Plasmodium malariae and P. ovale genomes provide insights into malaria parasite evolution.

Elucidation of the evolutionary history and interrelatedness of Plasmodium species that infect humans has been hampered by a lack of genetic information for three human-infective species: P. malariae and two P. ovale species (P. o. curtisi and P. o. wallikeri). These species are prevalent across most regions in which malaria is endemic and are often undetectable by light microscopy, rendering their study in human populations difficult. The exact evolutionary relationship of these species to the other human-infective species has been contested. Using a new reference genome for P. malariae and a manually curated draft P. o. curtisi genome, we are now able to accurately place these species within the Plasmodium phylogeny. Sequencing of a P. malariae relative that infects chimpanzees reveals similar signatures of selection in the P. malariae lineage to another Plasmodium lineage shown to be capable of colonization of both human and chimpanzee hosts. Molecular dating suggests that these host adaptations occurred over similar evolutionary timescales. In addition to the core genome that is conserved between species, differences in gene content can be linked to their specific biology. The genome suggests that P. malariae expresses a family of heterodimeric proteins on its surface that have structural similarities to a protein crucial for invasion of red blood cells. The data presented here provide insight into the evolution of the Plasmodium genus as a whole.

Recent Adaptive Acquisition by African Rainforest Hunter-Gatherers of the Late Pleistocene Sickle-Cell Mutation Suggests Past Differences in Malaria Exposure.

The hemoglobin ßS sickle mutation is a textbook case in which natural selection maintains a deleterious mutation at high frequency in the human population. Homozygous individuals for this mutation develop sickle-cell disease, whereas heterozygotes benefit from higher protection against severe malaria. Because the overdominant ßS allele should be purged almost immediately from the population in the absence of malaria, the study of the evolutionary history of this iconic mutation can provide important information about the history of human exposure to malaria. Here, we sought to increase our understanding of the origins and time depth of the ßS mutation in populations with different lifestyles and ecologies, and we analyzed the diversity of HBB in 479 individuals from 13 populations of African farmers and rainforest hunter-gatherers. Using an approximate Bayesian computation method, we estimated the age of the ßS allele while explicitly accounting for population subdivision, past demography, and balancing selection. When the effects of balancing selection are taken into account, our analyses indicate a single emergence of ßS in the ancestors of present-day agriculturalist populations ∼22,000 years ago. Furthermore, we show that rainforest hunter-gatherers have more recently acquired the ßS mutation from the ancestors of agriculturalists through adaptive gene flow during the last ∼6,000 years. Together, our results provide evidence for a more ancient exposure to malarial pressures among the ancestors of agriculturalists than previously appreciated, and they suggest that rainforest hunter-gatherers have been increasingly exposed to malaria during the last millennia.

Transmissible cancer and the evolution of sex.

The origin and subsequent maintenance of sex and recombination are among the most elusive and controversial problems in evolutionary biology. Here, we propose a novel hypothesis, suggesting that sexual reproduction not only evolved to reduce the negative effects of the accumulation of deleterious mutations and processes associated with pathogen and/or parasite resistance but also to prevent invasion by transmissible selfish neoplastic cheater cells, henceforth referred to as transmissible cancer cells. Sexual reproduction permits systematic change of the multicellular organism's genotype and hence an enhanced detection of transmissible cancer cells by immune system. Given the omnipresence of oncogenic processes in multicellular organisms, together with the fact that transmissible cancer cells can have dramatic effects on their host fitness, our scenario suggests that the benefits of sex and concomitant recombination will be large and permanent, explaining why sexual reproduction is, despite its costs, the dominant mode of reproduction among eukaryotes.

Can postfertile life stages evolve as an anticancer mechanism?

Why a postfertile stage has evolved in females of some species has puzzled evolutionary biologists for over 50 years. We propose that existing adaptive explanations have underestimated in their formulation an important parameter operating both at the specific and the individual levels: the balance between cancer risks and cancer defenses. During their life, most multicellular organisms naturally accumulate oncogenic processes in their body. In parallel, reproduction, notably the pregnancy process in mammals, exacerbates the progression of existing tumors in females. When, for various ecological or evolutionary reasons, anticancer defenses are too weak, given cancer risk, older females could not pursue their reproduction without triggering fatal metastatic cancers, nor even maintain a normal reproductive physiology if the latter also promotes the growth of existing oncogenic processes, e.g., hormone-dependent malignancies. At least until stronger anticancer defenses are selected for in these species, females could achieve higher inclusive fitness by ceasing their reproduction and/or going through menopause (assuming that these traits are easier to select than anticancer defenses), thereby limiting the risk of premature death due to metastatic cancers. Because relatively few species experience such an evolutionary mismatch between anticancer defenses and cancer risks, the evolution of prolonged life after reproduction could also be a rare, potentially transient, anticancer adaptation in the animal kingdom.

