Category Archives: Blog

Genomics of the longest lived mammal

This week the genome and transcriptome of the Bowhead whale was published in the journal Cell reports. For more please see our publications page for the pdf or click here

This work was carried out by Dr Andrew Webb (first author) and Dr Mary O’Connell in collaboration with an international team of experts and was led by Dr João Pedro de Magalhães at the University of Liverpool. The Bowhead whale is the longest lived mammal with life span estimates in the region of 200 years. Yet Bowhead whales appear immune to ageing related disorders such as cancer, metabolic disorders and cardiovascular disease. Uncovering the molecular and genetic underpinnings of their extraordinary longevity and resistance to disease is important for the improvement of health in the ageing human population.

http://www.iflscience.com/plants-and-animals/genome-earths-longest-lived-mammal-sequenced

Photograph of Fluke of bowhead whale (Balaena mysticetus), Foxe Basin (Nunavut, Canada) by Ansgar Walk. 

A matter of Taste

hummingbirdhummingbirdhummingbird“Evolution of sweet taste perception in hummingbirds by transformation of the ancestral umami receptor” Baldwin et al Science 2014

 

Why study birds to understand sensory perception?

Birds are a group of therapod dinosaurs that evolved during the mid Mesozoic era (~150 million years ago). They represent one of the most diverse extant vertebrate clades inhabiting almost all terrestrial environments across all seven continents, the Arctic and the Antarctic.  Birds also have radiated to fill a huge array of ecological niches from large birds of prey, to the very tiny nectar feeding hummingbirds. An essential part of species radiation and successful novel niche colonization is the ability to adapt sensory systems to new environments.  So birds represent a good model for understanding variation in sensory perception.

What sense, which species and why?

With sensory systems such as olfaction and bitter taste perception we know that there is a considerable amount of gene gain and loss across lineages reflective of ecological niche. However, sweet and savory taste receptors don’t vary in number and they have highly conserved sequence.  Sweet perception is governed by the combination of 2 proteins T1R2+T1R3 and savory by T1R1+T1R3. We observe an ancestral loss of the T1R2 in the bird lineage – meaning that birds cannot perceive sweetness. How is it then that we have nectar loving hummingbirds – how can they taste sweetness without an essential part of that receptor?

What did we find ?

A new vertebrate sweet taste receptor ! We tested the response of a variety of bird savory receptors (chicken, hummingbird, swift) to different amino acids and sugars. We found that the hummingbird savory receptor responded to several different sugars (sucrose, fructose and glucose) but not to artificial sweeteners. But the chicken and swift savory receptors did not respond to sugars. And so it appeared that the savory receptor in Hummingbirds can perceive sweetness. We wanted to know what changes in the savory receptor of hummingbirds have allowed a new function to evolve. So we made up chimeric proteins that had a range of different chicken (non-sugar detecting) and hummingbird (sugar detecting) savory receptor regions combined and we tested their abilities to detect sugars. By making a series of these chimeras we could narrow down the part of the protein complex that was involved in the new sugar detecting function and we found evidence of positive selection in these regions. So we had found a new vertebrate sweet taste receptor !

Does this new sweet taste receptor dictate behavior in hummingbirds? We studied the behavior of a captive ruby-throated hummingbird model and a wild population of Anna’s hummingbirds in response to different sugar, water, artificial sweeteners and amino acids etc just as we had tested for the receptor response assays in vitro. We tested whether the hummingbirds behavior showed a preference for sugar solutions over water and aspartame solutions as our in vitro tests had shown – they made their decision on calorific value within a staggering 200 milliseconds and showed a distinct preference for sugar. We also tested a wild population of hummingbirds from the Santa Monica mountains (CA, USA) and found again a strong preference for sugar solutions. Our study shows that several simple sugars (sucrose, fructose and glucose) all effect a rapid, appetitive flavor response in hummingbirds that is facilitated by the adaptive evolution of a savory receptor into a new sweet taste receptor.

A phylogenetic approach to test for evidence of parental conflict or gene duplications associated with protein-encoding imprinted orthologous genes in placental mammals

There are multiple theories on the evolution of genomic imprinting. We investigated whether the molecular evolution of true orthologs of known imprinted genes provides support for theories based on gene duplication or parental conflicts (where mediated by amino-acid changes). Our analysis of 34 orthologous genes demonstrates that the vast majority of mammalian imprinted genes have not undergone any subsequent significant gene duplication within placental species, suggesting that selection pressures against gene duplication events could be operating for imprinted loci. As antagonistic co-evolution between imprinted genes can regulate offspring growth, proteins mediating this interaction could be subject to rapid evolution via positive selection. Supporting this, we detect evidence of site specific positive selection for the imprinted genes OSBPL5 (and GNASXL), and detect lineage-specific positive selection for 14 imprinted genes where it is known that the gene is imprinted in a specific lineage, namely for: PLAGL1, IGF2, SLC22A18, OSBPL5, DCN, DLK1, RASGRF1, IGF2R, IMPACT, GRB10, NAPIL4, UBE3A, GATM and GABRG3. However, there is an overall lack of concordance between the known imprinting status of each gene (i.e. whether the gene is imprinted or biallelically expressed in a particular mammalian lineage) and positive selection. While only a small number of orthologs of imprinted loci display evidence of positive selection, we observe that the majority of orthologs of imprinted loci display high levels of micro-synteny conservation and have undergone very few cis– or trans-duplications in placental mammalian lineages.

