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1. Student Attitudes Contribute to the Effectiveness of a Genomics CURE

Author

David Lopatto, Anne G. Rosenwald, Rebecca C. Burgess, Catherine Silver Key, Melanie Van Stry, Matthew Wawersik, Justin R. DiAngelo, Amy T. Hark, Matthew Skerritt, Anna K. Allen, Consuelo Alvarez, Sara Anderson, Cindy Arrigo, Andrew Arsham, Daron Barnard, James E. J. Bedard, Indrani Bose, John M. Braverman, Martin G. Burg, Paula Croonquist, Chunguang Du, Sondra Dubowsky, Heather Eisler, Matthew A. Escobar, Michael Foulk, Thomas Giarla, Rivka L. Glaser, Anya L. Goodman, Yuying Gosser, Adam Haberman, Charles Hauser, Shan Hays, Carina E. Howell, Jennifer Jemc, Christopher J. Jones, Lisa Kadlec, Jacob D. Kagey, Kimberly L. Keller, Jennifer Kennell, Adam J. Kleinschmit, Melissa Kleinschmit, Nighat P. Kokan, Olga Ruiz Kopp, Meg M. Laakso, Judith Leatherman, Lindsey J. Long, Mollie Manier, Juan C. Martinez-Cruzado, Luis F. Matos, Amie Jo McClellan, Gerard McNeil, Evan Merkhofer, Vida Mingo, Hemlata Mistry, Elizabeth Mitchell, Nathan T. Mortimer, Jennifer Leigh Myka, Alexis Nagengast, Paul Overvoorde, Don Paetkau, Leocadia Paliulis, Susan Parrish, Stephanie Toering Peters, Mary Lai Preuss, James V. Price, Nicholas A. Pullen, Catherine Reinke, Dennis Revie, Srebrenka Robic, Jennifer A. Roecklein-Canfield, Michael R. Rubin, Takrima Sadikot, Jamie Siders Sanford, Maria Santisteban, Kenneth Saville, Stephanie Schroeder, Christopher D. Shaffer, Karim A. Sharif, Diane E. Sklensky, Chiyedza Small, Sheryl Smith, Rebecca Spokony, Aparna Sreenivasan, Joyce Stamm, Rachel Sterne-Marr, Katherine C. Teeter, Justin Thackeray, Jeffrey S. Thompson, Norma Velazquez-Ulloa, Cindy Wolfe, James Youngblom, Brian Yowler, Leming Zhou, Janie Brennan, Jeremy Buhler, Wilson Leung, Sarah C. R. Elgin, and Laura K. Reed

Subjects
active learning, bioinformatics, CUREs, genomics, undergraduate education, Special aspects of education, LC8-6691, Biology (General), QH301-705.5
Abstract

ABSTRACT The Genomics Education Partnership (GEP) engages students in a course-based undergraduate research experience (CURE). To better understand the student attributes that support success in this CURE, we asked students about their attitudes using previously published scales that measure epistemic beliefs about work and science, interest in science, and grit. We found, in general, that the attitudes students bring with them into the classroom contribute to two outcome measures, namely, learning as assessed by a pre- and postquiz and perceived self-reported benefits. While the GEP CURE produces positive outcomes overall, the students with more positive attitudes toward science, particularly with respect to epistemic beliefs, showed greater gains. The findings indicate the importance of a student’s epistemic beliefs to achieving positive learning outcomes.

Published
2022
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2. Evaluating the impact of universal Lynch syndrome screening in a publicly funded healthcare system

Author

Petra W. C. Lee, Angela C. Bedard, Setareh Samimi, Vivienne K. Beard, Quan Hong, James E. J. Bedard, Blake Gilks, David F. Schaeffer, Robert Wolber, Janice S. Kwon, Howard J. Lim, Sophie Sun, and Kasmintan A. Schrader

Subjects
colorectal cancer, endometrial cancer, DNA mismatch repair, genetic testing, immunohistochemistry, Lynch syndrome, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Purpose Referrals for Lynch syndrome (LS) assessment have traditionally been based on personal and family medical history. The introduction of universal screening practices has allowed for referrals based on immunohistochemistry tests for mismatch repair (MMR) protein expression. This study aims to characterize the effect of universal screening in a publicly funded healthcare system with comparison to patients referred by traditional criteria, from January 2012 to March 2017. Methods Patient files from the time of initiation of universal screening from 2012 to 2017 were reviewed. Patients were sorted into two groups: (a) universally screened and (b) referred by traditional methods. Mutation detection rates, analysis of traditional testing criteria met, and cascade carrier testing were evaluated. Results The mutation detection rate of the universal screening group was higher than the traditionally referred group (45/228 (19.7%) vs 50/390 (12.5%), P = .05), though each were able to identify unique patients. An analysis of testing criteria met by each patient showed that half of referred patients from the universal screening group could not meet any traditional testing criteria. Conclusion The implementation of universal screening in a publicly funded system will increase efficiency in detecting patients with LS. The resources available for genetic testing and counseling may be more limited in public systems, thus inclusion of secondary screening with BRAF and MLH1 promoter hypermethylation testing is key to further optimizing efficiency.

Published
2020
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3. Facilitating Growth through Frustration: Using Genomics Research in a Course-Based Undergraduate Research Experience