Is adaptive therapy natural?

Research suggests that progression-free survival can be prolonged by integrating evolutionary principles into clinical cancer treatment protocols. The goal is to prevent or slow the proliferation of resistant malignant cell populations. The logic behind this therapy relies on ecological and evolutionary processes. These same processes would be available to natural selection in decreasing the probability of an organism's death due to cancer. We propose that organisms' anticancer adaptions include not only ones for preventing cancer but also ones for directing and retarding the evolution of life-threatening cancer cells. We term this last strategy natural adaptive therapy (NAT). The body's NAT might include a lower than otherwise possible immune response. A restrained immune response might forego maximum short-term kill rates. Restraint would forestall immune-resistant cancer cells and produce long-term durable control of the cancer population. Here, we define, develop, and explore the possibility of NAT. The discovery of NAT mechanisms could identify new strategies in tumor prevention and treatments. Furthermore, we discuss the potential risks of immunotherapies that force the immune system to ramp up the short-term kill rates of malignant cancer cells in a manner that undermines the body's NAT and accelerates the evolution of immune resistance.

Plasmodium vivax-like genome sequences shed new insights into Plasmodium vivax biology and evolution.

Although Plasmodium vivax is responsible for the majority of malaria infections outside Africa, little is known about its evolution and pathway to humans. Its closest genetic relative, P. vivax-like, was discovered in African great apes and is hypothesized to have given rise to P. vivax in humans. To unravel the evolutionary history and adaptation of P. vivax to different host environments, we generated using long- and short-read sequence technologies 2 new P. vivax-like reference genomes and 9 additional P. vivax-like genotypes. Analyses show that the genomes of P. vivax and P. vivax-like are highly similar and colinear within the core regions. Phylogenetic analyses clearly show that P. vivax-like parasites form a genetically distinct clade from P. vivax. Concerning the relative divergence dating, we show that the evolution of P. vivax in humans did not occur at the same time as the other agents of human malaria, thus suggesting that the transfer of Plasmodium parasites to humans happened several times independently over the history of the Homo genus. We further identify several key genes that exhibit signatures of positive selection exclusively in the human P. vivax parasites. Two of these genes have been identified to also be under positive selection in the other main human malaria agent, P. falciparum, thus suggesting their key role in the evolution of the ability of these parasites to infect humans or their anthropophilic vectors. Finally, we demonstrate that some gene families important for red blood cell (RBC) invasion (a key step of the life cycle of these parasites) have undergone lineage-specific evolution in the human parasite (e.g., reticulocyte-binding proteins [RBPs]).

The evolution of resistance and tolerance as cancer defences.

Although there is a plethora of cancer associated-factors that can ultimately culminate in death (cachexia, organ impairment, metastases, opportunistic infections, etc.), the focal element of every terminal malignancy is the failure of our natural defences to control unlimited cell proliferation. The reasons why our defences apparently lack efficiency is a complex question, potentially indicating that, under Darwinian terms, solutions other than preventing cancer progression are also important contributors. In analogy with host-parasite systems, we propose to call this latter option 'tolerance' to cancer. Here, we argue that the ubiquity of oncogenic processes among metazoans is at least partially attributable to both the limitations of resistance mechanisms and to the evolution of tolerance to cancer. Deciphering the ecological contexts of alternative responses to the cancer burden is not a semantic question, but rather a focal point in understanding the evolutionary ecology of host-tumour relationships, the evolution of our defences, as well as why and when certain cancers are likely to be detrimental for survival.

Second-harmonic-generation enhancement in cavity resonator integrated grating filters.

We demonstrate numerically and experimentally second-harmonic generation (SHG) in a cavity resonator integrated grating filter (CRIGF, a planar cavity resonator made of Bragg grating reflectors) around 1550 nm. SHG is modeled numerically for several different systems, including a thin plane layer of LiNbO3 without and with a grating coupler to excite a waveguide mode. We demonstrate that when the waveguide mode is confined to a CRIGF, designed to work with focused incident beams, the SHG power is increased more than 30 times, compared to the case of a single grating coupler used with an almost collimated pump beam.

