An MRI-derived definition of MCI-to-AD conversion for long-term, automatic prognosis of MCI patients

Alzheimer''s disease (AD) and mild cognitive impairment (MCI) are of great current research interest. While there is no consensus on whether MCIs actually “convert” to AD, this concept is widely applied. Thus, the more important question is not whether MCIs convert, but what is the best such definition. We focus on automatic prognostication, nominally using only a baseline brain image, of whether an MCI will convert within a multi-year period following the initial clinical visit. This is not a traditional supervised learning problem since, in ADNI, there are no definitive labeled conversion examples. It is not unsupervised, either, since there are (labeled) ADs and Controls, as well as cognitive scores for MCIs. Prior works have defined MCI subclasses based on whether or not clinical scores significantly change from baseline. There are concerns with these definitions, however, since, e.g., most MCIs (and ADs) do not change from a baseline CDR = 0.5 at any subsequent visit in ADNI, even while physiological changes may be occurring. These works ignore rich phenotypical information in an MCI patient''s brain scan and labeled AD and Control examples, in defining conversion. We propose an innovative definition, wherein an MCI is a converter if any of the patient''s brain scans are classified “AD” by a Control-AD classifier. This definition bootstraps design of a second classifier, specifically trained to predict whether or not MCIs will convert. We thus predict whether an AD-Control classifier will predict that a patient has AD. Our results demonstrate that this definition leads not only to much higher prognostic accuracy than by-CDR conversion, but also to subpopulations more consistent with known AD biomarkers (including CSF markers). We also identify key prognostic brain region biomarkers.     

What is hierarchical selection?

It has been proposed that natural selection occurs on a hierarchy of levels, of which the organismic level is neither the top nor the bottom. This hypothesis leads to the following practical problem: in general, how does one tell if a given phenomenon is a result of selection on level X or level Y. How does one tell what the units of selection actually are? It is convenient to assume that a unit of selection may be defined as a type of entity for which there exists, among all entities on the same “level” as that entity, an additive component of variance for some specific component F of fitness which does not appear as an additive component of variance in any decomposition of this F among entities at any lower level. But such a definition implicitly assumes that if f(x, y) depends nonadditively on its arguments, there must be interaction between the quantities which x and y represent. This assumption is incorrect. And one cannot avoid this error by speaking of “transformability to additivity” instead of merely “additivity”. A general mathematical formulation of the concepts of interaction and non-interaction is proposed, followed by a correspondingly modified approach to the definition of a unit of selection. The practical difficulty of verifying the presence of hierarchical selection is discussed.     

The Humanness of Macaque Antibody Sequences

Chimeric, humanized and human antibodies have successively been exploited as therapeutics because their increasing human (‘self’) character is expected to correspond with decreased immunogenicity, which is critical for their clinical development. Thus, humanness has been inferred to predict antibody immunogenicity. Humanness of antibody variable regions (V-regions) has recently been studied using a parameter (here referred to as the H-score) that evaluates similarity to expressed human sequences. Macaque (Macaca fascicularis) antibody sequences are of particular interest because they have been suggested to have extremely human-like character and, recently, macaque single-chain variable fragments with very high affinity for various antigens have been isolated. In this study, the H-scores of all macaque antibody V-regions available in sequence data banks were compared with those of their human counterparts using statistical tests. The results were found to be influenced by the relative size of the human families to which the macaque V-regions are related. As the relevance of families to immunogenicity is suspected but unproven, a new parameter (the ‘G-score’) was derived from the H-score to avoid this influence, and macaque V-region sequences were reanalyzed using the G-score. Both parameters show that these regions cannot be regarded as human when they derive from heavy chains, but the humanness of light chains is variable. It was shown that ‘germline humanization’ of a macaque V-region favourably influenced its humanness, as evaluated by both H-score and G-score. In addition, the humanness of macaque sequences presented in patents has been analyzed. The H-score and G-score define objectively the humanness of antibody V-regions, and their use is exemplified here.     