Author

David Lopatto, Anne G. Rosenwald, Justin R. DiAngelo, Amy T. Hark, Matthew Skerritt, Matthew Wawersik, Anna K. Allen, Consuelo Alvarez, Sara Anderson, Cindy Arrigo, Andrew Arsham, Daron Barnard, Christopher Bazinet, James E. J. Bedard, Indrani Bose, John M. Braverman, Martin G. Burg, Rebecca C. Burgess, Paula Croonquist, Chunguang Du, Sondra Dubowsky, Heather Eisler, Matthew A. Escobar, Michael Foulk, Emily Furbee, Thomas Giarla, Rivka L. Glaser, Anya L. Goodman, Yuying Gosser, Adam Haberman, Charles Hauser, Shan Hays, Carina E. Howell, Jennifer Jemc, M. Logan Johnson, Christopher J. Jones, Lisa Kadlec, Jacob D. Kagey, Kimberly L. Keller, Jennifer Kennell, S. Catherine Silver Key, Adam J. Kleinschmit, Melissa Kleinschmit, Nighat P. Kokan, Olga Ruiz Kopp, Meg M. Laakso, Judith Leatherman, Lindsey J. Long, Mollie Manier, Juan C. Martinez-Cruzado, Luis F. Matos, Amie Jo McClellan, Gerard McNeil, Evan Merkhofer, Vida Mingo, Hemlata Mistry, Elizabeth Mitchell, Nathan T. Mortimer, Debaditya Mukhopadhyay, Jennifer Leigh Myka, Alexis Nagengast, Paul Overvoorde, Don Paetkau, Leocadia Paliulis, Susan Parrish, Mary Lai Preuss, James V. Price, Nicholas A. Pullen, Catherine Reinke, Dennis Revie, Srebrenka Robic, Jennifer A. Roecklein-Canfield, Michael R. Rubin, Takrima Sadikot, Jamie Siders Sanford, Maria Santisteban, Kenneth Saville, Stephanie Schroeder, Christopher D. Shaffer, Karim A. Sharif, Diane E. Sklensky, Chiyedza Small, Mary Smith, Sheryl Smith, Rebecca Spokony, Aparna Sreenivasan, Joyce Stamm, Rachel Sterne-Marr, Katherine C. Teeter, Justin Thackeray, Jeffrey S. Thompson, Stephanie Toering Peters, Melanie Van Stry, Norma Velazquez-Ulloa, Cindy Wolfe, James Youngblom, Brian Yowler, Leming Zhou, Janie Brennan, Jeremy Buhler, Wilson Leung, Laura K. Reed, and Sarah C. R. Elgin

Subjects
Special aspects of education, LC8-6691, Biology (General), QH301-705.5
Abstract

A hallmark of the research experience is encountering difficulty and working through those challenges to achieve success. This ability is essential to being a successful scientist, but replicating such challenges in a teaching setting can be difficult. The Genomics Education Partnership (GEP) is a consortium of faculty who engage their students in a genomics Course-Based Undergraduate Research Experience (CURE). Students participate in genome annotation, generating gene models using multiple lines of experimental evidence. Our observations suggested that the students’ learning experience is continuous and recursive, frequently beginning with frustration but eventually leading to success as they come up with defendable gene models. In order to explore our “formative frustration” hypothesis, we gathered data from faculty via a survey, and from students via both a general survey and a set of student focus groups. Upon analyzing these data, we found that all three datasets mentioned frustration and struggle, as well as learning and better understanding of the scientific process. Bioinformatics projects are particularly well suited to the process of iteration and refinement because iterations can be performed quickly and are inexpensive in both time and money. Based on these findings, we suggest that a dynamic of “formative frustration” is an important aspect for a successful CURE.

Published
2020
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4. Evaluating the impact of universal Lynch syndrome screening in a publicly funded healthcare system

Author

Sophie Sun, Kasmintan A. Schrader, Petra W. C. Lee, Vivienne K. Beard, Howard John Lim, James E. J. Bedard, Janice S. Kwon, David F. Schaeffer, Angela C. Bedard, Blake Gilks, Setareh Samimi, Robert Wolber, and Quan Hong

Subjects
0301 basic medicine, Male, Cancer Research, Financing, Government, National Health Programs, DNA mismatch repair, Cost-Benefit Analysis, DNA Mutational Analysis, 0302 clinical medicine, Early Detection of Cancer, Original Research, medicine.diagnostic_test, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Lynch syndrome, Oncology, 030220 oncology & carcinogenesis, endometrial cancer, immunohistochemistry, Female, Healthcare system, Primary screening, medicine.medical_specialty, colorectal cancer, Carrier testing, lcsh:RC254-282, genetic testing, 03 medical and health sciences, Promoter hypermethylation, Predictive Value of Tests, medicine, Biomarkers, Tumor, Humans, Radiology, Nuclear Medicine and imaging, Medical history, Mutation detection, Genetic Predisposition to Disease, Genetic testing, Public Sector, British Columbia, business.industry, Clinical Cancer Research, Reproducibility of Results, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, 030104 developmental biology, DNA Repair Enzymes, Family medicine, Mutation, business
Abstract

Purpose Referrals for Lynch syndrome (LS) assessment have traditionally been based on personal and family medical history. The introduction of universal screening practices has allowed for referrals based on immunohistochemistry tests for mismatch repair (MMR) protein expression. This study aims to characterize the effect of universal screening in a publicly funded healthcare system with comparison to patients referred by traditional criteria, from January 2012 to March 2017. Methods Patient files from the time of initiation of universal screening from 2012 to 2017 were reviewed. Patients were sorted into two groups: (a) universally screened and (b) referred by traditional methods. Mutation detection rates, analysis of traditional testing criteria met, and cascade carrier testing were evaluated. Results The mutation detection rate of the universal screening group was higher than the traditionally referred group (45/228 (19.7%) vs 50/390 (12.5%), P = .05), though each were able to identify unique patients. An analysis of testing criteria met by each patient showed that half of referred patients from the universal screening group could not meet any traditional testing criteria. Conclusion The implementation of universal screening in a publicly funded system will increase efficiency in detecting patients with LS. The resources available for genetic testing and counseling may be more limited in public systems, thus inclusion of secondary screening with BRAF and MLH1 promoter hypermethylation testing is key to further optimizing efficiency., Lynch syndrome detection rates were higher in a universal screening cohort as compared to those referred by traditional phenotypic‐based referral criteria. Optimizing efficiency for Lynch syndrome screening is important in publicly funded systems where genetic counseling and other resources may be limited.

