Biology subjects

Iyengar, B. R.

Publications and source records attributed to Iyengar, B. R..

9 recordsLinked to original sources

bioRxiv2026

Structure can emerge from disorder under neutral evolution

Mutations are often thought to destabilize protein structures. However, many proteins are naturally unstructured and the effect of mutations on such proteins especially in the absence of selection, remains unclear. Here, we develop a computational model to study the effects of mutations on structural disorder in both random and natural sequences, including those derived from evolutionary conserved proteins, and evolutionarily novel de novo proteins. We find that while structured proteins tend to lose structure, unstructured proteins exhibit the opposite trend, becoming more structured in the absence of directional selection. This bidirectional dynamics is robust to mutation biases, genetic code structure, and sequence origin, suggesting that it arises from the topology of the sequence-structure landscape rather than intrinsic directional mechanisms. Our results are consistent with a diffuse landscape in which structured and disordered sequences are interspersed throughout sequence space. These findings suggest that neutral evolution can result in structure formation and may facilitate the early structural evolution of de novo proteins prior to strong selection.

evolutionary biology↗

bioRxiv2024

In search for multifunctional lncRNAs

Long non-coding RNAs (lncRNAs) were so named because at the time of their discovery, no corresponding protein products were known. Despite the lack of evidence for translation, many lncRNAs perform essential cellular functions such as regulation of gene expression. Recent studies show that many lncRNAs, including those with known regulatory functions, bind to ribosomes and are translated, suggesting that RNAs can perform two different kinds of functions (a phenomenon known in proteins, called moonlighting). Using a formal mathematical model, I show that execution of one function limits that of the other. However, an RNA can transition from one function to the other, simply by a spatiotemporal regulation of its interacting partners. I further studied the properties of proteins encoded in functional human lncRNAs and found that many of them have complex sequences, and some of them can even adopt stable 3D structures. These findings may encourage further exploration of moonlighting lncRNAs, their regulation, and their role in the evolution of new protein coding genes.

evolutionary biology↗

bioRxiv2024

De novo ORFs are more likely to shrink than to elongate during neutral evolution.

For protein coding genes to emerge de novo from a non-genic DNA, the DNA sequence must gain an open reading frame (ORF) and the ability to be transcribed. The newborn de novo gene can further evolve to accumulate changes in its sequence. Consequently, it can also elongate or shrink with time. Existing literature shows that older de novo genes have longer ORF, but it is not clear if they elongated with time or remained of the same length since their inception. To address this question we developed mathematical model of ORF elongation as a Markov-jump process, and show that ORFs tend to keep their length in short evolutionary timescales. We also show that if change occurs it is likely to be a truncation. Our genomics and transcriptomics data analyses of seven Drosophila melanogaster populations is also in agreement with the models prediction. We conclude that selection could facilitate ORF length extension that may explain why longer ORFs were observed in old de novo genes in studies analysing longer evolutionary time scales. SignificanceNew protein coding genes can emerge from non-genic DNA through a process called de novo gene emergence. Genes thus emerged usually have a small open reading frame (ORF). However, studies show that de novo genes with an older evolutionary origin have longer ORF than younger genes. To understand how ORF length evolves, we use a combination of mathematical modeling and population level genome data analysis. We find that in the absence of evolutionary selection, ORFs tend to become shorter than becoming longer. Therefore, long ORFs are probably selected by evolution to be retained in the genome.

evolutionary biology↗

bioRxiv2023

A direct experimental test of Ohno's hypothesis

Gene duplication drives evolution by providing raw material for proteins with novel functions. The oldest and historically most influential hypothesis about the evolutionary fate and potential of duplicated genes has been proposed by Susumu Ohno in 1970. This hypothesis essentially posits that gene duplication can help genes tolerate new mutations and thus facilitates the evolution of new phenotypes. Competing hypotheses argue that deleterious mutations will usually inactivate gene duplicates too rapidly for Ohnos hypothesis to work. Here, we provide a first direct experimental test of Ohnos hypothesis. Specifically, we evolved one or exactly two copies of a gene encoding a fluorescent protein in Escherichia coli through multiple rounds of mutagenesis and selection. We then analyzed the genotypic and phenotypic evolutionary dynamics of the evolving populations through high-throughput DNA sequencing, biochemical assays, and engineering of selected variants. In support of Ohnos hypothesis, populations carrying two gene copies displayed higher mutational robustness than those carrying a single gene copy. As a consequence, the double-copy populations experienced relaxed purifying selection, evolved higher phenotypic and genetic diversity, carried more mutations and accumulated combinations of key beneficial mutations earlier. However, their phenotypic evolution was not accelerated, possibly because one gene copy rapidly became inactivated by deleterious mutations. Our work provides an experimental platform to test models of evolution by gene duplication, and it supports alternatives to Ohnos hypothesis that point to the importance of gene dosage.