Cancer adaptations: Atavism, de novo selection, or something in between?

From an evolutionary perspective, both atavism and somatic evolution/convergent evolution theories can account for the consistent occurrence, and astounding attributes of cancers: being able to evolve from a single cell to a complex organized system, and malignant transformations showing significant similarities across organs, individuals, and species. Here, we first provide an overview of these two hypotheses, including the possibility of them not being mutually exclusive, but rather potentially representing the two extremes of a continuum in which the diversity of cancers can emerge. In reviewing the current literature, we also discuss the criteria that should be applied to discriminate between the two competing theories and to determine their relevant contributions to oncogenesis and cancer progression. Finally, we deliberate on the potential applications of this conceptual framework in developing novel treatment strategies.

Ape malaria transmission and potential for ape-to-human transfers in Africa.

Recent studies have highlighted the large diversity of malaria parasites infecting African great apes (subgenus Laverania) and their strong host specificity. Although the existence of genetic incompatibilities preventing the cross-species transfer may explain host specificity, the existence of vectors with a high preference for a determined host represents another possibility. To test this hypothesis, we undertook a 15-mo-long longitudinal entomological survey in two forest regions of Gabon, where wild apes live, at different heights under the canopy. More than 2,400 anopheline mosquitoes belonging to 18 species were collected. Among them, only three species of Anopheles were found infected with ape Plasmodium: Anopheles vinckei, Anopheles moucheti, and Anopheles marshallii Their role in transmission was confirmed by the detection of the parasites in their salivary glands. Among these species, An. vinckei showed significantly the highest prevalence of infection and was shown to be able to transmit parasites of both chimpanzees and gorillas. Transmission was also shown to be conditioned by seasonal factors and by the heights of capture under the canopy. Moreover, human landing catches of sylvan Anopheles demonstrated the propensity of these three vector species to feed on humans when available. Our results suggest therefore that the strong host specificity observed in the Laveranias is not linked to a specific association between the vertebrate host and the vector species and highlight the potential role of these vectors as bridge between apes and humans.

Host manipulation by cancer cells: Expectations, facts, and therapeutic implications.

Similar to parasites, cancer cells depend on their hosts for sustenance, proliferation and reproduction, exploiting the hosts for energy and resources, and thereby impairing their health and fitness. Because of this lifestyle similarity, it is predicted that cancer cells could, like numerous parasitic organisms, evolve the capacity to manipulate the phenotype of their hosts to increase their own fitness. We claim that the extent of this phenomenon and its therapeutic implications are, however, underappreciated. Here, we review and discuss what can be regarded as cases of host manipulation in the context of cancer development and progression. We elaborate on how acknowledging the applicability of these principles can offer novel therapeutic and preventive strategies. The manipulation of host phenotype by cancer cells is one more reason to adopt a Darwinian approach in cancer research.

Malaria continues to select for sickle cell trait in Central Africa.

Sickle cell disease (SCD) is a genetic disorder that poses a serious health threat in tropical Africa, which the World Health Organization has declared a public health priority. Its persistence in human populations has been attributed to the resistance it provides to Plasmodium falciparum malaria in its heterozygous state, called sickle cell trait (SCT). Because of migration, SCT is becoming common outside tropical countries: It is now the most important genetic disorder in France, affecting one birth for every 2,400, and one of the most common in the United States. We assess the strength of the association between SCT and malaria, using current data for both SCT and malaria infections. A total of 3,959 blood samples from 195 villages distributed over the entire Republic of Gabon were analyzed. Hemoglobin variants were identified by using HPLCy (HPLC). Infections by three species of Plasmodium were detected by PCR followed by sequencing of a 201-bp fragment of cytochrome b. An increase of 10% in P. falciparum malaria prevalence is associated with an increase by 4.3% of SCT carriers. An increase of 10 y of age is associated with an increase by 5.5% of SCT carriers. Sex is not associated with SCT. These strong associations show that malaria remains a selective factor in current human populations, despite the progress of medicine and the actions undertaken to fight this disease. Our results provide evidence that evolution is still present in humans, although this is sometimes questioned by scientific, political, or religious personalities.

The Recent Evolution of a Maternally-Inherited Endosymbiont of Ticks Led to the Emergence of the Q Fever Pathogen, Coxiella burnetii.