Published
2020

5. Drosophila Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

Author

Raechel Harnoto, Morgan C. Anderson, Amy Z. Xu, Heather Hedeen, Arnaldo J. Santiago-Sanabria, Brandy L. Hammond, Kenneth Saville, Ross D. Kooienga, Christopher Chesley, Robert W. Morris, Aubree T. Gillis, Brittney Offenbacker, Katherine C. Palozola, Trisha Tomkins, Nicole Yu, Matthew Kwong, Megan E. Aldrup, Jordan E. Kus, Chelsey Friedrichs, Kenneth Stapleton, Carly E. Pelchen, Norma Chamma, Joshua F. Machone, Danielle Kulich, Andre Kennedy, Matt J. Crowley, Daniel Broomfield, Adeola Adebayo, Nicolas Ragland, Shady Messiah, Jonathan Misch, Meghan B. Rooney, Eva N. Rubio-Marrero, Will Sherrill, Joyce Stamm, Rachel R. Leads, Lindsey Shantzer, Alexis J. Scott, Andrew W. Waggoner, Kristen M. Cooper, Adam Haberman, Carmen A. Watchinski, Marcos A. Perez, Lisa Kadlec, Kiara N. Medina-Ortega, Kayla Chapman, Cheryl Bailey, Nicholas Fazzio, Insun Chong, Lasse Schmidt, Darla M. Balthaser, Megan DeShetler, Jien Shim, Anna Rogers, Chris Uitvlugt, Bryan Yarrington, Ruth A. Howe, Andrea Ochoa, Gregory J. Mullen, Young Lu Kim, Olivia L Knowles, Kevin M. Levine, Matthew M. Villerot, Thomas J. Rose, Jonathan E. Smith, Sukhjit Kaur, Roshni Patel, Olivia Plante, Tenzin Choeying, Jennifer R. Ramthun, Tiffany Y. Y. Choi, Michael Rahimi, Guzal Khayrullina, Lauren R. Boudreaux, James E. J. Bedard, Brian A. Dow, Christopher A. Louie, Kenneth S. Smith, Joannee Zumkehr, Marcus Gostelow, Melissa A. Tache, Tiffany Dai, Joan D. Zambrana-Burgos, Lauren R. Meyer, Carter Brown, Adam Brown, Travis Lamb, Carissa Belella, Hannah Gilman, David DuPuis, Ramón E. Rivera-Vicéns, Priyanka Naik, Anna L. Shipman, Jad El-Adaimi, Eric Spencer, Jonathan D. Marra, Melissa D. Patao, Sharon Ibarra, Jiayu Zhang, Ashley Vetor, Bobbi Botsford, Jenifer Winters, Nelson A. Valentín-Feliciano, Lauren M. Robinson, Christopher R. Macchi, Jennifer Hernández-Muñiz, E. Gloria C. Regisford, Jaelyn L. Johnson, Cory M. Dauphin, Tezin A. Walji, Matthew A. Zaborowicz, Stacey Winkler, Shannon M. Lowell, Marly R. McCracken, Andrew Adams, Lindsay A. Spaeder, Matthew W. Wolski, Adrese Kandahari, Fabiola Robles-Juarbe, Bryce A. Turner, Ángel L. Laboy-Corales, David T. Watson, Elaine J. Durchholz, Vanessa Rodriguez, Emily J. Teepe, Alaina C. Conturso, Eric Nyabeta Onsarigo, Tijana Martinov, Rohit Venkat, Charles R. Hauser, Priya Srikanth, Marwan Ibrahem, Karl E. Smith, Jessica M. Tucci, Ethan J. Brock, Aparna Sreenivasan, Jasmine Hales, Brianna K. Barnard, Andrew P. Stein, Jessica G. Thomas, Mallory Perella, Lorraine Rodriguez-Bonilla, Shekerah Primus, Zachary D. Moore, Caitlin M. Ament, Amber N. Hare, Brad Pamnani, Eugenia A. Soliterman, Christina Paluskievicz, Yashira M. Valentín-Feliciano, Alexandra K. Eckardt, Anya Goodman, Joseph W. Noynaert, Ashlee G. Johnson, Tyneshia C. P. Henry, Camille D. Ratliff, Ian O. Chase, Michel A. Conn, Jessica Koehler, Daniela Martiniuc, Allison J. Schepers, Megan B. Vylonis, Chrystel Dol, William Dirkes, Michelle S. Rivera-Llovet, Susana Rodríguez-Santiago, Heather L. Eisler, Mary L. Preuss, Daymon Peterson, Martin G. Burg, Aaditya Khatri, John R. Woytanowski, Holly Schiedermayer, Dara Cohn, Leah E Waldman, William M. Morris, Sharon C. Ehret, Marianna Defendini-Ávila, Jessica Fese, Suzette M. Arias-Mejias, Anna Kammrath, William D. Barshop, Edwin G. Ramírez-Aponte, Luis A. Jimenez, Carolina Marques dos Santos Vieira, Cody D. Kern, Francheska M. Delgado-Peraza, Tiffany Wan, Janice L. Krumm, Osagie Ighile, Eric D. Sassu, Jess M. Darusz, Laura Rodela, Daniel S. Nicolas, Shubha Govind, Mary Miller, Joseph E Marcus, Jason Pollack, Rostislav Castillo, Daniel Coomes, Matthew J. Borr, Diana Pérez-Afanador, Lucas A. Watson, Hannah C. Koaches, Amber Quintana, Faith H. Kung, Cameron B. Harris, Bridget M. Janssen, Cristina Zambrana-Echevarría, Jennifer K. Jones, Ian Dobbe, Benjamin M. Lewis, Lena N. Lupey, Julia A. Hilbrands, Cristina Montero Diez, Jorge L. Santiago-Ortiz, Dustin S. Woyski, Sandy D. Mach, Joseph Perez-Otero, Karim A. Sharif, Carlos Mendoza, John D. Fitzgibbons, Nelson H. Knudsen, Christy MacKinnon, Hayley M. Faber, Kwabea Agbley, Michelle Heslop, Olivia Cyrankowski, Priscilla Rodriguez, Melissa Jones, Jean M. Strelitz, Ryan A. Grove, Rachel A Greenstein, Michael Murillo, Elizabeth Greiner-Sosanko, Ciani Jean Sparks, Darryl McFarland, Franca G. Rossi, Heran Gebreyesus, Chris Kay, Danielle Ladzekpo, Chris Harward, Jordan S. Christie, Consuelo J. Alvarez, Elaine V. Morlock, Geoff Scott, Kelsey