Biology subjects

Cook, L. E.

Publications and source records attributed to Cook, L. E..

3 recordsLinked to original sources

bioRxiv2025

Dissecting functional regulatory convergence over 160 million years of therian evolution

Understanding the molecular mechanisms underpinning convergent traits can provide insight into the predictability of the evolutionary process. The thylacine, an extinct marsupial carnivore, has been long known to have a very similar craniofacial morphology to that of eutherian canids, despite having diverged{approx} 160 million years ago. Using a massively parallel reporter assay (MPRA), we tested the regulatory potential of a set of previously identified highly conserved craniofacial enhancers that showed convergent sequence acceleration in thylacine and wolf (TWARs). We compared orthologous sequences from six different taxa, including outgroup taxa with non-convergent craniofacial phenotypes (Tasmanian devil and giant panda) and ancestral reconstructions for marsupial and placental carnivores (Dasyuromorphia and Carnivora). Dense 10bp tiling allowed us to thoroughly examine features associated with activity, including percentage GC content and transcription factor binding motifs turnover. We identified marked conservation of levels and patterns of regulatory activity across all six taxa, as well as multiple cases of differentially active TWARs within each clade, with both thylacine and wolf driving functional divergence. However, evidence of convergent divergence was limited to a set of neighbouring TWARs near the neural crest gene Phox2b - one of which exhibited reduced activity in the wolf, and the other in the thylacine. Ultimately our findings suggest that shared gene regulatory potential is not a feature of these convergently accelerated regions in the thylacine and wolf.

genomics↗

bioRxiv2025

Mapping the gene regulatory landscape of archaic hominin introgression in modern Papuans

Interbreeding between anatomically modern humans and archaic hominins has contributed to the genomes of present-day human populations. However, our understanding of the specific gene regulatory consequences of Neanderthal, and particularly, Denisovan introgression is limited. Here, we used a massively parallel reporter assay to investigate the regulatory effects of 25,869 high-confidence introgressed SNPs segregating in present-day individuals of Papuan genetic ancestry in immune cell types. Overall, 8.22% of Denisovan and 8.58% of Neanderthal sequences showed active regulatory activity, and 9.22% of these displayed differential activity between alleles. We examined the properties of active and differentially active sequences, and found no impact of introgressed allele frequency on the probability of activity, but do observe an association with distance to the nearest transcription start site. Differential activity was also associated with differential transcription factor binding. Genes predicted to be regulated by differentially active sequences included IFIH1 and TNFAIP3, key immune genes and known examples of archaic introgression. Overall, this work provides insight into the regulatory activity of archaic variants in Papuan populations and, more broadly, the contribution of archaic introgression in shaping modern human genetic diversity.

evolutionary biology↗

bioRxiv2023

Cis-regulatory landscapes of the fat-tailed dunnart and mouse provide insights into the drivers of craniofacial heterochrony

Marsupials and placental mammals exhibit significant differences in reproductive and life history strategies. Marsupials are born highly underdeveloped after an extremely short period of gestation, leading to prioritization of the development of structures critical for post-birth survival in the pouch. Critically, they must undergo accelerated development of the oro-facial region compared to placentals. Previously we described the accelerated development of the oro-facial region in the carnivorous Australian marsupial, the fat-tailed dunnart Sminthopsis crassicaudata that has one of the shortest gestations of any mammal. By combining genome comparisons of the mouse and dunnart with functional data for the enhancer-associated chromatin modifications, H3K4me3 and H3K27ac, we investigated divergence of craniofacial regulatory landscapes between these species. This is the first description of genome-wide face regulatory elements in a marsupial, with 60,626 putative enhancers and 12,295 putative promoters described. We also generated craniofacial RNA-seq data for the dunnart to investigate expression dynamics of genes near predicted active regulatory elements. While genes involved in regulating facial development were largely conserved in mouse and dunnart, the regulatory landscape varied significantly. Additionally, a subset of dunnart-specific enhancers were associated with genes highly expressed only in dunnart relating to cranial neural crest proliferation, embryonic myogenesis and epidermis development. Comparative RNA-seq analyses of facial tissue revealed dunnart-specific expression of genes involved in the development of the mechanosensory system. Accelerated development of the dunnart sensory system likely relates to the sensory cues received by the nasal-oral region during the postnatal journey to the pouch. Together these data suggest that accelerated face development in the dunnart may be driven by dunnart-specific enhancer activity. Our study highlights the power of marsupial-placental comparative genomics for understanding the role of enhancers in driving temporal shifts in development.

developmental biology↗