Universität zu Köln

Joshi, Manas ORCID: 0000-0001-9486-0324 (2023). Comparative and population genomics analyses of TF-DNA interactions. PhD thesis, Universität zu Köln.

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Abstract

Molecular biology provides a unique insight into the workings of the evolutionary forces present in nature. As opposed to comparative anatomy, which relies on the structural makeup of species, molecular biology relies on the information contained within the biochemical makeup of the species. One of the salient features of a molecular evolution-based approach is that it relies on observations drawn from the changes occurring within the biomolecules for making inferences on the evolutionary forces in action. The overall makeup of such biomolecules is consistent across species, thus allowing for robust and comparable inferences across distantly related species. In many aspects, these biomolecules could be thought to carry the imprints of evolutionary forces. At the centre of these biomolecules is the DNA molecule, through which the necessary information on the species-specific traits is passed down from the parent generation to the offspring generation. DNA, in the form of genes, also codes for a specialized class of biomolecules, proteins, which are responsible for many functions within the cell, ranging from regulating pathways, aiding in response to pathogens, and controlling the expression of other genes. This transition of genes to proteins is tightly controlled by regulatory machinery that ensures the context-dependent activation of the genes and, consequently, the production of proteins. Hence, natural variants occurring within these regulatory elements could result in differential gene expression patterns and, potentially, alter the transition of genotype to phenotype. Given the central role of this regulatory machinery, it would be expected to be under a stronger influence of the evolutionary forces as compared to the genomic background. This study focused on understanding the impact of a specific evolutionary force, natural selection, on the gene regulatory elements through the perspective of the genetic variants occurring within them. Natural selection could be perceived as a force that confers fitness advantages to individuals based on their genotypic and phenotypic makeup. This study was specifically aimed at understanding the action of natural selection on the regulatory Transcription Factor (TF)- DNA interactions. These regulatory interactions have two motifs: DNA-binding domains (DNABDs), occurring on the TFs, and the Transcription Factor binding sites (TFBSs), occurring on the DNA molecules. The central aim of the study was to elucidate the action of negative/purifying and positive selection acting on these domains through a comparative framework. This study combined population and comparative genomics approaches to quantify the intensity of natural selection acting across two different evolutionary time scales. In the case of the DNABDs, we identified a signal of high constraint consistent across the evolutionary time scales and irrespective of the genomic control regions included in this study. This observation indicated that DNABDs are under an increased intensity of purifying selection, which could be explained by the pleiotropic nature of the TFs. However, we do not observe similar trends when investigating the action of positive selection. Specifically, the intensity of positive selection was observed to be comparatively high for the DNABD regions only in certain populations of species with larger effective population sizes (Ne). In the case of the TFBSs, given that they are primarily a part of the noncoding genome, we developed a summary statistic to quantify the intensity of natural selection that would also be comparable to the summary statistic from the coding regions. On comparing the summary statistics from the coding and noncoding regions, we identify the signal of a comparatively relaxed constraint acting on the TFBS regions compared to the DNABD and other control regions. In addition, we also highlight that, overall, the TFBS are under a reduced influence of positive selection. The signal of reduced constraint and a decreased intensity of positive selection was consistent across the two evolutionary time scales. Overall, by exploring the intensities of selection on the DNABDs and the TFBSs, this study contributes to our understanding of the impact of natural selection acting on the regulatory elements across coding and noncoding regions.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Joshi, Manas m.s.joshi@umg.nl orcid.org/0000-0001-9486-0324 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-703936
Date:	20 April 2023
Place of Publication:	Koeln
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Plant Breeding Research
Subjects:	Natural sciences and mathematics
Uncontrolled Keywords:	Keywords Language Population Genetics English Comparative Genomics English Evolutionary Biology English Regulatory Evolution English Transcription Factors English
Date of oral exam:	20 April 2023
Referee:	Name Academic Title Tsiantis, Miltos Prof Dr Wiehe, Thomas Prof Dr
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/70393