Biology subjects

Larijani, M.

Publications and source records attributed to Larijani, M..

5 recordsLinked to original sources

bioRxiv2026

Exon Targeted Retrieval and Classification Toolbox (ExTRaCT): a gene search pipeline to find APOBEC3 Z-domains in novel bat genomes

MotivationSeveral computation gene search tools exist to identify and annotate an ever-growing body of newly sequenced genomes of different species. Many annotation tools, however, fall short when the target species diverges from well-studied model organisms, and when searching for short genes with multiple copies. ResultsWe have developed the Exon Targeted Retrieval and Classification Toolbox, ExTRaCT, an automated pipeline to identify any gene exon with conserved structure in novel species genome assemblies. In the use cases presented here, we applied our search tool to 102 bat genomes to find APOBEC3 gene family members. We show that our homolog search algorithm is efficient (run time average of 5 hours for over 100 genomes), works well with reference sequences distantly related to the target (1 out of 498 misclassifications, 0 false positives and 2 false negatives), and is easy to use. As genomic sequencing becomes faster and more accessible, ExTRaCT has downstream applications in phylogenetic, biochemical and genomic studies. It is a simple computational tool that provides a solution to target gene identification, requiring neither whole-genome-assembly annotations, nor prior knowledge of closely related species. Availabilityhttps://doi.org/10.5281/zenodo.15769018 ContactBrenda.delamonica@stonybrook.edu Supplementary informationSupplementary data are available at Bioinformatics online.

genomics↗

bioRxiv2025

AID/APOBEC3 Dynamic Catalytic Pockets and AID-α7 Regulation Mechanisms

AID/APOBEC3s mutate dC to dU in ssDNA in the restriction of viruses, creation of anti-bodies, and when off-target affecting cancers. Little was known of the catalytic pocket dynamics of these enzymes in real time. As such, we utilised molecular dynamics analyses to determine catalytic pocket volumes and states. We found that most AID/APO-BECs remain predominantly in either a closed or indeterminate state to varying degrees while A3G-CD2 is predominantly open. This occurs chiefly from the catalytic residues themselves and the loop 1 serine/threonine in the "floor" of the catalytic pocket while other residues of the secondary catalytic loops 1, 3, 5, and 7 aid in these states. Surprisingly, we found that the presupposed stable position of AIDs unique 7 ({beta}-state) in contact with the {beta}-sheet and 6 was unstable while the -state in contact with 6 and loop7 was stable and caused pocket closure. Mutations could cause the destabilisation of the -state (R171Y and R178D) or stabilisation of the {beta}-state (R190D and R194A). Thus, pocket states are relatively similar in overall cause; however, multiple residues from secondary catalytic loops as well as AID-7 determine the rates at which these states occur, potentially affecting the chances any AID/APOBEC is able to have catalysis.

biochemistry↗

bioRxiv2024

Human and bats genome robustness under COSMIC mutational signatures

Carcinogenesis is an evolutionary process, and mutations can fix the selected phenotypes in selective microenvironments. Both normal and neoplastic cells are robust to the mutational stressors in the microenvironment to the extent that secure their fitness. To test the robustness of genes under a range of mutagens, we developed a sequential mutation simulator, Sinabro, to simulate single base substitution under a given mutational process. Then, we developed a pipeline to measure the robustness of genes and cells under those mutagenesis processes. We discovered significant human genome robustness to the APOBEC mutational signature SBS2, which is associated with viral defense mechanisms and is implicated in cancer. Robustness evaluations across over 70,000 sequences against 41 signatures showed higher resilience under signatures predominantly causing C-to-T (G-to-A) mutations. Principal component analysis indicates the GC content at the codons wobble position significantly influences robustness, with increased resilience noted under transition mutations compared to transversions. Then, we tested our results in bats at extremes of the lifespan-to-mass relationship and found the long-lived bat is more robust to APOBEC than the short-lived one. By revealing robustness to APOBEC ranked highest in human (and bats with much more than number of APOBEC) genome, this work bolsters the key potential role of APOBECs in aging and cancer, as well as evolved countermeasures to this innate mutagenic process. It also provides the baseline of the human and bat genome robustness under mutational processes associated with aging and cancer. HighlightsO_LISinabro, the sequential mutation simulator, facilitates measuring the robustness of human protein-coding sequences under all COSMIC mutational signatures. C_LIO_LIRobustness under APOBEC mutational signatures showed the largest mean and standard deviation in the human genome. C_LIO_LIRobustness to mutational signatures analysis reveals the role of APOBECs is complementary to cancer in the evolvability of cancer cells in later stages. C_LIO_LIPrincipal component analysis indicates that the GC content at the codons wobble position significantly influences robustness. C_LIO_LIA long-lived bat (Myotis myotis) has higher robustness to APOBECs than a short-lived one (Molossus molossus) than humans. C_LI

