Biology subjects

Manivannan, S. N.

Publications and source records attributed to Manivannan, S. N..

3 recordsLinked to original sources

bioRxiv2026

Deconstructing empirical fitness seascapes across scales of granularity

The fitness landscape metaphor remains resonant in evolutionary theory and has facilitated the birth of newer concepts--like the fitness seascape--that consider the role of environmental context in shaping the dynamics of evolution. Since the emergence of the fitness seascape, it has appeared in several studies that examine how different and fluctuating environments shape evolutionary outcomes. Despite a growing interest in these topics, we lack comprehensive examinations of the role of environmental context in shaping features of fitness seascapes. In this study, we address this gap by deconstructing empirical fitness seascapes across scales of granularity: mutational steps, loci, locus interactions, alleles, trajectories, and entire seascapes. For each, we examine how environmental context influences qualitative and quantitative aspects of seascapes, and find that they change appreciably, with patterns that are specific to individual systems of study. In summary, we reflect on the implications of the seascape metaphor with respect to the incorporation of environmental effects into theoretical population genetics, for understanding how the environment shapes evolution in disease systems, and for contemporary bioengineering excursions.

evolutionary biology↗

bioRxiv2021

Drosophila functional screening of de novo variants in autism uncovers deleterious variants and facilitates discovery of rare neurodevelopmental diseases

Individuals with autism spectrum disorders (ASD) exhibit an increased burden of de novo variants in a broadening range of genes. We functionally tested the effects of ASD missense variants using Drosophila through humanization rescue and overexpression-based strategies. We studied 79 ASD variants in 74 genes identified in the Simons Simplex Collection and found 38% of them caused functional alterations. Moreover, we identified GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in eight previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes point to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.

genetics↗

bioRxiv2020

Precise and programmable C:G to G:C base editing in genomic DNA

Many genetic diseases are caused by single-nucleotide polymorphisms (SNPs). Base editors can correct SNPs at single-nucleotide resolution, but until recently, only allowed for C:G to T:A and A:T to G:C transition edits, addressing four out of twelve possible DNA base substitutions. Here we developed a novel class of C:G to G:C Base Editors (CGBEs) to create single-base genomic transversions in human cells. Our CGBEs consist of a nickase CRISPR-Cas9 (nCas9) fused to a cytosine deaminase and base excision repair (BER) proteins. Characterization of >30 CGBE candidates and 27 guide RNAs (gRNAs) revealed that CGBEs predominantly perform C:G to G:C editing (up to 90% purity), with rAPOBEC-nCas9-rXRCC1 being the most efficient (mean C:G to G:C edits at 15% and up to 37%). CGBEs target cytosine in WCW, ACC or GCT sequence contexts and within a precise two-nucleotide window of the target protospacer. We further targeted genes linked to dyslipidemia, hypertrophic cardiomyopathy, and deafness, showing the therapeutic potential of CGBE in interrogating and correcting human genetic diseases.

synthetic biology↗