Publications
8 results found
Webb AE, Gerek ZN, Morgan CC, et al., 2015, Adaptive Evolution as a Predictor of Species-Specific Innate Immune Response., Mol Biol Evol, Vol: 32, Pages: 1717-1729
It has been proposed that positive selection may be associated with protein functional change. For example, human and macaque have different outcomes to HIV infection and it has been shown that residues under positive selection in the macaque TRIM5α receptor locate to the region known to influence species-specific response to HIV. In general, however, the relationship between sequence and function has proven difficult to fully elucidate, and it is the role of large-scale studies to help bridge this gap in our understanding by revealing major patterns in the data that correlate genotype with function or phenotype. In this study, we investigate the level of species-specific positive selection in innate immune genes from human and mouse. In total, we analyzed 456 innate immune genes using codon-based models of evolution, comparing human, mouse, and 19 other vertebrate species to identify putative species-specific positive selection. Then we used population genomic data from the recently completed Neanderthal genome project, the 1000 human genomes project, and the 17 laboratory mouse genomes project to determine whether the residues that were putatively positively selected are fixed or variable in these populations. We find evidence of species-specific positive selection on both the human and the mouse branches and we show that the classes of genes under positive selection cluster by function and by interaction. Data from this study provide us with targets to test the relationship between positive selection and protein function and ultimately to test the relationship between positive selection and discordant phenotypes.
Moran R, Morgan C, O'Connell M, 2015, A Guide to Phylogenetic Reconstruction Using Heterogeneous Models—A Case Study from the Root of the Placental Mammal Tree, Computation, Vol: 3, Pages: 177-196, ISSN: 2079-3197
There are numerous phylogenetic reconstruction methods and modelsavailable—but which should you use and why? Important considerations in phylogeneticanalyses include data quality, structure, signal, alignment length and sampling. If poorlymodelled, variation in rates of change across proteins and across lineages can lead toincorrect phylogeny reconstruction which can then lead to downstream misinterpretation ofthe underlying data. The risk of choosing and applying an inappropriate model can bereduced with some critical yet straightforward steps outlined in this paper. We use thequestion of the position of the root of placental mammals as our working example to illustratethe topological impact of model misspecification. Using this case study we focus on usingmodels in a Bayesian framework and we outline the steps involved in identifying andassessing better fitting models for specific datasets.
Morgan CC, Creevey CJ, O'Connell MJ, 2014, Mitochondrial data are not suitable for resolving placental mammal phylogeny, MAMMALIAN GENOME, Vol: 25, Pages: 636-647, ISSN: 0938-8990
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Liu S, Lorenzen ED, Fumagalli M, et al., 2014, Population genomics reveal recent speciation and rapid evolutionary adaptation in polar bears, Cell, Vol: 157, Pages: 785-794, ISSN: 0092-8674
Polar bears are uniquely adapted to life in the High Arctic and have undergone drastic physiological changes in response to Arctic climates and a hyperlipid diet of primarily marine mammal prey. We analyzed 89 complete genomes of polar bear and brown bear using population genomic modeling and show that the species diverged only 479–343 thousand years BP. We find that genes on the polar bear lineage have been under stronger positive selection than in brown bears; nine of the top 16 genes under strong positive selection are associated with cardiomyopathy and vascular disease, implying important reorganization of the cardiovascular system. One of the genes showing the strongest evidence of selection, APOB, encodes the primary lipoprotein component of low-density lipoprotein (LDL); functional mutations in APOB may explain how polar bears are able to cope with life-long elevated LDL levels that are associated with high risk of heart disease in humans.
