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Molecular Biosciences Research Group

Each of the Xiphophorus genomes have been greatly enhanced by PacBio sequencing and Bionano mapping. To take advantage of the improved genomes, the XGSC configured a platyfish genome hub that is hosted on the UCSC genome browser for genetic data visualization and data mining. See link for details.

The XGSC also configured a gene expression browser link to facilitate data visualization and tracking of genes of interest to determine gene basal expression level through light and dark phases over a 24-hr period.


WELCOME TO THE MOLECULAR BIOSCIENCES RESEARCH GROUP  


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Ronald B. Walter, PhD

 

 

Group

From top left: Angel Sandoval, Yuan Lu, Markita Savage, Christina Mendoza.
Second row: Rebecca Marks, Raquel Salinas, Mikki Boswell.
Bottom row: Sarah Voss, Ronald Walter, William Boswell.

MBRG: Recent Areas of Research

Studies in the Molecular Biosciences Research Group have focused on the molecular determinants of carcinogenesis using Xiphophorus interspecies hybrid melanoma models, biomarker discovery using the medaka fish models, bioinformatic exploration of the molecular genetics underlying gene interactions, and inheritance of complex traits. Recently, my program has been working on; (1) RNA-seq profiling of global shifts in gene expression within the skin and internal organs of several fish models (Xiphophorus, medaka, zebrafish) and mice, after exposure to different light sources, or specific light wavelengths between 300-600 nm, (2) employing transgenic medaka that carry a mutant EGFR to develop a screening methodology that use shifts in a defined melanoma transcriptional disease signature (TDS) to assess small molecule effects on tumor progression, (3) determination of the overall effects of interspecies hybridization on the gene expression and on genetic interactions that effect expression of complex traits. My group has long term collaborations with Drs. John Postlethwait (U. Oregon), Wes Warren (Washington Univ.), and Manfred Schartl (U. Wurzburg & Texas State Univ.) to sequence and assemble several Xiphophorus genomes (X. maculatus, X. couchianus, X. hellerii, and X. montezumae) and in development of TDS screening methodologies. We have considerable wet lab experience in experimental assessment of gene expression changes using a variety of small fish species (Xiphophorus, zebrafish, medaka, Fundulus). Notable recent examples include, allele specific gene expression in Xiphophorus interspecies hybrids (F1’s and BC1’s) for association with tumorigenesis, determination of expression patterns in partial triploid medaka, gene expression effects in Fundulus populations after Deep Water Horizon oil exposure, gene expression profile changes after specific light wavelength exposures, and effects of increasing heterozygosity on gene expression.

Development of Xiphophorus genomics capabilities

Beginning with classical genetic mapping in Xiphophorus interspecies backcross hybrids, moving through BAC library assembly, and now genome sequencing, the Walter lab has been enhancing Xiphophorus genomic capabilities for over 20 years. In 2009, the XGSC/MBRG spearheaded the first Xiphophorus genome project as part of a collaborative team between laboratories headed by Dr. Walter (Texas State University), Prof. Manfred Schartl (Univ. of Wurzburg), Dr. Wes Warren (Washington University-Genome Sequencing Center), and Dr. John Postlethwait (University of Oregon). This X. maculatus Jp 163 A genome assembly was published in 2013 and was followed by correlation of the genome assembly with the meiotic Rad-Tag gene map. This investigative team produced one of the first vertebrate genomes to have the de novo assembly contigs aligned with an independently produced (16,411 markers) Rad-Tag meiotic map and is one of most highly marked genetic maps among vertebrates. Recently, this collaborative group also sequenced and assembled three other Xiphophorus genomes (X. hellerii, X. couchianus, and X. montezumae) and a manuscript detailing these genomes has been published (2015). The four Xiphophorus genomes allow both chromosome structural comparison and allele specific expression analysis among interspecies hybrids genetically predisposed to induced carcinogenesis

