Armand M. Leroi

What evidence is there for the existence of individual genes with antagonistic pleiotropic effects

Classical evolutionary theory predicts the existence of genes with antagonistic effects on longevity and various components of early-life fitness. Quantitative genetic studies have provided convincing evidence that such genes exist. However, antagonistic pleiotropic effects have rarely been attributed to individual loci. We examine several classes of longevity-assurance genes: those involved in regulation of the gonad; the insulin-like growth factor pathway; free-radical scavenging; heat shock proteins and apoptosis. We find initial evidence that antagonistic pleiotropic effects are pervasive in each of these classes of genes and in various model systems--although most studies lack explicit studies of fitness components. This is particularly true of human studies. Very little is known about the early-life fitness effects of longevity loci. Given the possible medical importance of such effects we urge their future study.

Origins and Evolution of a Transmissible Cancer

Canine transmissible venereal tumor (CTVT) is an infectious disease of dogs. Remarkably, the infectious agent is the cancerous cell itself. To investigate its origin and spread, we collected 37 tumor samples from four continents and determined their evolutionary relationships using microsatellite length differences and microarray-based comparative genomic hybridization (aCGH). The different tumors show very little microsatellite variation, and the pattern of variation that does exist is consistent with a purely asexual mode of transmission. Approximately one quarter of the loci scored by aCGH show copy number variation relative to normal dogs, again with little variation among different tumor samples. Sequence analysis of the RPPH1 gene indicates an origin from either dogs or wolves, and microsatellite analysis indicates that the tumor is more than 6000 years old, and perhaps originated when dogs were first domesticated. By contrast, the common ancestor of extant tumors lived within the last few hundred years, long after the first tumor. The genetic and genomic patterns we observe are typical of those expected of asexual pathogens, and the extended time since first origin may explain the many remarkable adaptations that have enabled this mammalian cell lineage to live as a unicellular pathogen.

Molecular signals versus the Loi de Balancement

Life history tradeoffs are often thought to be caused by the allocation of limited resources among competing traits such as reproduction, somatic growth and maintenance. One line of evidence supporting this comes from eliminating reproduction, for example, by surgically removing gonads. However, recent evidence from the nematode Caenorhabditis elegans suggests that the apparent tradeoffs it shows might not be due to resource allocation at all but rather to the effects of a molecular signal originating in the germ line that represses longevity. These results should cause us to rethink the interpretation of many classic experiments in life history evolution.

A metabolic signature of long life in Caenorhabditis elegans

BackgroundMany Caenorhabditis elegans mutations increase longevity and much evidence suggests that they do so at least partly via changes in metabolism. However, up until now there has been no systematic investigation of how the metabolic networks of long-lived mutants differ from those of normal worms. Metabolomic technologies, that permit the analysis of many untargeted metabolites in parallel, now make this possible. Here we use one of these, 1H nuclear magnetic resonance spectroscopy, to investigate what makes long-lived worms metabolically distinctive.ResultsWe examined three classes of long-lived worms: dauer larvae, adult Insulin/IGF-1 signalling (IIS)-defective mutants, and a translation-defective mutant. Surprisingly, these ostensibly different long-lived worms share a common metabolic signature, dominated by shifts in carbohydrate and amino acid metabolism. In addition the dauer larvae, uniquely, had elevated levels of modified amino acids (hydroxyproline and phosphoserine). We interrogated existing gene expression data in order to integrate functional (metabolite-level) changes with transcriptional changes at a pathway level.ConclusionsThe observed metabolic responses could be explained to a large degree by upregulation of gluconeogenesis and the glyoxylate shunt as well as changes in amino acid catabolism. These responses point to new possible mechanisms of longevity assurance in worms. The metabolic changes observed in dauer larvae can be explained by the existence of high levels of autophagy leading to recycling of cellular components.See associated minireview: http://jbiol.com/content/9/1/7

A Caenorhabditis elegans TGF‐β, DBL‐1, controls the expression of LON‐1, a PR‐related protein, that regulates polyploidization and body length