Q fever is a highly infectious disease with a worldwide distribution. Its causative agent, the intracellular bacterium Coxiella burnetii, infects a variety of vertebrate species, including humans. Its evolutionary origin remains almost entirely unknown and uncertainty persists regarding the identity and lifestyle of its ancestors. A few tick species were recently found to harbor maternally-inherited Coxiella-like organisms engaged in symbiotic interactions, but their relationships to the Q fever pathogen remain unclear. Here, we extensively sampled ticks, identifying new and atypical Coxiella strains from 40 of 58 examined species, and used this data to infer the evolutionary processes leading to the emergence of C. burnetii. Phylogenetic analyses of multi-locus typing and whole-genome sequencing data revealed that Coxiella-like organisms represent an ancient and monophyletic group allied to ticks. Remarkably, all known C. burnetii strains originate within this group and are the descendants of a Coxiella-like progenitor hosted by ticks. Using both colony-reared and field-collected gravid females, we further establish the presence of highly efficient maternal transmission of these Coxiella-like organisms in four examined tick species, a pattern coherent with an endosymbiotic lifestyle. Our laboratory culture assays also showed that these Coxiella-like organisms were not amenable to culture in the vertebrate cell environment, suggesting different metabolic requirements compared to C. burnetii. Altogether, this corpus of data demonstrates that C. burnetii recently evolved from an inherited symbiont of ticks which succeeded in infecting vertebrate cells, likely by the acquisition of novel virulence factors.

Infections and cancer: the "fifty shades of immunity" hypothesis.

BACKGROUND: Since the beginning of the twentieth century, infection has emerged as a fundamental aspect of cancer causation with a growing number of pathogens recognized as oncogenic. Meanwhile, oncolytic viruses have also attracted considerable interest as possible agents of tumor destruction. DISCUSSION: Lost in the dichotomy between oncogenic and oncolytic agents, the indirect influence of infectious organisms on carcinogenesis has been largely unexplored. We describe the various ways - from functional aspects to evolutionary considerations such as modernity mismatches - by which infectious organisms could interfere with oncogenic processes through immunity. Finally, we discuss how acknowledging these interactions might impact public health approaches and suggest new guidelines for therapeutic and preventive strategies both at individual and population levels. Infectious organisms, that are not oncogenic neither oncolytic, may play a significant role in carcinogenesis, suggesting the need to increase our knowledge about immune interactions between infections and cancer.

High Prevalence of SXT/R391-Related Integrative and Conjugative Elements Carrying blaCMY-2 in Proteus mirabilis Isolates from Gulls in the South of France.

The genetic structures involved in the dissemination of blaCMY-2 carried by Proteus mirabilis isolates recovered from different gull species in the South of France were characterized and compared to clinical isolates. blaCMY-2 was identified in P. mirabilis isolates from 27/93 yellow-legged gulls and from 37/65 slender-billed gulls. It was carried by a conjugative SXT/R391-like integrative and conjugative element (ICE) in all avian strains and in 3/7 human strains. Two clinical isolates had the same genetic background as six avian isolates.

Evidence of lymphocytic choriomeningitis virus (LCMV) in domestic mice in Gabon: risk of emergence of LCMV encephalitis in Central Africa.

Lymphocytic choriomeningitis virus (LCMV) can cause acute fatal disease on all continents but was never detected in Africa. We report the first detection of LCMV RNA in a common European house mouse (Mus musculus domesticus) in Africa. Phylogenetic analyses show a close relationship with North American strains. These findings suggest that there is a risk of the appearance of LCMV acute encephalitis cases. This is a perfect example of virus dissemination by its natural host that may have dramatic public health consequences.

Cancer and life-history traits: lessons from host-parasite interactions.

Despite important differences between infectious diseases and cancers, tumour development (neoplasia) can nonetheless be closely compared to infectious disease because of the similarity of their effects on the body. On this basis, we predict that many of the life-history (LH) responses observed in the context of host-parasite interactions should also be relevant in the context of cancer. Parasites are thought to affect LH traits of their hosts because of strong selective pressures like direct and indirect mortality effects favouring, for example, early maturation and reproduction. Cancer can similarly also affect LH traits by imposing direct costs and/or indirectly by triggering plastic adjustments and evolutionary responses. Here, we discuss how and why a LH focus is a potentially productive but under-exploited research direction for cancer research, by focusing our attention on similarities between infectious disease and cancer with respect to their effects on LH traits and their evolution. We raise the possibility that LH adjustments can occur in response to cancer via maternal/paternal effects and that these changes can be heritable to (adaptively) modify the LH traits of their offspring. We conclude that LH adjustments can potentially influence the transgenerational persistence of inherited oncogenic mutations in populations.