Warren, W., García-Pérez, R., Xu, S., Lampert, K., Chalopin, D., Stöck, M., Loewe, L., Lu, Y., Kuderna, L., Minx, P., Montague, M., Tomlinson, C., Hillier, L., Murphy, D., Wang, J., Wang, Z., Garcia, C.M., Thomas, G., Volff, J-N., Farias, F., Aken, B., Walter, R.B., Pruitt, K., Marques-Bonet, T., Hahn, M., Kneitz, S., Lynch, M., Schartl. M. (2018). Clonal polymorphism and high heterozygosity in the celibate genome of the Amazon molly, Nature - Evolution and Ecology, 2:669–679. https://doi/10.1038/s41559-018-0473-y

Shen, Y., Chalopin, D., Garcia, T., Boswell, M., Boswell, W., Shiryayev, S., Agarwala. R., Volff, J-N, Postlethwait, J.H., Schartl, M., Minx, P., Warren, W.C., Walter, R.B. (2016). X. couchianus and X. hellerii genome models provide genomic variation insight among Xiphophorus species, BMC Genomics, 17:37-50.

Amores, A., Catchen, C., Nanda, I., Warren, W., Walter, R.B., and M. Schartl and J.H. Postlethwait (2014).  A Rad-tag genetic map for the playtfish (Xiphophorus maculatus) reveals mechanisms of karyotype evolution among teleost fish. Genetics, 197(2):625-641.

Schartl, M., Walter, R. B., Shen. Y., Garcia, T., Catchen, J., Amores. A., Braasch. I., Chapolin D., Volff, J-N., Lesch, K-P., Bisazza, A., Minx P., Wilson. R.K., Fuerstenberg, S., Boore, J., Postlethwait, J. H. and W.C. Warren (2013). The genome of the platyfish, Xiphophorus maculatus, Nature Genetics, 45(5):567-572.

Walter, R.B., Rains, J.D., Russell, J.E., Guerra, T.M., Daniels, C., Johnston, D.A., Kumar, J., Wheeler, A., Kelnar, K., Khanolkar, V.A., Williams, E.L., Hornecker, J.L., Hollek, L., Mamerow, M., Pedroza, A., and S. Kazianis (2004).  "A Microsatellite Genetic Linkage Map for Xiphophorus."  Genetics, 168:363-372.

 

Genetic determinants of carcinogenesis using Xiphophorus interspecies hybrids and models

Studies in the Walter laboratory have historically focused on the molecular determinants of carcinogenesis using Xiphophorus interspecies hybrids for spontaneous and inducible melanoma models.  With the sequence assemblies of four Xiphophorus species, we have more recently been performing RNA-Seq style global gene expression analyses to assess biochemical pathway modulation in various tissues upon exposure to select environmental agents. We are able to follow the expression of each parental allele within the interspecies hybrid genetic background to quantitatively assess the contribution of each allele to the development of complex traits. This genetic power is only now being realized and holds tremendous promise for producing new fundamental discoveries of gene interactions leading to the tumor predisposition. 

Lu, Y., Boswell, M., Boswell, W., Kneitz, S., Hausmann, M., Klotz, B., Regneri, J., Savage, M., Amores, A., Postlethwait, J., Warren, W., Schartl, M., Walter, R.B. (2018). Comparison of Xiphophorus and Human Melanoma Transcriptomes Reveals Conserved Pathway Interactions, Pigment Cell Melanoma Res., 2018:1-13, https://doi.org/10.1111/pcmr.12686

Regneri, J., Klotz, B., Wilde, B., Kottler, V., Hausmann, M., Kneitz, S., Regensburger, M., Maurus, K., Götz, R., Lu, Y., Walter, R.B., Herpin, A., Schartl, M. (2018). Analysis of the putative tumor suppressor gene cdkn2ab in pigment cells and melanoma of Xiphophorus and medaka, Pigment Cell Melanoma Res. 2018;00:1–11, https://doi.org/10.1111/pcmr.12729

Lu, Y., Boswell, M., Boswell, W., Kneitz, S., Hausmann, M., Klotz, B., Regneri, J., Savage, M., Amores, A., Postlethwait, J., Warren, W., Schartl, M., Walter, R.B. (2017). Molecular genetic analysis of the melanoma regulatory locus in Xiphophorus Interspecies hybrids, Molecular Carcinogenesis, 56(8):1935-1944.

