Research
Advances in genomic methods have allowed for the identification of loci, genes, interactions, and even mutations underlying phenotypic variants that are the putative targets of natural selection. Whilst there is a growing list of genetic changes and interactions, the list is biased towards observable traits and considering the current biodiversity crisis, it is critical to use integrative approaches to unravel the link between genetic variation and adaptive traits to 1) better preserve biodiversity; and 2) create strains resilient to disease or change. Most model organisms however do not belong to diversifying clades and thus, provide little information on how organisms adapt and diversify in the wild. Fortunately, there exists a unique model system with a vast collection of mutants, screened by natural selection for adaptive phenotypic differences; a staggering 2000 species of haplochromine cichlid fish have adaptively radiated in East Africa (EA) during the evolutionary time span of humans after the human-chimpanzee split ~5-7 million years ago. Despite the high levels of cichlid fish diversity, low levels of genetic diversity (<0.25%) are observed between lake species pairs, implying that gene regulatory differences are a key contributor to the observed phenotypic diversity.
Using a favoured reverse genetics approach based on multi ‘omics data followed by experimental verification, I demonstrated that the integration of noncoding, gene co-expression, and small RNA data in a gene regulatory network (GRN) reconstruction framework identifies GRN changes associated with traits under selection e.g., visual systems, and is a contributing mechanism of cichlid phenotypic diversity Evolution of regulatory networks associated with traits under selection in cichlids Evolution of miRNA-Binding Sites and Regulatory Networks in Cichlids. Using the predicted GRNs, I incorporated other genetic mechanisms of adaptation by 1) assessing the impact of structural variants Analysis of structural variants in four African cichlids highlights an association with developmental and immune related genes; 2) studying the evolution of genome-wide cis-regulatory elements (manuscript in preparation); and 3) optimising epigenetic techniques (ATAC-seq) to study regulatory activity in embryos and adult tissues of multiple cichlid species (manuscripts in preparation). All this work has established computational frameworks for determining genetic mechanisms underlying adaptive traits. Further work requires developing computational approaches for integrating other omics data e.g., spatial transcriptomics, to characterise and validate genetic variation of adaptive traits that segregate in diversifying clades.
Whilst some of my work focuses on unravelling the genetics driving speciation and adaptive radiations of haplochromine cichlids, other work focuses on non-radiating tilapia cichlid fish of the genus Oreochromis. With 37 described species, tilapia are adapted to diverse environments and owing to commercial interests of improving resilience traits for food sustainability, represent an important system to study the genomic signatures of adaptation. Tilapia, farmed in over 120 countries/territories, represent the second largest group, behind carp, of aquaculture fish globally. Some of my work tackles the threat of exotic species introductions leading to genetic swamping by generating SNP panels for species identification Whole genome resequencing data enables a targeted SNP panel for conservation and aquaculture of Oreochromis cichlid fishes, and revealing the genetic impact of hybridisation on modern tilapia diversity Ancient and ongoing hybridization in the Oreochromis cichlid fishes. However, greater threats to tilapia aquaculture more recently include 1) the recent emergence of a fatal disease of tilapia cultures, Tilapia Lake Virus (TiLV), causing up to 90% of global tilapia mortalities; and 2) extreme cold weather and decreasing freshwater resources. To sustain tilapia and inform other fish production, it is crucial to develop computational approaches that integrate further omics data e.g., eQTLs, to finely map genetic loci and variation responsible for disease resistance and environmental tolerance to breed resilient strains.
Tackling such challenges first involved generating a chromosome-level genome assembly of the genetically improved farmed tilapia (GIFT), an elite Nile tilapia strain developed by WorldFish, and using it to map genes, loci, and introgressed regions contributing to improved immunity and growth traits Chromosome-level genome sequence of the Genetically Improved Farmed Tilapia (GIFT, Oreochromis niloticus) highlights regions of introgression with O. mossambicus. Using this de novo genome, it is now important to identify and validate TiLV resistance trait loci using challenge experiments coupled with multi ‘omics approaches, as well as key sex determining loci for ongoing breeding success. By determining the genetic bases of other aquaculture traits, we can genotype and breed them into farmed strains. However, due to technical limitations, studies on environmental traits like salinity or cold temperature tolerance in tilapia yielded few implicated genes/pathways. As a pilot, I generated epigenetic (ATAC-seq) and gene expression data from Nile tilapia gill tissue Chromatin accessibility in gill tissue identifies candidate genes and loci associated with aquaculture relevant traits in tilapia, and through the integration of SNPs from 575 individuals of 27 tilapia species from our previous work Ancient and ongoing hybridization in the Oreochromis cichlid fishes, identified candidate genes e.g., prolactin receptor 1, genetic relationships, and noncoding loci associated with salinity and osmotic stress acclimation Chromatin accessibility in gill tissue identifies candidate genes and loci associated with aquaculture relevant traits in tilapia. Next is to investigate how such genes are regulated during environmental transition e.g., salinity and temperature changes. Since salinity and temperature tolerance in tilapia are polygenic traits involving several transporters/receptors and/or metabolic genes, multi ‘omic profiling of wild adapted and in vivo challenge experiment individuals could identify the genetic map of salinity or cold-temperature acclimation. This, coupled with interdisciplinary (systems/network biology) approaches like I have applied previously, and others in human disease traits, offer much promise for interrogating GRNs associated with polygenic traits and disease.
Ultimately, my research aims to innovate systems and network biology approaches, based on multi-omics data from genetic screens and functional validations, to identify the genetic underpinnings of vertebrate adaptive traits and disease response.
To provide fundamental genetic markers of economically important traits for enhancing global food security in the context of disease and climate change, my key objectives are to:
1) Innovate integrative approaches, ML algorithms, and pipelines for noncoding annotations and gene regulatory network (GRN) reconstruction;
2) Train pipelines to identify genetic signatures and variation of disease resistance and adaptation;
3) Adapt genetic engineering approaches to functionally verify markers for commercial traits.