Evolution of regulatory networks associated with traits under selection in cichlids

Abstract

Seminal studies in vertebrate protein evolution concluded that gene regulatory changes likely drive anatomical innovations. Even in the unparalleled East African cichlid fish radiation, we demonstrate cis-regulatory divergence as a contributor to phenotypic diversity. To further investigate this mechanism, we extended the Arboretum algorithm, initially designed for yeast adaptation to study the evolution of regulatory expression divergence in complex vertebrate species. For the first time, we reconstruct tissuespecific gene regulatory networks underpinning evolutionary adaptations from multiple vertebrate species in a phylogeny. Our framework consists of identifying ancestral reconstructed and extant species gene co-expression modules and integrating their associated regulators to investigate gene regulatory network evolution contributing to traits of phenotypic diversity in the East African cichlids. Along the phylogeny, we identify tissue-specific co-expression patterns across six tissues of five cichlids species that were predicted to be regulated by divergent suites of regulators. We report striking cases of rapid network rewiring for adaptive trait genes, such as the visual system. In regulatory regions of visual opsin genes e.g. sws1, in vitro assays confirm that single nucleotide polymorphisms (SNPs) in transcription factor binding sites (TFBSs) have driven network rewiring between species sharing the same visual palette. SNPs overlapping TFBSs segregate according to phylogeny and ecology suggesting ecotype-associated network rewiring in East African cichlid radiations. Our unique integrative approach inferring multispecies regulatory networks allowed us to identify regulatory changes associated with traits of phenotypic diversity in radiating cichlids.These species occupy a large diversity of ecological niches and differ dramatically in phenotypic traits, including skeletal morphology, dentition, color patterning, and a range of behavioral traits. Such explosive phenotypic diversification of East African cichlids is unparalleled among vertebrates making cichlid fishes an ideal model to investigate the evolution of gene regulatory networks associated with phenotypes under selection.Sequencing and analyses of representative East African cichlid genomes and transcriptomes suggested that bursts of gene duplication events combined with the rapid evolution of regulatory elements and selected protein coding genes contributed to evolutionary innovations 17 . This, coupled with low levels of nucleotide diversity between cichlid species pairs (Lake Malawi cichlids, 0.1-0.25%) 18 , implies high impact of low level regulatory sequence divergence to gene expression diversity. This likely fuels GRN rewiring, serving as a substrate for the evolution of phenotypic diversity in cichlids.To investigate the functional implications of changes in gene regulation on phenotypic and ecotypic diversity in cichlids, we developed a framework to characterize changes in gene regulation at the sequence, regulatory edge, expression and...

microRNA profiling in the Weddell seal suggests novel regulatory mechanisms contributing to diving adaptation

“…Recent studies in vertebrates have highlighted expression divergence between vertebrate lineages, and the crucial role of gene regulation in the evolution of adaptive phenotypes [70][71][72][73][74][75][76]. The short sequence of a miRNA can quickly be gained or lost in an evolutionary lineage, possibly leading to the rapid acquisition of novel regulatory patterns.…”

High performance single-cell gene regulatory network inference at scale: The Inferelator 3.0

“…Learning the true regulatory network that connects regulatory TFs to target genes is a key problem in biology (Thompson et al, 2015;Chasman et al, 2016). Determining the valid GRN is necessary to explain how mutations that cause gene dysregulation lead to complex disease states (Hu et al, 2016), how variation at the genetic level leads to phenotypic variation (Mehta et al, 2021;Peter and Davidson, 2011), and how to re-engineer organisms to efficiently produce industrial chemicals and enzymes (Huang et al, 2017).…”

The use of trade data to predict the source and spread of food safety outbreaks: An innovative mathematical modelling approach

“…Networks are defined by Newman (Newman, 2003) as "a set of items, which we will call vertices or sometimes nodes, with connections between them called "edges". For instance, they have been used to describe systems as diverse as the World Wide Web (Faloutsos, Faloutsos, & Faloutsos, 1999), citations between academic papers (Egghe, Rousseau, & Ferreiro, 1991) and protein metabolic networks of bacteria (Mehta et al, 2018;Métris et al, 2017). The network theory has also been applied to the analysis of global trade characteristics (De Benedictis, Nenci, Santoni, Tajoli, & Vicarelli, 2014), as well as their evolution through time (Baskaran, Blöchl, Brück, & Theis, 2011).…”