Natural environments,ancestral diets,and microbial ecology: is there a modern “paleo-deficit disorder”? Part I

Famed microbiologist René J. Dubos (1901–1982) was an early pioneer in the developmental origins of health and disease (DOHaD) construct. In the 1960s, he conducted groundbreaking experimental research concerning the ways in which early-life experience with nutrition, microbiota, stress, and other environmental variables could influence later-life health outcomes. He also wrote extensively on potential health consequences of a progressive loss of contact with natural environments (now referred to as green or blue space), arguing that Paleolithic experiences have created needs, particularly in the mental realm, that might not be met in the context of rapid global urbanization. He posited that humans would certainly adapt to modern urban landscapes and high technology, but there might be a toll to be paid in the form of higher psychological distress (symptoms of anxiety and depression) and diminished quality of life. In particular, there might be an erosion of humanness, exemplified by declines in altruism/empathy. Here in the first of a two-part review, we examine contemporary research related to natural environments and question to what extent Dubos might have been correct in some of his 50-year-old assertions.

“Human beings can almost certainly survive and multiply in the polluted cage of technological civilization, but we may sacrifice much of our humanness in adapting to such conditions…The maintenance of biological and mental health requires that technological societies provide in some form the biological freedom enjoyed by our Paleolithic ancestors”.Dr René Dubos, Invited Editorial, Life Magazine, 1970 [1].

     

ATTRIBUTES BELIEVED TO IMPACT FLAVOR: AN OPINION SURVEY

The definition of "flavor" is a term that appears to vary from one area to the next. A survey was conducted on 140 individuals in various areas of specialization (agriculture, food science, sensory evaluation, and the chemical senses) to see what sensations are thought to be involved in "flavor," as well as whether there were any differences in definitions across groups. The results demonstrate that while a fairly stable definition of the term does exist, there is some difference in what different groups of expertise mean when they refer to "flavor."     

How Could Language Have Evolved?

The evolution of the faculty of language largely remains an enigma. In this essay, we ask why. Language''s evolutionary analysis is complicated because it has no equivalent in any nonhuman species. There is also no consensus regarding the essential nature of the language “phenotype.” According to the “Strong Minimalist Thesis,” the key distinguishing feature of language (and what evolutionary theory must explain) is hierarchical syntactic structure. The faculty of language is likely to have emerged quite recently in evolutionary terms, some 70,000–100,000 years ago, and does not seem to have undergone modification since then, though individual languages do of course change over time, operating within this basic framework. The recent emergence of language and its stability are both consistent with the Strong Minimalist Thesis, which has at its core a single repeatable operation that takes exactly two syntactic elements a and b and assembles them to form the set {a, b}.It is uncontroversial that language has evolved, just like any other trait of living organisms. That is, once—not so long ago in evolutionary terms—there was no language at all, and now there is, at least in Homo sapiens. There is considerably less agreement as to how language evolved. There are a number of reasons for this lack of agreement. First, “language” is not always clearly defined, and this lack of clarity regarding the language phenotype leads to a corresponding lack of clarity regarding its evolutionary origins. Second, there is often confusion as to the nature of the evolutionary process and what it can tell us about the mechanisms of language. Here we argue that the basic principle that underlies language''s hierarchical syntactic structure is consistent with a relatively recent evolutionary emergence.     

Identifying biochemical phenotypic differences between cryptic species

Molecular genetic methods can distinguish divergent evolutionary lineages in what previously appeared to be single species, but it is not always clear what functional differences exist between such cryptic species. We used a metabolomic approach to profile biochemical phenotype (metabotype) differences between two putative cryptic species of the earthworm Lumbricus rubellus. There were no straightforward metabolite biomarkers of lineage, i.e. no metabolites that were always at higher concentration in one lineage. Multivariate methods, however, identified a small number of metabolites that together helped distinguish the lineages, including uncommon metabolites such as Nε-trimethyllysine, which is not usually found at high concentrations. This approach could be useful for characterizing functional trait differences, especially as it is applicable to essentially any species group, irrespective of its genome sequencing status.     

Characterization of genes encoding topoisomerase IV of Mycoplasma genitalium

A type-II topoisomerase (Topo-IV) encoded by the parC and parE genes in Escherichia coli and Salmonella typhimurium is thought to be involvd in cell septation and in the decatenation of newly replicated chromosomes. We have identified parC and parE homologs in the pleomorphic, wall-less organism Mycoplasma genitalium. Since the mechanics of cell septation in conventional eubacterial species is believed to be mediated by cell-wall constituents, there is no clear understanding of what coordinates that process in wall-less species. The presence of par genes in this bacterium, which has the smallest genome of any free-living organism, suggests that Top-IV has been evolutionarily conserved because of an essential role in mediating cell division.     