genomics↗

bioRxiv2024

Composite impact of genome-wide APOBEC mutations and HLA haplotype on cancer immunogenicity has a sex-biased survival impact

APOBEC3A and APOBEC3B genome mutators drive tumor evolution and drug resistance but may also generate neoepitopes for cytotoxic T cells (CTL). Given the extensive polymorphism of Class I HLA, the CTL immunopeptidome, comprised of all 8-11mer peptides presented by an individuals six HLA class I alleles, varies person-to-person. We predicted the genome-wide impact of APOBEC3A/B-driven mutations on the immunogenicity of the immunopeptidomes of several thousand class I HLA alleles. Analysis of several billion APOBEC3-mediated mutations revealed that HLA class I alleles vary markedly in the susceptibility of their immunopeptidome to mutations. A subset of alleles of A1-A3 and B44 supertype supported increased neoepitopes. Notably, the immunogenicity changes supported by an individuals HLA class I alleles in response to APOBEC3 mutations predict survival in APOBEC3-mutated tumors and correlate with CTL activation. Thus, immunogenicity changes mediated by APOBEC3s impact survival, making HLA class I genotype a prognostic marker in APOBEC3-mutated tumors.

cancer biology↗

bioRxiv2023

Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes

APOBEC3, an enzyme subfamily that plays a role in virus restriction by generating mutations at particular DNA motifs or mutational "hotspots," can drive viral mutagenesis with host-specific preferential hotspot mutations contributing to pathogen variation. While previous analysis of viral genomes from the 2022 Mpox (formerly Monkeypox) disease outbreak has shown a high frequency of C>T mutations at TC motifs, suggesting recent mutations are human APOBEC3-mediated, how emerging monkeypox virus (MPXV) strains will evolve as a consequence of APOBEC3-mediated mutations remains unknown. By measuring hotspot under-representation, depletion at synonymous sites, and a combination of the two, we analyzed APOBEC3-driven evolution in human poxvirus genomes, finding varying hotspot under-representation patterns. While the native poxvirus molluscum contagiosum exhibits a signature consistent with extensive coevolution with human APOBEC3, including depletion of TC hotspots, variola virus shows an intermediate effect consistent with ongoing evolution at the time of eradication. MPXV, likely the result of recent zoonosis, showed many genes with more TC hotspots than expected by chance (over-representation) and fewer GC hotspots than expected (under-representation). These results suggest the MPXV genome: 1) may have evolved in a host with a particular APOBEC GC hotspot preference, 2) has inverted terminal repeat (ITR) regions -which may be exposed to APOBEC3 for longer during viral replication- and longer genes likely to evolve faster, and therefore 3) has a heightened potential for future human APOBEC3-meditated evolution as the virus spreads in the human population. Our predictions of MPXV mutational potential can both help guide future vaccine development and identification of putative drug targets and add urgency to the task of containing human Mpox disease transmission and uncovering the ecology of the virus in its reservoir host.

bioinformatics↗