Hockenberger, Sepo Musokotwane, Adam Fearnow, Lauren J. Keny, Alaina J. Grantham, Evangelina Reza, Mike Colgan, Melanie K. Regan, Stephanie J. Potocny, Sasha L. Dorsett, Tara Skorupa, Valerie M. Gónzalez-Pérez, Vinayak S. Nikam, Anne C. Meier, Varun Sundaram, Helen B. Rankin, Andrew B. Nylander, Mariela Gines-Rosario, Laurell MacMillian, Jeannette M. Osterloh, Robert H. Allen, Melanie A. Smith, Sarah J. Spencer, Cheri M. Ackerman, Jeffrey L. Poet, Amanda J. Hay, Isaac O. Armistead, Laura K. Reed, Don W. Paetkau, Bib Yang, Enid M. Quintana-Torres, Kathryn L. Golden, Lauren A. DiLorenzo, Alen Ramic, Mark T. LeBlanc, Carl J. Minniti, Robert J. Bailey, Kristen M. Thomsen, Ashley L. Adams, Chad A. Koplinsky, Eliezer O. Perez-Colomba, Nicole A. Howey, Katie A. TerMeer, Stephanie Intriago, Christina N. Kufel, Mary Waters, Bo Liu, Thomas J. Bahr, Ashley R. Miller, Claire Pattison, Morgan R. Light, Amy T. Hark, Jennifer S. Doty, Catherine M. Mageeney, Adam J. Ronk, Nadezhda Fefelova, Andrew R. Armstrong, Maida Chen, Elizabeth Macias, Kim M. Chau, Paul Bilinski, Trevor G. Floyd, Cassidy T. Lee, Jenna C. Tenney, Bob Gardner, Patricia Ortiz-Ortiz, Elizabeth S. Jewell, Gabi Lucas, Brandon Lee, Jenifer N. Jarrell, Jimmy Hsiang-Chun Chang, Lorraine Malkowitz, Ulises Marrero-Llerena, Gabriel Stancu, Matthew R. Unzicker, Andrea P. Burgos-Bula, Michelle L. Miller, Elisandra Rivera, Kate Bagaeva, Jessica W. Polk, Jordan E. Carney, Maureen Corrielus, Jana Nietmann, Jeff Howenstein, Elizabeth Kiernan, Sabya A. Rauf, Brandon M. Katz, Elizabeth C. Nordman, Devon Shallman, Eric M. Clark, Lenin Lopez, Karen J. Kraftmann, Leslie Guadron, Julia Kuhn, Allison R. Schneiter, Satish C. Bhalla, Emily J. Howell, Blair Undem, Jeffrey S. Thompson, Arelys Flores-Vazquez, John Kiley, Cody M. Morrow, Joseline Serrano-González, John Mark Knepper, Christopher Beck, Calise Debow, Anna L. Smith, Angelica Garcia, Shelbi Christgen, Shadie Emiah, Tammy Mazur, Rachel E. VanDyken, Frank R. Soto delValle, Zachary Nichols, William R. Kennedy, Ameer Zidan, Douglas A. Herrick, Thomas Q. Xu, Elizabeth Shoop, Jessica A. Kampmeier, John M. Kerber, Caitlin Pozmanter, Emily L. Hong, Frederic J. Deuschle, Allyson B. Rivard, William Neutzling, Joseph V. Moran, Benjamin K. Johnson, Jacob Jipp, Shannon R. McCartha, Abby Vrable, Z. Goodwin, Suchita Rastogi, Alyssa M. Newman, Lionel Ortiz-Fuentes, Arjun A. Anilkumar, Bryan M. Hennessy, Hui-Min Chung, Katie L. Goeller, Carlos E. Santos-Ramos, Adam Dillman, Christine D. Wilson, Sarah J. Peacock, Andrew J. Kim, Carol I. Morales-Caraballo, Briana Brinkley, Justin Alldredge, Rebecca Krock, Kristen C. Davis, David Dunbar, Joshua L. Manghelli, Erica K. Earl, Katherine Gavinski, Sheryl T. Smith, Portia Mason, Lindsay J. Hoogenboom, Jessen T. Havill, Sonya G. Méndez-Castellanos, Darrin T. Schultz, Katherine J. Faber, Allison O’Rouke, Emily G. Miller, Yara Ashrawi, Curtiss E. Lane, Saryleine Ortiz-DeChoudens, Michael W. Sandusky, Andrew Montgomery, Rita Kabaso, Todd Aronhalt, Jonathan D. Foust, Jorge Ruiz, Eric Helmreich, Todd T. Eckdahl, Charlotte Lea, Kevin Coulson, Kristin M. French, Kate A. Woodard, Brandon J. Burkhart, Kylie McNeil, Curtis R. Edwards, Jimmy Ma, Darcie D. Elder, Tia DiTommaso, Nicholaus Monsma, Sarah A. Jelgerhuis, Stephanie J. Adams, Nichole Rigby, Heather L. Holderness, Charlotte Williams, Megan Donegan, Taylor S. Harding, Javier O. Martinez-Rodriguez, Sandeep Venkataram, Tiffany Wong, Anika Toorie, Jenny L. Rose, Ashley S. Brown, Sarah A. Popelka, Matthew Williams, Julie Bryant, Sarah C. R. Elgin, Sonali Kumar, Joshua Burkhardt, William J. Puetz, Erica L. Alvendia, Richard A. Tumminello, Kesley Parry, Joshua R. Smith, Ashley F. Custer, Carlos E. Ortiz, Yedda Li, April E. Bednarski, Simon Ng, Max Mandelbaum, Arlene J. Hoogewerf, Chelsea A. Walker, Ryan S. Lee, Jeannette Wong, Isabella Theresa Felzer-Kim, Harrison Friedman, Megan Bourland, Luis R. Colón-Cruz, Lucy Liu, Nicole C. Olson, Yi Ren, Adam P Lousararian, José M. Cruz-García, Charlie Manchee, Kyle Zoll, Kristina M. Stemler, Juliana Belén-Rodríguez, Ashley S. Timko, Jane Lopilato, England Raimey, Amy D. Melton, Joshua D. Forsyth, Christopher D. Savell, Himabindu Reddy, Alica B. Allen, Amanda Maffa, Daniel W. Cassidy, Luciann Bracero-Quiñones, Eric Lemmon, Justina R. Bartling, Bradley J. Ogden, Petros Svoronos, Mary Spratt, Lisa Sudmeier, Héctor A. Martell-Martínez, James F. Geary, Bridget J. Sessions, Christopher Campana, Kaitlyn A. Downey, Seth G. Dawson, Daniella Menillo, Casey Hanson, James