 

Complete Reference:

O’Connell, M.J.*, Loughran, N.B., Walsh, T.A., Donoghue, M.T.A., Schmid, K.J., Spillane, C. (2010) A phylogenetic approach to test for evidence of parental conflict or gene duplications associated with protein-encoding imprinted orthologous genes in placental mammals. DOI: 10.1007/s00335-010-9283-5. Mammalian Genomepdf

A role for TLR4 in Clostridium difficile infection and the recognition of surface layer proteins

Clostridium difficile is the etiological agent of antibiotic-associated diarrhoea (AAD) and pseudomembranous colitis in humans. The role of the surface layer proteins (SLPs) in this disease has not yet been fully explored. The aim of this study was to investigate a role for SLPs in the recognition of C. difficile and the subsequent activation of the immune system. Bone marrow derived dendritic cells (DCs) exposed to SLPs were assessed for production of inflammatory cytokines, expression of cell surface markers and their ability to generate T helper (Th) cell responses. DCs isolated from C3H/HeN and C3H/HeJ mice were used in order to viagra online discount examine whether SLPs are recognised by TLR4. The role of TLR4 in infection was examined in TLR4-deficient mice. SLPs induced maturation of cialis online pills DCs characterised by production of IL-12, TNFα and IL-10 and expression of MHC class II, CD40, CD80 and CD86. Furthermore, SLP-activated DCs generated Th cells producing IFNγ and IL-17. http://bluewaterropes.com/generic/ SLPs were unable to activate DCs isolated from TLR4-mutant C3H/HeJ mice and failed to induce a subsequent Th cell response. TLR4−/− and Myd88−/−, but not TRIF−/− mice were more susceptible than wild-type mice to C. difficile infection. Furthermore, SLPs activated NFκB, but not IRF3, downstream of TLR4. Our results indicate that SLPs isolated viagra online order from C. difficile can activate innate and adaptive immunity and that these effects are mediated by TLR4, with TLR4 having a functional role in experimental C. difficile infection. This suggests an important role for SLPs in the recognition of C. difficile by the immune system.

Complete Reference:

Ryan A, Lynch M, Smith SM, Amu S, Nel HJ, McCoy CE, Dowling JK, Draper E, O’Reilly E, McCarthy C, O’Brien J, Ni Eidhin D, O’Connell MJ, Keogh B, Morton CO, Rogers TR, Fallon PG, O’Neill LA, Kelleher D and Loscher CE. (2011) A role for TLR4 in Clostridium difficile infection and the recognition of surface layer proteins. DOI:10.1371/journal.ppat.1002076. PLoS Pathogens. pdf

Functional consequence of positive selection revealed through rational mutagenesis of human myeloperoxidase

Myeloperoxidase (MPO) is a member of the mammalian heme peroxidase (MHP) multigene family. Whereas all MHPs oxidize specific halides to generate the corresponding hypohalous acid, MPO is unique in its capacity to oxidize chloride at physiologic pH to produce hypochlorous acid (HOCl), a potent microbicide that contributes to neutrophil-mediated host defense against infection.

Continue reading Functional consequence of positive selection revealed through rational mutagenesis of human myeloperoxidase

Arabidopsis thaliana codon volatility scores reflect GC3 composition rather than selective pressure

Synonymous codon usage bias has typically been correlated with, and attributed to translational efficiency. However, there are other pressures on genomic sequence composition that can affect codon usage patterns such as mutational biases. This study provides an analysis of the codon usage patterns in Arabidopsis thaliana in relation to gene expression levels, codon volatility, mutational biases and selective pressures.

Continue reading Arabidopsis thaliana codon volatility scores reflect GC3 composition rather than selective pressure

Colon Cancer Genes Exhibit Signatures of Positive Selection at Functionally Important Sites

Cancer, much like most human disease, is routinely studied by utilizing model organisms. Of these model organisms, mice are often dominant. However, our assumptions of functional equivalence fail to consider the opportunity for divergence conferred by ~180 Million Years (MY) of independent evolution between these species. For a given set of human disease related genes, it is therefore important to determine if functional equivalency has been retained between species. In this study we test the hypothesis that cancer associated genes have different patterns of substitution akin to adaptive evolution in different mammal lineages.

Continue reading Colon Cancer Genes Exhibit Signatures of Positive Selection at Functionally Important Sites