Adaptive evolution of the human fatty acid synthase gene: Support for the cancer selection and fat utilization hypotheses?

Cancer may act as the etiological agent for natural selection in some genes. This selective pressure would act to reduce the success of neoplastic lineages over normal cell lineages in individuals of reproductive age. In addition, humanâs relatively larger brain and longer lifespan may have also acted as a selective force requiring new genotypes. One of the most important proteins in both processes is the fatty acid synthase (FAS) gene involved in fatty acid biosynthesis. Avariety of other proteins, including PTEN, MAPK1, SREBP1, SREBP2 and PI are also involved in the regulation of fatty acid biosynthesis. We have specifically analysed variability in selective pressure across all these genes in human, mouse and other vertebrates.We have found that the FAS gene alone has signatures indicative of adaptive evolution.We did not find any signatures of adaptive evolution in any of the other proteins. In the FAS gene, we have detected an excess of non-synonymous over synonymous substitutions in approximately 6% of sites in the human lineage. Contrastingly, the substitution process at these sites in other available vertebrates and mammals indicates strong purifying selection. This is likely to reflect a functional shift in human FAS and correlates well with previously observed changes in FAS biochemical activities. We speculate that the role played by FAS either in cancer development or in human brain development has created this selective pressure, although we cannot rule out the various other functions of FAS

Response to Teladorsagia circumcincta infection in Scottish Blackface lambs with divergent phenotypes for nematode resistance

peer-reviewedThe objective of this study was to identify Scottish Blackface lambs that were at the extremes of the spectrum of resistance to gastrointestinal nematodes and characterise their response to an experimental nematode challenge. Lambs (n = 90) were monitored for faecal egg count (FEC) (2 samples from each of 2 independent natural infections). The most resistant (n = 10) and susceptible (n = 10) individuals were selected and challenged with 30,000 Teladorsagia circumcincta larvae (L3) at 9 months of age. Response to infection was monitored by measuring FEC, plasma pepsinogen, serum antibodies against nematode larval antigens and haematology profile, until necropsy at 71 days post infection. Worm burden, worm fecundity and the level of anti-nematode antibodies in abomasal mucosa were determined at necropsy. FEC was consistently higher in susceptible animals (P < 0.05), validating the selection method. Worm fecundity was significantly reduced in resistant animals (P = 0.03). There was also a significant correlation (r = 0.88; P < 0.001) between the number of adult worms and FEC at slaughter. There was no effect of phenotype (resistance/susceptibility) on plasma pepsinogen or on haematology profile. Phenotype had a significant effect on the level of anti-nematode IgA antibodies in serum (P < 0.01), reflecting a higher peak in resistant animals at day 7 post infection. It is concluded that significant variation in the response to gastrointestinal nematode challenge exists within the Scottish Blackface population with resistant animals displaying significantly lower FEC, lower worm fecundity and higher concentration of anti-nematode IgA antibodies in serum.Kathryn McRae was supported by a Teagasc Walsh fellowship and the Allan and Grace Kay Overseas Scholarship

An extra double-stranded RNA binding domain confers high activity to a squid RNA editing enzyme

RNA editing by adenosine deamination is particularly prevalent in the squid nervous system. We hypothesized that the squid editing enzyme might contain structural differences that help explain this phenomenon. As a first step, a squid adenosine deaminase that acts on RNA (sqADAR2a) cDNA and the gene that encodes it were cloned from the giant axon system. PCR and RNase protection assays showed that a splice variant of this clone (sqADAR2b) was also expressed in this tissue. Both versions are homologous to the vertebrate ADAR2 family. sqADAR2b encodes a conventional ADAR2 family member with an evolutionarily conserved deaminase domain and two double-stranded RNA binding domains (dsRBD). sqADAR2a differs from sqADAR2b by containing an optional exon that encodes an “extra” dsRBD. Both splice variants are expressed at comparable levels and are extensively edited, each in a unique pattern. Recombinant sqADAR2a and sqADAR2b, produced in Pichia pastoris, are both active on duplex RNA. Using a standard 48-h protein induction, both sqADAR2a and sqADAR2b exhibit promiscuous self-editing; however, this activity is particularly robust for sqADAR2a. By decreasing the induction time to 16 h, self-editing was mostly eliminated. We next tested the ability of sqADAR2a and sqADAR2b to edit two K(+) channel mRNAs in vitro. Both substrates are known to be edited in squid. For each mRNA, sqADAR2a edited many more sites than sqADAR2b. These data suggest that the “extra” dsRBD confers high activity on sqADAR2a