M. Bellush, Justin A. Gonzales, Roy Song, Karvyn Torchon, Betsy Hoover, Michael Closser, Lacey Neufeld, Micah Shelton, Benjamin R. Does, Juan Carlos Martínez-Cruzado, Jordan S. Baumgardner, Nicole Chichearo, Mary T. Reilly, Colleen V. Kelley, Monica Yalamanchili, Dawn Lau, Abbie Morgan, Alyssa Cifelli, Milton R. Herrold, Ambreen Khan, James Messler, Kyle Westphal, James L. Kehoe, Juliana A. Wurzler, Garrett Salzman, Tracy Wang, Charlene Emerson, Lyndsey A. Reynolds, Alysha Moretti, Marita K. Abrams, Mara G. Cole, Michael B. Schultz, Samantha Cruz, Natalie Ngai, Nadia Safa, Vicente Velasquez, Ashley Townsend, Jonathan L. Crooke-Rosado, Amber M. Gygi, Ishwar S. Gill, Christopher McLaughlin, Dorianmarie Vargas-Franco, Alissa Beckett, Samantha Vue, Nadine L. Rossi, Justina Chinwong, Ryan Michael Rempe, Trip Freeburg, Amy J. Johnson, Omolara Glenn, Jade Lea Rekai, Hashini Gunasinghe, Vivienne Echendu, Marshall Strother, Morgan Baker, Christopher D. Smith, Paolo A. DaSilva, Noelle Delacruz, Tiara Tirasawasdichai, Yakov Shevin, Wilfried Guiblet, Shane M. Patao, Peterson R. Cullimore, Giancarlo F. Garbagnati, Adam E. Musick, Sarah C. Butzler, Jonathan D. Presley, Ana I. Correa-Muller, Christopher D. Shaffer, Chunguang Du, Ryan D. Mitchell, Jonathan P. Rennhack, Barbara L. Hopkins, Mary E. Shaw, Jessica E. Hill, Jeremy N. Wong, Anna Kim, Christopher B. Khoury, Julia Chapman, Amanda T. Mercer, Jessica A. Shuen, Joyce H. Lau, I.N. Falk, Sunil Rathore, Christopher J. Jones, Laura Simone Bisogno, Nighat P. Kokan, Paul Yenerall, Amber L. Price, Kelsey T. Bushhouse, Stephen L. McDaniel, Andrew P. Drake, Johnathan D. English, Sampson K. Boham, Robert A. Herbstsomer, Daniel S. Fosselman, Kevin Babilonia-Figueroa, Matthew Simon, Anne G. Rosenwald, Bryan J. Rupley, Heather Cohen, Victoria Scala, Avery B. Cromwell, Christopher E. Blunden, Yelena P. Davis, William B. Armstrong, Kristine Ostby, Joanna Haye, Lauren M. Wysocki, Lena Christiansen, Allison A. Throm, Sarah Flohr, Matthew Wawersik, Rebecca J. Cotteleer, Kristen R Ramirez, Dontae A. Jacobs, Sarah Woehlke, Gregory S. Messenger, Soham Aso, Nicole Clarke-Medley, Bryant R. Swanson, Lindsay K. Brouwer, S. Catherine Silver Key, Stephanie Zarrasola, Michael S. Salgado, Dong K. Rhee, Mai Abdelnabi, Eve VanEck, Jeremy Buhler, Sarah Kong, Turner Conrad, Jennifer Roecklein-Canfield, Marykathryn Tynon, Brian J. Maniaci, Alexa M. McDonough, Ivan G. Llavona-Cartagena, J. Devin Spencer, Todd D. Johnson, Azita Bashiri, Kimberley Ramsey, Mike Polen, Hien P Nguyen, Seantay D. Patterson, Lucia Wande, Nicholas U. Schwartz, Han Yuan, Albeliz Santiago-Colón, Joseph Medina, Samuel Thomas Crowley, Emma Shoemaker, Alex J. Feliciano-Cancela, Alexander J. Kujawski, Lillyann Asencio-Zayas, Gentry L. Pickett, Matt J. Randazzo, Erica Stagaard, Kristin M. LaForge, Gabriela A. Llaurador-Caraballo, Anastasia K. Yemelyanova, Alan Tseng, Erika E. Menyes, Julie Azarewicz, Christa Burke, Samuel I. Smith, Nazanin Ghavam, Carolina Gomez, Cameron Fick, Anthony Pinto, Lindsay Rios, Gary A Kuleck, Ashley Rich, Kayla A. Florian, Martin N. Cheramie, Yuki Kwan Wa Shum, Atlee Baker, LaJerald Augustine, Alyson Greenwell, Rasleen K. Saluja, Jason S. Macias, Wesley W. Winn, Samantha M. Schmuecker, Michelle E. M. Eisen, Pedro Benitez, Jeanette Hauke, Nora C. Goscinski, Justin R. DiAngelo, Carter T. Docking, David D. Xiong, Brittany D. Pasierb, Matt Van Camp, Yin Zheng, Nikie L. McCabe, Emily Reed, Katie Homa, Kimberly S. Kolibas, Elizabeth A. Karaska, Grace A. Dougherty, John P. Fanning, Michael Fasano, Joseph E. Sable, Robert W. Schulz, San Francisco Nguyen, Michael L. Rojas-Vargas, Kierstin L. Naylor, Emily Peoples, Jessica Neely, Lejla Cesko, Brionna D. Davis-Reyes, Roxanne Banker, Amanda K. Tilot, Jordan P. Brand, William H. Newhart, Lauriaun Johnson, Michelle M. Giddens, Nicole B. Clark, Anant Agarwalla, Thomas F. Minton, Dana W. Brooks, Amanda D. Garrett, Bethany M. Klett, Kristin M. Starkey, Antoinette E. Fafara-Thompson, Michael R. Rubin, Jonathon M. Benson, Erica Enoch, Amanda M. Damsteegt, Zackary W. Scott, Elisabeth A. Kelly, Jason M. Barnett, Wilson Leung, Luke J. Rodriguez-Giron, Krishna C. Mudumbi, Francis J. May, Nadyan M. Vargas-Barreto, Geeta Statton, José L. Torres-Castillo, Sarah Hirsch, Rachel M. Reem, Linghui Li, Deirdre Robinett, Jason Caronna, Abneris E. Rodríguez-Laboy, Samantha Lawrence, Katherine R. Reynolds, Corinne Weeks, Allison M. Sterling, Chun Leung Ng, Roman E. Ramirez, Daron C. Barnard, Leming Zhou, Eric P. Spana, John A. Toth, Alvin