Morgan CC, Mc Cartney AM, Donoghue MTA, et al., 2013, Molecular adaptation of telomere associated genes in mammals, BMC Evolutionary Biology, Vol: 13, Pages: 251-251, ISSN: 1471-2148
Morgan CC, Foster PG, Webb AE, et al., 2013, Heterogeneous Models Place the Root of the Placental Mammal Phylogeny, Molecular Biology and Evolution, Vol: 30, Pages: 2145-2156-2145-2156
Heterogeneity among life traits in mammals has resulted in considerable phylogenetic conflict, particularly concerning the position of the placental root. Layered upon this are gene- and lineage-specific variation in amino acid substitution rates and compositional biases. Life trait variations that may impact upon mutational rates are longevity, metabolic rate, body size, and germ line generation time. Over the past 12 years, three main conflicting hypotheses have emerged for the placement of the placental root. These hypotheses place the Atlantogenata (common ancestor of Xenarthra plus Afrotheria), the Afrotheria, or the Xenarthra as the sister group to all other placental mammals. Model adequacy is critical for accurate tree reconstruction and by failing to account for these compositional and character exchange heterogeneities across the tree and data set, previous studies have not provided a strongly supported hypothesis for the placental root. For the first time, models that accommodate both tree and data set heterogeneity have been applied to mammal data. Here, we show the impact of accurate model assignment and the importance of data sets in accommodating model parameters while maintaining the power to reject competing hypotheses. Through these sophisticated methods, we demonstrate the importance of model adequacy, data set power and provide strong support for the Atlantogenata over other competing hypotheses for the position of the placental root.
Morgan C, Shakya K, Webb A, et al., 2012, Colon cancer associated genes exhibit signatures of positive selection at functionally significant positions, BMC Evolutionary Biology, Vol: 12, Pages: 114-114, ISSN: 1471-2148
BACKGROUND: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.RESULTS:Our analysis of the current literature and colon cancer databases identified 22 genes exhibiting colon cancer associated germline mutations. We identified orthologs for these 22 genes across a set of high coverage (>6X) vertebrate genomes. Analysis of these orthologous datasets revealed significant levels of positive selection. Evidence of lineage-specific positive selection was identified in 14 genes in both ancestral and extant lineages. Lineage-specific positive selection was detected in the ancestral Euarchontoglires and Hominidae lineages for STK11, in the ancestral primate lineage for CDH1, in the ancestral Murinae lineage for both SDHC and MSH6 genes and the ancestral Muridae lineage for TSC1.CONCLUSION:Identifying positive selection in the Primate, Hominidae, Muridae and Murinae lineages suggests an ancestral functional shift in these genes between the rodent and primate lineages. Analyses such as this, combining evolutionary theory and predictions - along with medically relevant data, can thus provide us with important clues for modeling human diseases.
Morgan C, Loughran N, Walsh T, et al., 2010, Positive selection neighboring functionally essential sites and disease-implicated regions of mammalian reproductive proteins, BMC Evolutionary Biology, Vol: 10, Pages: 39-39, ISSN: 1471-2148
BACKGROUND:Reproductive proteins are central to the continuation of all mammalian species. The evolution of these proteins has been greatly influenced by environmental pressures induced by pathogens, rival sperm, sexual selection and sexual conflict. Positive selection has been demonstrated in many of these proteins with particular focus on primate lineages. However, the mammalia are a diverse group in terms of mating habits, population sizes and germ line generation times. We have examined the selective pressures at work on a number of novel reproductive proteins across a wide variety of mammalia.RESULTS:We show that selective pressures on reproductive proteins are highly varied. Of the 10 genes analyzed in detail, all contain signatures of positive selection either across specific sites or in specific lineages or a combination of both. Our analysis of SP56 and Col1a1 are entirely novel and the results show positively selected sites present in each gene. Our findings for the Col1a1 gene are suggestive of a link between positive selection and severe disease type. We find evidence in our dataset to suggest that interacting proteins are evolving in symphony: most likely to maintain interacting functionality.CONCLUSION:Our in silico analyses show positively selected sites are occurring near catalytically important regions suggesting selective pressure to maximize efficient fertilization. In those cases where a mechanism of protein function is not fully understood, the sites presented here represent ideal candidates for mutational study. This work has highlighted the widespread rate heterogeneity in mutational rates across the mammalia and specifically has shown that the evolution of reproductive proteins is highly varied depending on the species and interacting partners. We have shown that positive selection and disease are closely linked in the Col1a1 gene.
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