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1. Guidelines for releasing a variant effect predictor

Author

Livesey, Benjamin J., Badonyi, Mihaly, Dias, Mafalda, Frazer, Jonathan, Kumar, Sushant, Lindorff-Larsen, Kresten, McCandlish, David M., Orenbuch, Rose, Shearer, Courtney A., Muffley, Lara, Foreman, Julia, Glazer, Andrew M., Lehner, Ben, Marks, Debora S., Roth, Frederick P., Rubin, Alan F., Starita, Lea M., and Marsh, Joseph A.

Subjects
Quantitative Biology - Other Quantitative Biology
Abstract

Computational methods for assessing the likely impacts of mutations, known as variant effect predictors (VEPs), are widely used in the assessment and interpretation of human genetic variation, as well as in other applications like protein engineering. Many different VEPs have been released to date, and there is tremendous variability in their underlying algorithms and outputs, and in the ways in which the methodologies and predictions are shared. This leads to considerable challenges for end users in knowing which VEPs to use and how to use them. Here, to address these issues, we provide guidelines and recommendations for the release of novel VEPs. Emphasising open-source availability, transparent methodologies, clear variant effect score interpretations, standardised scales, accessible predictions, and rigorous training data disclosure, we aim to improve the usability and interpretability of VEPs, and promote their integration into analysis and evaluation pipelines. We also provide a large, categorised list of currently available VEPs, aiming to facilitate the discovery and encourage the usage of novel methods within the scientific community., Comment: 14 pages, 1 figure

Published
2024

5. Minimum information and guidelines for reporting a Multiplexed Assay of Variant Effect

Author

Claussnitzer, Melina, Parikh, Victoria N., Wagner, Alex H., Arbesfeld, Jeremy A., Bult, Carol J., Firth, Helen V., Muffley, Lara A., Ba, Alex N. Nguyen, Riehle, Kevin, Roth, Frederick P., Tabet, Daniel, Bolognesi, Benedetta, Glazer, Andrew M., and Rubin, Alan F.

Subjects
Quantitative Biology - Other Quantitative Biology
Abstract

Multiplexed Assays of Variant Effect (MAVEs) have emerged as a powerful approach for interrogating thousands of genetic variants in a single experiment. The flexibility and widespread adoption of these techniques across diverse disciplines has led to a heterogeneous mix of data formats and descriptions, which complicates the downstream use of the resulting datasets. To address these issues and promote reproducibility and reuse of MAVE data, we define a set of minimum information standards for MAVE data and metadata and outline a controlled vocabulary aligned with established biomedical ontologies for describing these experimental designs.

Published
2023

6. Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve KCNH2-LQTS Variant Classification and Cardiac Event Risk Stratification

Author

O’Neill, Matthew J., Ng, Chai-Ann, Aizawa, Takanori, Sala, Luca, Bains, Sahej, Winbo, Annika, Ullah, Rizwan, Shen, Qianyi, Tan, Chek-Ying, Kozek, Krystian, Vanags, Loren R., Mitchell, Devyn W., Shen, Alex, Wada, Yuko, Kashiwa, Asami, Crotti, Lia, Dagradi, Federica, Musu, Giulia, Spazzolini, Carla, Neves, Raquel, Bos, J. Martijn, Giudicessi, John R., Bledsoe, Xavier, Gamazon, Eric R., Lancaster, Megan C., Glazer, Andrew M., Knollmann, Bjorn C., Roden, Dan M., Weile, Jochen, Roth, Frederick, Salem, Joe-Elie, Earle, Nikki, Stiles, Rachael, Agee, Taylor, Johnson, Christopher N., Horie, Minoru, Skinner, Jonathan R., Ackerman, Michael J., Schwartz, Peter J., Ohno, Seiko, Vandenberg, Jamie I., and Kroncke, Brett M.

Published
2024
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7. Multicenter clinical and functional evidence reclassifies a recurrent noncanonical filamin C splice-altering variant

Author

O’Neill, Matthew J., Chen, Suet Nee, Rumping, Lynne, Johnson, Renee, van Slegtenhorst, Marjon, Glazer, Andrew M., Yang, Tao, Solus, Joseph F., Laudeman, Julie, Mitchell, Devyn W., Vanags, Loren R., Kroncke, Brett M., Anderson, Katherine, Gao, Shanshan, Verdonschot, Job A.J., Brunner, Han, Hellebrekers, Debby, Taylor, Matthew R.G., Roden, Dan M., Wessels, Marja W., Lekanne Dit Deprez, Ronald H., Fatkin, Diane, Mestroni, Luisa, and Shoemaker, M. Benjamin

Published
2023
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10. Neptune: an environment for the delivery of genomic medicine

