Abstract This chapter applies evolutionary thinking to issues in public health. It first discusses the conflicts between individual and societal interests, the socio-economic determinants of health, and the global burden of disease. Phenotypic responses to mismatch help to explain metabolic diseases. Important population consequences of individual decisions include the herd immunity produced by vaccination and its breakdown when too few people get vaccinated and the evolution of antibiotic resistance through the accumulation of many decisions to treat individuals. Emerging diseases are public health problems increasingly affected by population growth and global change. Vaccination is a key option for controlling them. We discuss vaccine development and application for influenza, Ebola, Covid-19, and HIV/AIDS.

Previous articleNext article No AccessHistory, Philosophy, and Ethics of BiologyGeorge C. Williams and Evolutionary Literacy. Literatures, Cultures, and the Environment. By Michael P. Cohen. Cham (Switzerland): Palgrave Macmillan (Springer). $149.99. xiv + 364 p.; ill.; index. ISBN: 978-3-031-11649-0 (hc); 978-3-031-11650-6 (eb). 2022.Stephen C. StearnsStephen C. StearnsEcology & Evolutionary Biology, Yale University, New Haven, Connecticut Search for more articles by this author PDFPDF PLUSFull Text Add to favoritesDownload CitationTrack CitationsPermissionsReprints Share onFacebookTwitterLinkedInRedditEmailPrint SectionsMoreDetailsFiguresReferencesCited by The Quarterly Review of Biology Volume 98, Number 4December 2023 Published in association with Stony Brook University Article DOIhttps://doi.org/10.1086/727920 Views: 21Total views on this site For permission to reuse, please contact [email protected].PDF download Crossref reports no articles citing this article.

Article Figures and data Abstract eLife digest Introduction Results Discussion Materials and methods Appendix 1 Data availability References Decision letter Author response Article and author information Metrics Abstract The risk of developing cancer is correlated with body size and lifespan within species. Between species, however, there is no correlation between cancer and either body size or lifespan, indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Elephants and their relatives (Proboscideans) are a particularly interesting lineage for the exploration of mechanisms underlying the evolution of augmented cancer resistance because they evolved large bodies recently within a clade of smaller-bodied species (Afrotherians). Here, we explore the contribution of gene duplication to body size and cancer risk in Afrotherians. Unexpectedly, we found that tumor suppressor duplication was pervasive in Afrotherian genomes, rather than restricted to Proboscideans. Proboscideans, however, have duplicates in unique pathways that may underlie some aspects of their remarkable anti-cancer cell biology. These data suggest that duplication of tumor suppressor genes facilitated the evolution of increased body size by compensating for decreasing intrinsic cancer risk. eLife digest From the gigantic blue whale to the minuscule bumblebee bat, animals come in all shapes and sizes. Any species can develop cancer, but some are more at risk than others. In theory, if every cell has the same probability of becoming cancerous, then bigger animals should get cancer more often since they have more cells than smaller ones. Amongst the same species, this relationship is true: taller people and bigger dogs have a greater cancer risk than their smaller counterparts. Yet this correlation does not hold when comparing between species: remarkably large creatures, like elephants and whales, are not more likely to have cancer than any other animal. But how have these gigantic animals evolved to be at lower risk for the disease? To investigate, Vazquez and Lynch compared the cancer risk and the genetic information of a diverse group of closely related animals with different body sizes. This included elephants, woolly mammoths and mastodons as well as their small relatives, the manatees, armadillos, and marmot-sized hyraxes. Examining these species’ genomes revealed that, during evolution, elephants had acquired extra copies of ‘tumour suppressor genes’ which can sense and repair the genetic and cellular damages that turn healthy