Bergmann's Rule – what's in a name?

Despite the great interest it generates, the definition of Bergmann's Rule is vague and often contested. Debate focuses on whether the rule should be described in terms of pattern or process, what taxa it should apply to and what taxonomic level it should be associated with. Here I review the historical development of studies of Bergmann's Rule. I suggest that Bergmann thought that his rule should be strongest at the intra‐specific level, rather than between closely related species as is usually thought. I argue that the rule is a pattern that can be studied regardless of mechanism in any taxon and at any taxonomic level.     

Experiments on the origins of optical activity

Two recent reports claim that (1) aqueous L-aspartic acid polymerizes faster than D-Asplin the presence of kaolin at 90°, and (2) L-phenylalanine is adsorbed by kaolin more extensively than D-Phe at pH 6 (the reverse being true at pH 2). The novelty of these observations and their potential significance for the origin of optical activity has prompted us to duplicate these experiments using more sensitive methods. L- and D, L-Asp in 0.01M solution were incubated with kaolin at 90° for 8 days. Careful examination of the aqueous residues from such experiments failed to demonstrate any preferential polymerization of L-Asp over D-Asp, or indeed any significant gross polymerization of Asp at all. In other experiments 0.001M solutions of D, L-Phe at pH 6 and pH 2 were stirred with large excesses of kaolin for 24 hr, and the aqueous extracts from these mixtures were examined for gross adsorption using the amino acid analyzer. No significant gross adsorption was noted. We then looked for asymmetric adsorption in the aqueous residues using optical ratatory dispersion, gas chromatography and thin layer chromatography. By none of these analytical criteria could we find any evidence whatsoever for the preferential adsorption of D- versus L-Phe from either pH 6 or pH 2 solutions. Finally, in experiments bearing on the origin of optical activity by parity violation during β-decay, we have irradiated solid samples of D-, L- and D, L-leucine in a 61700 Ci Sr-90 source at Oak Ridge National Lab. for 1.34 yr (total dose: 4.2×10⁸ rad). Gas chromatographic examination of the (appropriately derivitized) recovered samples showed that the L-Leu was 16.7% decomposed, the D-Leu 11.4% and the D,L-Leu 13.8% decomposed. The recovered D,L-Leu sample had a gas-chromatographically determined enantiomeric composition of 50.8% D-leu and 49.2% L-Leu. These data, though very close to expermental error, may indicate a slight preferential radiolysis of L-Leu compared to D-Leu by the Bremsstrahlung from Sr-90 β-decay. These high intensity irradiation experiments are being continued on a prolonged basis in order to reach more definitive conclusions.     

Gene losses during human origins

Pseudogenization is a widespread phenomenon in genome evolution, and it has been proposed to serve as an engine of evolutionary change, especially during human origins (the “less-is-more” hypothesis). However, there has been no comprehensive analysis of human-specific pseudogenes. Furthermore, it is unclear whether pseudogenization itself can be selectively favored and thus play an active role in human evolution. Here we conduct a comparative genomic analysis and a literature survey to identify 80 nonprocessed pseudogenes that were inactivated in the human lineage after its separation from the chimpanzee lineage. Many functions are involved among these genes, with chemoreception and immune response being outstandingly overrepresented, suggesting potential species-specific features in these aspects of human physiology. To explore the possibility of adaptive pseudogenization, we focus on CASPASE12, a cysteinyl aspartate proteinase participating in inflammatory and innate immune response to endotoxins. We provide population genetic evidence that the nearly complete fixation of a null allele at CASPASE12 has been driven by positive selection, probably because the null allele confers protection from severe sepsis. We estimate that the selective advantage of the null allele is about 0.9% and the pseudogenization started shortly before the out-of-Africa migration of modern humans. Interestingly, two other genes related to sepsis were also pseudogenized in humans, possibly by selection. These adaptive gene losses might have occurred because of changes in our environment or genetic background that altered the threat from or response to sepsis. The identification and analysis of human-specific pseudogenes open the door for understanding the roles of gene losses in human origins, and the demonstration that gene loss itself can be adaptive supports and extends the “less-is-more” hypothesis.     