Lu, Krizia C. Menéndez-Serrano, Jonathan M. Heckman, Ben Chlebina, Matthew C. Fadus, Helmet T. Karim, Shailly Gaur, Timothy R. Jelsema, Nicholas Keysock, Thomas J. Carr, Zach Fusco, Evan M. Verbofsky, Monal Naik, Amanda H. Flores, Kristin A. Knouse, Olga R. Kopp, Elizabeth Feenstra, Edward P. Sweeney, Christen Johnson, Justin Crawford, Damian Urick, Victor W. Mullen, Carrie A. Dunham, Gabriella A. DeMichele, Mengyang Sun, William Harrington, Jessica M. Bodenberg, Xavier A. Collado-Méndez, T. Aaron Wiles, Michelle K. Powers, Phillip J. Minnick, Lourdes N. Irizarry-González, Valeria Silva, Steven Ovu, Nik Kolba, Peter Lindbeck, Jerome M. Molleston, Ifeanyi Obiorah, David Carranza, Lauren R. Beck, Alina M. Tamayo-Figueroa, Elaine R. Mardis, Rachel N. Lippert, Ingrid T. Rivera-Pagán, Mahdi Soos, Trung T. Nguyen, Megan Martinez, Van Kim, Benjamin L. Danner, Randall J. DeJong, Melissa M. Trieu, Andrea M. Senquiz-Gonzalez, Mary Grace Schueler, Emily E. Magnuson, Lesley E. Jackson, Hendrick Pagán-Torres, Fareed Sanusi, Dana Koenig, Vidya Chandrasekaran, Chinmoy I. Bhatiya, Dongyeon Kim, Paul J. Overvoorde, Reece Watson, Jennifer Schottler, Devry Lin, Jim Youngblom, Taylor Schauder, Nigel Madden, Isabel Valdez, Thomas John Reynolds, Kelly M. Deranek, Anne A. Welker, Jackie X. White, Nicole C. Riddle, Jacob Pfeil, Aldo Heredia-Negrón, Christine Langner, Tao Jian He, Jonathan P. Mecoli, Lissett Mayorga, Scott Chiang, Rishi Singhal, Julia C. Peairs, Michael Quach, Anne M. Eime, GiNell Elliott, Meleah J. Gross, Melissa Drewry, Julia A. Emerson, Anthony K. Lambright, Isaac Appiah, Gregory M. Robertson, Nathaniel Regenold, Philip Pham, George Odisho, Alexi Archambault, Matthew Dothager, Shana M. Baldassari, Paul J. Lee, Callie R. Merry, Jesse R. Farek, Archana Tare, Srebrenka Robic, William Vernon, Tam Vuong, Bethany Grace Bonifield, Katrina Thistle, Rose M. Dowd, Noor Tazudeen, Jennifer Weaver, Manpreet Kaur, Nicole M. Caesar, Yi Zhang, Michael C. Cristostomo, Albert Tzeng, Kayla Vondy, Emily Perling, Ramiro A. Chavez, Lanor S. Horton, Matt Kroll, Levent H. Beken, Justin R. Starcher, Sam Asinof, Nathalia M. Cruz, Eunice George, Adam T. Morrow, Heather Milnthorp, Cheryl Mazzeo, Kristen R. Hatfield, Anna L. Boudoures, Ashley A. Tewilliager, Edna P. Tascón-Peñaranda, Vilma F. Huerta, Sarah Tuberty, Mallory A. Williams, Rachel E. Weber, Sarah Spencer, Emily C. Leatherman, Yuying Gosser, Steve DeFazio, Patrick Ng, Jeri Sparks, Pavan Bhat, Mindy E. Bower, Jordan E. Matthews, Cyrus E. Kuschner, Anne Bertolet, Matt Kusner, Thomas C. Giarla, Jessica Penn, Gerard P. McNeil, Mariam Meghdari, Michael J. Wolyniak, Matthew Juergens, Karla I. Velázquez-Soto, Maria Kaisler, Jeanine Schibler, Alexis Nagengast, Susan Parrish, Frances Marín-Maldonado, Shiv Mohini, Jessica King, Danny Mammo, Katherine S. Harker, Allyson P. Hawkins, Kelly Drumm, Jennifer A. Lammers, Allyson P Mallya, Ashley Bryant, Katie Weihbrecht, Pete Wendland, Gabriela V. Bernal-Vega, Nestor A. Gutierrez, Armando G. Bermudez-Capo, Luke R. Salbert, Kirk Haltaufderhyde, Michelle L. Kappes, Mary A. Smith, York Chen, Miguel Vélez-Vázquez, Brittany E. Plescher, Francis D. Beauchamp-Pérez, Alyssa Ward, Andrea N. Clary, Don Foret, Mitchell J McDonald, Mariela Colon-Vazquez, Amanda L. Blaker, Hao Yang, James Z. Liu, Austin B. Limle, Henry Huang, Luis Vilanova-Velez, Edgar Garibay, Philip J. Freda, Laura L. Mays Hoopes, Maureen S. Hammond, Marian M. Kaehler, Rebecca Shuford, Ray Sunjed, Cynthia K. Hanson, Marielle VanderVennen, Idaliz M. Martínez-Traverso, Jack Y. Yu, Spencer L. Franchi, Michael Snavely, John E. Anderson, Lainey S. Rubin, Kelly K. Jones, Stephanie F. Mel, Stacey Lytle, Danny L. Tran, Chelsea R. Barberi, Max Mian Liu, Eric A. Nollet, Sarah E. Muller, Diana Norton, John M. Braverman, Thu A. Phan, Nelson Membreno, Colin Khoshabian, John Gooch, Cassandra Kubricky, Priscila M. Rodríguez-García, Anna Wylie, Diana L. E. Johnson, Anna K. Unruh, Deborah Hammett, Jon Sarezky, Marie Brown, Carolina Riascos-Cuero, Emily J. Diekema, Emmy E. Ogawa, Miranda Chavez, Zuzana Kocsisova, Dennis Revie, Anniken M. Lydon, Peter A. Cognetti, Ashley A. Collins, Tariq Abusheikh, Erin K. Luippold, Kevin Myirski, Brian O. Rodríguez-Echevarría, Haley J. Plasman, Lara Baatenburg, Jesse Hendriksma, Christopher R. Knob, Max Semon, Cassandra Farrar, Xiao Zhu, Ali Dobbe, Marie-Isabelle B. Seydoux, Griffin Sadovsky, Shreya Prasad, Victoria Newcomb, Chad Gier, Dmitri Serjanov, Jules Wellinghoff, Maxwell T. Smith-Gee, and Alexandra H. Scoma