Using cDNA‐based array analysis combined with double‐stranded RNA interference (dsRNAi), we have identified yk298h6 as a target gene of Caenorhabditis elegans TGF‐β signaling. Worms overexpressing dbl‐1, a TGF‐β ligand, are 16% longer than wild type. Array analysis shows yk298h6 to be one of several genes suppressed in such worms. Disruption of yk298h6 function by dsRNAi also resulted in long worms, suggesting that it is a negative regulator of body length. yk298h6 was then mapped to, and shown to be identical to, lon‐1, a known gene that affects body length. lon‐1 encodes a 312 amino acid protein with a motif sequence that is conserved from plants to humans. Expression studies confirm that LON‐1 is repressed by DBL‐1, suggesting that LON‐1 is a novel downstream component of the C.elegans TGF‐β growth regulation pathway. Consistent with this, LON‐1 is expressed mainly in the larval and adult hypodermis and has dose‐dependent effects on body length associated with changes in hypodermal ploidy, but not hypodermal cell proliferation.

Mitochondrial Capture by a Transmissible Cancer

A clonal cancer in feral dogs has likely acquired mitochondria from its host by horizontal transfer. Canine transmissible venereal tumor (CTVT) is an infectious cell line circulating in many feral dog populations. It originated once, about 10,000 years ago. Phylogenetic analyses of mitochondrial sequences from dogs, wolves, and a geographically diverse collection of CTVT samples indicate that the cancer has periodically acquired mitochondria from its host. We suggest that this may be because the cancer’s own mitochondria have a tendency to degenerate, due to high mutation rates and relaxed selection, resulting in host mitochondria being more fit.

A novel mode of ecdysozoan growth in Caenorhabditis elegans

SUMMARY Whereas growth in many ecdysozoa is associated with only molting, larval growth in nematodes, specifically Caenorhabditis elegans, is thought to be continuous and exponential. However, this has never been closely investigated. Here we report several detailed studies of growth in wild‐type and dwarf C. elegans strains. We find that apparent exponential growth between hatching and adulthood comprises a series of linear phases, one per larval stage, with the linear growth rate increasing at successive molts. Although most structures grow continuously, the buccal cavity does not; instead, it grows saltationally at molts, like arthropod structures. We speculate that these saltational changes in mouth size permit changes in growth rate and that molting exists in nematodes to facilitate rapid growth. We study the cellular basis of this growth in the hypodermis. At each larval stage, lateral seam cells produce daughters that fuse with hyp7, a syncytium covering most of the worm. We find that seam cells and fusing daughter cells obtain larger sizes in successive molts. The total seam cell volume remains constant relative to the size of the worm. However, fusing daughter cells contributes only a very small amount directly to hypodermal growth, suggesting that most hyp7 growth must be intrinsic. Thus, dwarfism mutations studied principally act via adult syncytial growth, with cell size being near normal in both dbl‐1 and dpy‐2 mutant worms. We speculate that the main function of seam cell proliferation may be to supply the hypodermis with additional genomes for the purpose of growth.