Diversity, host switching and evolution of Plasmodium vivax infecting African great apes.

Plasmodium vivax is considered to be absent from Central and West Africa because of the protective effect of Duffy negativity. However, there are reports of persons returning from these areas infected with this parasite and observations suggesting the existence of transmission. Among the possible explanations for this apparent paradox, the existence of a zoonotic reservoir has been proposed. May great apes be this reservoir? We analyze the mitochondrial and nuclear genetic diversity of P. vivax parasites isolated from great apes in Africa and compare it to parasites isolated from travelers returning from these regions of Africa, as well as to human isolates distributed all over the world. We show that the P. vivax sequences from parasites of great apes form a clade genetically distinct from the parasites circulating in humans. We show that this clade's parasites can be infectious to humans by describing the case of a traveler returning from the Central African Republic infected with one of them. The relationship between this P. vivax clade in great apes and the human isolates is discussed.

Can Peto's paradox be used as the null hypothesis to identify the role of evolution in natural resistance to cancer? A critical review.

BACKGROUND: Carcinogenesis affects not only humans but almost all metazoan species. Understanding the rules driving the occurrence of cancers in the wild is currently expected to provide crucial insights into identifying how some species may have evolved efficient cancer resistance mechanisms. Recently the absence of correlation across species between cancer prevalence and body size (coined as Peto's paradox) has attracted a lot of attention. Indeed, the disparity between this null hypothesis, where every cell is assumed to have an identical probability to undergo malignant transformation, and empirical observations is particularly important to understand, due to the fact that it could facilitate the identification of animal species that are more resistant to carcinogenesis than expected. Moreover it would open up ways to identify the selective pressures that may be involved in cancer resistance. However, Peto's paradox relies on several questionable assumptions, complicating the interpretation of the divergence between expected and observed cancer incidences. DISCUSSIONS: Here we review and challenge the different hypotheses on which this paradox relies on with the aim of identifying how this null hypothesis could be better estimated in order to provide a standard protocol to study the deviation between theoretical/theoretically predicted and observed cancer incidence. We show that due to the disproportion and restricted nature of available data on animal cancers, applying Peto's hypotheses at species level could result in erroneous conclusions, and actually assume the existence of a paradox. Instead of using species level comparisons, we propose an organ level approach to be a more accurate test of Peto's assumptions. SUMMARY: The accuracy of Peto's paradox assumptions are rarely valid and/or quantifiable, suggesting the need to reconsider the use of Peto's paradox as a null hypothesis in identifying the influence of natural selection on cancer resistance mechanisms.

Genetic diversity of Plasmodium falciparum isolates from Baka Pygmies and their Bantu neighbours in the north of Gabon.

BACKGROUND: There have been many reports on the population genetic structure of Plasmodium falciparum from different endemic regions especially sub-Saharan Africa. However, few studies have been performed on neglected populations, such as the Pygmy populations. In this study, the population genetic structure of P. falciparum was investigated in the Baka Pygmies of Gabon and compared to that observed in neighboring villages composed mostly of Bantu farmers. METHODS: A total of 342 blood samples were collected from 170 Baka Pygmies and 172 Bantus in the north of Gabon (Woleu Ntem Province). Plasmodium infections were characterized by sequencing a portion of the parasite cytochrome b gene. Population genetic structure of P. falciparum in the different villages was analysed using microsatellite markers and genes coding for antigenic proteins (MSP1, MSP2, GLURP, and EBA-175). RESULTS: Overall, prevalence of P. falciparum was around 57 % and no significant difference of prevalence was observed between Pygmies and Bantus. No significant differences of population genetic structure of P. falciparum was found between Pygmy and Bantu people except for one antigen-coding gene, glurp, for which genetic data suggested the existence of a potentially disruptive selection acting on this gene in the two types of populations. The genetic structure of P. falciparum followed a pattern of isolation by distance at the scale of the study. CONCLUSION: The prevalence and genetic diversity of P. falciparum observed in Baka demonstrates a significant transmission of the parasite in this population, and some exchanges of parasites with Bantu neighbours. Despite that, some antigen-coding genes seem to have had a particular evolutionary trajectory in certain Pygmy populations due to specific local human and/or mosquito characteristics.