RESUMO
Correctly delimiting species and populations is a prerequisite for studies of connectivity, adaptation and conservation. Genomic data are particularly useful to test species differentiation for organisms with few informative morphological characters or low discrimination of cytoplasmic markers, as in Scleractinians. Here we applied Restriction site Associated DNA sequencing (RAD-sequencing) to the study of species differentiation and genetic structure in populations of Pocillopora spp. from Oman and French Polynesia, with the objectives to test species hypotheses, and to study the genetic structure among sampling sites within species. We focused here on coral colonies morphologically similar to P. acuta (damicornis type ß). We tested the impact of different filtering strategies on the stability of the results. The main genetic differentiation was observed between samples from Oman and French Polynesia. These samples corresponded to different previously defined primary species hypotheses (PSH), i.e., PSHs 12 and 13 in Oman, and PSH 5 in French Polynesia. In Oman, we did not observe any clear differentiation between the two putative species PSH 12 and 13, nor between sampling sites. In French Polynesia, where a single species hypothesis was studied, there was no differentiation between sites. Our analyses allowed the identification of clonal lineages in Oman and French Polynesia. The impact of clonality on genetic diversity is discussed in light of individual-based simulations.
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Antozoários , Animais , Antozoários/genética , Estruturas Genéticas , Metagenômica , Análise de Sequência de DNA , Especificidade da EspécieRESUMO
Deep hydrothermal vents are highly fragmented and unstable habitats at all temporal and spatial scales. Such environmental dynamics likely play a non-negligible role in speciation. Little is, however, known about the evolutionary processes that drive population-level differentiation and vent species isolation and, more specifically, how geography and habitat specialisation interplay in the species history of divergence. In this study, the species range and divergence of Alviniconcha snails that occupy active Western Pacific vent fields was assessed by using sequence variation data of the mitochondrial Cox1 gene, RNAseq, and ddRAD-seq. Combining morphological description and sequence datasets of the three species across five basins, we confirmed that A. kojimai, A. boucheti, and A. strummeri, while partially overlapping over their range, display high levels of divergence in the three genomic compartments analysed that usually encompass values retrieved for reproductively isolated species with divergences rang from 9% to 12.5% (mtDNA) and from 2% to 3.1% (nuDNA). Moreover, the three species can be distinguished on the basis of their external morphology by observing the distribution of bristles and the shape of the columella. According to this sampling, A. boucheti and A. kojimai form an east-to-west species abundance gradient, whereas A. strummeri is restricted to the Futuna Arc/Lau and North Fiji Basins. Surprisingly, population models with both gene flow and population size heterogeneities among genomes indicated that these three species are still able to exchange genes due to secondary contacts at some localities after a long period of isolation.
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Fontes Hidrotermais , Animais , DNA Mitocondrial/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Filogenia , CaramujosRESUMO
House mice (Mus musculus) have spread globally as a result of their commensal relationship with humans. In the form of laboratory strains, both inbred and outbred, they are also among the most widely used model organisms in biomedical research. Although the general outlines of house mouse dispersal and population structure are well known, details have been obscured by either limited sample size or small numbers of markers. Here we examine ancestry, population structure, and inbreeding using SNP microarray genotypes in a cohort of 814 wild mice spanning five continents and all major subspecies of Mus, with a focus on M. m. domesticus. We find that the major axis of genetic variation in M. m. domesticus is a south-to-north gradient within Europe and the Mediterranean. The dominant ancestry component in North America, Australia, New Zealand, and various small offshore islands are of northern European origin. Next we show that inbreeding is surprisingly pervasive and highly variable, even between nearby populations. By inspecting the length distribution of homozygous segments in individual genomes, we find that inbreeding in commensal populations is mostly due to consanguinity. Our results offer new insight into the natural history of an important model organism for medicine and evolutionary biology.