Author

Eric, Venner, Yi, Victoria, Murdock, David, Kalla, Sara E., Wu, Tsung-Jung, Sabo, Aniko, Li, Shoudong, Meng, Qingchang, Tian, Xia, Murugan, Mullai, Cohen, Michelle, Kovar, Christie, Wei, Wei-Qi, Chung, Wendy K., Weng, Chunhua, Wiesner, Georgia L., Jarvik, Gail P., Muzny, Donna, Gibbs, Richard A., Abrams, Debra, Adunyah, Samuel E., Albertson-Junkans, Ladia, Almoguera, Berta, Ames, Darren C., Appelbaum, Paul, Aronson, Samuel, Aufox, Sharon, Babb, Lawrence J., Balasubramanian, Adithya, Bangash, Hana, Basford, Melissa, Bastarache, Lisa, Baxter, Samantha, Behr, Meckenzie, Benoit, Barbara, Bhoj, Elizabeth, Bielinski, Suzette J., Bland, Harris T., Blout, Carrie, Borthwick, Kenneth, Bottinger, Erwin P., Bowser, Mark, Brand, Harrison, Brilliant, Murray, Brodeur, Wendy, Caraballo, Pedro, Carrell, David, Carroll, Andrew, Castillo, Lisa, Castro, Victor, Chandanavelli, Gauthami, Chiang, Theodore, Chisholm, Rex L., Christensen, Kurt D., Chung, Wendy, Chute, Christopher G., City, Brittany, Cobb, Beth L., Connolly, John J., Crane, Paul, Crew, Katherine, Crosslin, David R., Dayal, Jyoti, De Andrade, Mariza, De la Cruz, Jessica, Denny, Josh C., Denson, Shawn, DeSmet, Tim, Dikilitas, Ozan, Dinsmore, Michael J., Dodge, Sheila, Dunlea, Phil, Edwards, Todd L., Eng, Christine M., Fasel, David, Fedotov, Alex, Feng, Qiping, Fleharty, Mark, Foster, Andrea, Freimuth, Robert, Friedrich, Christopher, Fullerton, Stephanie M., Funke, Birgit, Gabriel, Stacey, Gainer, Vivian, Gharavi, Ali, Glazer, Andrew M., Glessner, Joseph T., Goehringer, Jessica, Gordon, Adam S., Graham, Chet, Green, Robert C., Gundelach, Justin H., Hain, Heather S., Hakonarson, Hakon, Harden, Maegan V., Harley, John, Harr, Margaret, Hartzler, Andrea, Hayes, M. Geoffrey, Hebbring, Scott, Henrikson, Nora, Hershey, Andrew, Hoell, Christin, Holm, Ingrid, Howell, Kayla M., Hripcsak, George, Hu, Jianhong, Hynes, Elizabeth Duffy, Jayaseelan, Joy C., Jiang, Yunyun, Joo, Yoonjung Yoonie, Jose, Sheethal, Josyula, Navya Shilpa, Justice, Anne E., Kalra, Divya, Karlson, Elizabeth W., Keating, Brendan J., Kelly, Melissa A., Kenny, Eimear E., Key, Dustin, Kiryluk, Krzysztof, Kitchner, Terrie, Klanderman, Barbara, Klee, Eric, Kochan, David C., Korchina, Viktoriya, Kottyan, Leah, Kudalkar, Emily, Rahm, Alanna Kulchak, Kullo, Iftikhar J., Lammers, Philip, Larson, Eric B., Lebo, Matthew S., Leduc, Magalie, Lee, Ming Ta (Michael), Lennon, Niall J., Leppig, Kathleen A., Leslie, Nancy D., Li, Rongling, Liang, Wayne H., Lin, Chiao-Feng, Linder, Jodell E., Lindor, Noralane M., Lingren, Todd, Linneman, James G., Liu, Cong, Liu, Wen, Liu, Xiuping, Lynch, John, Lyon, Hayley, Macbeth, Alyssa, Mahadeshwar, Harshad, Mahanta, Lisa, Malin, Bradley, Manolio, Teri, Marasa, Maddalena, Marsolo, Keith, McGowan, Michelle L., McNally, Elizabeth, Meldrim, Jim, Mentch, Frank, Rasouly, Hila Milo, Mosley, Jonathan, Mukherjee, Shubhabrata, Mullen, Thomas E., Muniz, Jesse, Murdock, David R., Murphy, Shawn, Myers, Melanie F., Namjou, Bahram, Ni, Yizhao, Onofrio, Robert C., Obeng, Aniwaa Owusu, Person, Thomas N., Peterson, Josh F., Petukhova, Lynn, Pisieczko, Cassandra J., Pratap, Siddharth, Prows, Cynthia A., Puckelwartz, Megan J., Raj, Ritika, Ralston, James D., Ramaprasan, Arvind, Ramirez, Andrea, Rasmussen, Luke, Rasmussen-Torvik, Laura, Raychaudhuri, Soumya, Rehm, Heidi L., Ritchie, Marylyn D., Rives, Catherine, Riza, Beenish, Roden, Dan M., Rosenthal, Elisabeth A., Santani, Avni, Dan, Schaid, Scherer, Steven, Scott, Stuart, Scrol, Aaron, Sengupta, Soumitra, Shang, Ning, Sharma, Himanshu, Sharp, Richard R., Singh, Rajbir, Sleiman, Patrick M.A., Slowik, Kara, Smith, Joshua C., Smith, Maureen E., Smoot, Duane T., Smoller, Jordan W., Sohn, Sunghwan, Stanaway, Ian B., Starren, Justin, Stroud, Mary, Su, Jessica, Taylor, Casey Overby, Tolwinski, Kasia, Van Driest, Sara L., Vargas, Sean M., Varugheese, Matthew, Veenstra, David, Venner, Eric, Verbitsky, Miguel, Vicente, Gina, Wagner, Michael, Walker, Kimberly, Walunas, Theresa, Wang, Liwen, Wang, Qiaoyan, Weiss, Scott T., Wells, Quinn S., White, Peter S., Wiley, Ken L., Jr, Williams, Janet L., Williams, Marc S., Wilson, Michael W., Witkowski, Leora, Woods, Laura Allison, Woolf, Betty, Wynn, Julia, Yang, Yaping, Zhang, Ge, Zhang, Lan, and Zouk, Hana

Published
2021
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15. Multifocal Ectopic Purkinje Premature Contractions due to neutralization of an SCN5A negative charge: structural insights into the gating pore hypothesis

