Ting Wu (Professor, Department of Genetics, Harvard Medical School) joined us at the Festival of Genomics and Biodata 2021 to discuss ultraconserved elements and how developments in genome imaging, such as in situ sequencing, are helping us to understand the complexity of the genome.
Under the radar
Wu began her talk by discussing her fascination with the mystery behind ultraconserved elements within the human genome. Despite initial beliefs that these regions did not exist, in 2004, Bejerano et al surprisingly identified 481 segments > 200 base pairs that were absolutely conserved between regions of the human, rat and mouse genomes. In fact, within all of our genomes there are sequences that essentially haven’t changed for 3-5 hundred million years since before mammals, birds and reptiles diverged. Shockingly, we still don’t know what they do! These regions, as Wu described, them are unique. But there are currently no known unique functions for these regions that demand this level of conservation. Wu went on to demonstrate that these ultraconserved elements are distributed across the entire genome which she believes is telling us that the genome works as an integrated unit.
Wu’s team use a particular model for explaining ultraconserved elements that argues that when the maternal and paternal chromosomes pair up, any mutations that arise cause the genome to buckle. This leads to cell death, disease or reduced fertility and as a result, gives rise to ultraconserved elements. Wu described that if you take the genome and compile all breakpoints from healthy individuals, there will be places where breakpoints don’t occur. The team found that these regions are enriched for ultraconserved elements. However, if you get a break, this will incur disease, which the team observed within individuals with cancer and neurodevelopmental disorders. Wu’s team believe that ultraconserved elements protect the regions around them. Wu emphasised that if their model is correct, understanding how they protect the regions around them will provide us with another way of protecting ourselves from diseases (like cancer) before they manifest.
Imaging the genome
Imaging of the genome enables the acquisition and analysis of cells at the individual level while also providing direct visualisation and analysis of the 3D genome organisation. Wu discussed the development of Oligopaints – which are highly efficient, renewable, strand-specific fluorescence in situ hybridisation (FISH) probes. This method, developed by Beliveau et al, enables single and multicolour imaging of genomic regions. Several developments of this method have since emerged, which have made them sensitive to SNPs. This has allowed researchers to distinguish between maternal and paternal chromosomes. Wu discussed several research papers that have explored the interaction of maternal and paternal chromosomes with the integration of CHIP-seq to identify epigenetic marks on the surface of the genome. From these developments, it has become apparent that the genome is an in fact an object with a surface and is also hugely dynamic.
Additionally, Wu’s team also recently combined Oligopaints with FISSEQ (OligoFISSEQ) to enable the rapid visualisation of many targeted genomic regions. This approach enables visualisation of hundreds to potentially thousands of genomes at the same time under the microscope. The advantage of this approach is that it vastly increases the number of targets that can be visualised, putting us within reach of genome-wide imaging. The team also combined OligoFISSEQ with OligoSTORM which lays the foundation for accelerated single-molecule super-resolution imaging of large genomic regions (Figure 1).
When questioned what the value of this research is, Wu stated that “the genome is beautiful, and we really hardly know it”. She explained that while it was previously thought that individual experiences cannot be passed onto progeny, it is now suspected that the way the genome folds can in fact provide us with insight into disease. In addition, she noted that we currently diagnose based on symptoms or identify the cause based on a protein that has gone wrong, but actually identifying that first step is critical. She explained that only by looking for that first step can we intervene before the disease manifests.
Registration for on-demand access to watch this talk and all our other talks from the Festival will end on February 12th. Register now.