The real war on cancer: the evolutionary dynamics of cancer suppression.

Cancer is a disease of multicellular animals caused by unregulated cell division. The prevailing model of cancer (multistage carcinogenesis) is based on the view that cancer results after a series of (generally somatic) mutations that knock out the genetic mechanisms suppressing unregulated cell growth. The chance of these mutations occurring increases with size and longevity, leading to Peto's paradox: why don't large animals have a higher lifetime incidence of cancer than small animals? The solution to this paradox is evolution. From an evolutionary perspective, an increasing frequency of prereproductive cancer deaths results in natural selection for enhanced cancer suppression. The expected result is a prereproductive risk of cancer across species that is independent of life history. However, within species, we still expect cancer risk to increase with size and longevity. Here, I review the evolutionary model of cancer suppression and some recent empirical evidence supporting it. Data from humans and domestic dogs confirm the expected intraspecific association between size and cancer risk, while results from interspecific comparisons between rodents provide the best evidence to date of the predicted recruitment of additional cancer suppression mechanisms as species become larger or longer lived

The expression of tumour suppressors and proto-oncogenes in tissues susceptible to their hereditary cancers.

BackgroundStudies of familial cancers have found that only a small subset of tissues are affected by inherited mutations in a given tumour suppressor gene (TSG) or proto-oncogene (POG), even though the mutation is present in all tissues. Previous tests have shown that tissue specificity is not due to the presence vs absence of gene expression, as TSGs and POGs are expressed in nearly every type of normal human tissue. Using published microarray expression data we tested the related hypothesis that tissue-specific expression of a TSG or POG is highest in tissue where it is of oncogenic importance.MethodsWe tested this hypothesis by examining whether individual TSGs and POGs had higher expression in the normal (noncancerous) tissues where they are implicated in familial cancers relative to those tissues where they are not. We examined data for 15 TSGs and 8 POGs implicated in familial cancer across 12 human tissue types.ResultsWe found a significant difference between expression levels in susceptible vs nonsusceptible tissues. It was found that 9 (60%, P<0.001) of the TSGs and 5 (63%, P<0.001) of the POGs had their highest expression level in the tissue type susceptible to their oncogenic effect.ConclusionsThis highly significant association supports the hypothesis that mutation of a specific TSG or POG is likely to be most oncogenic in the tissue where the gene has its highest level of expression. This suggests that high expression in normal tissues is a potential marker for linking cancer-related genes with their susceptible tissues

Host and symbiont genetic contributions to fitness in a Trichogramma-Wolbachia symbiosis.

The fitness effects associated with Wolbachia infection have wide-ranging ecological and evolutionary consequences for host species. How these effects are modulated by the relative influence of host and Wolbachia genomes has been described as a balancing act of genomic cooperation and conflict. For vertically transmitted symbionts, like cytoplasmic Wolbachia, concordant host-symbiont fitness interests would seem to select for genomic cooperation. However, Wolbachia's ability to manipulate host reproductive systems and distort offspring sex ratios presents an evolutionary conflict of interest with infected hosts. In the parthenogenesis-inducing (PI) form of Wolbachia found in many haplodiploid insects, Wolbachia fitness is realized through females and is enhanced by their feminization of male embryos and subsequent parthenogenetic reproduction. In contrast, as long as Wolbachia is not fixed in a population and sexual reproduction persists, fitness for the host species is realized through both male and female offspring production. How these cooperating and competing interests interact and the relative influence of host and Wolbachia genomes were investigated in the egg parasitoid Trichogramma kaykai, where Wolbachia infection has remained at a low frequency in the field. A factorial design in which laboratory cultures of Wolbachia-infected T. kaykai were cured and re-infected with alternative Wolbachia strains was used to determine the relative influence of host and Wolbachia genomes on host fitness values. Our results suggest fitness variation is largely a function of host genetic background, except in the case of offspring sex ratio where a significant interaction between host and Wolbachia genomes was found. We also find a significant effect associated with the horizontal transfer of Wolbachia strains, which we discuss in terms of the potential for coadaptation in PI-Wolbachia symbioses

Intragenomic conflict in populations infected by Parthenogenesis Inducing Wolbachia ends with irreversible loss of sexual reproduction

