Spring 2008 Edition

Congratulations!

Chuck Perou

To Chuck Perou for winning a Phillip and Ruth Hettleman Prize for Artistic and Scholarly Achievement by Young Faculty at UNC-Chapel Hill.  The prize, which carries a $5,000 stipend, recognizes the achievements of outstanding junior tenure-track faculty or recently tenured faculty.

Helena Furberg

To Helena Furberg for being awarded one of the first round of Innovation Awards from the University Cancer Research Fund.  Helena’s grant will establish a Tobacco and Genetics (TAG) Consortium to identify novel genetic factors that contribute to nicotine dependence.  The Consortium will conduct a meta-analysis of the relationship of 2.2 million genetic markers to nicotine dependence using pooled data of more than 75,000 individuals from existing genome-wide association studies (GWAS) for other traits.  The results of this project have the potential to inform research efforts and cancer prevention thereby making a significant impact on the cancer burden in our population.

Pat Sullivan

To Pat Sullivan for being named as Ray M. Hayworth and Family Distinguished Professor of Mood and Anxiety Disorders.

Genetics Faculty in the News

The April 14 (HealthDay News) issue of MEDLINE PLUS featured work by Kathleen Christine and Frank Conlon on the involvement of the CASTOR (CST) gene in heart development, which was published in Developmental Cell.  They used morpholinos to deplete Xenopus embryos of CST and found that cardiomyocytes at the ventral midline arrested and were maintained as cardiac progenitors, while cells in more dorsal regions of the heart went through their normal program of differentiation.  It had been thought previously that these cells all responded to the same signal.  Continuing studies will be done to determine how many different types of heart cell progenitors actually exist. 

“This is profoundly important work,” said Cam Patterson, M.D., professor of medicine, chair of cardiology and director of the Carolina Cardiovascular Biology Center. “Not only does it tell us about how stem cells differentiate to create the heart, but it provides us with knowledge that may very well help us to repair heart muscle after a heart attack.”

link to news story:  http://www.nlm.nih.gov/medlineplus/news/fullstory_63401.html

Christine, K.S., & Conlon F.L. Vertebrate CASTOR is required for differentiation of cardiac precursor cells at the ventral midline. Dev. Cell 14, 616-23 (2008).

Karen Mohlke and Collaborators Report Results of a Genome-Wide Association Study on Human Height

Karen is corresponding author on the report of this multicenter study of genomewide association analyses of height.  The study populations using ~2.28 million common genetic variants in more than 35,000 individuals. Their data show that common variants in the osteoarthritis-associated
locus2 GDF5-UQCC contribute to variation in height with an estimated additive effect of 0.44 cm. These results indicate that there may be a link between the genetic basis of height and osteoarthritis, potentially mediated through alterations in bone growth and development.

Sanna, S. et al. Common variants in the GDF5-UQCC region are associated with variation in human height. Nat Genet 40, 198-203 (2008).

From Fig. 1. The green triangle represents the association P value for the rs6060369 SNP and height in all samples.

David Threadgill's lab show that there is a genetic basis for differences in types of colorectal cancers

Josh Uronis in David's lab has studied the progression of colorectal adenomas to carcinomas in different mouse inbred strains. They and their colleagues followed the development of azoxymethane-induced tumors in I/LNJ and KK/HIJ mice, which form predominantly flat vs. polypoid tumors, respectively. They found that flat carcinomas can develop directly from flat adenomas, whereas it had been argued previously that all colorectal carcinomas had to develop through a polypoid stage.  Both types of tumors had a significant increase in the level of nuclear
b-catenin (CATNNB1) and similar frequencies of mutations in the phosphorylation domain–coding region (codons 32–41) of the Catnnb1 gene. Flat adenomas are more difficult to recognize at colonoscopy than polypoid adenomas; therefore, it will be important to develop more sensitive methods for their detection.

Uronis, J.M., Herfarth, H.H., Rubinas, T.C., Bissahoyo, A.C., Hanlon, K. & Threadgill, D.W. Flat colorectal cancers are genetically determined and progress to invasion without going through a polypoid stage. Cancer Res 67, 11594-600 (2007).

Student and Postdoc News

The Genetics Dept. is growing and changing with many new graduate students and postdoctoral fellows joining the department, as well as many graduate students and postdocs/fellows finishing their education/training and moving on to the next level. We would like to welcome the newcomers and acknowledge some of the accomplishments.

Welcome to new Genetics Department members.