Subjects
Transposable element, Codon Adaptation Index, Euchromatin, Heterochromatin, transposons, evolution of heterochromatin, Investigations, Genome, Evolution, Molecular, 03 medical and health sciences, gene size, 0302 clinical medicine, melting characteristics, Species Specificity, codon bias, Genetics, Animals, Drosophila Proteins, Selection, Genetic, Codon, Molecular Biology, Genetics (clinical), 030304 developmental biology, Polytene Chromosomes, Repetitive Sequences, Nucleic Acid, Gene Rearrangement, 0303 health sciences, biology, Computational Biology, Molecular Sequence Annotation, Gene rearrangement, Exons, Genomics, biology.organism_classification, Introns, Drosophila melanogaster, Codon usage bias, DNA Transposable Elements, Drosophila, 030217 neurology & neurosurgery
Abstract

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.

Published
2015

6. A Course-Based Research Experience: How Benefits Change with Increased Investment in Instructional Time

Author

Juan Carlos Martínez-Cruzado, Gary A Kuleck, Shubha Govind, Christopher D. Smith, Judith Leatherman, Jeffrey S. Thompson, Daron C. Barnard, Christopher J. Jones, Paul J. Overvoorde, Matthew Wawersik, Amy Frary, Randall J. DeJong, Dale L. Beach, Todd T. Eckdahl, Laura L. Mays Hoopes, Marian M. Kaehler, David Lopatto, Justin R. DiAngelo, Michael R. Rubin, Mary A. Smith, Carina E. Howell, Donald R. Frohlich, Chunguang Du, Leming Zhou, Eric P. Spana, Stephanie F. Mel, John M. Braverman, Karim A. Sharif, Consuelo J. Alvarez, Gary R. Skuse, Cheryl Bailey, Anya Goodman, Kari Clase, Laura K. Reed, Anne G. Rosenwald, Don W. Paetkau, James E. J. Bedard, Mary L. Preuss, Gerard P. McNeil, Michael J. Wolyniak, Martin G. Burg, Lisa Kadlec, Alexis Nagengast, Susan Parrish, Hemlata Mistry, Hui-Min Chung, Joyce Stamm, April E. Bednarski, Sheryl T. Smith, Aparna Sreenivasan, Paul Szauter, Celeste Peterson, Stephanie Schroeder, Nighat P. Kokan, Satish C. Bhalla, Arlene J. Hoogewerf, Heather L. Eisler, Christy MacKinnon, Mary Spratt, Christopher Bazinet, Amy T. Hark, Wilson Leung, Olga R. Kopp, Diana S Johnson, Elaine R. Mardis, Mary E. Shaw, Catherine Reinke, David Dunbar, Yuying Gosser, Jane Lopilato, Vidya Chandrasekaran, Srebrenka Robic, Sarah C. R. Elgin, Kenneth Saville, Adam Haberman, Dennis Revie, Christopher D. Shaffer, Jennifer Roecklein-Canfield, Julia A. Emerson, Adam Kleinschmit, Jeremy Buhler, Charles R. Hauser, James J. Youngblom, S. Catherine Silver Key, and O'Dowd, Diane K

Subjects
Value (ethics), Program evaluation, Time Factors, General Biochemistry, Genetics and Molecular Biology, Information science, Education, Surveys and Questionnaires, Mathematics education, ComputingMilieux_COMPUTERSANDEDUCATION, Humans, Learning, Cooperative Behavior, Curriculum, Biology, Mathematics, Data collection, Genome, Data Collection, Research, Molecular Sequence Annotation, Articles, Genomics, Investment (macroeconomics), Faculty, Research Personnel, Variety (cybernetics), Knowledge, Undergraduate research, Attitude, Self Report, Curriculum and Pedagogy, Program Evaluation
Abstract

While course-based research in genomics can generate both knowledge gains and a greater appreciation for how science is done, a significant investment of course time is required to enable students to show gains commensurate to a summer research experience. Nonetheless, this is a very cost-effective way to reach larger numbers of students., There is widespread agreement that science, technology, engineering, and mathematics programs should provide undergraduates with research experience. Practical issues and limited resources, however, make this a challenge. We have developed a bioinformatics project that provides a course-based research experience for students at a diverse group of schools and offers the opportunity to tailor this experience to local curriculum and institution-specific student needs. We assessed both attitude and knowledge gains, looking for insights into how students respond given this wide range of curricular and institutional variables. While different approaches all appear to result in learning gains, we find that a significant investment of course time is required to enable students to show gains commensurate to a summer research experience. An alumni survey revealed that time spent on a research project is also a significant factor in the value former students assign to the experience one or more years later. We conclude: 1) implementation of a bioinformatics project within the biology curriculum provides a mechanism for successfully engaging large numbers of students in undergraduate research; 2) benefits to students are achievable at a wide variety of academic institutions; and 3) successful implementation of course-based research experiences requires significant investment of instructional time for students to gain full benefit.

Published
2014

7. Identification of a novel ZIC3 isoform and mutation screening in patients with heterotaxy and congenital heart disease

Author

Stephanie M. Ware, Allison Haaning, and James E. J. Bedard

Subjects
Male, Heart malformation, Gene Identification and Analysis, lcsh:Medicine, Dextrocardia, Heterotaxy Syndrome, Cardiovascular, medicine.disease_cause, Gene Splicing, Mice, Exon, 0302 clinical medicine, Protein Isoforms, lcsh:Science, Zinc finger, Genetics, 0303 health sciences, Mutation, Multidisciplinary, Reverse Transcriptase Polymerase Chain Reaction, Congenital Heart Disease, Genetic Diseases, X-Linked, Zinc Fingers, Exons, Medicine, Female, Research Article, Gene isoform, Molecular Sequence Data, Biology, Molecular Genetics, 03 medical and health sciences, Sequence Homology, Nucleic Acid, GLI3, medicine, Animals, Humans, Amino Acid Sequence, Genetic Testing, 030304 developmental biology, Homeodomain Proteins, Base Sequence, Sequence Homology, Amino Acid, Gene Expression Profiling, Alternative splicing, lcsh:R, Computational Biology, Molecular biology, Mice, Inbred C57BL, Alternative Splicing, NIH 3T3 Cells, lcsh:Q, Heterotaxy, 030217 neurology & neurosurgery, HeLa Cells, Transcription Factors
Abstract