cells into tumours. This allowed the species to evolve large bodies while lowering their risk of cancer. Further studies could investigate whether other gigantic animals evolved similar ways to shield themselves from cancer; these could also examine precisely how having additional copies of cancer-protecting genes helps reduce cancer risk, potentially paving the way for new approaches to treat or prevent the disease. Introduction Among the constraints on the evolution of large bodies and long lifespans in animals is an increased risk of developing cancer. If all cells in all organisms have a similar risk of malignant transformation and equivalent cancer suppression mechanisms, then organisms with many cells should have a higher prevalence of cancer than organisms with fewer cells, particularly because large and small animals have similar cell sizes (Savage et al., 2007). Consistent with this expectation there is a strong positive correlation between body size and cancer incidence within species; for example, cancer incidence increases with increasing adult height in humans (Million Women Study collaborators et al., 2011; Nunney, 2018) and with increasing body size in dogs, cats, and cattle (Dobson, 2013; Dorn et al., 1968; Lucena et al., 2011). There is no correlation, however, between body size and cancer risk between species; this lack of correlation is often referred to as ‘Peto’s Paradox’ (Caulin and Maley, 2011; Leroi et al., 2003; Peto et al., 1975). Indeed, cancer prevalence is relatively stable at ~5% across species with diverse body sizes ranging from the minuscule 51 g grass mouse to the gargantuan 4800 kg African elephant (Abegglen et al., 2015; Boddy et al., 2020; Tollis et al., 2020). The ultimate resolution to Peto’s Paradox is trivial, large-bodied and long-lived species evolved enhanced cancer protection mechanisms, but identifying and characterizing the mechanisms that underlie the evolution of augmented cancer protection has proven difficult (Ashur-Fabian et al., 2004; Seluanov et al., 2008; Gorbunova et al., 2012; Tian et al., 2013; Sulak et al., 2016). One of the challenges for discovering how animals evolved enhanced cancer protection mechanisms is identifying lineages in which large-bodied species are nested within species with small body sizes. Afrotherian mammals are generally small-bodied, but also include the largest extant land mammals. For example, maximum adult weights are ~70 g in golden moles,~120 g in tenrecs,~170 g in elephant shrews,~3 kg in hyraxes, and ~60 kg in aardvarks (Tacutu et al., 2013). In contrast, while extant hyraxes are relatively small, the extinct Titanohyrax is estimated to have weighed ~1300 kg (Schwartz et al., 1995). The largest living Afrotheria are also dwarfed by the size of their recent extinct relatives: extant sea cows such as manatees are large bodied (~322–480 kg) but are relatively small compared to the extinct Stellar’s sea cow which is estimated to have weighed ~8000–10,000 kg (Scheffer, 1972). Similarly African Savannah (4800 kg) and Asian elephants (3200 kg) are large, but are dwarfed by the truly gigantic extinct Proboscideans such as Deinotherium (~12,000 kg), Mammut borsoni (16,000 kg), and the straight-tusked elephant (~14,000 kg) (Larramendi, 2015). Remarkably, these large-bodied Afrotherian lineages are nested deeply within small-bodied species (Figure 1; O Leary et al., 2013a; Springer et al., 2013; O Leary et al., 2013b; Puttick and Thomas, 2015), indicating that gigantism independently evolved in hyraxes, sea cows, and elephants (Paenungulata). Thus, Paenungulates are an excellent model system in which to explore the mechanisms that underlie the evolution of large body sizes and augmented cancer resistance. Figure 1 Download asset Open asset Large-bodied Afrotherians are nested within species with smaller body sizes (Tacutu et al., 2013; Puttick and Thomas, 2015). (A) Phylogenetic relationships between Eutherian orders, examples of each order are given in parenthesis. Horizontal branch lengths are proportional to time since divergence between lineages (see scale, Millions of Ago [MYA]). The clades Atlantogenata and Boreoeutheria are indicated, the order Proboscidea is colored blue, Sirenia is colored orange, and Hyracoidea is colored red. (B) Phylogenetic relationships of extant and