Postdoctoral fellows who have joined Genetics labs:
Mark Heise’s lab

• Marty Ferris, Ph.D., UNC-CH, (dissertation research with Dr. Christina Burch, Biology)

Terry Magnuson’s lab

• Mauro Calabrese, Ph.D., MIT
• Ron Chandler, Ph.D., Vanderbilt University
• Yuna Kim, Ph.D., Duke University
• Michael Pohlers, Ph.D., Humboldt University of Berlin
• Karl Shpargel, Ph.D., Case Western Reserve University

David Threadgill and Fernando Pardo-Manuel

• David Aylor, Ph.D., NCSU

Graduate Students who have joined Genetics labs include:

• Jeff Gray, Curriculum in Toxicology has joined Terry Magnuson’s lab.

 Research Staff joining the department include:

• Jill Steigerwalt has joined David Threadgill’s lab as Lab Manager.

A record number of graduate students from Genetics Dept. Labs have recently completed their graduate work and will soon be moving on to other positions. Congratulations and best wishes to all of these new PhDs!

Shawn Ahmed’s lab

• Mia Lowden (graduate student in Biology) defended March 2008.

Frank Conlon’s lab

• Elizabeth Mandel (graduate student in Biology) Fall of 2007. Elizabeth is currently a post-doc with Dr. Rudolf Grosschedl at the Max Planck Institute of Immunobiology.

• Yvette Langdon (graduate student in Biology) March 2008. Yvette will be completing postdoctoral training with Dr. Mary Mullins at UPenn.

Kathleen Caron's lab

• Ryan Dackor (Curriculum in Genetics and Molecular Biology) defended January 2008, Ryan is currently at NIEHS (Darryl Zeldin’s lab) as a postdoc.

Chuck Perou's lab

• Jason Herschkowitz (Curriculum in Genetics and Molecular Biology) defended September 2007. Jason is currently a postdoc at Baylor College of Medicine (Jeffrey Rosen’s lab).

David Threadgill’s lab
Defenses in December 2007

• Tang-Cheng Lee, Curriculum in Genetics and Molecular Biology
• Ming Yu, Program in Oral Biology

Defenses in March, 2008

• Jennifer Dackor, Curriculum in Genetics and Molecular Biology, Jenn will be joining the laboratories of Patrick Sullivan and Helena Furberg-Barnes as a Project Manager for the Tobacco and Genetics Consortium (TAG).
• Erica Rinella, Curriculum in Genetics and Molecular Biology
• Josh Uronis, Curriculum in Genetics and Molecular Biology, Josh will be starting a postdoc in the laboratory of Christian Jobin, UNC Dept. of Medicine.
• Michele La Merrill, Curriculum in Toxicology, Michele will be an Environmental Pediatric Fellow of the Dept. of Community and Preventative Medicine at Mt. Sinai Medical School beginning July 1.

Terry Van Dyke's lab

• Mark Schliekelman defended April 2008

Congratulations to Genetics department members completing their postdoctoral training.

• Courtney Griffin (Postdoctoral Fellow in Terry Magnuson’s lab) will be assuming a position as Assistant Professor at the Oklahoma Medical Research Foundation beginning September 1.
• Tem Morrison (Postdoctoral Fellow in Mark Heise’s lab) has accepted a position as Assistant Professor at University of Colorado Health Sciences Center in Denver. He will be starting March 1st 2009.

Congratulations also to Genetics Department trainees awarded honors/prizes.

Postdoctoral fellows:
David Threadgill’s lab

• Christine Powell was awarded an NRSA Individual Postdoctoral Award from the National Institute of Alcohol Abuse and Alcoholism in Dec. 2007 for her research entitled “Epigenetic Analysis of Alcohol-induced Liver Injury”. Christine also received a scholarship to cover registration and course fees for the 16th Annual Short Course on Experimental Genetics of the Laboratory Mouse in Cancer Research at Jackson Laboratories, Aug 19 - Aug 30 2007.

Debbie Threadgill’s lab

• Michael LaGier (SPIRE postdoctoral fellow) was one of only two postdocs selected to attend the registration restricted ASM sponsored BioQuest Bioinformatics Institute held March 6-9, 2008, in Washington, D.C. Bioquest is usually reserved for faculty members from Undergraduate serving institutions. Mike has recently had his first author manuscript detailing comparative genomic studies in Campylobacter accepted for publication in Oral Microbiology.

