Bio

Honors & Awards


  • Albert J. Ryan fellowship, Harvard University (2011)
  • Edward C. Horn Memorial Prize for Excellence in Biology, Duke University (2008)
  • Graduation with High Distinction in Biology, Duke University (2008)
  • Summa Cum Laude, Duke University (2008)
  • American Foundation for Aging Research (AFAR) Scholarship, AFAR (2007)
  • Phi Beta Kappa Honor Society, Duke University (2007)

Professional Education


  • Doctor of Philosophy, Harvard University (2014)
  • Bachelor of Science, Duke University (2008)

Stanford Advisors


Research & Scholarship

Current Research and Scholarly Interests


Studying the role of the p53 tumor suppressor in embryonic development

Publications

Journal Articles


  • Sclerostin Inhibition Reverses Skeletal Fragility in an Lrp5-Deficient Mouse Model of OPPG Syndrome SCIENCE TRANSLATIONAL MEDICINE Kedlaya, R., Veera, S., Horan, D. J., Moss, R. E., Ayturk, U. M., Jacobsen, C. M., Bowen, M. E., Paszty, C., Warman, M. L., Robling, A. G. 2013; 5 (211)

    Abstract

    Osteoporosis pseudoglioma syndrome (OPPG) is a rare genetic disease that produces debilitating effects in the skeleton. OPPG is caused by mutations in LRP5, a WNT co-receptor that mediates osteoblast activity. WNT signaling through LRP5, and also through the closely related receptor LRP6, is inhibited by the protein sclerostin (SOST). It is unclear whether OPPG patients might benefit from the anabolic action of sclerostin neutralization therapy (an approach currently being pursued in clinical trials for postmenopausal osteoporosis) in light of their LRP5 deficiency and consequent osteoblast impairment. To assess whether loss of sclerostin is anabolic in OPPG, we measured bone properties in a mouse model of OPPG (Lrp5(-/-)), a mouse model of sclerosteosis (Sost(-/-)), and in mice with both genes knocked out (Lrp5(-/-);Sost(-/-)). Lrp5(-/-);Sost(-/-) mice have larger, denser, and stronger bones than do Lrp5(-/-) mice, indicating that SOST deficiency can improve bone properties via pathways that do not require LRP5. Next, we determined whether the anabolic effects of sclerostin depletion in Lrp5(-/-) mice are retained in adult mice by treating 17-week-old Lrp5(-/-) mice with a sclerostin antibody for 3 weeks. Lrp5(+/+) and Lrp5(-/-) mice each exhibited osteoanabolic responses to antibody therapy, as indicated by increased bone mineral density, content, and formation rates. Collectively, our data show that inhibiting sclerostin can improve bone mass whether LRP5 is present or not. In the absence of LRP5, the anabolic effects of SOST depletion can occur via other receptors (such as LRP4/6). Regardless of the mechanism, our results suggest that humans with OPPG might benefit from sclerostin neutralization therapies.

    View details for DOI 10.1126/scitranslmed.3006627

    View details for Web of Science ID 000327012900005

    View details for PubMedID 24225945

  • Perspectives for identification of mutations in the zebrafish: Making use of next-generation sequencing technologies for forward genetic approaches METHODS Henke, K., Bowen, M. E., Harris, M. P. 2013; 62 (3): 185-196

    Abstract

    The ability to identify a phenotype causing mutation is essential for successful use of mutagenesis screens in many model organisms. Mapping mutations was for a long time a bottleneck in zebrafish research, as the standard method for mapping and identification of mutations was time consuming and expensive. The development of new sequencing technologies in the last couple of years has enabled the rapid and cost-effective sequencing of whole genomes. This has led to the establishment of new strategies for mapping and identification of mutations in several model organisms. The application of these techniques to the zebrafish model, with its large genome and the high level of variation in and between strains, was not trivial. Several techniques have been developed recently, taking the specific characteristics of the zebrafish genome into account. Here we give an overview on how to plan a mapping experiment, detail the critical parameters and discuss available tools for mapping and identification of mutations in zebrafish using next-generation sequencing. Using these methods, zebrafish mutants can now be mapped in a couple of weeks for a fraction of the costs. The increased efficiency of identification of mutations in the zebrafish broadens the utility of the model and allows for systematic analysis of gene function in a vertebrate model.

    View details for DOI 10.1016/j.ymeth.2013.05.015

    View details for Web of Science ID 000324454000002

    View details for PubMedID 23748111

  • Presphenoidal synchondrosis fusion in DBA/2J mice MAMMALIAN GENOME Adams, A., McBratney-Owen, B., Newby, B., Bowen, M. E., Olsen, B. R., Warman, M. L. 2013; 24 (1-2): 54-62

    Abstract

    Cranial base growth plates are important centers of longitudinal growth in the skull and are responsible for the proper anterior placement of the face and the stimulation of normal cranial vault development. We report that the presphenoidal synchondrosis (PSS), a midline growth plate of the cranial base, closes in the DBA/2J mouse strain but not in other common inbred strains. We investigated the genetics of PSS closure in DBA/2J mice by evaluating F1, F1 backcross, and/or F1 intercross offspring from matings with C57BL/6J and DBA/1J mice, whose PSS remain open. We observed that PSS closure is genetically determined, but not inherited as a simple Mendelian trait. Employing a genome-wide SNP array, we identified a region on chromosome 11 in the C57BL/6J strain that affected the frequency of PSS closure in F1 backcross and F1 intercross offspring. The equivalent region in the DBA/1J strain did not affect PSS closure in F1 intercross offspring. We conclude that PSS closure in the DBA/2J strain is complex and modified by different loci when outcrossed with C57BL/6J and DBA/1J mice.