<p>Abstract</p> <p>Background</p> <p>The maternally inherited, bacterial symbiont, parthenogenesis inducing (PI) <it>Wolbachia</it>, causes females in some haplodiploid insects to produce daughters from both fertilized and unfertilized eggs. The symbionts, with their maternal inheritance, benefit from inducing the production of exclusively daughters, however the optimal sex ratio for the nuclear genome is more male-biased. Here we examine through models how an infection with PI-<it>Wolbachia </it>in a previously uninfected population leads to a genomic conflict between PI-<it>Wolbachia </it>and the nuclear genome. In most natural populations infected with PI-<it>Wolbachia </it>the infection has gone to fixation and sexual reproduction is impossible, specifically because the females have lost their ability to fertilize eggs, even when mated with functional males.</p> <p>Results</p> <p>The PI <it>Wolbachia </it>infection by itself does not interfere with the fertilization process in infected eggs, fertilized infected eggs develop into biparental infected females. Because of the increasingly female-biased sex ratio in the population during a spreading PI-<it>Wolbachia </it>infection, sex allocation alleles in the host that cause the production of more sons are rapidly selected. In haplodiploid species a reduced fertilization rate leads to the production of more sons. Selection for the reduced fertilization rate leads to a spread of these alleles through both the infected and uninfected population, eventually resulting in the population becoming fixed for both the PI-<it>Wolbachia </it>infection and the reduced fertilization rate. Fertilization rate alleles that completely interfere with fertilization ("virginity alleles") will be selected over alleles that still allow for some fertilization. This drives the final resolution of the conflict: the irreversible loss of sexual reproduction and the complete dependence of the host on its symbiont.</p> <p>Conclusions</p> <p>This study shows that dependence among organisms can evolve rapidly due to the resolution of the conflicts between cytoplasmic and nuclear genes, and without requiring a mutualism between the partners.</p

Understanding and Estimating Effective Population Size for Practical Application in Marine Species Management

Effective population size (Ne) determines the strength of genetic drift in a population and has long been recognized as an important parameter for evaluating conservation status and threats to genetic health of populations. Specifically, an estimate of Ne is crucial to management because it integrates genetic effects with the life history of the species, allowing for predictions of a population’s current and future viability. Nevertheless, compared with ecological and demographic parameters, Ne has had limited influence on species management, beyond its application in very small populations. Recent developments have substantially improved Ne estimation; however, some obstacles remain for the practical application of Ne estimates. For example, the need to define the spatial and temporal scale of measurement makes the concept complex and sometimes difficult to interpret. We reviewed approaches to estimation of Ne over both long-term and contemporary time frames, clarifying their interpretations with respect to local populations and the global metapopulation. We describe multiple experimental factors affecting robustness of contemporary Ne estimates and suggest that different sampling designs can be combined to compare largely independent measures of Ne for improved confidence in the result. Large populations with moderate gene flow pose the greatest challenges to robust estimation of contemporary Ne and require careful consideration of sampling and analysis to minimize estimator bias. We emphasize the practical utility of estimating Ne by highlighting its relevance to the adaptive potential of a population and describing applications in management of marine populations, where the focus is not always on critically endangered populations. Two cases discussed include the mechanisms generating Ne estimates many orders of magnitude lower than census N in harvested marine fishes and the predicted reduction in Ne from hatchery-based population supplementation

Understanding and Estimating Effective Population Size for Practical Application in Marine Species Management

Effective population size (Ne) determines the strength of genetic drift in a population and has long been recognized as an important parameter for evaluating conservation status and threats to genetic health of populations. Specifically, an estimate of Ne is crucial to management because it integrates genetic effects with the life history of the species, allowing for predictions of a population’s current and future viability. Nevertheless, compared with ecological and demographic parameters, Ne has had limited influence on species management, beyond its application in very small populations. Recent developments have substantially improved Ne estimation; however, some obstacles remain for the practical application of Ne estimates. For example, the need to define the spatial and temporal scale of measurement makes the concept complex and sometimes difficult to interpret. We reviewed approaches to estimation of Ne over both long-term and contemporary time frames, clarifying their interpretations with respect to local populations and the global metapopulation. We describe multiple experimental factors affecting robustness of contemporary Ne estimates and suggest that different sampling designs can be combined to compare largely independent measures of Ne for improved confidence in the result. Large populations with moderate gene flow pose the greatest challenges to robust estimation of contemporary Ne and require careful consideration of sampling and analysis to minimize estimator bias. We emphasize the practical utility of estimating Ne by highlighting its relevance to the adaptive potential of a population and describing applications in management of marine populations, where the focus is not always on critically endangered populations. Two cases discussed include the mechanisms generating Ne estimates many orders of magnitude lower than census N in harvested marine fishes and the predicted reduction in Ne from hatchery-based population supplementation

The Complex Biogeography of the Plant Pathogen Xylella fastidiosa: Genetic Evidence of Introductions and Subspecific Introgression in Central America