Graduate students:
Larysa Pevny’s lab

• Natalia Surzenko (Curriculum in Neurobiology) has been awarded a "Dissertation Completion Fellowship", by the UNC Graduate School. Title of dissertation: "Investigating Temporal Function of SOX2 in Retinal Neural Progenitors".

David Threadgill’s lab

• Michele La Merrill received the President’s Award from the Genetic and Environmental Mutagene Society in 2007. She received a travel award of $1800 to travel to the EMS meeting in Puerto Rico in 2008. Michele also received second place for Best Student or Postdoctoral Abstract in the Reproductive and Developmental Toxicology Specialty Section, at the Annual Meeting of the Society of Toxicology (SOT) March 16-20, 2008.
• Melanie Weed (Curriculum in Toxicology) received the Leon Golberg Memorial Travel Award from UNC's Tox Curriculum for the SOT meeting.  She is also now the Secretary of the Regional Chapter Graduate Committee as well as the NCSOT Regional Rep for another year. Melanie also received a travel award and was selected to attend the Endocrine Trainee Day from the Endocrine Society for a conference in June in San Francisco.

Undergraduates:
Frank Conlon’s lab

• Elizabeth Jarvis (graduating senior in Biology) received the H.V.P. Wilson Award for Excellence in Research in Cellular and Molecular Biology as part of the Spring Biology Honors Colloquium for her research entitled “Expression of the Xenopus Transcription Factor Tbx20 in Early Neurogenesis”. Elizabeth’s graduate student mentor was Elizabeth Mandel.

David Threadgill’s lab

• Richard Frye (graduating senior in Biology) received Research Commendation in Biology for 'Characterization of epidermal growth factor receptor independent colorectal tumors in the Apcmin mouse model', during the Spring Biology Honors Colloquium. Richard completed his research under the direction of Ming Yu.
• Rachel Harper, (rising senior in Biology) presented her research entitled 'Dietary fat and dioxin exposure increase mammary cancer incidence through Cyp1b1 and Comt expression' at the 9th Annual UNC Celebration of Undergraduate Research. Rachel completed her research under the direction of Michele La Merrill.

Debbie Threadgill’s lab

• Sarah Hoyt (rising junior in Biostatistics) has been awarded a second summer internship to work at NIEHS/RTP with Dr. Donald Cook studying dendritic cells in pulmonary allergic response.

For more information about current graduate students and postdoctoral fellows in Genetics Dept. Labs, please visit individual researcher’s web pages. If you would like to see news from your lab here, please contact Debbie Threadgill.

Recent Publications

Bultman, Perou and Magnuson

Bultman, S.J., Herschkowitz, J.I., Godfrey, V., Gebuhr, T.C., Yaniv, M., Perou, C.M. & Magnuson, T. Characterization of mammary tumors from Brg1 heterozygous mice. Oncogene 27, 460-8 (2008).

Caron

Dackor, R. & Caron, K. Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock. Peptides 28, 2164-70 (2007).

Fritz-Six, K.L., Dunworth, W.P., Li, M. & Caron, K.M. Adrenomedullin signaling is necessary for murine lymphatic vascular development. J Clin Invest 118, 40-50 (2008).

Conlon

Christine, K.S., & Conlon F.L. Vertebrate CASTOR is required for differentiation of cardiac precursor cells at the ventral midline. Dev. Cell 14, 616-23 (2008).

Langdon, Y.G., Goetz, S.C., Berg, A.E., Swanik, J.T. & Conlon, F.L. SHP-2 is required for the maintenance of cardiac progenitors. Development 134, 4119-30 (2007).

Evans

Evans, J. & Khoury, M.J. Evidence based medicine meets genomic medicine. Genet Med 9, 799-800 (2007).

Evans, J.P. Health care in the age of genetic medicine. Jama 298, 2670-2 (2007).
11.
    
Evans, J.P. Health care in the age of genetic medicine. Genet Med 10, 1-3 (2008).

Susswein, L.R., Skrzynia, C., Lange, L.A., Booker, J.K., Graham, M.L., 3rd & Evans, J.P. Increased uptake of BRCA1/2 genetic testing among African American women with a recent diagnosis of breast cancer. J Clin Oncol 26, 32-6 (2008).

Farber

Boyer, J.C., Hawk, J.D., Stefanovic, L. & Farber, R.A. Sequence-dependent effect of interruptions on microsatellite mutation rate in mismatch repair-deficient human cells. Mutat Res 640, 89-96 (2008).

