Hughes Group: Genome Biology
Molecular biology and the biological sciences in general have undergone a technical revolution over the last decade, due to our ability to sequence and reconstruct an organism's genomic blueprint in its entirety. Subsequent technical advances such as high-throughput sequencing technologies (HTS) allow us to investigate, on the scale of the whole genome, how and in what situations particular parts of that blueprint are actually used. Although the biological questions remain the same as those asked at an individual gene, the methods to generate, analyse and combine these whole-genome data-types are different and require specialist approaches and skills.
A fundamental question in molecular biology is how are specific parts of the genomic blueprint used in specific situations when the underlying genomic sequence is the same in every cell in the body? The most basic expression of a genome's activity is the RNA it produces or "expresses" from genes as messenger RNA (mRNA), which are the templates needed to build particular proteins. Although many mechanisms exist that can alter this gene “expression” it is now known that a class of elements in the genome, often called “regulatory elements” or “enhancers”, are critical controllers of gene activity in every cell. Studying these elements can be very challenging as they are generally only active in the specific cell types where they are needed and they are distributed unpredictably around the genes they control, often at very large genomic distances; hence linking a gene with its functioning regulatory elements is challenging.
Although finding ways of interrogating these systems addresses a fundamental biological question, it also has profound implications for human health. It is now known from comprehensive “Genome-Wide Association Studies” (GWAS) that the sequence variations in each of our genomes that pre-dispose us all to common human diseases likely effect these regulatory elements rather than the genes themselves. It is equally likely that genetic damage to these elements will be a poorly diagnosed cause of heritable diseases.
The Hughes group is expert in a wide range of the genomics methods and technologies that can address different aspects of this question: such as RNA-seq methods, which show whether a gene is expressed or not and at what level; DNase-seq and ATAC-seq, which can generate maps of all of the active elements in the genome; and ChIP-seq, which can assess which types of proteins or chemical modification are found at these elements and so indicate their likely function.
Where suitable approaches are not available, the group develops novel methods such as the Capture-C approaches, which allow thousands of genes to be linked to their regulatory elements in a single assay. Developed with the specific problem of linking GWAS hits to the genes they effect, this assay is the only high resolution Chromatin Conformation Capture (3C) assay that multiplexes both viewpoints and cell samples in a single assay and so maps the interactions between genes and regulatory elements with high throughput, sensitivity and statistical rigour.
Due to the huge amounts of data these technologies generate, the group has an equally large computational component, with many members having expertise in both.