RESEARCH OFFICER, Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine, University of Cape Town

(1 year contract possible renewal)

______

A. THE CONTEXT

Our project will be the first to apply current genomic sequencing approaches to study schizophrenia in a sub-Saharan population of African lineage. We have assembled a team with the capacity and commitment to complete such a study in South Africa. Our team comprises psychiatrists (Drs Susser, Stein, and McClellan) and geneticists (Drs King, Ramesar, Walsh) who have worked together over decades, both within and across South Africa and the United States.

Each site has defined roles critical to achieving the study aims. Columbia University (CU) will serve as the coordinating center for the study, and will be the primary liaison with the National Institutes of Mental Health (NIMH). The Columbia team will oversee the coordination of subject recruitment, analysis of diagnostic and cognitive data, and manuscript development. The University of Cape Town (UCT) will recruit, evaluate, and sample African cases and controls. They will provide phenotypic information, participate in the interpretation of genomic results, help prioritize candidate genes, and follow-up on potential associations between the rare deleterious mutations and clinical subtypes within their patients. Dr Ramesar’s laboratory at UCT will carry out CNV discovery and analyses, and with the resources provided by this grant, develop the capacity to conduct exome and genomic sequencing. The University of Washington (UW) will conduct exome and targeted genomic sequencing, and with UCT, analyze genomic data. The Illumina-based HiSeq platform used by the King laboratory at UW for exome, targeted genome, and whole genome sequencing is now widely used, but has not previously been applied to a study of complex disease in a sub-Saharan African population.

Each site will be a full partner in the research and participate in decisions affecting the implementation of the study or interpretation of the data produced by the study. All protocols will be monitored by institutional IRBs.

B. THE RESEARCH PROJECT

The goal of this project is to identify genes important for schizophrenia, based on genomic analysis of the Xhosa population of South Africa. We propose to identify and characterize rare mutations present in Xhosa with schizophrenia but not in age and gender–matched Xhosa controls. Rare point mutations, small insertions and deletions (indels), and copy number variants (CNVs) will be identified. Genomic approaches will include whole exome sequencing, targeted genome sequencing, and CNV analysis. This project will be the first to use current genomic approaches to study schizophrenia in an ancient African population.

The Xhosa are the largest population of the South African Eastern Cape region. Because the number of alleles to be found in ancient African populations is far greater than in non-African populations, genomic analysis of schizophrenia in the Xhosa offers the opportunity to identify critical mutations for this illness not detectable elsewhere. Importantly, the genes harbouring such mutations in the Xhosa are very likely to harbour other damaging mutations in other populations worldwide.

We and others previously demonstrated that genomes of individuals with schizophrenia are enriched for rare structural mutations, including those that are de novo or arose in recent generations. Genes impacted by these rare CNVs in patients disproportionately contribute to cellular signalling and neurodevelopmental processes, including neuregulin and glutamate pathways1. Recurrent deletions or duplications at genomic hotspots, e.g., 1q21.1, 15q13.3, and 22q11.2; are associated with substantial disease risk5, although none of these regions explains more than ~1 % of the illness. Thus, schizophrenia is characterized by marked genetic heterogeneity, to the remarkable extent that most patients may have a different genetic cause5.

We hypothesize that a gene important to schizophrenia will harbour different disease-causing mutations indifferent affected individuals. We will use a gene-based approach to identify genes that harbour multiple rare orde novo deleterious mutations in cases but not in controls. Given the genetic diversity of African populations, our project will potentially find novel candidate genes for schizophrenia that have not yet emerged from studies of other populations. This grant will also foster the development of gene discovery research for neuropsychiatric disorders in Africa.

Aim 1: Identify candidate genes for schizophrenia in a discovery sample of 200 Xhosa individuals with the illness compared to 200 age- and gender-matched Xhosa controls.

Aim 1A: Identify all rare point mutations and indels using exome sequencing (Illumina HiSeq platform at UW).

Aim 1B: Identify all rare, gene-impacting copy number variants (CNVs) genome-wide using the Affymetrix6.0platform (at UCT).

Aim 1C: Characterize the predicted impact of rare mutations identified in Aims 1A and 1B on gene function.

Prioritize candidate genes for Aim 2 based on (i) genes harbouringde novo deleterious mutations in cases but not controls; (ii) genes harbouring putatively deleterious events in more than one case but not controls; (iii) genes with biological relevance for schizophrenia that harbour putatively deleterious mutations in cases but not controls. Using these criteria, we will identify approximately 250 candidate genes to use for genediscoveryin Aim 2.