Lehner, K.R., Stone, M.M., Farber, R.A. & Petes, T.D. Ninety-six haploid yeast strains with individual disruptions of open reading frames between YOR097C and YOR192C, constructed for the Saccharomyces genome deletion project, have an additional mutation in the mismatch repair gene MSH3. Genetics 177, 1951-3 (2007).

Lange, EM

Lange, E.M., Sarma, A.V., Ray, A., Wang, Y., Ho, L.A., Anderson, S.A., Cunningham, J.M. & Cooney, K.A. The androgen receptor CAG and GGN repeat polymorphisms and prostate cancer susceptibility in African-American men: results from the Flint Men's Health Study. J Hum Genet 53, 220-6 (2008).

Lange, LA, and Lange, EM

Lange, L.A., Reiner, A.P., Carty, C.L., Jenny, N.S., Cushman, M. & Lange, E.M. Common genetic variants associated with plasma fibrin D-dimer concentration in older European- and African-American adults. J Thromb Haemost 6, 654-9 (2008).

Magnuson

Griffin, C.T., Brennan, J. & Magnuson, T. The chromatin-remodeling enzyme BRG1 plays an essential role in primitive erythropoiesis and vascular development. Development 135, 493-500 (2008).

Montgomery, N.D., Yee, D., Montgomery, S.A. & Magnuson, T. Molecular and functional mapping of EED motifs required for PRC2-dependent histone methylation. J Mol Biol 374, 1145-57 (2007).

Mohlke

Franks, P.W., Rolandsson, O., Debenham, S.L., Fawcett, K.A., Payne, F., Dina, C., Froguel, P., Mohlke, K.L., Willer, C., Olsson, T., Wareham, N.J., Hallmans, G., Barroso, I. & Sandhu, M.S. Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations. Diabetologia 51, 458-63 (2008).

Sanna, S., Jackson, A.U., Nagaraja, R., Willer, C.J., Chen, W.M., Bonnycastle, L.L., Shen, H., Timpson, N., Lettre, G., Usala, G., Chines, P.S., Stringham, H.M., Scott, L.J., Dei, M., Lai, S., Albai, G., Crisponi, L., Naitza, S., Doheny, K.F., Pugh, E.W., Ben-Shlomo, Y., Ebrahim, S., Lawlor, D.A., Bergman, R.N., Watanabe, R.M., Uda, M., Tuomilehto, J., Coresh, J., Hirschhorn, J.N., Shuldiner, A.R., Schlessinger, D., Collins, F.S., Davey Smith, G., Boerwinkle, E., Cao, A., Boehnke, M., Abecasis, G.R. & Mohlke, K.L. Common variants in the GDF5-UQCC region are associated with variation in human height. Nat Genet 40, 198-203 (2008).

Willer, C.J., Sanna, S., Jackson, A.U., Scuteri, A., Bonnycastle, L.L., Clarke, R., Heath, S.C., Timpson, N.J., Najjar, S.S., Stringham, H.M., Strait, J., Duren, W.L., Maschio, A., Busonero, F., Mulas, A., Albai, G., Swift, A.J., Morken, M.A., Narisu, N., Bennett, D., Parish, S., Shen, H., Galan, P., Meneton, P., Hercberg, S., Zelenika, D., Chen, W.M., Li, Y., Scott, L.J., Scheet, P.A., Sundvall, J., Watanabe, R.M., Nagaraja, R., Ebrahim, S., Lawlor, D.A., Ben-Shlomo, Y., Davey-Smith, G., Shuldiner, A.R., Collins, R., Bergman, R.N., Uda, M., Tuomilehto, J., Cao, A., Collins, F.S., Lakatta, E., Lathrop, G.M., Boehnke, M., Schlessinger, D., Mohlke, K.L. & Abecasis, G.R. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40, 161-9 (2008).

Pardo-Manuel de Villena

Szatkiewicz, J.P., Beane, G.L., Ding, Y., Hutchins, L., Pardo-Manuel de Villena, F. & Churchill, G.A. An imputed genotype resource for the laboratory mouse. Mamm Genome (2008).

Pardo-Manuel de Villena, Sullivan and Wilhelmsen

Wright, F.A., Huang, H., Guan, X., Gamiel, K., Jeffries, C., Barry, W.T., de Villena, F.P., Sullivan, P.F., Wilhelmsen, K.C. & Zou, F. Simulating association studies: a data-based resampling method for candidate regions or whole genome scans. Bioinformatics 23, 2581-8 (2007).

Perou

Peppercorn, J., Perou, C.M. & Carey, L.A. Molecular subtypes in breast cancer evaluation and management: divide and conquer. Cancer Invest 26, 1-10 (2008).

