Vatsan Raman

Position title: Assistant Professor

Email: sraman4@wisc.edu

Address:
High-throughput functional assays, variant effect prediction, human and microbial genomics

Research Interests
Understanding and engineering biomolecular and cellular systems using high-throughput and multiplexed functional approaches
Research Fields
Computational systems and synthetic biology, disease biology, functional genomics
Address
Room 441B, 433 Babcock Drive, Madison, WI

Research Description

The goal of our research is to understand and engineer biomolecular and cellular systems by large scale mutational perturbation of genes and genomes coupled to functional screens. We employ and develop different functional screens including massively parallel reporter assays, cellular fitness and single-cell RNA sequencing. These measurements are coupled to a readout based on deep sequencing (Illumina, Pacbio etc) allowing us to easily scale to thousands to millions of mutational perturbations resulting in a comprehensive sequence-function landscape of the biomolecular/cellular system. We apply this principle to three problem areas:

Protein allostery: Allostery is a property of proteins where perturbation at one site of a protein causes a functional effect at a distant site. The study of allostery has a central place in biology due to the myriad roles of allosteric proteins in cellular function. Designing allosteric proteins, such as biosensors, is of high interest in biological engineering to create better enzymes, rewire signaling pathways, build synthetic gene circuits and sense environmental signals.

Using computational protein design and high-throughput mutational scanning, our goal is to understand the general principles of protein structure that underlies allosteric communication at molecular resolution and to design allosteric proteins.

Phage bacterial interactions: Bacteriophages (or “phages”) shape microbial ecosystems by infecting and killing targeted bacterial species. As a result, they are promising tools for treatment of antibiotic resistant bacterial infections and microbiome manipulation. The goal of our bacteriophage research program is to understand the interaction landscape between phages and bacteria by systematic mutational and genome-wide perturbations using high-throughput tools. We are also motivated by phage therapy emerging as a promising alternative to address antibiotic resistance crisis. To bring phages to the forefront of antimicrobials therapies, we have developed a broad technology platform for designing customized phages to kill pathogenic microbes using synthetic biology tools.

Functional genomics of human disease genes: Functional genomic studies to characterize cellular and clinical consequences of genetic variants lags far behind the pace of genome sequencing. Only a very small fraction of the millions of currently catalogued missense mutations in the human genome have functional annotation. Our goal is to use massively parallel reporter assays, single cell RNA sequencing and high-throughput genome editing with deep sequencing to enable pooled assessment of large numbers of genetic variants in parallel in disease relevant human genes, particularly nuclear hormone receptors. This will allow us advance precision medicine by estimating the pathogenicity of SNPs, classifying mutations into phenotypic subgroups and tailor drug screens for each subgroup.

Representative Publications:

Epistasis shapes the fitness landscape of an allosteric specificity switch Nishikawa KK, Hoppe N, Smith R, Bingman C, Raman S https://www.biorxiv.org/content/10.1101/2020.10.21.348920v1
Mapping the functional landscape of the receptor binding domain of bacteriophage T7 by deep mutational scanning Huss P, Meger A, Leander M, Nishikawa K, Raman S https://www.biorxiv.org/content/10.1101/2020.07.28.225284v1
Computation-guided design of split protein systems Dolberg TB*, Meger AT*, Boucher JD, Corcoran WK, Schauer EE, Prybutok AN, Raman S*, Leonard JN* https://www.biorxiv.org/content/10.1101/863530v2
Functional plasticity and evolutionary adaptation of allosteric regulation Leander M, Yuan Y, Meger AT, Cui Q, Raman S Proceedings of the National Academy of Sciences, 2020, 117, 25445-54
Engineered bacteriophages as programmable biocontrol agents Huss P, Raman S Current Opinion in Biotechnology, 2019, 61, 116-121
Design of a transcriptional biosensor for the portable, on-demand detection of cyanuric acid Liu X, Silverman AD, Alam KK, Iverson E, Lucks JB, Jewett MC, Raman S ACS Synthetic Biology, 2020, 9, 84-94
De novo design of programmable inducible promoters Liu X, Gupta STP, Bhimsaria D, Reed JL, Rodriguez-Martinez JA, Ansari AZ, Raman S Nucleic Acids Research, 2019, 47, 10452-10463
A regulatory NADH/NAD+ redox biosensor for bacteria. Liu Y, Landick R, Raman S ACS Synthetic Biology, 2019, 8, 264-273