evolutionary biology↗

bioRxiv2023

How antisense transcripts can evolve to encode novel proteins

Protein coding features can emerge de novo in non coding transcripts, resulting in emer- gence of new protein coding genes. Studies across many species show that a large frac- tion large fraction of evolutionarily novel non-coding RNAs have an antisense overlap with protein coding genes. The open reading frames (ORFs) in these antisense RNAs could also overlap with existing ORFs. In this study, we investigate how the evolution an ORF could be constrained by its overlap with an existing ORF in three different read- ing frames. Using a combination of mathematical modeling and genome/transcriptome data analysis in two different model organisms, we show that antisense overlap can increase the likelihood of ORF emergence and reduce the likelihood of ORF loss, es- pecially in one of the three reading frames. In addition to rationalising the repeatedly reported prevalence of de novo emerged genes in antisense transcripts, our work also provides a generic modeling and an analytical framework that can be used to under- stand evolution of antisense genes.

evolutionary biology↗

bioRxiv2023

Neutral models of de novo gene emergence suggest that gene evolution has a preferred trajectory

New protein coding genes can emerge from genomic regions that previously did not contain any genes, via a process called de novo gene emergence. To synthesize a protein, DNA must be transcribed as well as translated. Both processes need certain DNA sequence features. Stable transcription requires promoters and a polydenylation signal, while translation requires at least an open reading frame (ORF). We develop mathematical models based on mutation probabilities, and the assumption of neutral evolution, to find out how quickly genes emerge and are lost. We also investigate the effect of the order by which DNA features evolve, and if sequence composition is biased by mutation rate. We rationalize how genes are lost much more rapidly than they emerge, and how genes with long ORFs preferentially arise in regions that are already transcribed. Our study not only answers some fundamental questions on the topic of de novo emergence but also provides a modeling framework for future studies.

evolutionary biology↗

bioRxiv2021

GroEL/S helps purge deleterious mutations and reduce genetic diversity during adaptive protein evolution

Chaperones are proteins that help other proteins fold. They also affect the adaptive evolution of their client proteins by buffering deleterious mutations and increasing the genetic diversity of evolving proteins. We study how the bacterial chaperone GroE (GroEL + GroES) affects the evolution of green fluorescent protein (GFP). To this end we subjected GFP to multiple rounds of mutation and selection for its color phenotype in four replicate E. coli populations, and studied its evolutionary dynamics through high-throughput sequencing and mutant engineering. We evolved GFP both under stabilizing selection for its ancestral (green) phenotype, and to directional selection for a new (cyan) phenotype. We did so both under low and high expression of the chaperone GroE. In contrast to prevailing wisdom, we observe that GroE does not just buffer but also helps purge deleterious mutations from evolving populations. In doing so, GroE helps reduce the genetic diversity of evolving populations. In addition, it causes phenotypic heterogeneity in mutants with the same genotype, potentiating their effect in some cells, and buffering it in others. Our observations show that chaperones can affect adaptive evolution through more than one mechanism. HighlightsO_LIGroE reduces genetic diversity C_LIO_LIGroE potentiates the effect of deleterious mutations C_LIO_LIGroE intensifies purifying selection and leads to higher activity of client proteins C_LI

evolutionary biology↗

bioRxiv2018

Identification of novel circadian transcripts in the zebrafish retina

High fecundity, transparent embryos for monitoring the rapid development of organs and the availability of a well-annotated genome has made zebrafish a model organism of choice for developmental biology and neurobiology. This vertebrate model, a favourite in chronobiology studies, shows striking circadian rhythmicity in behaviour. Here, we identify novel genes in the zebrafish genome, which shows their expression in the zebrafish retina. We further resolve the expression pattern over time and assign specific novel transcripts to the retinal cell type, predominantly in the inner nuclear layer. Using chemical ablation and free run experiments we segregate the transcripts that are rhythmic when entrained by light from those that show sustained oscillations in the absence of external cues. The transcripts reported here with rigorous annotation and specific functions in circadian biology provide the groundwork for functional characterisation of novel players in the zebrafish retinal clock.

neuroscience↗

bioRxiv2018

Intronic non-coding RNAs within ribosomal protein coding genes can regulate biogenesis of yeast ribosome

The genome of the budding yeast (Saccharomyces cerevisiae) has selectively retained introns in ribosomal protein coding genes. The function of these introns has remained elusive in spite of experimental evidence that they are required for the fitness of yeast. Here, we computationally predict novel small RNAs that arise from the intronic regions of ribosomal protein (RP) coding genes in Saccharomyces cerevisiae. Further, we experimentally validated the presence of seven intronic small RNAs (isRNAs). Computational predictions suggest that these isRNAs potentially bind to the ribosomal DNA (rDNA) locus or the corresponding rRNAs. Several isRNA candidates can also interact with transcripts of transcription factors and small nucleolar RNAs (snoRNAs) involved in the regulation of rRNA expression. We propose that the isRNAs derived from intronic regions of ribosomal protein coding genes may regulate the biogenesis of the ribosome through a feed-forward loop, ensuring the coordinated regulation of the RNA and protein components of the ribosomal machinery. Ribosome biogenesis and activity are fine-tuned to the conditions in the cell by integrating nutritional signals, stress response and growth to ensure optimal fitness. The enigmatic introns of ribosomal proteins may prove to be a novel and vital link in this regulatory balancing act.

bioinformatics↗