The problem of astrocyte identity

Astrocytes were the original neuroglia of Ramón y Cajal but after 100 years there is no satisfactory definition of what should comprise this class of cells. This essay takes a historical and philosophical approach to the question of astrocytic identity. The classic approach of identification by morphology and location are too limited to determine new members of the astrocyte population. I also critically evaluate the use of protein markers measured by immunoreactivity, as well as the newer technique of marking living cells by using promoters for these same proteins to drive reporter genes. These two latter approaches have yielded an expanded population of astrocytes with diverse functions, but also mark cells that traditionally would not be defined as astrocytes. Thus we need a combination of measures to define an astrocyte but it is not clear what this combination should be. The molecular approach, especially promoter driven fluorescent reporter genes, does have the advantage of pre marking living astrocytes for electrophysiological or imaging recordings. However, lack of sufficient understanding of the behavior of the inserted constructs has led to unclear results. This approach will no doubt be perfected with time but at present an acceptable, practical definition of what constitutes the class of astrocytes remains elusive.     

Spatial variation in colour morph, spotting and allozyme frequencies in the candy-stripe spider, Enoplognatha ovata (Theridiidae) on two Swedish archipelagos

The selective significance, if any, of many invertebrate visible polymorphisms is still not fully understood. Here we examine colour- and black spotting-morph frequencies in the spider Enoplognatha ovata in populations on two Swedish archipelagos with respect to different spatial scales and, in one archipelago, against the background of variation at four putative neutral allozyme marker loci. Every population studied was polymorphic for colour and 28 out of 30 contained all three colour morphs – lineata, redimita and ovata. We found no evidence for a breakdown in the traditional colour morph designation previously suggested for other northern European populations of this species. For colour there is no significant heterogeneity at spatial scales greater than between local populations within islands. Black spotting frequencies show a similar lack of pattern over larger spatial scales except that there are significant differences between the Stockholm and Göteborg archipelagos. Measures of population differentiation (θ) within the Stockholm islands for the two visible systems show them to be significantly more differentiated than the neutral markers, suggesting local selection acting on them in a population-specific manner. On the basis of previous observations and the distribution of spotting phenotypes on a European scale, it is argued that thermal selection might operate on black spotting during the juvenile stages favouring more spots in continental climates. It is not clear what selective forces act on colour.     

The individuality of the species: A Darwinian theory? — from Buffon to Ghiselin, and back to Darwin

Since the 1970s, there has been a tremendous amount of literature on Ghiselin's proposal that “species are individuals”. After recalling the origins and stakes of this thesis in contemporary evolutionary theory, I show that it can also be found in the writings of the French naturalist Buffon in the 18th Century. Although Buffon did not have the conception that one species could be derived from another, there is an interesting similarity between the modern argument and that of Buffon regarding the “individuality of species’. The analogy is strong enough to force us to recognize that genuine evolutionary (or Darwinian) questions might be of secondary importance in the discussion. In consequence, the third section of the paper proposes an alternative schema for the “logical structure” of the Darwinian concept of species. Darwin distinguished the problem of the designation of a concrete species, and the problem of its signification of species within his theory of descent? The resulting notion of species involves a logical structure based on the fusion of the logical operations of classification and ordering. The difficulty — and interest — is that this interpretation of species does not entail any precise operational definition of species; it can only tell us what the ultimate signification of classification is within the theory of descent with modification through natural selection.     