The public goods hypothesis for the evolution of life on Earth

It is becoming increasingly difficult to reconcile the observed extent of horizontal gene transfers with the central metaphor of a great tree uniting all evolving entities on the planet. In this manuscript we describe the Public Goods Hypothesis and show that it is appropriate in order to describe biological evolution on the planet. According to this hypothesis, nucleotide sequences (genes, promoters, exons, etc.) are simply seen as goods, passed from organism to organism through both vertical and horizontal transfer. Public goods sequences are defined by having the properties of being largely non-excludable (no organism can be effectively prevented from accessing these sequences) and non-rival (while such a sequence is being used by one organism it is also available for use by another organism). The universal nature of genetic systems ensures that such non-excludable sequences exist and non-excludability explains why we see a myriad of genes in different combinations in sequenced genomes. There are three features of the public goods hypothesis. Firstly, segments of DNA are seen as public goods, available for all organisms to integrate into their genomes. Secondly, we expect the evolution of mechanisms for DNA sharing and of defense mechanisms against DNA intrusion in genomes. Thirdly, we expect that we do not see a global tree-like pattern. Instead, we expect local tree-like patterns to emerge from the combination of a commonage of genes and vertical inheritance of genomes by cell division. Indeed, while genes are theoretically public goods, in reality, some genes are excludable, particularly, though not only, when they have variant genetic codes or behave as coalition or club goods, available for all organisms of a coalition to integrate into their genomes, and non-rival within the club. We view the Tree of Life hypothesis as a regionalized instance of the Public Goods hypothesis, just like classical mechanics and euclidean geometry are seen as regionalized instances of quantum mechanics and Riemannian geometry respectively. We argue for this change using an axiomatic approach that shows that the Public Goods hypothesis is a better accommodation of the observed data than the Tree of Life hypothesis

The phylogeny of the mammalian heme peroxidases and the evolution of their diverse functions

The mammalian heme peroxidases (MHPs) are a medically important group of enzymes. Included in this group are myeloperoxidase, eosinophil peroxidase, lactoperoxidase, and thyroid peroxidase. These enzymes are associated with such diverse diseases as asthma, Alzheimer’s disease and inflammatory vascular disease. Despite much effort to elucidate a clearer understanding of the function of the 4 major groups of this multigene family, we still do not have a clear understanding of their relationships to each other

Stability properties of an ancient plant peroxidase

Plant (Class III) peroxidases have numerous applications throughout biotechnology but their thermal and oxidative stabilities may limit their usefulness. Horseradish peroxidase isoenzyme C (HRPC) has good catalytic turnover and is moderately resistant to heat and to excess (oxidizing) concentrations of hydrogen peroxide. In contrast, HRP isoenzyme A2 (HRPA2) has better oxidative but poorer thermal stability, while soybean peroxidase (SBP) displays enhanced thermal stability. Intrigued by these variations amongst closely related enzymes, we previously used maximum likelihood methods (with application of Bayesian statistics) to infer an amino acid sequence consistent with their most recent common ancestor, the ‘Grandparent’ (GP). Here, we report the cloning and expression of active recombinant GP protein in Escherichia coli. GP’s half-inactivation temperature was 45 oC, notably less than HRPC’s, but its resistance to excess H2O2 was 2-fold greater. This resurrected GP protein enables a greater understanding of plant peroxidase evolution and serves as a test-bed to explore their ancestral properties

Membrane-Based Water Evaporator for a Space Suit

A membrane-based water evaporator has been developed that is intended to serve as a heat-rejection device for a space suit. This evaporator would replace the current sublimator that is sensitive to contamination of its feedwater. The design of the membrane-based evaporator takes advantage of recent advances in hydrophobic micropore membranes to provide robust heat rejection with much less sensitivity to contamination. The low contamination sensitivity allows use of the heat transport loop as feedwater, eliminating the need for the separate feedwater system used for the sublimator. A cross section of the evaporator is shown in the accompanying figure. The space-suit cooling loop water flows into a distribution plenum, through a narrow annulus lined on both sides with a hydrophobic membrane, into an exit plenum, and returns to the space suit. Two perforated metal tubes encase the membranes and provide structural strength. Evaporation at the membrane inner surface dissipates the waste heat from the space suit. The water vapor passes through the membrane, into a steam duct and is vented to the vacuum environment through a back-pressure valve. The back-pressure setting can be adjusted to regulate the heat-rejection rate and the water outlet temperature

Positive selection neighboring functionally essential sites and disease-implicated regions of mammalian reproductive proteins

<p>Abstract</p> <p>Background</p> <p>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 <it>mammalia </it>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 <it>mammalia</it>.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>Our <it>in silico </it>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 <it>mammalia </it>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.</p

Heterogeneous models place the root of the placental mammal phylogeny

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