A family tree in every gene

Shortly after last year’s tsunami devastated the lands on the Indian Ocean, The Times of India ran an article with this headline: ‘Tsunami may have rendered threatened tribes extinct’. The tribes in question were the Onge, Jarawa, Great Andamanese and Sentinelese – all living on the Andaman Islands and they numbered some 400 people in all. The article, noting that several of the archipelago’s islands were low-lying, in the direct path of the wave, and that casualties were expected to be high, said, ‘Some beads may have just gone missing from the Emerald Necklace of India’. The metaphor is as colorful as it is well intentioned. But what exactly does it mean? After all, in a catastrophe that cost more than 150,000 lives, why should the survival of a few hundred tribal people have any special claim on our attention? There are several possible answers to this question. The people of the Andamans have a unique way of life. True, their material culture does not extend beyond a few simple tools, and their visual art is confined to a few geometrical motifs, but they are hunter-gatherers and so a rarity in the modern world. Linguists, too, find them interesting since they collectively speak three languages seemingly unrelated to any others. But The Times of India took a slightly different tack. These tribes are special, it said, because they are of ‘Negrito racial stocks’ that are ‘remnants of the oldest human populations of Asia and Australia’. It’s an old-fashioned, even Victorian, sentiment. Who speaks of ‘racial stocks’ anymore? After all, to do so would be to speak of something that many scientists and scholars say does not exist. If modern anthropologists mention the concept of race, it is invariably only to warn against and dismiss it. Likewise many geneticists. ‘Race is a social concept, not a scientific one’, according to Dr Craig Venter – and he should know, since he was first to sequence the human genome. The idea that human races are only social constructs has been the consensus for at least 30 years. But now, perhaps, that is about to change. Last fall, the prestigious journal Nature Genetics devoted a large supplement to the question of whether human races exist and, if so, what they mean. The journal did this in part because various American health agencies are making race an important part of their policies to best protect the public – often over the protests of scientists. In the supplement, some two dozen geneticists offered their views. Beneath the jargon, cautious phrases and academic courtesies, one thing was clear: the consensus about social constructs was unraveling. Some even argued that, looked at the right way, genetic data show that races clearly do exist. The notion that human races do not exist can be dated to 1972. This is when Richard Lewontin, a Harvard geneticist, wrote an influential review showing that most human genetic variation can be found within any given ‘race’ (Lewontin 1972). If one looked at genes rather than faces, he claimed, the difference between an African and a European would be scarcely greater than the difference between any two Europeans. A few years later he wrote that the continued popularity of race as an idea was an ‘indication of the power of socioeconomically based ideology over the supposed objectivity of knowledge’ (Lewontin 1974). Most scientists are thoughtful, liberal-minded and socially aware people. It was just what they wanted to hear. Three decades later, it seems that Dr Lewontin’s facts were correct, and have been abundantly confirmed by ever better techniques of detecting genetic variety (e.g. Barbujani et al. 1997). His reasoning, however, was wrong. His error was an elementary one, but such was the appeal of his argument that it was only a couple of years ago that a Cambridge University statistician, A. W. F. Edwards, put his finger on it (Edwards 2003). The error is easily illustrated. If one were asked to judge the ancestry of 100 New Yorkers, one could look at the colour of their skin. That would do much to single out the Europeans, but little to distinguish the Senegalese from the Solomon Islanders. The same is true for any other feature of our bodies. The shapes of our eyes, noses and skulls; the colour of our eyes and our hair; the heaviness, height and hairiness of our bodies are all, individually, poor guides to ancestry. But this is not true when the features are taken together. Certain skin colours tend to go with certain kinds of eyes, noses, skulls and bodies. When we glance at a stranger’s face we use those associations to infer what continent, or even what country, he or his ancestors came from – and we usually get it right. To put it more abstractly, human physical variation is correlated; and correlations contain information. INVITED EDITORIAL

Regulation of growth by ploidy in Caenorhabditis elegans

Some animals, such as the larvae of Drosophila melanogaster, the larvae of the Appendicularian chordate Oikopleura, and the adults of the nematode Caenorhabditis elegans, are unusual in that they grow largely by increases in cell size. The giant cells of such species are highly polyploid, having undergone repeated rounds of endoreduplication. Since germline polyploid strains tend to have large cells, it is often assumed that endoreduplication drives cell growth, but this remains controversial. We have previously shown that adult growth in C. elegans is associated with the endoreduplication of nuclei in the epidermal syncitium, hyp 7. We show here that this relationship is causal. Manipulation of somatic ploidy both upwards and downwards increases and decreases, respectively, adult body size. We also establish a quantitative relationship between ploidy and body size. Finally, we find that TGF-beta (DBL-1) and cyclin E (CYE-1) regulate body size via endoreduplication. To our knowledge, this is the first experimental evidence establishing a cause-and-effect relationship between somatic polyploidization and body size in a metazoan.

The scale independence of evolution.

SUMMARY In this paper, I argue that the ultimate causes of morphological, and hence developmental, evolution are scale independent. In other words, micro‐ and macroevolutionary patterns show fundamental similarities and therefore are most simply explained as being caused by the same kinds of evolutionary forces. I begin by examining the evolution of single lineages and argue that dynamics of adaptive evolution are the same for bacteria in test‐tube evolution experiments and fossil lineages. Similarly, I argue that the essential features of adaptive radiations large and small can be attributed to conventional forces such as mutation and diversifying natural selection due to competition. I then address recent claims that the molecular features of metazoan development are the result of clade‐level selection for evolvability, and suggest that these features can be more easily explained by conventional individual‐level selection for the suppression of deleterious pleiotropic effects. Finally, I ask what must be known if we are to understand the ultimate causes of molecular and developmental diversity.