    View details for DOI 10.1007/s00335-012-9437-8

    View details for Web of Science ID 000314298600005

    View details for PubMedID 23179633

  • Identification of mutations in zebrafish using next-generation sequencing. Current protocols in molecular biology / edited by Frederick M. Ausubel ... [et al.] Henke, K., Bowen, M. E., Harris, M. P. 2013; 104: 7 13 1-7 13 33

    Abstract

    Whole-genome sequencing (WGS) has been used in many invertebrate model organisms as an efficient tool for mapping and identification of mutations affecting particular morphological or physiological processes. However, the application of WGS in highly polymorphic, larger genomes of vertebrates has required new experimental and analytical approaches. As a consequence, a wealth of different analytical tools has been developed. As the generation and analysis of data stemming from WGS can be unwieldy and daunting to researchers not accustomed to many common bioinformatic analyses and Unix-based computational tools, we focus on how to manage and analyze next-generation sequencing datasets without an extensive computational infrastructure and in-depth bioinformatic knowledge. Here we describe methods for the analysis of WGS for use in mapping and identification of mutations in the zebrafish. We stress key elements of the experimental design and the analytical approach that allow the use of this method across different sequencing platforms and in different model organisms with annotated genomes. Curr. Protoc. Mol. Biol. 104:7.13.1-7.13.33. © 2013 by John Wiley & Sons, Inc.

    View details for DOI 10.1002/0471142727.mb0713s104

    View details for PubMedID 24510885

  • Somatic Mosaic Activating Mutations in PIK3CA Cause CLOVES Syndrome AMERICAN JOURNAL OF HUMAN GENETICS Kurek, K. C., Luks, V. L., Ayturk, U. M., Alomari, A. I., Fishman, S. J., Spencer, S. A., Mulliken, J. B., Bowen, M. E., Yamamoto, G. L., Kozakewich, H. P., Warman, M. L. 2012; 90 (6): 1108-1115

    Abstract

    Congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) is a sporadically occurring, nonhereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. We hypothesized that CLOVES syndrome would be caused by a somatic mutation arising during early embryonic development. Therefore, we employed massively parallel sequencing to search for somatic mosaic mutations in fresh, frozen, or fixed archival tissue from six affected individuals. We identified mutations in PIK3CA in all six individuals, and mutant allele frequencies ranged from 3% to 30% in affected tissue from multiple embryonic lineages. Interestingly, these same mutations have been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity. We conclude that CLOVES is caused by postzygotic activating mutations in PIK3CA. The application of similar sequencing strategies will probably identify additional genetic causes for sporadically occurring, nonheritable malformations.

    View details for DOI 10.1016/j.ajhg.2012.05.006

    View details for Web of Science ID 000305262600016

    View details for PubMedID 22658544

  • Efficient Mapping and Cloning of Mutations in Zebrafish by Low-Coverage Whole-Genome Sequencing GENETICS Bowen, M. E., Henke, K., Siegfried, K. R., Warman, M. L., Harris, M. P. 2012; 190 (3): 1017-U229

    Abstract

    The generation and analysis of mutants in zebrafish has been instrumental in defining the genetic regulation of vertebrate development, physiology, and disease. However, identifying the genetic changes that underlie mutant phenotypes remains a significant bottleneck in the analysis of mutants. Whole-genome sequencing has recently emerged as a fast and efficient approach for identifying mutations in nonvertebrate model organisms. However, this approach has not been applied to zebrafish due to the complicating factors of having a large genome and lack of fully inbred lines. Here we provide a method for efficiently mapping and detecting mutations in zebrafish using these new parallel sequencing technologies. This method utilizes an extensive reference SNP database to define regions of homozygosity-by-descent by low coverage, whole-genome sequencing of pooled DNA from only a limited number of mutant F(2) fish. With this approach we mapped each of the five different zebrafish mutants we sequenced and identified likely causative nonsense mutations in two and candidate mutations in the remainder. Furthermore, we provide evidence that one of the identified mutations, a nonsense mutation in bmp1a, underlies the welded mutant phenotype.

    View details for DOI 10.1534/genetics.111.136069

    View details for Web of Science ID 000301531900013

    View details for PubMedID 22174069

  • Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome PLOS GENETICS Bowen, M. E., Boyden, E. D., Holm, I. A., Campos-Xavier, B., Bonafe, L., Superti-Furga, A., Ikegawa, S., Cormier-Daire, V., Bovee, J. V., Pansuriya, T. C., de Sousa, S. B., Savarirayan, R., Andreucci, E., Vikkula, M., Garavelli, L., Pottinger, C., Ogino, T., Sakai, A., Regazzoni, B. M., Wuyts, W., Sangiorgi, L., Pedrini, E., Zhu, M., Kozakewich, H. P., Kasser, J. R., Seidman, J. G., Kurek, K. C., Warman, M. L. 2011; 7 (4)

    Abstract

    Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a "second hit," that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.

    View details for DOI 10.1371/journal.pgen.1002050

    View details for Web of Science ID 000289977000031

    View details for PubMedID 21533187

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