TEMPLE: analysing population genetic variation at transcription factor binding sites

Stefan Jean Laurent, Maria Litovchenko
Wiley-Blackwell, 2016
Journal paper

Abstract

Genetic variation occurring at the level of regulatory sequences can affect phenotypes and fitness in natural populations. This variation can be analysed in a population genetic framework to study how genetic drift and selection affect the evolution of these functional elements. However, doing this requires a good understanding of the location and nature of regulatory regions and has long been a major hurdle. The current proliferation of genomewide profiling experiments of transcription factor occupancies greatly improves our ability to identify genomic regions involved in specific DNA-protein interactions. Although software exists for predicting transcription factor binding sites (TFBS), and the effects of genetic variants on TFBS specificity, there are no tools currently available for inferring this information jointly with the genetic variation at TFBS in natural populations. We developed the software Transcription Elements Mapping at the Population LEvel (TEMPLE), which predicts TFBS, evaluates the effects of genetic variants on TFBS specificity and summarizes the genetic variation occurring at TFBS in intraspecific sequence alignments. We demonstrate that TEMPLE's TFBS prediction algorithms gives identical results to PATSER, a software distribution commonly used in the field. We also illustrate the unique features of TEMPLE by analysing TFBS diversity for the TF Senseless (SENS) in one ancestral and one cosmopolitan population of the fruit fly Drosophila melanogaster. TEMPLE can be used to localize TFBS that are characterized by strong genetic differentiation across natural populations. This will be particularly useful for studies aiming to identify adaptive mutations. TEMPLE is a java-based cross-platform software that easily maps the genetic diversity at predicted TFBSs using a graphical interface, or from the Unix command line.

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Stefan Jean Laurent, Maria Litovchenko
Wiley-Blackwell, 2016
Journal paper

Abstract

Official source

https://infoscience.epfl.ch/record/223171?ln=en

About this result

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Public Library of Science2012

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EPFL2013

Evolution can be described as the change of allele frequencies over time. Four forces - mutation, migration, genetic drift, and selection, drive this change. The aim of my thesis was to accurately estimate and differentiate the parameters governing each of these four mechanisms by utilizing various types of Next-Generation Sequencing datasets. More specifically, in chapters 1 and 2, I focused on investigating how the past demographic history of African and European D. melanogaster affected its genomic polymorphism. Modern genomes of flies carry signatures of past events such as migration to new regions, adaptation to new environments, and population size changes. By studying whole genome sequences of 29 wild strains from West Africa, 14 from Sweden and comparing them with genomes from Zambia (the putative ancestral range of the species), we were able to report for the first time, colonization time of the Western part of the African continent at approximately 72k years ago. Additionally, we demonstrated the importance of gene flow between the two populations, as well as, current and past effective population sizes. Our estimations confirmed already published predictions (Current Zambian and Swedish population size, ancestral African population size). Finally, we demonstrated the importance of inversions when accounting for demographic events of D. melanogaster. In chapter 3 of my thesis, I evaluated the importance of selection acting on the DNA-binding residues of the biggest family of transcription factors in the primates, namely KRAB-ZF genes. We were able to demonstrate the existence of two distinct sub-groups, based on the type of polymorphism (synonymous or not) carried by the DNA-contacting nucleotides. The two groups of genes differ by their expression breadth and intensity, as well as at the number of paralogs and orthologs and their evolutionary age. Additionally, we manually annotated the complete catalog of human KRAB-ZF genes, thereby providing a valuable resource for further investigation of this family of genes. In conclusion, the work carried during my thesis enabled to refine the evolution and demography of D. melanogaster African and Northern European populations, underlying the importance of modelling migration flows between populations for accurate estimation of split time. The second component of my thesis demonstrated the applicability of transcriptomics and epigenomics datasets to study evolution of the KRAB-ZF family. The proposed methodologies are applicable to other transcription factor gene families and our manually curated dataset is relevant to other scientists deciphering the function of these genes.

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EPFL2013

EPFL2018