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Genoma , Endogamia , Animais , Evolução Biológica , Europa (Continente) , Humanos , Camundongos , Nova ZelândiaRESUMO
Hydrothermal vents form archipelagos of ephemeral deep-sea habitats that raise interesting questions about the evolution and dynamics of the associated endemic fauna, constantly subject to extinction-recolonization processes. These metal-rich environments are coveted for the mineral resources they harbour, thus raising recent conservation concerns. The evolutionary fate and demographic resilience of hydrothermal species strongly depend on the degree of connectivity among and within their fragmented metapopulations. In the deep sea, however, assessing connectivity is difficult and usually requires indirect genetic approaches. Improved detection of fine-scale genetic connectivity is now possible based on genome-wide screening for genetic differentiation. Here, we explored population connectivity in the hydrothermal vent snail Ifremeria nautilei across its species range encompassing five distinct back-arc basins in the Southwest Pacific. The global analysis, based on 10,570 single nucleotide polymorphism (SNP) markers derived from double digest restriction-site associated DNA sequencing (ddRAD-seq), depicted two semi-isolated and homogeneous genetic clusters. Demogenetic modeling suggests that these two groups began to diverge about 70,000 generations ago, but continue to exhibit weak and slightly asymmetrical gene flow. Furthermore, a careful analysis of outlier loci showed subtle limitations to connectivity between neighbouring basins within both groups. This finding indicates that migration is not strong enough to totally counterbalance drift or local selection, hence questioning the potential for demographic resilience at this latter geographical scale. These results illustrate the potential of large genomic data sets to understand fine-scale connectivity patterns in hydrothermal vents and the deep sea.
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Fontes Hidrotermais , Animais , Ecossistema , Fluxo Gênico , Análise de Sequência de DNA , Caramujos/genéticaRESUMO
Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
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DNA Mitocondrial , Cromossomo X , Alelos , Animais , Haplótipos , Humanos , Proteínas de Membrana/genética , Camundongos , Mutação , Vitamina K Epóxido Redutases/genéticaRESUMO
Reports of morphological differences between European anchovy (Engraulis cf. encrasicolus) from coastal and marine habitats have long existed in the ichthyologic literature and have given rise to a long-standing debate on their taxonomic status. More recently, molecular studies have confirmed the existence of genetic differentiation between the two anchovy ecotypes. Using ancestry-informative markers, we show that coastal anchovies throughout the Mediterranean share a common ancestry and that substantial genetic differentiation persists in different pairs of coastal/marine populations despite the presence of limited gene flow. On the basis of genetic and ecological arguments, we propose that coastal anchovies deserve a species status of their own (E. maeoticus) and argue that a unified taxonomical framework is critical for future research and management.
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Peixes , Alimentos Marinhos , Animais , Ecossistema , Peixes/genética , Fluxo Gênico , Deriva GenéticaRESUMO
Understanding how new species arise through the progressive establishment of reproductive isolation (RI) barriers between diverging populations is a major goal in Evolutionary Biology. An important result of speciation genomics studies is that genomic regions involved in RI frequently harbor anciently diverged haplotypes that predate the reconstructed history of species divergence. The possible origins of these old alleles remain much debated, as they relate to contrasting mechanisms of speciation that are not yet fully understood. In the European sea bass (Dicentrarchus labrax), the genomic regions involved in RI between Atlantic and Mediterranean lineages are enriched for anciently diverged alleles of unknown origin. Here, we used haplotype-resolved whole-genome sequences to test whether divergent haplotypes could have originated from a closely related species, the spotted sea bass (Dicentrarchus punctatus). We found that an ancient admixture event between D. labrax and D. punctatus is responsible for the presence of shared derived alleles that segregate at low frequencies in both lineages of D. labrax. An exception to this was found within regions involved in RI between the two D. labrax lineages. In those regions, archaic tracts originating from D. punctatus locally reached high frequencies or even fixation in Atlantic genomes but were almost absent in the Mediterranean. We showed that the ancient admixture event most likely occurred between D. punctatus and the D. labrax Atlantic lineage, while Atlantic and Mediterranean D. labrax lineages were experiencing allopatric isolation. Our results suggest that local adaptive introgression and/or the resolution of genomic conflicts provoked by ancient admixture have probably contributed to the establishment of RI between the two D. labrax lineages.
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The house mouse (Mus musculus) represents the extreme of globalization of invasive mammals. However, the timing and basis of its origin and early phases of dispersal remain poorly documented. To track its synanthropisation and subsequent invasive spread during the develoment of complex human societies, we analyzed 829 Mus specimens from 43 archaeological contexts in Southwestern Asia and Southeastern Europe, between 40,000 and 3,000 cal. BP, combining geometric morphometrics numerical taxonomy, ancient mitochondrial DNA and direct radiocarbon dating. We found that large late hunter-gatherer sedentary settlements in the Levant, c. 14,500 cal. BP, promoted the commensal behaviour of the house mouse, which probably led the commensal pathway to cat domestication. House mouse invasive spread was then fostered through the emergence of agriculture throughout the Near East 12,000 years ago. Stowaway transport of house mice to Cyprus can be inferred as early as 10,800 years ago. However, the house mouse invasion of Europe did not happen until the development of proto urbanism and exchange networks - 6,500 years ago in Eastern Europe and 4000 years ago in Southern Europe - which in turn may have driven the first human mediated dispersal of cats in Europe.