Molecular fossils probe life's origins

Molecular fossils allow evolutionary biologists to look deep into the history of life on the Earth, far beyond the fossil record and possibly to the first living organisms.The fossil record—surviving mineral components or imprints of multicellular life—has provided valuable insights into how animals and plants evolved over millennia, but offers limited scope for discerning the origins of life itself or the separation of organisms into the three domains of eukaryotes, prokaryotes and archaea. The development of new technologies, however, is enabling scientists to analyse molecular fossils, such as the remnants of ancient nucleic acids, sugars, proteins, carbohydrates and lipids, to study the evolution of key metabolic pathways. This knowledge should enable researchers to peer back through time as far as the great oxidation event (GOE) that enabled the emergence of eukaryotic life. In addition to the analysis of the organic molecules themselves, the study of modern genomes to look for ancestral clues might yield knowledge about the protein structures present in the earliest forms of life.The GOE is thought to have occurred when cyanobacteria released free oxygen into the atmosphere through oxidative photosynthesis. While there is reasonable consensus that this occurred around 2.4 billion years ago, there is still uncertainty over how long it took until sufficient free oxygen accumulated to enable oxidative metabolism and, eventually, the emergence of new life forms. Initially, minerals, including iron, which would have been present in metallic form and plentiful, are thought to have taken up the oxygen produced by cyanobacteria. Atmospheric oxidation would not have started until the Earth''s surface minerals had become saturated, but the estimated time to that point ranges from 100 million years to 1 billion years. Because cyanobacteria are widely believed to be one of the first lifeforms because of their ability to thrive in anoxic conditions, resolution of this question could move scientists closer to establishing the origins of life.…molecular fossils provide information about the organisms they are derived from and the biosynthetic pathways in operation at the time of their formationUnlike physical fossils, molecular fossils do not contain material derived directly from the original organism itself, but rather are biomarkers that represent some of its specific chemical composition and provide a ‘signature''. Molecular fossils are embedded in rock or sediment and are altered over time by chemical and physical processes. As such, they can only be dated indirectly by analysis of the surrounding rock or sediment. Although direct dating methods are now considered fairly reliable, indirect methods are controversial because they rely on various assumptions, notably that the sample has not been contaminated and has remained fixed relative to its surroundings. “It is assumed the molecules of the microbes present in these rocks are of similar age,” said Stefan Schouten, an organic geochemist at the Royal Netherlands Institute for Sea Research, Texel, Netherlands. “Generally this assumption is correct, though in recent sediments offsets of up to 5,000 years have been noted.”The molecules are commonly separated from one another by using gas or high-pressure liquid chromatography and identified by mass spectrometry. The surrounding material is dated, usually by using well-established radiometric methods, often combined with stratigraphy: the analysis of rock or sediment formation through the accumulation of successive layers, which assumes that a lower layer must be older than the one above it.Despite the challenges, molecular fossils provide information about the organisms they are derived from and the biosynthetic pathways in operation at the time of their formation. Some of the key biomarkers in old deposits include sesquiterpenes, which indicate that a fossil came from a plant or insect; biphytanes, which point to archaea; hopanes, which suggest bacteria; 2-methylhopanes, which are specifically associated with cyanobacteria; and steranes, which point to eukaryotes. Hopanes, for instance, are derived from hopanoids, which give strength and rigidity to the plasma membranes of bacteria. Sterols fulfil a similar role in eukaryotes and form steranes under the action of sedimentary processes.The most extensive use of molecular fossils to date has been to search for biomarkers […] of the [great oxidation event] and the associated emergence of eukaryotic lifeThe most extensive use of molecular fossils to date has been to search for biomarkers that provide evidence of the GOE and the associated emergence of eukaryotic life. Notable advances have been made, but have raised major controversy over the duration of the GOE. In 1999, Jochen Brocks and colleagues at the University of Sydney, Australia, reported evidence that eukaryotes were present up to 2.7 billion years ago, which is 1 billion years earlier than had previously been believed [1]. In a paper published in Science, the researchers argued that the presence of abundant 2α-methylhopanes, which are characteristic of cyanobacteria, indicated that oxygenic photosynthesis evolved well before the atmosphere became oxidizing. They also wrote that, “the presence of steranes, particularly cholestane and its 28- to 30-carbon analogues, provides persuasive evidence for the existence of eukaryotes 500 million to 1 billion years before the extant fossil record indicates that the lineage arose.”The paper was heralded as a breakthrough and highly cited during the following decade. Brocks, however, discovered that some of the sediment samples that his team had used had been contaminated. In 2008, he coauthored a paper with different colleagues that essentially overturned the findings of the 1999 paper [2]. “The most