Modeling human genetic diseases in worms
The decreasing cost of whole genome sequencing and the push toward personalized medicine is driving an exponential growth in the number of human patients who have their genomes sequenced. As a result, more than 80 million variations in the genome, including single nucleotide polymorphisms, insertions, deletions, and other structural variants have been identified. The challenge is thus twofold: first, to identify which human genetic variations cause disease, and second, to elucidate how, at the molecular and cellular level, the genetic changes cause the diseases. The goal of this project is to generate human disease-associated genetic variations in the orthologous genes of C. elegans.
These variations are a subset of the total variations observed in the human genome because not all human genes have orthologs in worms and the sequence of orthologs is never identical. However, by focusing on variations in amino acids that were conserved over 500 million years of evolution we are biasing our screen toward changes in amino acids that are more likely to be of functional importance.
Despite its relative simplicity, the roundworm C. elegans has proven to be an excellent model for investigating the molecular and cellular basis of many human diseases, including proteinopathies, neurodegenerative, metabolic, muscular atrophy, and kidney-related diseases. CRISPR-Cas9 mediated genome editing works efficiently in C. elegans when Cas9 nuclease, guide RNAs and DNA repair templates are co-injected into the germline.
We work together with geneticists from several hospitals in Israel to examine, in C. elegans, human mutations that were found in unhealthy families and are suspected to be pathological, i.e. to cause disease.