Author

Glazer, Andrew M., primary, Yang, Tao, additional, Li, Bian, additional, Page, Dana, additional, Fouda, Mohamed, additional, Wada, Yuko, additional, Lancaster, Megan C., additional, O’Neill, Matthew J., additional, Muhammad, Ayesha, additional, Gao, Xiaozhi, additional, Ackerman, Michael J., additional, Sanatani, Shubhayan, additional, Ruben, Peter C., additional, and Roden, Dan M., additional

Published
2024
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16. Prognostic Value of Multiplexed Assays of Variant Effect and Automated Patch-clamping forKCNH2-LQTS Risk Stratification

Author

O’Neill, Matthew J., primary, Ng, Chai-Ann, additional, Aizawa, Takanori, additional, Sala, Luca, additional, Bains, Sahej, additional, Denjoy, Isabelle, additional, Winbo, Annika, additional, Ullah, Rizwan, additional, Shen, Qianyi, additional, Tan, Chek-Ying, additional, Kozek, Krystian, additional, Vanags, Loren R., additional, Mitchell, Devyn W., additional, Shen, Alex, additional, Wada, Yuko, additional, Kashiwa, Asami, additional, Crotti, Lia, additional, Dagradi, Federica, additional, Musu, Giulia, additional, Spazzolini, Carla, additional, Neves, Raquel, additional, Bos, J. Martijn, additional, Giudicessi, John R., additional, Bledsoe, Xavier, additional, Lancaster, Megan, additional, Glazer, Andrew M., additional, Roden, Dan M., additional, Leenhardt, Antoine, additional, Salem, Joe-Elie, additional, Earle, Nikki, additional, Stiles, Rachael, additional, Agee, Taylor, additional, Johnson, Christopher N., additional, Horie, Minoru, additional, Skinner, Jonathan, additional, Extramiana, Fabrice, additional, Ackerman, Michael J., additional, Schwartz, Peter J., additional, Ohno, Seiko, additional, Vandenberg, Jamie I., additional, and Kroncke, Brett M., additional

Published
2024
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17. Partially repeatable genetic basis of benthic adaptation in threespine sticklebacks

Author

Erickson, Priscilla A, Glazer, Andrew M, Killingbeck, Emily E, Agoglia, Rachel M, Baek, Jiyeon, Carsanaro, Sara M, Lee, Anthony M, Cleves, Phillip A, Schluter, Dolph, and Miller, Craig T

Subjects
Biological Sciences, Ecology, Genetics, Human Genome, Adaptation, Physiological, Animals, Biological Evolution, British Columbia, Chromosome Mapping, Crosses, Genetic, Genetic Linkage, Lakes, Phenotype, Quantitative Trait Loci, Selection, Genetic, Smegmamorpha, Convergent evolution, genotyping-by-sequencing, parallel evolution, QTL, skeleton, Evolutionary Biology, Evolutionary biology
Abstract

The extent to which convergent adaptation to similar ecological niches occurs by a predictable genetic basis remains a fundamental question in biology. Threespine stickleback fish have undergone an adaptive radiation in which ancestral oceanic populations repeatedly colonized and adapted to freshwater habitats. In multiple lakes in British Columbia, two different freshwater ecotypes have evolved: a deep-bodied benthic form adapted to forage near the lake substrate, and a narrow-bodied limnetic form adapted to forage in open water. Here, we use genome-wide linkage mapping in marine × benthic F2 genetic crosses to test the extent of shared genomic regions underlying benthic adaptation in three benthic populations. We identify at least 100 Quantitative Trait Loci (QTL) harboring genes influencing skeletal morphology. The majority of QTL (57%) are unique to one cross. However, four genomic regions affecting eight craniofacial and armor phenotypes are found in all three benthic populations. We find that QTL are clustered in the genome and overlapping QTL regions are enriched for genomic signatures of natural selection. These findings suggest that benthic adaptation has occurred via both parallel and nonparallel genetic changes.

Published
2016

18. Genome Assembly Improvement and Mapping Convergently Evolved Skeletal Traits in Sticklebacks with Genotyping-by-Sequencing

Author

Glazer, Andrew M, Killingbeck, Emily E, Mitros, Therese, Rokhsar, Daniel S, and Miller, Craig T

Subjects
Genetics, Human Genome, Animals, Chromosome Mapping, Chromosomes, Gene Library, Genetic Linkage, Genome, Genotype, Phenotype, Quantitative Trait Loci, Smegmamorpha, genotyping-by-sequencing, linkage map, quantitative trait locus, convergent evolution, stickleback
Abstract

Marine populations of the threespine stickleback (Gasterosteus aculeatus) have repeatedly colonized and rapidly adapted to freshwater habitats, providing a powerful system to map the genetic architecture of evolved traits. Here, we developed and applied a binned genotyping-by-sequencing (GBS) method to build dense genome-wide linkage maps of sticklebacks using two large marine by freshwater F2 crosses of more than 350 fish each. The resulting linkage maps significantly improve the genome assembly by anchoring 78 new scaffolds to chromosomes, reorienting 40 scaffolds, and rearranging scaffolds in 4 locations. In the revised genome assembly, 94.6% of the assembly was anchored to a chromosome. To assess linkage map quality, we mapped quantitative trait loci (QTL) controlling lateral plate number, which mapped as expected to a 200-kb genomic region containing Ectodysplasin, as well as a chromosome 7 QTL overlapping a previously identified modifier QTL. Finally, we mapped eight QTL controlling convergently evolved reductions in gill raker length in the two crosses, which revealed that this classic adaptive trait has a surprisingly modular and nonparallel genetic basis.

