![]() A method for calculating probabilities of fitness consequences for point mutations across the human genome. This paper uses the pathogenicity GERP++ method to give nucleotide and element-level constraint scores from profiling substitution rates in multiple sequence alignments. Identifying a high fraction of the human genome to be under selective constraint using GERP++. This paper uses the PhastCons method to give per-base estimates of negative selection within conserved elements using multiple sequence alignments and hidden Markov models.ĭavydov, E. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. The NIH Roadmap Epigenomics Mapping Consortium. An integrated encyclopedia of DNA elements in the human genome. ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. The UK Biobank resource with deep phenotyping and genomic data. A global reference for human genetic variation. More specifically, we highlight existing methods and key challenges and opportunities in identifying specific disease-causing genetic variants and linking them to molecular pathways and, ultimately, to disease phenotypes.ġ000 Genomes Project Consortium, et al. In this Review, we discuss recent developments in machine learning algorithms for genome interpretation and for integrative molecular-level modelling of cells, tissues and organs relevant to disease. Integrative computational models can leverage these data to understand variant impact, elucidate the effect of dysregulated genes on biological pathways in specific disease and tissue contexts, and interpret disease risk beyond what is feasible with experiments alone. Modern experimental technologies are enabling the generation of massive compendia of human genome sequence data and associated molecular and phenotypic traits, together with genome-scale expression, epigenomics and other functional genomic data. Interpreting the effects of genetic variants is key to understanding individual susceptibility to disease and designing personalized therapeutic approaches. ![]()
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