Kneitz, S., Mishra, R., Chalopin, D., Postlethwait, J.H., Warren, W., Walter, R.B., Schartl, M. (2016). Germ cell and tumor associated piRNAs in the medaka and Xiphophorus melanoma models, BMC Genomics, 17:357, https://doi.org/10.1186/s12864-016-2697-z

Laisney, J., Braasch, I., Walter, R.B., Meierjohann, S. and M. Schartl (2010) Lineage-specific Co-evolution of the EGFR/EGFR Ligand Signalling System. BMC Evolutionary Biology, 10:27-34.

Wood, S.R., Berwick, M., Ley, R.D., Walter, R.B., and G.S. Timmins (2006)  "UV Causation of melanoma in Xiphophorus Is Dominated by Melanin Photosensitized Oxidant Production."  Proc. of the National Academy of Sciences (USA), 103 (11):4111-4115.

 

Development of genomics and transcriptomics in aquatic models for biomedical research

The Walter lab organized and hosted the first biannual "Aquatic Models of Human Disease Conference” (AQMHD) in 2000. This conference has become a premier gathering for those working with the myriad of different aquatic models being applied to biomedical questions. In Fall 2015, we hosted the 7th AQMHD conference in Austin, TX. The Walter lab has made scientific contributions utilizing many varied aquatic models such as Xiphophorus, medaka, zebrafish, Fundulus, and whales, and recently, developed  contemporary genomic and transcriptomic resources for aquatic models research. We have organized NIH workshops on “Realizing the Scientific Potential of Transcriptomics in Aquatic Models" (2010), and recently “The Medaka Model for Comparative Assessment of Human Disease Mechanisms" (2015).      

Lu, Y., Boswell, W., Boswell, M., Klotz, B, Kneitz, S., Regneri, J., Savage, M., Mendoza. C., Postlethwait. J., Warren, W.C., Schartl, M., Walter, R.B. (2018). Application of the Transcriptional Disease Signatures (TDSs) to Screen Melanoma-Effective Compounds in a Small Fish Model, Scientific Reports, 9:530-543. https://doi.org/10.1038/s44158-018-36656-x

Warren, W.C., Kuderna, L., Alexander, A., Catchen, J., Pérez-Silva, J.G., López-Otín, Víctor Quesada, C., Minx, P., Tomlinson, C., Montague, M., Farias, F.H.G., Walter, R.B., Marques-Bonet, T., Glenn, T., Kieran, T.J., Wise, S.S., Wise Jr., J.P., Waterhouse, R.M., and J.P. Wise, Sr. (2018). The novel evolution of the sperm whale genome, Genome Biol. Evolution, 9(12):3260-3264. https://doi.org/10.1093/gbe/evx187

Warren, W., García-Pérez, R., Xu, S., Lampert, K., Chalopin, D., Stöck, M., Loewe, L., Lu, Y., Kuderna, L., Minx, P., Montague, M., Tomlinson, C., Hillier, L., Murphy, D., Wang, J., Wang, Z., Garcia, C.M., Thomas, G., Volff, J-N., Farias, F., Aken, B., Walter, R.B., Pruitt, K., Marques-Bonet, T., Hahn, M., Kneitz, S., Lynch, M., Schartl, M. (2018). Clonal polymorphism and high heterozygosity in the celibate genome of the Amazon molly, Nature - Evolution & Ecology, 2:669–679, https://doi.org/10.1038/s41559-018-0473-y

Schartl, M., Shen, Y., Maurus, K., Walter, R.B., Wilson, R.K., Postlethwait, J.H., Warren, W.C. (2015). Whole body melanoma Ttranscriptome response in medaka, PLoS-ONE, 10:2 (Dec. 2015), https://doi.org/10.1371/journal.pone.0143057

Garcia T.I., Matos I., Shen, Y., Pabuwal V., Coelho, M.M., Wakamatsu, Y., Schartl, M., and R.B. Walter (2014). Novel Method for Analysis of Allele Specific Expression in Triploid Oryzias latipes Reveals Consistent Pattern of Allele Exclusion. PLOS ONE 9(6): e100250.

Garcia, T.I., Shen, Y., Whitehead, A., Oleksiak, M., Crawford, D.C., and R.B. Walter (2012). RNA-Seq reveals complex genetic response to Deepwater Horizon oil release in Fundulus grandis. BMC Genomics, 13:474-483. 13:474-483.