Published
2015

20. Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network

Author

Zouk, Hana, Venner, Eric, Lennon, Niall J., Muzny, Donna M., Abrams, Debra, Adunyah, Samuel, Albertson-Junkans, Ladia, Ames, Darren C., Appelbaum, Paul, Aronson, Samuel, Aufox, Sharon, Babb, Lawrence J., Balasubramanian, Adithya, Bangash, Hana, Basford, Melissa, Bastarache, Lisa, Baxter, Samantha, Behr, Meckenzie, Benoit, Barbara, Bhoj, Elizabeth, Bielinski, Suzette J., Bland, Harris T., Blout, Carrie, Borthwick, Kenneth, Bottinger, Erwin P., Bowser, Mark, Brand, Harrison, Brilliant, Murray, Brodeur, Wendy, Caraballo, Pedro, Carrell, David, Carroll, Andrew, Almoguera, Berta, Castillo, Lisa, Castro, Victor, Chandanavelli, Gauthami, Chiang, Theodore, Chisholm, Rex L., Christensen, Kurt D., Chung, Wendy, Chute, Christopher G., City, Brittany, Cobb, Beth L., Connolly, John J., Crane, Paul, Crew, Katherine, Crosslin, David, De Andrade, Mariza, De la Cruz, Jessica, Denson, Shawn, Denny, Josh, DeSmet, Tim, Dikilitas, Ozan, Friedrich, Christopher, Fullerton, Stephanie M., Funke, Birgit, Gabriel, Stacey, Gainer, Vivian, Gharavi, Ali, Glazer, Andrew M., Glessner, Joseph T., Goehringer, Jessica, Gordon, Adam S., Graham, Chet, Green, Robert C., Gundelach, Justin H., Dayal, Jyoti, Hain, Heather S., Hakonarson, Hakon, Harden, Maegan V., Harley, John, Harr, Margaret, Hartzler, Andrea, Hayes, M. Geoffrey, Hebbring, Scott, Henrikson, Nora, Hershey, Andrew, Hoell, Christin, Holm, Ingrid, Howell, Kayla M., Hripcsak, George, Hu, Jianhong, Jarvik, Gail P., Jayaseelan, Joy C., Jiang, Yunyun, Joo, Yoonjung Yoonie, Jose, Sheethal, Josyula, Navya Shilpa, Justice, Anne E., Kalla, Sara E., Kalra, Divya, Karlson, Elizabeth, Kelly, Melissa A., Keating, Brendan J., Kenny, Eimear E., Key, Dustin, Kiryluk, Krzysztof, Kitchner, Terrie, Klanderman, Barbara, Klee, Eric, Kochan, David C., Korchina, Viktoriya, Kottyan, Leah, Kovar, Christie, Kudalkar, Emily, Kullo, Iftikhar J., Lammers, Philip, Larson, Eric B., Lebo, Matthew S., Leduc, Magalie, Lee, Ming Ta (Michael), Leppig, Kathleen A., Leslie, Nancy D., Li, Rongling, Liang, Wayne H., Lin, Chiao-Feng, Linder, Jodell, Lindor, Noralane M., Lingren, Todd, Linneman, James G., Liu, Cong, Liu, Wen, Liu, Xiuping, Lynch, John, Lyon, Hayley, Macbeth, Alyssa, Mahadeshwar, Harshad, Mahanta, Lisa, Malin, Brad, Manolio, Teri, Marasa, Maddalena, Marsolo, Keith, Dinsmore, Michael J., Dodge, Sheila, Hynes, Elizabeth Duffy, Dunlea, Phil, Edwards, Todd L., Eng, Christine M., Fasel, David, Fedotov, Alex, Feng, Qiping, Fleharty, Mark, Foster, Andrea, Freimuth, Robert, McGowan, Michelle L., McNally, Elizabeth, Meldrim, Jim, Mentch, Frank, Mosley, Jonathan, Mukherjee, Shubhabrata, Mullen, Thomas E., Muniz, Jesse, Murdock, David R., Murphy, Shawn, Murugan, Mullai, Myers, Melanie F., Namjou, Bahram, Ni, Yizhao, Obeng, Aniwaa Owusu, Onofrio, Robert C., Taylor, Casey Overby, Person, Thomas N., Peterson, Josh F., Petukhova, Lynn, Pisieczko, Cassandra J., Pratap, Siddharth, Prows, Cynthia A., Puckelwartz, Megan J., Rahm, Alanna Kulchak, Raj, Ritika, Ralston, James D., Ramaprasan, Arvind, Ramirez, Andrea, Rasmussen, Luke, Rasmussen-Torvik, Laura, Rasouly, Hila Milo, Raychaudhuri, Soumya, Ritchie, Marylyn D., Rives, Catherine, Riza, Beenish, Roden, Dan, Rosenthal, Elisabeth A., Santani, Avni, Schaid, Dan, Scherer, Steven, Scott, Stuart, Scrol, Aaron, Sengupta, Soumitra, Shang, Ning, Sharma, Himanshu, Sharp, Richard R., Singh, Rajbir, Sleiman, Patrick M.A., Slowik, Kara, Smith, Joshua C., Smith, Maureen E., Smoller, Jordan W., Sohn, Sunghwan, Stanaway, Ian B., Starren, Justin, Stroud, Mary, Su, Jessica, Tolwinski, Kasia, Van Driest, Sara L., Vargas, Sean M., Varugheese, Matthew, Veenstra, David, Verbitsky, Miguel, Vicente, Gina, Wagner, Michael, Walker, Kimberly, Walunas, Theresa, Wang, Liwen, Wang, Qiaoyan, Wei, Wei-Qi, Weiss, Scott T., Wiesner, Georgia L., Wells, Quinn, Weng, Chunhua, White, Peter S., Wiley, Ken L., Jr., Williams, Janet L., Williams, Marc S., Wilson, Michael W., Witkowski, Leora, Woods, Laura Allison, Woolf, Betty, Wu, Tsung-Jung, Wynn, Julia, Yang, Yaping, Yi, Victoria, Zhang, Ge, Zhang, Lan, Rehm, Heidi L., and Gibbs, Richard A.