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DNA Mitocondrial/genética , Camundongos/classificação , Mitocôndrias/genética , Análise de Sequência de DNA/veterinária , Animais , Arqueologia , Ásia Ocidental , Chipre , Europa Oriental , Humanos , Espécies Introduzidas , Camundongos/genética , Datação RadiométricaRESUMO
Understanding the genetic underpinnings of fitness trade-offs across spatially variable environments remains a major challenge in evolutionary biology. In Mediterranean gilthead sea bream, first-year juveniles use various marine and brackish lagoon nursery habitats characterized by a trade-off between food availability and environmental disturbance. Phenotypic differences among juveniles foraging in different habitats rapidly appear after larval settlement, but the relative role of local selection and plasticity in phenotypic variation remains unclear. Here, we combine phenotypic and genetic data to address this question. We first report correlations of opposite signs between growth and condition depending on juvenile habitat type. Then, we use single nucleotide polymorphism (SNP) data obtained by Restriction Associated DNA (RAD) sequencing to search for allele frequency changes caused by a single generation of spatially varying selection between habitats. We found evidence for moderate selection operating at multiple loci showing subtle allele frequency shifts between groups of marine and brackish juveniles. We identified subsets of candidate outlier SNPs that, in interaction with habitat type, additively explain up to 3.8% of the variance in juvenile growth and 8.7% in juvenile condition; these SNPs also explained significant fraction of growth rate in an independent larval sample. Our results indicate that selective mortality across environments during early-life stages involves complex trade-offs between alternative growth strategies.
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Interação Gene-Ambiente , Aptidão Genética/genética , Dourada/genética , Seleção Genética/genética , Animais , Ecossistema , Meio Ambiente , Frequência do Gene , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genéticaRESUMO
Evaluating species dispersal across the landscape is essential to design appropriate management and conservation actions. However, technical difficulties often preclude direct measures of individual movement, while indirect genetic approaches rely on assumptions that sometimes limit their application. Here, we show that the temporal decay of admixture tracts lengths can be used to assess genetic connectivity within a population introgressed by foreign haplotypes. We present a proof-of-concept approach based on local ancestry inference in a high gene flow marine fish species, the European sea bass (Dicentrarchus labrax). Genetic admixture in the contact zone between Atlantic and Mediterranean sea bass lineages allows the introgression of Atlantic haplotype tracts within the Mediterranean Sea. Once introgressed, blocks of foreign ancestry are progressively eroded by recombination as they diffuse from the western to the eastern Mediterranean basin, providing a means to estimate dispersal. By comparing the length distributions of Atlantic tracts between two Mediterranean populations located at different distances from the contact zone, we estimated the average per-generation dispersal distance within the Mediterranean lineage to less than 50 km. Using simulations, we showed that this approach is robust to a range of demographic histories and sample sizes. Our results thus support that the length of admixture tracts can be used together with a recombination clock to estimate genetic connectivity in species for which the neutral migration-drift balance is not informative or simply does not exist.
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North Africa is now recognized as a major area for the emergence and dispersal of anatomically modern humans from at least 315 kya. The Mediterranean Basin is thus particularly suited to study the role of climate versus human-mediated changes on the evolutionary history of species. The Algerian mouse (Mus spretus Lataste) is an endemic species from this basin, with its distribution restricted to North Africa (from Libya to Morocco), Iberian Peninsula and South of France. A rich paleontological record of M. spretus exists in North Africa, suggesting hypotheses concerning colonization pathways, and the demographic and morphologic history of this species. Here we combined genetic (3 mitochondrial DNA loci and 18 microsatellites) and climatic niche modeling data to infer the evolutionary history of the Algerian mouse. We collected 646 new individuals in 51 localities. Our results are consistent with an anthropogenic translocation of the Algerian mouse from North Africa to the Iberian Peninsula via Neolithic navigators, probably from the Tingitane Peninsula. Once arrived in Spain, suitable climatic conditions would then have favored the dispersion of the Algerian mice to France. The morphological differentiation observed between Spanish, French and North African populations could be explained by a founder effect and possibly local adaptation. This article helps to better understand the role of climate versus human-mediated changes on the evolutionary history of mammal species in the Mediterranean Basin.