Aim 2: Characterize the mutational spectra of candidate genes prioritized in Aim 1 in a validation sample of 900 Xhosa individuals with schizophrenia and 900 Xhosa controls.

Create a cRNA oligonucleotide solution capture pool to detect all exonic mutations in every candidate gene identified in Aim 1 (~1.5 MB). Capture, barcode, and multiplex sequence genomic DNA from 900 cases and900 controls. Identify all rare variants and characterize the potential impact of each on protein functioning usingbioinformatic tools.

Aim 3: Identify genes enriched for deleterious mutations in African individuals with schizophrenia.

From the genomic analyses in Aim 2, identify the total burden of rare putatively deleterious mutations in each candidate gene. Identify genes disproportionately disrupted in cases or in controls. Compare the total number and ontogeny profiles of these outlier genes in cases versus controls. In future projects, we will determine the biological impact of candidate mutations on protein function and expression, and examine the mutational spectra of outlier genes in other schizophrenia cohorts.

C. THE POST

This is a one year contract post located in theDivision of Human Genetics, IIDMM, University of Cape Town. This post could possibly be renewed.

D. ROLE OF THE INCUMBENT

The Research Officer will conduct and contribute to the research project with minimal supervision. The candidate should develop research capacity regarding bioinformatics/molecular genetics. S/he will oversee that all relevant information for biological samples is collected, that biological materials are correctly received and processed in the laboratory, and shipped where this is necessary. While having oversight of these operational issues, this person will have extensive knowledge of state-of-the-art molecular genetic technologies, and will have technical and analytical expertise with high throughput technologies (e.g. microarray technology, DNA sequencing) and data analysis. S/he will be responsible for all bioinformatic processing required by the project and the division. S/he will be expected to train other students in bioinformatics.

E. JOB DESCRIPTION

JOB TITLE:Research Officer

AREA: Human Genetics, IIDMM

REPORTS TO: Prof Raj Ramesar, Head of Division

JOB PURPOSE:

To conduct and contribute to the research process with minimal supervision and to continue to develop individual research capacity.

KEY PERFORMANCE AREAS:

  1. Research
  • Collect and manage project data
  • Perform wet lab-based molecular genetics and dry-lab based bioinformatic analyses
  • Conduct research projects related to the project
  • Manage research projects with regard to effective project planning, implementation, co-ordination and data management
  • Process and analyse results from high-throughput DNA analysis
  • Present research findings
  • Co-author peer reviewed publications
  1. Teaching & Learning
  • Undergraduate co-supervision
  • Co-facilitate bioinformatics workshops
  • Support training and development activities
  • Development bioinformatic research capabilities within our own division
  1. Social responsiveness
  • Engage with relevant public entities and stakeholders
  • Translate probable research findings into practice for public benefit under the appropriate supervision
  1. Leadership, Management and Administration
  • Attend and participate in project Management Meetings,
  • Provide and present updated relevant information at meetings
  • Contribute to strategic planning goal setting
  • Communication and liaison between collaborators
  • Support the project director
  • Coordinates the arrival of biological samples containing all the necessary information and ensuring that those samples are shipped to Collaborators in the correct format within the appropriate time frame and according to their specificities

Characteristics of the incumbent

Desirable personal attributes and competencies:

  • The ability to work in a team, foster co-operation between team members, build team spirit, and manage people and co-ordinate their involvement in projects
  • The ability to be innovative, to look for creative solutions to difficult problems, to seek and propose new opportunities and to enhance effectiveness
  • The ability to effect appropriate leadership in the attainment of goals and objectives, express opinions in a constructive and assertive way, sharing information and encouraging feedback
  • The ability to think analytically and independently and aggressively tackle new challenges, breaking down complex tasks into manageable parts in a systematic way

Qualification

MSc degree, preferably PhD degree, in Human Molecular Genetics (or a relevant course pertinent to population and statistical genetics). Bioinformatics knowledge and exposure is an inherent requirement.

Skills and Abilities

  • Bioinformatic analysis (programming would be an advantage)
  • Skills and experience in molecular genetic techniques and technologies
  • Skills and experience in teaching
  • Experience in group facilitation
  • Skills and experience in research methods
  • Excellent communication and writing skills
  • Sound administration skills
  • Computer Literacy and basic data management skills
  • Basic biostatistics knowledge and skills
  • Leadership skills
  • Good interpersonal skills
  • Management skills
  • Sound presentation skills

Experience

  • At least two to three years relevant research experience (this could be concurrent to doing a higher degree)
  • Experience regarding high throughput technologies and data analysis
  • Bioinformatics analysis (programming would be advantageous)

Publications

  • Evidence of contribution to research publications

1