Whitehead, A., Dubansky, B., Bodiner, C., Garcia, T., Miles, S., Pilley, C., Raghunathan, V., Roach, J., Walker, N., Walter, R.B., Rice, C.D., and F. Glavez  (2012). Genomic and Physiological Footprint of the Deepwater Horizon Oil Spill on Resident Marsh Fishes. Proc. of the National Academy of Sciences (USA), 109(50): 20298-20302.

 

Wavelength Dependent Gene Expression

Evolution occurred over 3 billion years nearly exclusively under the full spectrum of sunlight.  Thus, all spectral wavebands were represented during vertebrate evolution. It seems likely that organisms may have adaptively paired select genetic responses with different spectral regions (wavebands) and/or light intensities. If vertebrates have indeed evolved specific genetic responses regulated by select light wavebands within the solar spectrum, there may be genetic consequences to substantially reducing the spectral complexity of light, such as the use of fluorescent lighting, in service for only about 60 years. To begin to address the question of light waveband induced genetic response, we have recently employed several fish models, Xiphophorus, zebrafish and medaka, to perform RNA-seq experiments detailing modulation of gene expression patterns in skin and other organs (brain, liver) after exposure of the intact animal to narrow wavelength regions of light between 350-600 nm (i.e., 50 nm or 10 nm wavelength regions, termed ”wavebands”).

Boswell, M., Lu, Y., Boswell, W., Savage, M., Hildreth, K., Salinas, R., Walter. C.A, Walter, R.B. (2019). Fluorescent light incites a highly conserved immune and inflammatory genetic response within internal and external organs of vertebrates (Danio rerio, Oryzias latipes and Mus musculus), Genes, 10.271.,  https://www.mdpi.com/2073-4425/10/4/271

Walter, R.B., Boswell, M, Chang, J., Boswell, W.T., Lu, Y., Navarro, K, Walter, S.M., Walter, D.J., Salinas, R. and M. Savage (2018). Waveband specific transcriptional control of select genetic pathways in vertebrate Skin, BMC Genomics, 19:355-373.  https://doi.org/10.1186/s12864-018-4735-5

Gonzalez, T. J., Lu, Y., Boswell, M., Boswell, W., Medrano, G., Walter, S., Ellis, S., Savage, M., Varga, Z.M., Lawrence, C., Walter, R.B. (2018). Fluorescent light exposure incites acute and prolonged Immune responses in zebrafish (Danio rerio) skin, Comp. Biochem. & Physiology, Part C, 208:87-95.  https://doi.org/10.1016/j.cbpc.2017.09.009

Boswell, M., Boswell, W., Lu, Y., Savage, M., Mazurek, Z., Chang, J., Muster, J., Walter, R.B. (2018). The Transcriptional response of skin to fluorescent light exposure in viviparous (Xiphophorus) and oviparous (Danio, Oryzias) fishes, Comp. Biochem. & Physiology, Part C, 208:77-86. https://doi.org/10.1016/j.cbpc.2017.10.003


Undergraduate and graduate science education

Dr. Walter has spent his 28-year academic career at a primarily undergraduate campus that has just recently been designated an “Emerging Research Institution.” He has served in the Department of Biology (9 years) and then moved to the Department of Chemistry & Biochemistry to assist in development of a Biochemistry undergraduate program. Dr. Walter developed partnership grant proposals aimed towards providing scholarships for student groups that are underrepresented in the sciences (URM). In Fall 2013, he was awarded a Bridges to Biomedicine (B2B) grant wherein Texas State University is partnering with two Alamo Community College campuses to establish a program focused on increasing success of URM students in the biomedical sciences upon transfer to the baccalaureate institution. The B2B program addresses the most important obstacles to upper-division degree completion experienced by students showing an early commitment to a biomedical career. Additionally, Dr. Walter serves as Co-PI for the South Texas Doctoral Bridge Program (STDBP).  The STDBP is aimed at student matriculation from the MS degree into highly competitive doctoral programs. The STDBP is established between the Univ. of Texas Health Science Center at San Antonio (UTHSCSA, medical school) and Texas State University. The STDBP is designed to provide a combination of mentoring and student development activities as well as enhance didactics and research training during a thesis-based M.S. degree in Biochemistry.