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Migração Animal , Camundongos/crescimento & desenvolvimento , África do Norte , Animais , Clima , DNA Mitocondrial/genética , Europa (Continente) , Camundongos/classificação , Camundongos/genética , Camundongos/fisiologia , Repetições de Microssatélites , Filogenia , EspanhaRESUMO
The originally published version of this Article contained errors in Figure 5, whereby the sign for Spearman's rho was incorrect in panels b and c. These errors have now been corrected in both the PDF and HTML versions of the Article.
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Speciation is a complex process that leads to the progressive establishment of reproductive isolation barriers between diverging populations. Genome-wide comparisons between closely related species have revealed the existence of heterogeneous divergence patterns, dominated by genomic islands of increased divergence supposed to contain reproductive isolation loci. However, this divergence landscape only provides a static picture of the dynamic process of speciation, during which confounding mechanisms unrelated to speciation can interfere. Here we use haplotype-resolved whole-genome sequences to identify the mechanisms responsible for the formation of genomic islands between Atlantic and Mediterranean sea bass lineages. Local ancestry patterns show that genomic islands first emerged in allopatry through linked selection acting on a heterogeneous recombination landscape. Then, upon secondary contact, preexisting islands were strongly remolded by differential introgression, revealing variable fitness effects among regions involved in reproductive isolation. Interestingly, we find that divergent regions containing ancient polymorphisms conferred the strongest resistance to introgression.
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Bass/genética , Especiação Genética , Genoma , Ilhas Genômicas , Polimorfismo Genético , Animais , Oceano Atlântico , Bass/classificação , Mapeamento Cromossômico , Feminino , Fluxo Gênico , Genética Populacional , Haplótipos , Masculino , Mar Mediterrâneo , Filogenia , Isolamento Reprodutivo , Seleção GenéticaRESUMO
Investigating gene flow between closely related species and its variation across the genome is important to understand how reproductive barriers shape genome divergence before speciation is complete. An efficient way to characterize differential gene flow is to study how the genetic interactions that take place in hybrid zones selectively filter gene exchange between species, leading to heterogeneous genome divergence. In the present study, genome-wide divergence and introgression patterns were investigated between two sole species, Solea senegalensis and Solea aegyptiaca, using restriction-associated DNA sequencing (RAD-Seq) to analyze samples taken from a transect spanning the hybrid zone. An integrative approach combining geographic and genomic clines methods with an analysis of individual locus introgression accounting for the demographic history of divergence was conducted. Our results showed that the two sole species have come into secondary contact postglacially, after experiencing a prolonged period (ca. 1.1 to 1.8 Myrs) of allopatric separation. Secondary contact resulted in the formation of a tension zone characterized by strong reproductive isolation, which only allowed introgression in a limited fraction of the genome. We found multiple evidence for a preferential direction of introgression in the S. aegyptiaca genetic background, indicating a possible recent or ongoing movement of the hybrid zone. Deviant introgression signals found in the opposite direction suggested that S. senegalensis could have possibly undergone adaptive introgression that has not yet spread throughout the entire species range. Our study thus illustrates the varied outcomes of genetic interactions between divergent gene pools that recently met after a long history of divergence.
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Linguados/genética , Genoma , Geografia , Animais , Pool Gênico , Hibridização Genética , Probabilidade , Especificidade da EspécieRESUMO
BACKGROUND: Although the term holobiont has been popularized in corals with the advent of the hologenome theory of evolution, the underlying concepts are still a matter of debate. Indeed, the relative contribution of host and environment and especially thermal regime in shaping the microbial communities should be examined carefully to evaluate the potential role of symbionts for holobiont adaptation in the context of global changes. We used the sessile, long-lived, symbiotic and environmentally sensitive reef-building coral Pocillopora damicornis to address these issues. RESULTS: We sampled Pocillopora damicornis colonies corresponding to two different mitochondrial lineages in different geographic areas displaying different thermal regimes: Djibouti, French Polynesia, New Caledonia, and Taiwan. The community composition of bacteria and the algal endosymbiont Symbiodinium were characterized using high-throughput sequencing of 16S rRNA gene and internal transcribed spacer, ITS2, respectively. Bacterial microbiota was very diverse with high prevalence of Endozoicomonas, Arcobacter, and Acinetobacter in all samples. While Symbiodinium sub-clade C1 was dominant in Taiwan and New Caledonia, D1 was dominant in Djibouti and French Polynesia. Moreover, we also identified a high background diversity (i.e., with proportions < 1%) of A1, C3, C15, and G Symbiodinum sub-clades. Using redundancy analyses, we found that the effect of geography was very low for both communities and that host genotypes and temperatures differently influenced Symbiodinium and bacterial microbiota. Indeed, while the constraint of host haplotype was higher than temperatures on bacterial composition, we showed for the first time a strong relationship between the composition of Symbiodinium communities and minimal sea surface temperatures. CONCLUSION: Because Symbiodinium assemblages are more constrained by the thermal regime than bacterial communities, we propose that their contribution to adaptive capacities of the holobiont to temperature changes might be higher than the influence of bacterial microbiota. Moreover, the link between Symbiodinium community composition and minimal temperatures suggests low relative fitness of clade D at lower temperatures. This observation is particularly relevant in the context of climate change, since corals will face increasing temperatures as well as much frequent abnormal cold episodes in some areas of the world.
