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Engineering radiation resistant animals (in C. elegans)

Nature is full of amazing tools which were developed over the course of evolution to help organisms adapt to a wide variety of extreme ecosystems.

One such tool is a tardigrade-unique protein known as DSUP. Some tardigrade species utilize DSUP to prevent double strand breaks due to oxidative stress caused by desiccation.

Coincidentally, DNA damage via oxidative stress is the primary mechanism of DNA damage in radiation exposure. As a result, tardigrades are not only resistant to complete desiccation but also extremely high levels of radiation.

This project aims to test the viability and effectiveness of DSUP expression in C. elegans as a means of increasing their radiation resistance, desiccation resistance, and lifespan.

Hidden gene pathways

So far, thousands of human genes have not been annotated. We are using phylogenetic profiling to connect uncharacterized genes and identify new biological pathways.

We will characterize these genes and pathways in C. elegans and human cell lines.

An example of a gene network based on phylogenetic profiling interacitons
An example of a gene network based on phylogenetic profiling interacitons

Annotating the plant genome using thousands of genomes

We are working on phylogenetic profiling as a platform to group genes by their evolutionary patterns and connect them to known biological processes.

We will use that platform to assign new annotations to genes, especially in plant-related pathways.

   

Enhancing the co-evolution signal in thousands of species (Phylogenetic profiling)

Phylogenetic profiling optimization Phylogenetic profiling is a method for elucidation of gene function based on similarities in evolutionary histories between genes.

We study how to optimize the signal to better identify functional interaction between genes.

We built the CladeOScope web tool to enable all researchers look at co-evolved genes in multiple clades. We also used machine learning to improve the PP signal.

Predicting pathogenic variants (in genetic diseases & breast cancer)

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.


Controlling aging

Ablation of the AGE-1 gene in c. elegans nematodes causes remarkable extension in lifespan.

We investigate AGE-1 gene network, using comparative genomics and data integration, to reveal novel interactors of age-1.

Our working hypothesis is that the AGE-1-interacting network presents a promising opportunity for therapeutic intervention to counter proteotoxicity, which is mechanistically linked to aging.

We plan to test the functional relevance of our identified genes using proteotoxicity model nematodes.

Decoding genetics & treatment of Rett syndrome

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.

Toxic RNA (in neurodegenerative diseases)

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.

Mapping novel DNA repair genes

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

Decoding genetics & treatment of rare diseases

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