recently extinct Atlantogenatans with available genomes are shown along with clade names and maximum body sizes. Note that horizontal branch lengths are arbitrary, species indicated with skull and crossbones are extinct, and those in parentheses do not have genomes. The order Proboscidea is colored blue, Sirenia is colored orange, and Hyracoidea is colored red. Box 1. Eutherian phylogenetic relationships. Eutheria (eu- ‘good’ or ‘right’ and thēríon ‘beast’, hence ‘true beasts’) is one of three living (extant) mammalian lineages (Monotremes, Marsupials, and Eutherians) that diverged in the early–late Cretaceous. Eutheria was named in 1872 by Theodore Gill and refined by Thomas Henry Huxley in 1880. Living Eutherians are comprised of 18 orders, divided into two major clades (Figure 1A): Atlantogenata including the superorders Xenarthra (armadillos, anteaters, and sloths) and Afrotheria (Proboscidea, Sirenia, Hyracoidea, Tublidentata, Afroinsectivora, Cingulata, and Pilosa), and Boreoeutheria including the superorders Laurasiatheria (Insectivora, Artodactyla, Pholidota, and Carnovora) and Euarchontoglires (Lagomorpha, Rodentia, Scandentia, Dermoptera, and Primates). In our analyses, we have focused on identifying gene duplications in Afrotherian and Xenarthran genomes (Figure 1B), using the Xenarthrans Hoffmans two-toed sloth (Choloepus hoffmanni) and nine-banded armadillo (Dasypus novemcinctus) as out-groups to the Afrotherians. This approach allows us to use phylogenetic methods to polarize gene duplication events and identify genes that duplicated in the Afrotherian stem-lineage. Many mechanisms have been suggested to resolve Peto’s paradox, including a decrease in the copy number of oncogenes, an increase in the copy number of tumor suppressor genes (Caulin and Maley, 2011; Leroi et al., 2003; Nunney, 1999), reduced metabolic rates, reduced retroviral activity and load (Katzourakis et al., 2014), and selection for ‘cheater’ tumors that parasitize the growth of other tumors (Nagy et al., 2007), greater sensitivity of cells to DNA damage (Abegglen et al., 2015; Sulak et al., 2016), enhanced recognition of neoantigens by T cells, among many others. Among the most parsimonious routes to enhanced cancer resistance may be through an increased copy number of tumor suppressors. For example, transgenic mice with additional copies of TP53 have reduced cancer rates and extended lifespans (García-Cao et al., 2002), suggesting that changes in the copy number of tumor suppressors can affect cancer rates. Indeed, candidate genes studies have found that elephant genomes encode duplicate tumor suppressors such as TP53 and LIF (Abegglen et al., 2015; Sulak et al., 2016; Vazquez et al., 2018) as well as other genes with putative tumor suppressive functions (Caulin et al., 2015; Doherty and de Magalhães, 2016). These studies, however, focused on a priori candidate genes; thus it is unclear whether duplication of tumor suppressor genes is a general phenomenon in the elephant lineage or reflects an ascertainment bias. Here we trace the evolution of body mass, cancer risk, and gene copy number variation across Afrotherian genomes, including multiple living and extinct Proboscideans (Figure 1), to investigate whether duplications of tumor suppressors coincided with the evolution of large body sizes. Our estimates of the evolution of body mass across Afrotheria show that large body masses evolved in a stepwise manner, similar to previous studies (O Leary et al., 2013a; Springer et al., 2013; O Leary et al., 2013b; Puttick and Thomas, 2015) and coincident with dramatic reductions in intrinsic cancer risk. To explore whether duplication of tumor suppressors occurred coincident with the evolution of large body sizes, we used a genome-wide Reciprocal Best BLAT Hit (RBBH) strategy to identify gene duplications and used maximum likelihood to infer the lineages in which those duplications occurred. Unexpectedly, we found that duplication of tumor suppressor genes was common in Afrotherians, both large and small. Gene duplications in the Proboscidean lineage, however, were uniquely enriched in pathways that may explain some of the unique cancer protection mechanisms observed in elephant cells. These data suggest that duplication of tumor suppressor genes is pervasive in Afrotherians and preceded