Published
2019
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22. Two developmentally temporal quantitative trait loci underlie convergent evolution of increased branchial bone length in sticklebacks

Author

Erickson, Priscilla A, Glazer, Andrew M, Cleves, Phillip A, Smith, Alyson S, and Miller, Craig T

Subjects
Biological Sciences, Genetics, Underpinning research, 1.1 Normal biological development and functioning, Adaptation, Biological, Animals, Biological Evolution, Bone Development, British Columbia, Female, Fresh Water, Gills, Male, Phenotype, Quantitative Trait Loci, Seawater, Smegmamorpha, convergent evolution, parallel evolution, quantitative trait loci, skeletal development, endochondral bone, stickleback, Agricultural and Veterinary Sciences, Medical and Health Sciences, Agricultural, veterinary and food sciences, Biological sciences, Environmental sciences
Abstract

In convergent evolution, similar phenotypes evolve repeatedly in independent populations, often reflecting adaptation to similar environments. Understanding whether convergent evolution proceeds via similar or different genetic and developmental mechanisms offers insight towards the repeatability and predictability of evolution. Oceanic populations of threespine stickleback fish, Gasterosteus aculeatus, have repeatedly colonized countless freshwater lakes and streams, where new diets lead to morphological adaptations related to feeding. Here, we show that heritable increases in branchial bone length have convergently evolved in two independently derived freshwater stickleback populations. In both populations, an increased bone growth rate in juveniles underlies the convergent adult phenotype, and one population also has a longer cartilage template. Using F2 crosses from these two freshwater populations, we show that two quantitative trait loci (QTL) control branchial bone length at distinct points in development. In both populations, a QTL on chromosome 21 controls bone length throughout juvenile development, and a QTL on chromosome 4 controls bone length only in adults. In addition to these similar developmental profiles, these QTL show similar chromosomal locations in both populations. Our results suggest that sticklebacks have convergently evolved longer branchial bones using similar genetic and developmental programmes in two independently derived populations.

Published
2014

23. Modular skeletal evolution in sticklebacks is controlled by additive and clustered quantitative trait Loci.

Author

Miller, Craig T, Glazer, Andrew M, Summers, Brian R, Blackman, Benjamin K, Norman, Andrew R, Shapiro, Michael D, Cole, Bonnie L, Peichel, Catherine L, Schluter, Dolph, and Kingsley, David M

Subjects
Bone and Bones, Chromosomes, Animals, Smegmamorpha, Cluster Analysis, Fresh Water, Evolution, Molecular, Species Specificity, Sex Characteristics, Alleles, Quantitative Trait Loci, Female, Male, Aquatic Organisms, QTL mapping, dominance, evolutionary genetics, skeleton, stickleback, Human Genome, Biotechnology, Genetics, Underpinning research, 1.1 Normal biological development and functioning, Developmental Biology
Abstract

Understanding the genetic architecture of evolutionary change remains a long-standing goal in biology. In vertebrates, skeletal evolution has contributed greatly to adaptation in body form and function in response to changing ecological variables like diet and predation. Here we use genome-wide linkage mapping in threespine stickleback fish to investigate the genetic architecture of evolved changes in many armor and trophic traits. We identify >100 quantitative trait loci (QTL) controlling the pattern of serially repeating skeletal elements, including gill rakers, teeth, branchial bones, jaws, median fin spines, and vertebrae. We use this large collection of QTL to address long-standing questions about the anatomical specificity, genetic dominance, and genomic clustering of loci controlling skeletal differences in evolving populations. We find that most QTL (76%) that influence serially repeating skeletal elements have anatomically regional effects. In addition, most QTL (71%) have at least partially additive effects, regardless of whether the QTL controls evolved loss or gain of skeletal elements. Finally, many QTL with high LOD scores cluster on chromosomes 4, 20, and 21. These results identify a modular system that can control highly specific aspects of skeletal form. Because of the general additivity and genomic clustering of major QTL, concerted changes in both protective armor and trophic traits may occur when sticklebacks inherit either marine or freshwater alleles at linked or possible "supergene" regions of the stickleback genome. Further study of these regions will help identify the molecular basis of both modular and coordinated changes in the vertebrate skeleton.

Published
2014

24. Parallel developmental genetic features underlie stickleback gill raker evolution

Author

Glazer, Andrew M, Cleves, Phillip A, Erickson, Priscilla A, Lam, Angela Y, and Miller, Craig T

Subjects
Biological Sciences, Evolutionary Biology, Genetics, Convergent evolution, Gasterosteus, Quantitative trait locus, Stickleback, Gill raker, Biochemistry and Cell Biology, Evolutionary biology
Abstract

