Malaysia is blessed with a multiracial population that offers diversity at the human genome. In this project, we intend to extend our expertise and improve our capability and capacity in genome-scale analysis of the diverse human genomes of the various ethnic and indigenous groups in Malaysia. Initially we will focus on the human major histocompatibility complex (MHC) loci (4 megabases of DNA sequence). The human MHC loci are important not only in medicine but forensics and anthropology. Extension of this study to other nuclear and mitochondrial sequences will also be carried out. Initial efforts will be focused on using SNP (single nucleotide polymorphism) technology to study schizophrenia and mitochondrial DNA. Later, other common complex diseases such as neurological disorders, cardiovascular diseases, diabetes, obesity, and cancers pertaining to the Malaysian population will be investigated.

Existing evidence leads us to believe that autoimmune diseases such as Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Graves' Disease (GD), and IDDM are essentially polygenic in nature. We have completed preliminary investigations and have published findings that certain types of HLA genes confer susceptibility with high relative risk in various ethnic groups. The current study will allow us to pinpoint, if possible, which exact genes in the human MHC are involved in conferring susceptibility or protection. In addition, much needs to be done in trying to understand the underlying mechanisms of autoimmunity, cell expression, infectious and environmental agents in precipitating different forms of these diseases.

Studies on the HLA genes (and types) are also important in ensuring successful outcome of organ transplants. At present, we do not have sufficient data in Malaysia regarding the HLA types in the multiracial population, hence no HLA database. The HLA database is a prerequisite for active transplantation programmes and is a useful national resource. HLA typing, or tissue typing, is a necessity and currently practiced in stem cell transplant matching.

Recent findings suggest that, apart from HLA, other parts of the genome that lie within the MHC are also important in post-transplant outcome. Our study will include such regions, like the recently discovered MIC and PerB11 genes, and also the polymorphic human endogenous retroviral sequence (HERVs), to characterise their possible role in autoimmune and non-autoimmune diseases.

In recent years, DNA sequences have been used as an informative source for human identification and in anthropological studies. As an extension of our studies on nuclear and mitochondrial markers, we propose to determine the human Y-STR haplotypes in Malaysia. Later Y-chromosome SNP will also be carried out.

Project Title:

Analyses of Human Genomic Diversity in the Malaysian Population for
Potential Medical and Forensic Applications

 

In preparation for gene therapy in humans, we propose to investigate Escherichia coli-based linear artificial chromosome (LAC) vectors for delivery of human genomic loci into mammalian cells by using an invading E. coli vector system.

Furthermore, to initiate genome-based stem-cell research in Malaysia, we propose to investigate genes activated during the differentiation of haematopoietic stem cells.

In summary, the objectives of this project are:

· To investigate the human MHC and identify genes and human endogenous retroviral elements (HERVs) involved in autoimmune diseases
· To elucidate important genomic regions and develop improved technology for transplantation
· To characterise the structure, properties, and sequence diversity of polymorphic retroviral elements (HERVs) within the MHC
· To elucidate single nucleotide polymorphisms (SNPs) within the human MHC associated with diseases and within other regions (nuclear and mitochondrial) for disease association (e.g., schizophrenia) and forensic applications
· To determine human Y-STR haplotypes and Y-chromosome SNP in Malaysia
· To catalogue the data obtained and to develop relevant databases with the view towards developing a national resource
· To generate national sequence polymorphism databases for use in forensics and anthropological studies
· To develop Escherichia coli-based linear artificial chromosome (LAC) vectors for delivery of human genomic loci into mammalian cells by using an invading E. coli vector system
· To investigate genes activated during the differentiation of haematopoietic stem cells

Period of the project : 3 Years (2001 - 2004)

Achievements

Progress/Achievements for year one

- Nill

Project Status

- On-going