important point is whether these biomarkers in 2.7 [billion year] old rocks are indeed that old,” Brocks said. “After many years of scientific dispute about them, others embraced the earlier findings and published follow up papers apparently vindicating the original 1999 results, but the community has come to the consensus that these hydrocarbons have entered the Archaean rocks at a later point in time” [3].Simon George, leader of the organic geochemistry group in the Department of Earth and Planetary Sciences at Macquarie University in Sydney, Australia, argues that although the discovery of contamination was a setback for Brocks and others, it does not disprove the validity of all other findings based on samples of an apparently similar age. “Jochen Brocks''s […] inference is that everybody''s work is based on contamination. He''s certainly proven that some of the samples he worked on were affected by contamination, but it''s a bit of a leap to say everyone else''s is,” George explained. He argued that findings of steranes in ancient samples have been repeated in different geographical locations and by a variety of people at several leading institutions. “I''d be surprised if everyone was seeing contamination,” he said.Gordon Love, an organic geochemist at the University of California Riverside, CA, USA, is more cautious. He commented that findings based on archaean rocks are often unreliable because the levels of biomarkers are very low, which makes it harder to sift out contaminants. “The pursuit of Archean lipid biomarkers has always been viewed as a very extreme application of molecular organic geochemistry requiring the most sophisticated and sensitive instrumentation to detect any signals at all,” he said. “We are talking about trace quantities of biomarkers that wouldn''t normally adversely affect ancient biomarker studies or even show up in routine analyses since the absolute yields of these compounds are so low, but which become significant when dealing with highly overmature Archean organic matter [original matter that has been transformed by thermal and chemical processes into oil and gas].” Nevertheless, Love noted that the conclusion that eukaryotes evolved over 2.5 billion years ago might still be correct. “We cannot say that the absence of steranes shows that eukaryotes had not evolved. The most appropriate conclusion, in my strong opinion, is that that organic matter found in Archean rocks has been so thermally transformed that we have no way of knowing whether eukaryotic biomarkers were ever present as original lipid constituents.”Answers might ultimately come from another promising line of research into archaean evolution that relies on the analysis of molecular fossils obtained from ‘fluid inclusions'' within sediment rocks. These are small microscopic bubbles of liquid and gas—typically 0.1–1.0 mm in diameter—trapped within crystals. Because they have been trapped since their formation, they are almost guaranteed to be free from contamination. The problem so far is that they have had to be analysed in bulk to provide enough fluid for separation and mass spectrometry. This requirement makes the work less reliable the further back you go because there is not enough fluid in single samples to date accurately anything that is older than 2.4 billion years.George and colleagues are now applying the well-known technique of ‘time-of-flight'' mass spectrometry to analyse individual fluid inclusions without having to extract them. This technique was developed more than 60 years ago and has long been used in inorganic chemistry. It works by directing ion beams at a sample to identify molecules by their mass-to-charge ratio. “You use beams of ions to drill down into rock and then when you get to the required depth you put the analysis beam on,” George explained. The principle is that the velocity of an ion depends on its mass-to-charge ratio, which can be calculated by measuring the time that it takes for the particle to reach a detector, thus identifying the particle. “It''s a way of assessing very small samples,” George said; adding that a lot more work on instrument development and the interpretation of results will be needed before we can say which biomarkers are present in fluid inclusion zones. “We think there are steranes in there, but it is hard for us to prove it,” George said. “We can definitely see hydrocarbons in there and be sure it is really old material, but because we can''t do gas chromatography separation on these we can''t be sure […] If we are able to prove fluid inclusions are holding this larger chemical record of life, it becomes a very important tool for understanding life''s origins, because we can go back as far as 3.2 billion years.”Love said that analysis of oil-bearing fluid inclusions, as practised by Simon George''s group, is a promising approach because the effects of extreme thermal maturity on organic molecules are often not as acute for migrated petroleum fluids trapped in sandstones under high pressure as they are for rock bitumens found in the parent rocks. But he cautioned that the migration of these fluid inclusions away from the parent rock where they originated introduces some uncertainty over dating. “There will always be some degree of ambiguity concerning the age and stratigraphic position of the parent source rock that actually generated the oil trapped in the inclusion,” Love explained. “At the same time, I look forward to seeing what they will generate from new, cleanly drilled Archean cores using the fluid inclusion approach.”Schouten likewise anticipates the results of this research and suggested that such work could finally settle the question of whether eukaryotes diverged from archaea and prokaryotes during the archaen period. “It is the work of Simon George on fluid inclusions which makes me think that we cannot fully dismiss