BackgroundConvergent evolution, the repeated evolution of similar phenotypes in independent lineages, provides natural replicates to study mechanisms of evolution. Cases of convergent evolution might have the same underlying developmental and genetic bases, implying that some evolutionary trajectories might be predictable. In a classic example of convergent evolution, most freshwater populations of threespine stickleback fish have independently evolved a reduction of gill raker number to adapt to novel diets. Gill rakers are a segmentally reiterated set of dermal bones important for fish feeding. A previous large quantitative trait locus (QTL) mapping study using a marine × freshwater F2 cross identified QTL on chromosomes 4 and 20 with large effects on evolved gill raker reduction.ResultsBy examining skeletal morphology in adult and developing sticklebacks, we find heritable marine/freshwater differences in gill raker number and spacing that are specified early in development. Using the expression of the Ectodysplasin receptor (Edar) gene as a marker of raker primordia, we find that the differences are present before the budding of gill rakers occurs, suggesting an early change to a lateral inhibition process controlling raker primordia spacing. Through linkage mapping in F2 fish from crosses with three independently derived freshwater populations, we find in all three crosses QTL overlapping both previously identified QTL on chromosomes 4 and 20 that control raker number. These two QTL affect the early spacing of gill raker buds.ConclusionsCollectively, these data demonstrate that parallel developmental genetic features underlie the convergent evolution of gill raker reduction in freshwater sticklebacks, suggesting that even highly polygenic adaptive traits can have a predictable developmental genetic basis.

Published
2014

25. The electrophysiologic effects of KCNQ1 extend beyond expression of IKs: evidence from genetic and pharmacologic block.

Author

Wada, Yuko, Wang, Lili, Hall, Lynn D, Yang, Tao, Short, Laura L, Solus, Joseph F, Glazer, Andrew M, and Roden, Dan M

Subjects
GENE expression, PLURIPOTENT stem cells, ACTION potentials, LONG QT syndrome, CELL populations
Abstract

Aims While variants in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small I Ks in cardiomyocytes from human-induced pluripotent stem cells (iPSC-CMs) or human ventricular myocytes. Methods and results We studied population control iPSC-CMs and iPSC-CMs from a patient with Jervell and Lange-Nielsen (JLN) syndrome due to compound heterozygous loss-of-function (LOF) KCNQ1 variants. We compared the effects of pharmacologic I Ks block to those of genetic KCNQ1 ablation, using JLN cells, cells homozygous for the KCNQ1 LOF allele G643S, or siRNAs reducing KCNQ1 expression. We also studied the effects of two blockers of I Kr, the other major cardiac repolarizing current, in the setting of pharmacologic or genetic ablation of KCNQ1 : moxifloxacin, associated with a very low risk of drug-induced long QT, and dofetilide, a high-risk drug. In control cells, a small I Ks was readily recorded but the pharmacologic I Ks block produced no change in action potential duration at 90% repolarization (APD90). In contrast, in cells with genetic ablation of KCNQ1 (JLN), baseline APD90 was markedly prolonged compared with control cells (469 ± 20 vs. 310 ± 16 ms). JLN cells displayed increased sensitivity to acute I Kr block: the concentration (μM) of moxifloxacin required to prolong APD90 100 msec was 237.4 [median, interquartile range (IQR) 100.6–391.6, n = 7] in population cells vs. 23.7 (17.3–28.7, n = 11) in JLN cells. In control cells, chronic moxifloxacin exposure (300 μM) mildly prolonged APD90 (10%) and increased I Ks, while chronic exposure to dofetilide (5 nM) produced greater prolongation (67%) and no increase in I Ks. However, in the siRNA-treated cells, moxifloxacin did not increase I Ks and markedly prolonged APD90. Conclusion Our data strongly suggest that KCNQ1 expression modulates baseline cardiac repolarization, and the response to I Kr block, through mechanisms beyond simply generating I Ks. [ABSTRACT FROM AUTHOR]

Published
2024
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26. Multi-site validation of a functional assay to adjudicate SCN5A Brugada Syndrome-associated variants

Author

Ma, Joanne G, primary, O'Neill, Matthew James, additional, Richardson, Ebony, additional, Thomson, Kate, additional, Ingles, Jodie, additional, Muhammad, Ayesha, additional, Solus, Joseph F, additional, Davogustto, Giovanni E, additional, Anderson, Katherine C, additional, Shoemaker, Moore Ben, additional, Stergachis, Andrew B, additional, Floyd, Brendan James, additional, Dunn, Kyla, additional, Parikh, Victoria N, additional, Chubb, Henry, additional, Perrin, Mark, additional, Roden, Dan M, additional, Vandenberg, Jamie I, additional, Ng, Chai Ann, additional, and Glazer, Andrew M, additional

Published
2023
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29. Multicenter Clinical and Functional Evidence Reclassifies a Recurrent Non-canonical Filamin C Splice-altering Variant

Author

O’Neill, Matthew J., primary, Chen, Suet Nee, additional, Rumping, Lynne, additional, Johnson, Renee, additional, van Slegtenhorst, Marjon, additional, Glazer, Andrew M., additional, Yang, Tao, additional, Solus, Joseph F., additional, Laudeman, Julie, additional, Mitchell, Devyn W., additional, Vanags, Loren R., additional, Kroncke, Brett M., additional, Anderson, Katherine, additional, Gao, Shanshan, additional, Verdonschot, Job A.J., additional, Brunner, Han, additional, Hellebrekers, Debby, additional, Taylor, Matthew R.G., additional, Roden, Dan M., additional, Wessels, Marja W., additional, Lekanne Dit Deprez, Ronald H., additional, Fatkin, Diane, additional, Mestroni, Luisa, additional, and Shoemaker, M. Benjamin, additional

Published
2023
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31. High-throughput functional mapping of variants in an arrhythmia gene,KCNE1, reveals novel biology

Author

Muhammad, Ayesha, primary, Calandranis, Maria E, additional, Li, Bian, additional, Yang, Tao, additional, Blackwell, Daniel J, additional, Harvey, Margaret L, additional, Smith, Jeremy E, additional, Chew, Ashli E, additional, Capra, John A, additional, Matreyek, Kenneth A, additional, Fowler, Douglas M, additional, Roden, Dan M, additional, and Glazer, Andrew M, additional