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Acinetobacter/isolamento & purificação , Antozoários/microbiologia , Antozoários/parasitologia , Arcobacter/isolamento & purificação , Dinoflagellida/isolamento & purificação , Oceanospirillaceae/isolamento & purificação , Acinetobacter/genética , Animais , Arcobacter/genética , DNA Intergênico/genética , Dinoflagellida/genética , Sequenciamento de Nucleotídeos em Larga Escala , Microbiota/genética , Oceanospirillaceae/genética , RNA Ribossômico 16S/genética , Simbiose/fisiologiaRESUMO
The house mouse is a powerful model to dissect the genetic basis of phenotypic variation, and serves as a model to study human diseases. Despite a wealth of discoveries, most classical laboratory strains have captured only a small fraction of genetic variation known to segregate in their wild progenitors, and existing strains are often related to each other in complex ways. Inbred strains of mice independently derived from natural populations have the potential to increase power in genetic studies with the addition of novel genetic variation. Here, we perform exome-enrichment and high-throughput sequencing (~8× coverage) of 26 wild-derived strains known in the mouse research community as the "Montpellier strains." We identified 1.46 million SNPs in our dataset, approximately 19% of which have not been detected from other inbred strains. This novel genetic variation is expected to contribute to phenotypic variation, as they include 18,496 nonsynonymous variants and 262 early stop codons. Simulations demonstrate that the higher density of genetic variation in the Montpellier strains provides increased power for quantitative genetic studies. Inasmuch as the power to connect genotype to phenotype depends on genetic variation, it is important to incorporate these additional genetic strains into future research programs.
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Animais Selvagens/genética , Sequenciamento do Exoma , Variação Genética/genética , Genótipo , Camundongos Endogâmicos/genética , Fenótipo , Animais , Códon de Terminação , Simulação por Computador , Cruzamentos Genéticos , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Camundongos , Camundongos Endogâmicos/classificação , Filogenia , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
Hybrid zones provide natural experiments where new combinations of genotypes and phenotypes are produced. Studying the reshuffling of genotypes and remodeling of phenotypes in these zones is of particular interest to document the building of reproductive isolation and the possible emergence of transgressive phenotypes that can be a source of evolutionary novelties. Here, we specifically investigate the morphological variation patterns associated with introgressive hybridization between two species of sole, Solea senegalensis and Solea aegyptiaca. The relationship between genetic composition at nuclear loci and individual body shape variation was studied in four populations sampled across the hybrid zone located in northern Tunisia. A strong correlation between genetic and phenotypic variation was observed among all individuals but not within populations, including the two most admixed ones. Morphological convergence between parental species was observed close to the contact zone. Nevertheless, the samples taken closest to the hybrid zone also displayed deviant segregation of genotypes and phenotypes, as well as transgressive phenotypes. In these samples, deviant body shape variation could be partly attributed to a reduced condition index, and the distorted genetic composition was most likely due to missing allelic combinations. These results were interpreted as an indication of hybrid breakdown, which likely contributes to postmating reproductive isolation between the two species.
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Similar to seemingly maladaptive genes in general, the persistence of inherited cancer-causing mutant alleles in populations remains a challenging question for evolutionary biologists. In addition to traditional explanations such as senescence or antagonistic pleiotropy, here we put forward a new hypothesis to explain the retention of oncogenic mutations. We propose that although natural defenses evolve to prevent neoplasm formation and progression thus increasing organismal fitness, they also conceal the effects of cancer-causing mutant alleles on fitness and concomitantly protect inherited ones from purging by purifying selection. We also argue for the importance of the ecological contexts experienced by individuals and/or species. These contexts determine the locally predominant fitness-reducing risks, and hence can aid the prediction of how natural selection will influence cancer outcomes.
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Evolução Biológica , Carcinogênese/genética , Hereditariedade , Mutação , Animais , Aptidão Genética , Humanos , Seleção GenéticaRESUMO
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.