that possibility yet,” he said.Modern genomes and proteins are also fossils in their own way, littered with evidence of genes that were useful to ancestral organisms but that have been abandoned or adapted in today''s species. The comparative analysis of genomes and surface proteins, for example, could help scientists understand how viruses evolved before the three domains of life split. Viruses are believed to have been around at the time, having coevolved with early life, but their presence is impossible to establish directly because they do not even leave molecular fossils. As such, viral evolution can only be studied through observation of their comparative structures and genetic sequences across life''s three domains. Only recently have virologists been able to look at viral origins and correlate them with the emergence of prokaryotes, eukaryotes and archaea.Sarah Butcher, from the Institute of Biotechnology at the University of Helsinki, Finland, led an international team that made a significant breakthrough in March 2013, based on an archaeal virus found in a salt pan [4]. “The major insight in the paper was to show that the molecular architecture of an archaeal virus is conserved both with the most common bacterial viruses and a wide range of eukaryotic viruses in the herpes family,” Butcher said. The study combined genomic analysis with electron microscopy and computerized image reconstruction to determine that the major coat protein of the isolated archaeal Haloarcula sinaiiensis tailed virus 1 (HSTV-1) has an almost identical structure to that of the bacterial virus Hong Kong 97 (HK97), which is one of the so called head-tailed dsDNA bacteriophages. This similarity had been predicted, but the study provided the first physical proof, backed up by equally compelling genomic evidence, according to Butcher. The analysis revealed that hallmark proteins found in dsDNA bacteriophages, such as terminases and portals, are present in the HSTV-1 genome. Furthermore, the genomes themselves had common structural features.Modern genomes and proteins are also fossils in their own way, littered with evidence of genes that were useful to ancestral organisms…Earlier work had already identified the same fold in herpes viruses, which infect a wide variety of animals, including humans [5]. As Butcher pointed out, the same lineage identified first in the HK97 bacteriophage has now been found in viruses from all three domains of life. Viruses have evolved unique mechanisms for infecting cells dependent on their hosts, but the capsid proteins seem to share common structural features. “The basic argument is that capsid proteins with the same fold share common ancestry, even when, as is often the case, they no longer share any detectable sequence similarity,” commented Roger Hendrix, a viral evolution specialist at the University of Pittsburgh, PA, USA. He explained that the idea is that the adaptation to different host environments led to fundamental sequence changes in ancestral viruses as new functions were acquired, but that there was no corresponding selective pressure to alter the fold of the capsid. “The simple interpretation of this is that there were viruses with some resemblance to modern viruses before cells started to divide into the three current domains and some of the then-existing viruses stuck with and coevolved with each of the three emerging cellular domains,” he said.He cautioned, however, that another explanation for the common fold could be that at some stage in evolution, after the three cellular domains of life split, a virus jumped across the domains, spreading the common fold. This is not likely to have occurred recently because the cells of the different domains have diverged so far that such a viral jump would be difficult, though it could have occurred only shortly after life split into three domains and cannot be ruled out.A third possible explanation for the common fold would be that it coevolved in parallel in each of the three domains, but this is less likely to have happened, according to Hendrix. “Co-evolution is a formal possibility but […] unlikely since I think it would imply that some protein folds are ‘ideal'' and selected in certain viruses of all three domains but not others,” he said. “There are too many successful ways to make a viral capsid for this to make sense, at least to me.”At any rate, the evidence does indicate that diverse viruses were around at the time of the last common ancestor of the three domains of life and contributed to their evolution through their ability to mutate quickly and donate genes to host genomes. As such, the work being done to untangle viral evolution by studying modern viruses is very much related to the advances being made with molecular fossils to probe our way back towards the origins of life.     

Assessing the non-target impacts of classical biological control agents: is host-testing always necessary?

Release of a biocontrol agent in New Zealand is typically preceded by non-target testing of native or valued species. Nevertheless, if both the target pest and the natural enemy are very different from any native fauna, then there may be no scientific justification for host testing. Gonatocerus ashmeadi (Girault) (Hymenoptera: Mymaridae) is being considered as a biocontrol agent for glassy winged sharpshooter, Homalodisca vitripennis (Germar) (Hemiptera: Cicadellidae), should the pest arrive. An assessment of the potential impact of G. ashmeadi on New Zealand’s Cicadellidae and Membracidae, from published literature data, indicates that none of these insects is at risk, as their eggs will not be recognised by the parasitoid because either their size or location places them outside the parasitoid’s search pattern. Consequently, there is no scientific case for any non-target host-testing to be carried out in containment.