. We have developed quantitative metrics for the evolutionary signatures specific to protein-coding regions and applied them genome-wide, resulting in 1193 candidate new protein-coding exons in the D. melanogaster genome. We have reviewed these predictions by manual curation and validated a subset by directed cDNA screening and sequencing, revealing both new genes and new alternative splice forms of known genes. We also used these evolutionary signatures to evaluate existing gene annotations, resulting in the validation of 87% of genes lacking descriptive names and identifying 414 poorly conserved genes that are likely to be spurious predictions, noncoding, or species-specific genes. Furthermore, our methods suggest a variety of refinements to hundreds of existing gene models, such as modifications to translation start codons and exon splice boundaries. Finally, we performed directed genome-wide searches for unusual protein-coding structures, discovering 149 possible examples of stop codon readthrough, 125 new candidate ORFs of polycistronic mRNAs, and several candidate translational frameshifts. These results affect >10% of annotated fly genes and demonstrate the power of comparative genomics to enhance our understanding of genome organization, even in a model organism as intensively studied as Drosophila melanogaster.
MeSH term(s)	Animals ; Base Sequence ; Codon/genetics ; Conserved Sequence ; Drosophila Proteins/chemistry ; Drosophila Proteins/genetics ; Drosophila melanogaster/genetics ; Evolution, Molecular ; Genes, Insect ; Genome, Insect ; Molecular Sequence Data ; Reading Frames ; Sequence Alignment
Chemical Substances	Codon ; Drosophila Proteins
Language	English
Publishing date	2007-11-07
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	1284872-4
ISSN	1549-5469 ; 1088-9051 ; 1054-9803
ISSN (online)	1549-5469
ISSN	1088-9051 ; 1054-9803
DOI	10.1101/gr.6679507
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