Published
2023
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33. Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization

Author

Bersell, Kevin R., primary, Yang, Tao, additional, Mosley, Jonathan D., additional, Glazer, Andrew M., additional, Hale, Andrew T., additional, Kryshtal, Dmytro O., additional, Kim, Kyungsoo, additional, Steimle, Jeffrey D., additional, Brown, Jonathan D., additional, Salem, Joe-Elie, additional, Campbell, Courtney C., additional, Hong, Charles C., additional, Wells, Quinn S., additional, Johnson, Amanda N., additional, Short, Laura, additional, Blair, Marcia A., additional, Behr, Elijah R., additional, Petropoulou, Evmorfia, additional, Jamshidi, Yalda, additional, Benson, Mark D., additional, Keyes, Michelle J., additional, Ngo, Debby, additional, Vasan, Ramachandran S., additional, Yang, Qiong, additional, Gerszten, Robert E., additional, Shaffer, Christian, additional, Parikh, Shan, additional, Sheng, Quanhu, additional, Kannankeril, Prince J., additional, Moskowitz, Ivan P., additional, York, John D., additional, Wang, Thomas J., additional, Knollmann, Bjorn C., additional, and Roden, Dan M., additional

Published
2023
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37. Hypogonadism as a Reversible Cause of Torsades de Pointes in Men

Author

Salem, Joe-Elie, Waintraub, Xavier, Courtillot, Carine, Shaffer, Christian M., Gandjbakhch, Estelle, Maupain, Carole, Moslehi, Javid J., Badilini, Fabio, Haroche, Julien, Gougis, Paul, Fressart, Veronique, Glazer, Andrew M., Hidden-Lucet, Francoise, Touraine, Philippe, Lebrun-Vignes, Benedicte, Roden, Dan M., Bachelot, Anne, Funck-Brentano, Christian, Bretagne, Marie, Dureau, Pauline, Saqué, Valentin, Zarhrate-Ghoul, Aida, Bourguignon, Clément, Leban, Monique, Grouthier, Virginie, and Vaglio, Martino

Published
2018
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39. Multicenter clinical and functional evidence reclassifies a recurrent noncanonical filamin C splice-altering variant.

Author

O'Neill, Matthew J., Chen, Suet Nee, Rumping, Lynne, Johnson, Renee, van Slegtenhorst, Marjon, Glazer, Andrew M., Yang, Tao, Solus, Joseph F., Laudeman, Julie, Mitchell, Devyn W., Vanags, Loren R., Kroncke, Brett M., Anderson, Katherine, Gao, Shanshan, Verdonschot, Job A.J., Brunner, Han, Hellebrekers, Debby, Taylor, Matthew R.G., Roden, Dan M., and Wessels, Marja W.

Abstract

Truncating variants in filamin C (FLNC) can cause arrhythmogenic cardiomyopathy (ACM) through haploinsufficiency. Noncanonical splice-altering variants may contribute to this phenotype. The purpose of this study was to investigate the clinical and functional consequences of a recurrent FLNC intronic variant of uncertain significance (VUS), c.970-4A>G. Clinical data in 9 variant heterozygotes from 4 kindreds were obtained from 5 tertiary health care centers. We used in silico predictors and functional studies with peripheral blood and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Isolated RNA was studied by reverse transcription polymerase chain reaction. iPSC-CMs were further characterized at baseline and after nonsense-mediated decay (NMD) inhibition, using quantitative polymerase chain reaction (qPCR), RNA-sequencing, and cellular electrophysiology. American College of Medical Genetics and Genomics (ACMG) criteria were used to adjudicate variant pathogenicity. Variant heterozygotes displayed a spectrum of disease phenotypes, spanning from mild ventricular dysfunction with palpitations to severe ventricular arrhythmias requiring device shocks or progressive cardiomyopathy requiring heart transplantation. Consistent with in silico predictors, the c.970-4A>G FLNC variant activated a cryptic splice acceptor site, introducing a 3-bp insertion containing a premature termination codon. NMD inhibition upregulated aberrantly spliced transcripts by qPCR and RNA-sequencing. Patch clamp studies revealed irregular spontaneous action potentials, increased action potential duration, and increased sodium late current in proband-derived iPSC-CMs. These findings fulfilled multiple ACMG criteria for pathogenicity. Clinical, in silico , and functional evidence support the prediction that the intronic c.970-4A>G VUS disrupts splicing and drives ACM, enabling reclassification from VUS to pathogenic. [ABSTRACT FROM AUTHOR]

Published
2023
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40. Mortality Among Patients With Early-Onset Atrial Fibrillation and Rare Variants in Cardiomyopathy and Arrhythmia Genes

Author

Yoneda, Zachary T., primary, Anderson, Katherine C., additional, Ye, Fei, additional, Quintana, Joseph A., additional, O’Neill, Matthew J., additional, Sims, Richard A., additional, Sun, Lili, additional, Glazer, Andrew M., additional, Davogustto, Giovanni, additional, El-Harasis, Majd, additional, Laws, James L., additional, Saldivar, Brittany N., additional, Crawford, Diane M., additional, Stricker, Thomas, additional, Wells, Quinn, additional, Darbar, Dawood, additional, Michaud, Gregory F., additional, Stevenson, Lynne W., additional, Lubitz, Steven A., additional, Ellinor, Patrick T., additional, Roden, Dan M., additional, and Shoemaker, M. Benjamin, additional

