Ravinesh Kumar

RAVINESH ANAND KUMAR- PhD DEFENSE

“Genetic & Genomic Studies of Mouse & Human NR2E1 in Cortical Disorders, Aggressive Behaviour, & Psychiatric Disease”

B.Sc., Simon Fraser University, 1999
Thursday, September 21, 2006, 4:00 pm Room 200, Graduate Student Centre

Ravinesh Kumar- PhD Defense program- pdf

SUPERVISORY COMMITTEE

Dr. Elizabeth M. Simpson, Research Supervisor (Medical Genetics)
Dr. Jan M. Friedman (Medical Genetics)
Dr. Diana Juriloff (Medical Genetics)
Dr. Kelly McNagny (Medical Genetics)

EXAMINING COMMITTEE

Chair: To be completed by FoGS
Supervisory Committee: Dr. Elizabeth M. Simpson, Research Supervisor (Medical Genetics), Dr. Jan M. Friedman (Medical Genetics)
University Examiners: Dr. William G. Honer (Psychiatry), Dr. Weihong Song (Neuroscience)
External Examiner: To be completed by FoGS

ABSTRACT

Brain and behavioural disorders represent a leading cause of morbidity and suffering worldwide. The ‘fierce’ mouse has a spontaneous deletion of Nr2e1 that results in a complex phenotype that includes cortical hypoplasia and socially abnormal behaviours. Notably, functional protein and regulatory equivalency of mouse and human NR2E1 has been established. Furthermore, human studies implicate the genomic region containing NR2E1 in mental illness, although a role for NR2E1 in humans is currently unknown. Here, I integrate mouse models and human molecular genetics to understand the involvement of NR2E1 in human brain- behaviour development. First, we test the hypothesis that the spontaneous ‘fierce’ deletion involves only Nr2e1. It was demonstrated that the ‘fierce’ mutation results in the loss of all Nr2e1 exons without affecting neighbouring genes. Next, the hypothesis that some humans with cortical malformations will harbour NR2E1 mutations was tested by sequencing the coding, untranslated, splice-site, proximal promoter, and evolutionarily conserved regions of this gene in 60 subjects with microcephaly. Four candidate regulatory mutations were identified. To help interpret these findings, the genomic architecture and molecular evolution of NR2E1 were characterized in 94 ethnically-diverse humans and 13 non-human primates, which indicated strong functional constraint. Finally, the hypothesis that some humans with behavioural and psychiatric disorders will harbour mutations in NR2E1 was tested by sequencing the regions outlined above in 126 humans with impulsive-aggressive disorders, bipolar disorder, and schizophrenia. Eleven candidate regulatory mutations were identified. Taken together, the findings presented in this thesis is consistent with the proposal that non-coding regulatory mutations may be important to the pathogenesis of brain-behavioural disorders in some humans.

PUBLICATIONS

Kumar RA, Leach S, Bonaguro R, McLean A, Abrahams BA, Hodgins S, Turecki G, Coccarro E, Muir W, Blackwood D, Brooks-Wilson AR, and Simpson EM. Mutation, Association, and Expression Studies of Human NR2E1: A Genetic Candidate for Impulsive-Aggressive Behaviours, Bipolar Disorder, and Schizophrenia. In Preparation

Kumar RA, Leach S, Bonaguro R, Chen J, Yokom DW, Abrahams B, Seaver L, Schwartz C, Dobyns W, Brooks-Wilson AR, and Simpson EM. Mutation and Evolutionary Analyses of NR2E1 Identify Candidate Regulatory Mutations in Humans with Severe Cortical Malformations. Genes, Brain, and Behavior,
In Press

Janssen PA, Nicholls TL, Kumar RA, Stefankis H, Spidel A, and Simpson EM. Of mice and men: will the intersection of social science and genetics create new approaches to intimate partner violence? Journal of Interpersonal Violence 20(1): 61-71. (2005).

Kumar RA, Chan K, Wong AHW, Little QL, Rajcan-Separovic E, Abrahams BS, and Simpson EM. Unexpected embryonic stem (ES) mutations represent a concern in gene targeting: lessons from ‘fierce’ mice. Genesis 38(2): 51-57 (2004).

Kumar RA. Violence begets violence, or does it? A brain enzyme protects victims of childhood abuse from becoming antisocial and criminal. Clinical Genetics 63(3): 180-183 (2003). 6. Zhao Y, Kumar RA, Baser ME, Evans DG, Wallace A, Kluwe L, Mautner VF, Parry DM, Rouleau GA, Joe H, Friedman JM. Intrafamilial correlation of clinical manifestations in neurofibromatosis 2 (NF2). Genetic Epidemiology 23(3): 245- 59 (2002).

SELECTED PRESENTATIONS

Kumar RA et al. Mutation, association, and expression studies of human NR2E1: A genetic candidate for impulsive-aggressive Behaviours, bipolar disorder, and schizophrenia. Sardinia, Italy (October 2006). Oral (Accepted)

Kumar RA et al. NR2E1 variants are unlikely to contribute to the microcephaly, microcephaly, ectrodactyly, and prognathism (MMEP) phenotype. Am J Med Genet 138B (2005). Boston, USA. Poster

Kumar RA and Simpson EM. Towards screening patients with ocular abnormalities for mutations in NR2E1, a neural stem cell gene involved in brain-behaviour-eye development. Whistler, Canada (September 2005). Oral

Kumar RA et al. Molecular evolution of NR2E1: A candidate for pathological violence and 6q-linked brain-behaviour disorders.
Am J Med Genet 130B (2004). Dublin, Ireland. Poster

Kumar RA and Simpson EM. Screening individuals with ‘fierce-like’ phenotypes for mutations and allelic variation in the brain-specific nuclear receptor NR2E1. Vancouver, Canada (April 2004). Oral

Kumar RA et al. An unexpected gene-targeting event generates a mouse model of pathological violence (fierce), and identifies a novel confound in gene-disruption experiments. Am J Med Genet 122B (2003). Quebec City, Canada. Poster

Kumar RA et al. Intrafamilial correlation of clinical manifestations in neurofibromatosis type 2 (NF2). Am J Hum Genet 65 Supplement (1999) San Francisco, USA. Oral

AWARDS

C&W Excellence in Education Award with Distinction (May 2006)
Young Scientist Travel Award (September 2005)
Jack & Doris Brown Foundation Graduate Studentship Award (Jan 04/05)
BCRICWH Research Methodology Training Award (August 2003)
Burroughs Wellcome Bursary in Genomics (July 2003)
World Congress on Psychiatric Genetics Travel Fellowship (June 2003) BCRICWH Graduate Studentship Award (June 2001-2003)
Burroughs Wellcome Life Science Award (February 2002)
BC Medical Services Foundation Summer Research Scholarship (April 1999) NSERC Summer Undergraduate Research Award (June 1993)

GRADUATE STUDIES

Field of Study: Psychiatric and Behaviour Genetics

Courses:
MEDG 520 Advanced Human Molecular Genetics, Dr. C. Brown
MEDG 521 Cancer Genetics, Dr. F. Takeo
MEDG 525 Medical Population Genetics, Dr. W. Robinson
MEDG 530 Advanced Human Genetics, Dr. J. Friedman
MEDG 540 Medical Genetics Seminar, Dr. F. Dill
PSYC 574 Biopsychology, Dr. B. Gorzalka

Ravinesh Kumar- PhD Defense program- pdf