The focus of my research is to understand the mechanism of incomplete penetrant cancer causing mutations.
Penetrance is defined as the probability that an individual carrying a pathogenic mutation will become sick because of it.
In my research, I apply selective pressure on C. elegans bearing a mutation over many generations.
Desired outcome will be the stabilization of the wild type phenotype for subsequent understanding of the compensatory mechanism. Better understanding of the mechanisms underlying incomplete penetrance will allow clinicians to predict disease onset and severity, and could lead to the development of drugs that mimic the compensatory mechanism.
Predicting the pathogenicity of variants of uncertain significance (VUS) in BRCA is critical for estimating the risk of hereditary breast and ovarian cancer (HBOC).
High level of conservation at a genomic position is a strong predictor for the pathogenicity of variants in this position. However, single nucleotide variants (SNVs) are frequently located at positions with complex conservation patterns, where the nucleotides are sporadically conserved across vertebrates. The meaning of these patterns, their variability among genes, and their association with variant pathogenicity were never assessed.
Here we analysed the conservation patterns of SNVs in 115 disease-associated genes that include BRCA genes, across 99 species, to extract additional information from conservation data.
We developed EvoDiagnostics, a random forest-based model that uses nucleotide conservation patterns and outperforms baselines in predicting variants in BRCA1 (AUC-0.925), BRCA2 (AUC-0.930), and in the entire variant pool of the 115 disease-genes (AUC-0.933). We found that the pathogenicity of variants is better learned from their complex conservation patterns, compared to naïve conservation, and that the conservation of some species is more informative than others in the context of specific genes. Our work characterizes conservation patterns and their variability among genes and species, and highlights the significance of conservation patterns in variant prioritization.
EvoDiagnostics could be either used as a stand-alone prediction tool or as a complementary measurement for ensemble prediction methods.
Inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Rett syndrome (RTT).
Despite extensive research into MECP2 function, no treatments for RTT are currently available. Here we use an evolutionary genomics approach to construct an unbiased MECP2 gene network, using 1,028 eukaryotic genomes to prioritize proteins with strong co-evolutionary signatures with MECP2.
Focusing on proteins targeted by FDA approved drugs led to three promising candidates, two of which were previously linked to MECP2 function (IRAK, KEAP1) and one that was not (EPOR).
We show that each of these compounds has the ability to rescue different phenotypes of MECP2 inactivation in cultured human neural cell types.
Expansions of DNA repeats are a unique hallmark of over 40 neuromuscular degenerative diseases. In the non-coding repeat expansion disorders, the repeats transcribe to long RNAs and cause RNA toxicity. Despite substantial research, there is little understanding of the RNA toxicity mechanism.
My research is focused on a new mechanism by which trinucleotide repeat expansions cause the disease phenotype and maternal bias, through the RNA interference pathway. Furthermore, our experimental data from nematode model animals offers the potential for a first-ever targeted intervention for repeat expansion disorders.
The homologous recombination repair (HRR) pathway is involved in many types of cancer, including breast and ovarian cancers. In this project we used clade-based phylogenetic profiling to identify new HRR genes. We validated their role in HRR in nematodes and in human cell lines. Currently, we are characterizing new HRR genes and validating their role in cancer
In collaboration with clinicians, we are identifying the genetic causes of hereditary diseases using comparative genomics
Pedigree of a family displaying the phenotypic presentation and the NPRL3 ~38‐kb deletion and PDCD10 c.322C>T, p.Arg108* variant genotypes of the sampled individuals
To understand the zoonotic nature of SARS-CoV-2 and identify novel drugs to treat COVID-19, we investigated its entry receptor ACE2. We conducted a systematic analysis of the ACE2 conservation and co-evolution protein network across 1671 eukaryotes, revealing unexpected conservation patterns. We then mapped the co-evolved protein network and identified potential drugs that can target it.