Patients with heterotaxy have characteristic cardiovascular malformations, abnormal arrangement of their visceral organs, and midline patterning defects that result from abnormal left-right patterning during embryogenesis. Loss of function of the transcription factor ZIC3 causes X-linked heterotaxy and isolated congenital heart malformations and represents one of the few known monogenic causes of congenital heart disease. The birth incidence of heterotaxy-spectrum malformations is significantly higher in males, but our previous work indicated that mutations within ZIC3 did not account for the male over-representation. Therefore, cross species comparative sequence alignment was used to identify a putative novel fourth exon, and the existence of a novel alternatively spliced transcript was confirmed by amplification from murine embryonic RNA and subsequent sequencing. This transcript, termed Zic3-B, encompasses exons 1, 2, and 4 whereas Zic3-A encompasses exons 1, 2, and 3. The resulting protein isoforms are 466 and 456 amino acid residues respectively, sharing the first 407 residues. Importantly, the last two amino acids in the fifth zinc finger DNA binding domain are altered in the Zic3-B isoform, indicating a potential functional difference that was further evaluated by expression, subcellular localization, and transactivation analyses. The temporo-spatial expression pattern of Zic3-B overlaps with Zic3-A in vivo, and both isoforms are localized to the nucleus in vitro. Both isoforms can transcriptionally activate a Gli binding site reporter, but only ZIC3-A synergistically activates upon co-transfection with Gli3, suggesting that the isoforms are functionally distinct. Screening 109 familial and sporadic male heterotaxy cases did not identify pathogenic mutations in the newly identified fourth exon and larger studies are necessary to establish the importance of the novel isoform in human disease.

Published
2011

8. Development of a Species-Specific Probe for Pythium insidiosum and the Diagnosis of Pythiosis

Author

James E. J. Bedard, Leonel Mendoza, Arthur W. A. M. de Cock, Andrew M. Schurko, and Glen R. Klassen

Subjects
Microbiology (medical), biology, Hybridization probe, Nucleic Acid Hybridization, Pythium, Mycology, Pythium insidiosum, biology.organism_classification, Infections, Sensitivity and Specificity, Prototheca wickerhamii, Microbiology, Pythiosis, genomic DNA, Species Specificity, Humans, Restriction fragment length polymorphism, DNA Probes, Ribosomal DNA
Abstract

Pythium insidiosum, the only species in the genus that infects mammals, is the etiological agent of pythiosis, a granulomatous disease characterized by cutaneous and subcutaneous lesions and vascular diseases. Accurate diagnosis of pythiosis and identification of its causal agent are often inconsistent with current immunological diagnostic methods. A species-specific DNA probe was constructed by using a 530-bp HinfI fragment from the ribosomal DNA intergenic spacer of P. insidiosum. When the probe was incubated with dot blots of genomic DNA from 104 Pythium species, it hybridized only to the DNA of P. insidiosum and P. destruens—two species that have been considered conspecific. The probe also hybridized to DNA from 22 P. insidiosum isolates in this study, regardless of their geographic origin or animal host. When tested against genomic DNA from other pathogenic organisms (Aspergillus fumigatus, Basidiobolus ranarum, Conidiobolus coronatus, Lagenidium giganteum, Paracoccidioides brasiliensis, and Prototheca wickerhamii), no cross-hybridization of the probe was detected. The specificity of the probe to hybridize to genomic DNA from all isolates of P. insidiosum and not cross-react with DNA from other Pythium species or pathogens that cause symptoms similar to pythiosis in their hosts makes it a powerful tool for the accurate diagnosis of pythiosis. In addition, the probe has the potential for pathological and environmental diagnostic applications. Pythium insidiosum (11) is the etiological agent of pythiosis, a granulomatous disease that affects animals including equines, canines, felines, cattle, and humans. The symptoms of pythiosis include cutaneous and subcutaneous infections, bone lesions, esophagitis, gastrointestinal diseases, and pulmonary infections. Pythium is a genus in the class Oomycetes in the Kingdom Straminipila (39) that is comprised of over 120 described species (53). However, P. insidiosum is the only species in the genus capable of infecting mammalian hosts, whereas the other species are saprophytic or pathogenic to plants. Results from restriction fragment length polymorphism analysis (46) and sequence analysis (47) revealed three clades of P. insidiosum isolates representing geographical variants or cryptic speciation. Like most Pythium species, P. insidiosum is difficult to identify morphologically. Gomori’s methenamine-silver nitrate stains P. insidiosum hyphae in tissue nonspecifically. In the infected tissues, short, septate hyphae with perpendicular branching are rarely visible, but members of the Zygomycetes have a similar appearance in histological sections (12). Perhaps the most important cultural identification feature is the production of motile biflagellate zoospores (33), but this is relatively nonspecific and may take weeks to observe, and for some

Published
2004

9. Identification of a novel ZIC3 isoform and mutation screening in patients with heterotaxy and congenital heart disease.

Author

James E J Bedard, Allison M Haaning, and Stephanie M Ware

Subjects
Medicine, Science
Abstract

Patients with heterotaxy have characteristic cardiovascular malformations, abnormal arrangement of their visceral organs, and midline patterning defects that result from abnormal left-right patterning during embryogenesis. Loss of function of the transcription factor ZIC3 causes X-linked heterotaxy and isolated congenital heart malformations and represents one of the few known monogenic causes of congenital heart disease. The birth incidence of heterotaxy-spectrum malformations is significantly higher in males, but our previous work indicated that mutations within ZIC3 did not account for the male over-representation. Therefore, cross species comparative sequence alignment was used to identify a putative novel fourth exon, and the existence of a novel alternatively spliced transcript was confirmed by amplification from murine embryonic RNA and subsequent sequencing. This transcript, termed Zic3-B, encompasses exons 1, 2, and 4 whereas Zic3-A encompasses exons 1, 2, and 3. The resulting protein isoforms are 466 and 456 amino acid residues respectively, sharing the first 407 residues. Importantly, the last two amino acids in the fifth zinc finger DNA binding domain are altered in the Zic3-B isoform, indicating a potential functional difference that was further evaluated by expression, subcellular localization, and transactivation analyses. The temporo-spatial expression pattern of Zic3-B overlaps with Zic3-A in vivo, and both isoforms are localized to the nucleus in vitro. Both isoforms can transcriptionally activate a Gli binding site reporter, but only ZIC3-A synergistically activates upon co-transfection with Gli3, suggesting that the isoforms are functionally distinct. Screening 109 familial and sporadic male heterotaxy cases did not identify pathogenic mutations in the newly identified fourth exon and larger studies are necessary to establish the importance of the novel isoform in human disease.

Published
2011
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