Bioinformatics and Genomics Technologies in the Analysis of Human Genome Diversity and Disease

The human genome contains ~30,000 genes that together encode mankind’s ‘blueprint for life'. However, the detailed content of ‘the genome’ differs quite considerably between individuals. Many million single nucleotide polymorphisms (SNPs) distinguish one person’s DNA from that of another, along with thousands of very small to very large regions of structural variability and copy number variation (CNV) that affect genes and their intervening sequences. Chemical modifications of these sequences also occur, adding an additional layer of variability. All this variability contributes to making each person unique in their appearance and behavior, as well as in terms of the diseases they suffer and how they react to drugs.

Across the globe, major research projects endeavor to elucidate the biological mechanisms of action of genetic variation, and increasingly genome sequences are being tested in healthcare settings to inform diagnostic, prognostic and therapeutic approaches. This is especially true for rare inherited genetic disorders. Increasingly these efforts are using modern ‘next-generation sequencing’ (NGS) technologies that enable a whole genome to be sequenced within timeframes and budgets barely imaginable just a few years ago.

However, to benefit from the many opportunities raised by these advanced research and healthcare approaches, a range of new challenges must be met in terms of achieving effective data and knowledge management (capture, quality, storage, integration, analysis, discovery, sharing, visualisation), creating good informatics tools (standards, processing, databasing, utilisation) and information control (ethics, legalities, consent, sanctions). Furthermore, to be truly useful the devised solutions have to accommodate a diversity of approaches and constraints across nations, and the different requirements of research and healthcare settings.

Our laboratory program therefore has two areas of focus:

1) By local efforts and international collaboration, we explore previously unknown structural characteristics of the human genome, innovate new technologies for genome analysis, and investigate how the genome varies in normal and disease contexts.

2) We work within, often in a leadership capacity, major international consortia seeking to devise informatics solutions that will enable efficient and appropriate use of biomedical data and knowledge, especially aiming to bi-directionally bridge the divide between research and healthcare.

Wet-lab projects (as of September 2014) include:

• Transferring the Dynamic Allele-Specific Hybridisation (DASH) method onto micro-arrays, as a highly robust and generic method for targeted and quantitative DNA Diagnostics. This system tracks DNA melting in real time, thereby quickly and cost-effectively detecting all sequence variants down to 1% representation in all sequence contexts by means of standardised run conditions

• Using a range of advanced methods to characterise the melting behavior of the genome, in particular to create a high resolution map of regions that do not fully denature even at 130 degrees Celcius and which are consequently difficult or impossible to examine by standard procedures.

• Characterising a particular class of genome structural variation that is created in populations by a mutation process called ‘non-alleleic homologous recombination’. Importantly, we have shown these sequences are enriched for disease predisposing genes which consequently vary in copy number between individuals, and thereby we have found a possible major genetic contributor (giving many fold increased risk) to disease traits such as arthritis, dementia, and cancer, as well as normal differences such as heart rate.

Bioinformatics projects (as of September 2014) include:

• Developing new tools and strategies (Café Variome, OmicsConnect, eDAS) that will facilitate the comprehensive ‘discovery’ of where data or knowledge of interest exists when such data cannot be openly exposed (e.g., private patient data, sensitive commercial data, unpublished information). Particular use cases being explored include diagnostics and research pertaining to Rare Disease, connecting biobank datasets, cohort creation for clinical trials, and pre-competitive collaboration between pharmaceutical companies.

• Running the world’s largest open access Genome Wide Association Study database, ‘GWAS Central’, which provides a centralized compilation of summary level findings from all published genetic association studies, both large and small.

• Undertaking data collection and knowledge management for translational research consortia REQUITE and COPD-MAP.


Research Links

Search PubMed at the US National Library of Medicine for this author: Prof A. Brookes
Search Leicester Research ArchiveProf A. Brookes
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