Datos y artículo incluido por Lisela Moreira Carmona, responsable de depósitos de publicaciones del área de Patógenos y Plagas del CIBCMThe bacterium Xylella fastidiosa is a plant pathogen with a history of economically damaging introductions of subspecies to regions where its other subspecies are native. Genetic evidence is presented demonstrating the introduction of two new taxa into Central America and their introgression into the native subspecies, X. fastidiosa subsp. fastidiosa. The data are from 10 genetic outliers detected by multilocus sequence typing (MLST) of isolates from Costa Rica. Six (five from oleander, one from coffee) defined a new sequence type (ST53) that carried alleles at six of the eight loci sequenced (five of the seven MLST loci) diagnostic of the South American subspecies Xylella fastidiosa subsp. pauca which causes two economically damaging plant diseases, citrus variegated chlorosis and coffee leaf scorch. The two remaining loci of ST53 carried alleles from what appears to be a new South American form of X. fastidiosa. Four isolates, classified as X. fastidiosa subsp. fastidiosa, showed a low level of introgression of non-native DNA. One grapevine isolate showed introgression of an allele from X. fastidiosa subsp. pauca while the other three (from citrus and coffee) showed introgression of an allele with similar ancestry to the alleles of unknown origin in ST53. The presence of X. fastidiosa subsp. pauca in Central America is troubling given its disease potential, and establishes another route for the introduction of this economically damaging subspecies into the US or elsewhere, a threat potentially compounded by the presence of a previously unknown form of X. fastidiosa.Universidad de Costa Rica/[801-B2-516]/UCR/Costa RicaUniversidad de Costa Rica/[801-A1-801]/UCR/Costa RicaInternational Foundation for Science/[grant C/5152-1]/IFS/SueciaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM

Population Genomic Analysis of a Bacterial Plant Pathogen: Novel Insight into the Origin of Pierce's Disease of Grapevine in the U.S.

Invasive diseases present an increasing problem worldwide; however, genomic techniques are now available to investigate the timing and geographical origin of such introductions. We employed genomic techniques to demonstrate that the bacterial pathogen causing Pierce's disease of grapevine (PD) is not native to the US as previously assumed, but descended from a single genotype introduced from Central America. PD has posed a serious threat to the US wine industry ever since its first outbreak in Anaheim, California in the 1880s and continues to inhibit grape cultivation in a large area of the country. It is caused by infection of xylem vessels by the bacterium Xylella fastidiosa subsp. fastidiosa, a genetically distinct subspecies at least 15,000 years old. We present five independent kinds of evidence that strongly support our invasion hypothesis: 1) a genome-wide lack of genetic variability in X. fastidiosa subsp. fastidiosa found in the US, consistent with a recent common ancestor; 2) evidence for historical allopatry of the North American subspecies X. fastidiosa subsp. multiplex and X. fastidiosa subsp. fastidiosa; 3) evidence that X. fastidiosa subsp. fastidiosa evolved in a more tropical climate than X. fastidiosa subsp. multiplex; 4) much greater genetic variability in the proposed source population in Central America, variation within which the US genotypes are phylogenetically nested; and 5) the circumstantial evidence of importation of known hosts (coffee plants) from Central America directly into southern California just prior to the first known outbreak of the disease. The lack of genetic variation in X. fastidiosa subsp. fastidiosa in the US suggests that preventing additional introductions is important since new genetic variation may undermine PD control measures, or may lead to infection of other crop plants through the creation of novel genotypes via inter-subspecific recombination. In general, geographically mixing of previously isolated subspecies should be avoided

Simulation Results

Results of all simulations used to create figure and tables

Resolving Peto's paradox: Modeling the potential effects of size-related metabolic changes, and of the evolution of immune policing and cancer suppression.

The intrinsic risk of cancer increases with body size and longevity; however, big long-lived species do not exhibit this increase, a contradiction named Peto's paradox. Five hypotheses potentially resolving this paradox were modeled using the multistage model of carcinogenesis. The five hypotheses were based on (1) intrinsic changes in metabolic rate with body size; adaptive increase in immune policing of (2) cancer cells or (3) cells with driver mutations; or adaptive increase in cancer suppression via (4) decreased somatic mutation rate, or (5) increased genetic control. Parameter changes needed to stabilize cancer risk in three types of cancer were estimated for tissues scaled from mouse size and longevity to human and blue whale levels. The metabolic rate hypothesis alone was rejected due to a conflict between the required interspecific effect with the observed intraspecific effect of size on cancer risk, but some metabolic change was optionally incorporated in the other models. Necessary parameter changes in immune policing and somatic mutation rate far exceeded values observed; however, natural selection increasing the genetic suppression of cancer was generally consistent with data. Such adaptive increases in genetic control of cancers in large and/or long-lived animals raise the possibility that nonmodel animals will reveal novel anticancer mechanisms