Published
2022
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41. Veratridine Can Bind to a Site at the Mouth of the Channel Pore at Human Cardiac Sodium Channel NaV1.5

Author

Gulsevin, Alican, Glazer, Andrew M., Shields, Tiffany, Kroncke, Brett M., Roden, Dan M., Meiler, Jens, Gulsevin, Alican, Glazer, Andrew M., Shields, Tiffany, Kroncke, Brett M., Roden, Dan M., and Meiler, Jens

Abstract

The cardiac sodium ion channel (NaV1.5) is a protein with four domains (DI-DIV), each with six transmembrane segments. Its opening and subsequent inactivation results in the brief rapid influx of Na+ ions resulting in the depolarization of cardiomyocytes. The neurotoxin veratridine (VTD) inhibits NaV1.5 inactivation resulting in longer channel opening times, and potentially fatal action potential prolongation. VTD is predicted to bind at the channel pore, but alternative binding sites have not been ruled out. To determine the binding site of VTD on NaV1.5, we perform docking calculations and high-throughput electrophysiology experiments in the present study. The docking calculations identified two distinct binding regions. The first site was in the pore, close to the binding site of NaV1.4 and NaV1.5 blocking drugs in experimental structures. The second site was at the “mouth” of the pore at the cytosolic side, partly solvent-exposed. Mutations at this site (L409, E417, and I1466) had large effects on VTD binding, while residues deeper in the pore had no effect, consistent with VTD binding at the mouth site. Overall, our results suggest a VTD binding site close to the cytoplasmic mouth of the channel pore. Binding at this alternative site might indicate an allosteric inactivation mechanism for VTD at NaV1.5

Published
2022

42. Abstract 14477: Integrating Patient-Specific Cardiomyocyte Function With Population Multi-omics Identifies a Novel Arrhythmia Pathway

Author

Bersell, Kevin R, Yang, Tao, Mosley, Jonathan D, Glazer, Andrew M, Brown, Jonathan D, Campbell, Courtney M, Hong, Charles C, Wells, Quinn S, Johnson, Amanda N, Short, Laura, Blair, Marcia A, Behr, Elijah R, Petropoulou, Evmorfia, Jamshidi, Yalda, Gerszten, Rob, Benson, Mark D, Vasan, Ramachandran S, Yang, Qiong, Jarvik, Gail P, Namjou, Bahram, Shaffer, Christian M, Parikh, Shan, Sheng, Quanhu, Kannankeril, Prince J, Wang, Thomas J, Knollmann, Bjorn C, and Roden, Dan M

Published
2017

43. BS-469619-003 GRANULAR VARIANT-SPECIFIC FEATURES IMPROVE KCNH2-LONG QT SYNDROME RISK STRATIFICATION

Author

O'Neill, Matthew, Ng, Chai-ann, Aizawa, Takanori, Sala, Luca, Bains, Sahej, Denjoy, Isabelle, Winbo, Annika, Ullah, Rizwan, Shen, Qianyi, Tan, Chek-ying, Kozek, Krystian, Vanags, Loren, Mitchell, Devyn, Shen, Alex, Wada, Yuko, Kashiwa, Asami, Crotti, Lia, Dagradi, Federica, Musu, Giulia, Spazzolini, Carla, Neves, Raquel A., Bos, Johan M., Giudicessi, John, Lancaster, Megan, Glazer, Andrew M., Roden, Dan M., Leenhardt, Antoine, Salem, Joe-Elie, Earle, Nikki, Stiles, Rachael, Agee, Taylor, Johnson, Christopher N., Horie, Minoru, Skinner, Jonathan R., Extramiana, Fabrice, Ackerman, Michael J., Schwartz, Peter J., Ohno, Seiko, Vandenberg, Jamie I., and Kroncke, Brett

Published
2024
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46. Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes

Author

Yoneda, Zachary T., primary, Anderson, Katherine C., additional, Quintana, Joseph A., additional, O’Neill, Matthew J., additional, Sims, Richard A., additional, Glazer, Andrew M., additional, Shaffer, Christian M., additional, Crawford, Diane M., additional, Stricker, Thomas, additional, Ye, Fei, additional, Wells, Quinn, additional, Stevenson, Lynne W., additional, Michaud, Gregory F., additional, Darbar, Dawood, additional, Lubitz, Steven A., additional, Ellinor, Patrick T., additional, Roden, Dan M., additional, and Shoemaker, M. Benjamin, additional

Published
2021
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48. Dominant negative effects ofSCN5Amissense variants

Author

O’Neill, Matthew J., primary, Muhammad, Ayesha, additional, Li, Bian, additional, Wada, Yuko, additional, Hall, Lynn, additional, Solus, Joseph F., additional, Short, Laura, additional, Roden, Dan M., additional, and Glazer, Andrew M., additional

Published
2021
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49. B-PO05-026 AGE-RELATED PREVALENCE OF RARE DISEASE-ASSOCIATED VARIANTS IN 1293 PATIENTS WITH EARLY-ONSET ATRIAL FIBRILLATION

Author

Yoneda, Zachary, primary, Anderson, Katherine C., additional, Quintana, Joseph A., additional, O'Neill, Matthew J., additional, Glazer, Andrew M., additional, Shaffer, Christian M., additional, Crawford, Diane M., additional, Stricker, Thomas, additional, Wells, Quinn, additional, Stevenson, Lynne W., additional, Michaud, Gregory F., additional, Darbar, Dawood, additional, Lubitz, Steven A., additional, Ellinor, Patrick T., additional, Roden, Dan M., additional, and Shoemaker, Moore B., additional

Published
2021
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