Shabalin, A.A., Tjelmeland, H., Fan, C., Perou, C.M. & Nobel, A.B. Merging Two Gene Expression Studies via Cross Platform Normalization. Bioinformatics (2008).

Pomp and Threadgill

Gordon, R.R., Hunter, K.W., La Merrill, M., Sorensen, P., Threadgill, D.W. & Pomp, D. Genotype x diet interactions in mice predisposed to mammary cancer: II. Tumors and metastasis. Mamm Genome (2008).

Sharpless

Kaufmann, W.K., Nevis, K.R., Qu, P., Ibrahim, J.G., Zhou, T., Zhou, Y., Simpson, D.A., Helms-Deaton, J., Cordeiro-Stone, M., Moore, D.T., Thomas, N.E., Hao, H., Liu, Z., Shields, J.M., Scott, G.A. & Sharpless, N.E. Defective cell cycle checkpoint functions in melanoma are associated with altered patterns of gene expression. J Invest Dermatol 128, 175-87 (2008).

Petermann, K.B., Rozenberg, G.I., Zedek, D., Groben, P., McKinnon, K., Buehler, C., Kim, W.Y., Shields, J.M., Penland, S., Bear, J.E., Thomas, N.E., Serody, J.S. & Sharpless, N.E. CD200 is induced by ERK and is a potential therapeutic target in melanoma. J Clin Invest 117, 3922-9 (2007).

Sullivan

Bulik, C.M., Slof-Op't Landt, M.C., van Furth, E.F. & Sullivan, P.F. The genetics of anorexia nervosa. Annu Rev Nutr 27, 263-75 (2007).

Crowley, J.J., Keefe, R.S., Perkins, D.O., Stroup, T.S., Lieberman, J.A. & Sullivan, P.F. The neuregulin 1 promoter polymorphism rs6994992 is not associated with chronic schizophrenia or neurocognition. Am J Med Genet B Neuropsychiatr Genet (2008).

Pinheiro, A.P., Bulik, C.M., Sullivan, P.F. & Machado, P.P. An empirical study of the typology of bulimic symptoms in young Portuguese women. Int J Eat Disord 41, 251-258 (2007).

Sullivan, P.F. Schizophrenia genetics: the search for a hard lead. Curr Opin Psychiatry 21, 157-60 (2008).

Sullivan, P.F., Kuo, P.H., Webb, B.T., Neale, M.C., Vittum, J., Furberg, H., Walsh, D., Patterson, D.G., Riley, B., Prescott, C.A. & Kendler, K.S. Genomewide linkage survey of nicotine dependence phenotypes. Drug Alcohol Depend 93, 210-6 (2008).

Lee, S., Sullivan, P.F., Wright, F.A. Comment on a simple and improved correction for population stratification. Am. J. Hum. Genet. 82, 524-526.

Threadgill, DW

Barrick, C.J., Yu, M., Chao, H.H. & Threadgill, D.W. Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice. Toxicol Appl Pharmacol (2008).

Dackor, J., Strunk, K.E., Wehmeyer, M.M. & Threadgill, D.W. Altered trophoblast proliferation is insufficient to account for placental dysfunction in Egfr null embryos. Placenta 28, 1211-8 (2007).

Threadgill, D.W. Down's syndrome: Paradox of a tumour repressor. Nature 451, 21-22 (2008).

Uronis, J.M., Herfarth, H.H., Rubinas, T.C., Bissahoyo, A.C., Hanlon, K. & Threadgill, D.W. Flat colorectal cancers are genetically determined and progress to invasion without going through a polypoid stage. Cancer Res 67, 11594-600 (2007).

Wilhelmsen

Ehlers, C.L., Gilder, D.A., Slutske, W.S., Lind, P.A. & Wilhelmsen, K.C. Externalizing disorders in American Indians: Comorbidity and a genome wide linkage analysis. Am J Med Genet B Neuropsychiatr Genet (2008).

Quinzii, C.M., Vu, T.H., Min, K.C., Tanji, K., Barral, S., Grewal, R.P., Kattah, A., Camano, P., Otaegui, D., Kunimatsu, T., Blake, D.M., Wilhelmsen, K.C., Rowland, L.P., Hays, A.P., Bonilla, E. & Hirano, M. X-linked dominant scapuloperoneal myopathy is due to a mutation in the gene encoding four-and-a-half-LIM protein 1. Am J Hum Genet 82, 208-13 (2008).