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Biology subjects

Garvin, M. R.

Publications and source records attributed to Garvin, M. R..

5 recordsLinked to original sources

Telomere-to-telomere assemblies reveal complex adaptive variation of 3-ketoacyl-CoA-synthases in Populus trichocarpa likely driven by helitrons

BackgroundThe model woody plant Populus trichocarpa displays an atypical alkene-diverse wax cuticle likely driven by copy number variation (CNV) of 3-ketoacyl-CoA synthases (KCS), which has been difficult to confirm based on short-read assemblies. New long-read sequencing provides opportunities to develop telomere-to-telomere resources to detect cryptic variation, including CNVs, which are currently missed in traditional analyses. Integrating this information can improve genomic prediction for breeding and provide insights into the evolutionary basis of important traits. ResultsOur analysis of 78 telomere-to-telomere long-read haplotypes identified more than twice as many KCS genes as previously reported, along with numerous intragenic non-synonymous substitutions. Random forest predictive models highlighted the importance of Potri.010G079500 in producing very long chain alkenes; however, its absence did not predict previously reported alkene-deficient phenotypes. Instead, alkene levels are best predicted by the combinations of KCS copies. Amino acid substitutions clustered around ligand and donor binding pockets, suggesting they contribute to differing wax cuticle composition. Finally, each KCS gene and copy was linked to a helitron transposon. A phylogenetic analysis indicates they are the evolutionary mechanism for generating KCS tandem arrays. ConclusionsLong-read sequencing and telomere-to-telomere assembles revealed large-effect loci critical to genetic studies that are unattainable from short-reads. These approaches also have the potential to reveal novel insights into genome structure and function, such as the helitrons identified here. Our results highlight that, given current challenges in annotation and assembly, detailed and focused long-read sequences are key to interpreting complex genomic regions that contain tandem copy number variants.

genomics↗

Clustering the Planet: An Exascale Approach to Determining Global Climatype Zones

We present an exascale approach for producing global scale, high resolution, longitudinally based geoclimate classifications. Using a GPU implementation of the DUO Similarity Metric on the Summit supercomputer, we calculated the pairwise environmental similarity of 156,384,190 vectors of 414,640 encoded elements derived from 71 environmental variables over a 50-year time span at 1km2 resolution. GPU matrix-matrix (GEMM) kernels were optimized for the GPU architecture and their outputs were managed through aggressive concurrent MPI rank CPU communication, calculations, and transfers. Using vector transformation and highly optimized operations of generalized distributed dense linear algebra, calculation of all-vector-pairs similarity resulted in 5.07 x 1021 element comparisons and reached a peak performance of 2.31 exaflops. We demonstrated this method using existing and synthesized climate layers to show how geography can be parsed using high-performance computing. Geoclimate zones are important tools for understanding how environmental variables impact natural systems, particularly for agriculture and conservation with relevance to climate change. Historically, classification systems have been low resolution, based on limited variables, or subjective. To identify climate classes, we clustered DUO outputs at varying stringency, producing 69, 133, 340, and 717 global geoclimate zones. Our approach produced global scale, high resolution, longitudinally informed climate classifications that can be used in precision agriculture, cultivar breeding efforts, and conservation programs.

bioinformatics↗

Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro

In addition to its essential role in viral polyprotein processing, the SARS-CoV-2 3C-like (3CLpro) protease can cleave human immune signaling proteins, like NF-{kappa}B Essential Modulator (NEMO) and deregulate the host immune response. Here, in vitro assays show that SARS-CoV-2 3CLpro cleaves NEMO with fine-tuned efficiency. Analysis of the 2.14 [A] resolution crystal structure of 3CLpro C145S bound to NEMO226-235 reveals subsites that tolerate a range of viral and host substrates through main chain hydrogen bonds while also enforcing specificity using side chain hydrogen bonds and hydrophobic contacts. Machine learning- and physics-based computational methods predict that variation in key binding residues of 3CLpro- NEMO helps explain the high fitness of SARS-CoV-2 in humans. We posit that cleavage of NEMO is an important piece of information to be accounted for in the pathology of COVID-19.

molecular biology↗

The emergence of highly fit SARS-CoV-2 variants accelerated by recombination

The SARS-CoV-2 pandemic recently entered an alarming new phase with the emergence of the variants of concern (VOC) and understanding their biology is paramount to predicting future ones. Current efforts mainly focus on mutations in the spike glycoprotein (S), but changes in other regions of the viral proteome are likely key. We analyzed more than 900,000 SARS-CoV-2 genomes with a computational systems biology approach including a haplotype network and protein structural analyses to reveal lineage-defining mutations and their critical functional attributes. Our results indicate that increased transmission is promoted by epistasis, i.e., combinations of mutations in S and other viral proteins. Mutations in the non-S proteins involve immune-antagonism and replication performance, suggesting convergent evolution. Furthermore, adaptive mutations appear in geographically disparate locations, suggesting that either independent, repeat mutation events or recombination among different strains are generating VOC. We demonstrate that recombination is a stronger hypothesis, and may be accelerating the emergence of VOC by bringing together cooperative mutations. This emphasizes the importance of a global response to stop the COVID-19 pandemic.

evolutionary biology↗

Confronting the COVID-19 Pandemic with Systems Biology

Using a Systems Biology approach, we integrated genomic, transcriptomic, proteomic, and molecular structure information to provide a holistic understanding of the COVID-19 pandemic. The expression data analysis of the Renin Angiotensin System indicates mild nasal, oral or throat infections are likely and that the gastrointestinal tissues are a common primary target of SARS-CoV-2. Extreme symptoms in the lower respiratory system likely result from a secondary-infection possibly by a comorbidity-driven upregulation of ACE2 in the lung. The remarkable differences in expression of other RAS elements, the elimination of macrophages and the activation of cytokines in COVID-19 bronchoalveolar samples suggest that a functional immune deficiency is a critical outcome of COVID-19. We posit that using a non-respiratory system as a major pathway of infection is likely determining the unprecedented global spread of this coronavirus. One Sentence SummaryA Systems Approach Indicates Non-respiratory Pathways of Infection as Key for the COVID-19 Pandemic

systems biology↗