GTB - an online genome tolerance browser.

BACKGROUND: Accurate methods capable of predicting the impact of single nucleotide variants (SNVs) are assuming ever increasing importance. There exists a plethora of in silico algorithms designed to help identify and prioritize SNVs across the human genome for further investigation. However, no tool exists to visualize the predicted tolerance of the genome to mutation, or the similarities between these methods. RESULTS: We present the Genome Tolerance Browser (GTB, http://gtb.biocompute.org.uk ): an online genome browser for visualizing the predicted tolerance of the genome to mutation. The server summarizes several in silico prediction algorithms and conservation scores: including 13 genome-wide prediction algorithms and conservation scores, 12 non-synonymous prediction algorithms and four cancer-specific algorithms. CONCLUSION: The GTB enables users to visualize the similarities and differences between several prediction algorithms and to upload their own data as additional tracks; thereby facilitating the rapid identification of potential regions of interest.

An integrative approach to predicting the functional effects of small indels in non-coding regions of the human genome.

BACKGROUND: Small insertions and deletions (indels) have a significant influence in human disease and, in terms of frequency, they are second only to single nucleotide variants as pathogenic mutations. As the majority of mutations associated with complex traits are located outside the exome, it is crucial to investigate the potential pathogenic impact of indels in non-coding regions of the human genome. RESULTS: We present FATHMM-indel, an integrative approach to predict the functional effect, pathogenic or neutral, of indels in non-coding regions of the human genome. Our method exploits various genomic annotations in addition to sequence data. When validated on benchmark data, FATHMM-indel significantly outperforms CADD and GAVIN, state of the art models in assessing the pathogenic impact of non-coding variants. FATHMM-indel is available via a web server at indels.biocompute.org.uk. CONCLUSIONS: FATHMM-indel can accurately predict the functional impact and prioritise small indels throughout the whole non-coding genome.

Enabling Global Clinical Collaborations on Identifiable Patient Data: The Minerva Initiative.

The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health.

Predicting the Pathogenic Impact of Sequence Variation in the Human Genome.

Sequencing data will become widely available in clinical practice within the near future. Uptake of sequence data is currently being stimulated within the UK through the government-funded 100,000 genomes project (Genomics England), with many similar initiatives being planned and supported internationally. The analysis of the large volumes of data derived from sequencing programmes poses a major challenge for data analysis. In this paper we outline progress we have made in the development of predictors for estimating the pathogenic impact of single nucleotide variants, indels and haploinsufficiency in the human genome. The accuracy of these methods is enhanced through the development of disease-specific predictors, trained on appropriate data, and used within a specific disease context. We outline current research on the development of disease-specific predictors, specifically in the context of cancer research.