the evolution of species with exceptionally large body sizes. Results Step-wise evolution of body size in Afrotherians Similar to previous studies of Afrotherian body size (Puttick and Thomas, 2015; Elliot and Mooers, 2014), we found that the body mass of the Afrotherian ancestor was inferred to be small (0.26 kg, 95% CI: 0.31–3.01 kg) and that substantial accelerations in the rate of body mass evolution occurred coincident with a 67.36× increase in body mass in the stem-lineage of Pseudoungulata (17.33 kg); a 1.45× increase in body mass in the stem-lineage of Paenungulata (25.08 kg); a 11.82× increase in body mass in the stem-lineage of Tehthytheria (296.56 kg); a 1.39× increase in body mass in the stem-lineage of Proboscidea (412.5 kg); and a 2.69× increase in body mass in the stem-lineage of Elephantimorpha (4114.39 kg), which is the last common ancestor of elephants and mastodons using the fossil record (Figure 2A,B). The ancestral Hyracoidea was inferred to be relatively small (2.86–118.18kg), and rate accelerations were coincident with independent body mass increases in large hyraxes such as Titanohyrax andrewsi (429.34 kg, 67.36× increase) (Figure 2A,B). While the body mass of the ancestral Sirenian was inferred to be large (61.7–955.51 kg), a rate acceleration occurred coincident with a 10.59× increase in body mass in Stellar’s sea cow (Figure 2A,B). Rate accelerations also occurred coincident with dramatic reductions in body mass (36.6× decrease) in the stem-lineage of the dwarf elephants Elephas (Palaeoloxodon) antiquus falconeri and Elephas cypriotes (Figure 2A,B). These data indicate that gigantism in Afrotherians evolved step-wise, from small to medium bodies in the Pseudoungulata stem-lineage, medium to large bodies in the Tehthytherian stem-lineage and extinct hyraxes, and from large to exceptionally large bodies independently in the Proboscidean stem-lineage and Stellar’s sea cow (Figure 2A,B). Figure 2 Download asset Open asset Convergent evolution of large-bodied, cancer resistant Afrotherians. (A) Atlantogenatan phylogeny, with branch lengths scaled by log2 change in body size (left) or log2 change in intrinsic cancer risk (right). Branches are colored according to ancestral state reconstruction of body mass or estimated intrinsic cancer risk. Clades and lineages leading to extant Proboscideans and dwarf elephants are labeled. (B) Extant and ancestral body size (left), lifespan (middle), and estimated intrinsic cancer risk reconstructions; data are shown as mean (dot) and 95% confidence interval (CI, whiskers). Step-wise reduction of intrinsic cancer risk in large, long-lived Afrotherians In order to account for a relatively stable cancer rate across species (Abegglen et al., 2015; Boddy et al., 2020; Tollis et al., 2020), intrinsic cancer risk must also evolve with changes in body size and lifespan across species. We used empirical body size and lifespan data from extant species and empirical body size and estimated lifespan data from extinct species to estimate intrinsic cancer risk (K) with the simplified multistage cancer risk model K≈Dt6, where D is the maximum body size and t is the maximum lifespan (Peto et al., 1975: Peto, 2015; Armitage, 1985; Armitage and Doll, 2004). As expected, intrinsic cancer risk in Afrotheria also varies with changes in body size and longevity (Figure 2A,B), with a 6.41-log2 decreases in the stem-lineage of Xenarthra, followed by a 13.37-log2 decrease in Pseudoungulata, and a 1.49-log2 decrease in Aardvarks (Figure 2A). In contrast to the Paenungulate stem-lineage, there is a 7.84-log2 decrease in cancer risk in Tethytheria, a 0.67-log2 decrease in Manatee, a 3.14-log2 decrease in Elephantimorpha, and a 1.05-log2 decrease in Proboscidea. Relatively minor decreases occurred within Proboscidea including a 0.83-log2 decrease in Elephantidae and a 0.57-log2 decrease in the American Mastodon. Within the Elephantidae, Elephantina and Loxodontini have a 0.06-log2 decrease in cancer susceptibility, while susceptibility is relatively stable in Mammoths. The three extant Proboscideans, Asian Elephant, African Savana Elephant, and the African Forest Elephant, meanwhile, have similar decreases in body size, with slight increases in cancer susceptibility (Figure 2A,B). Pervasive duplication of tumor suppressor genes in Afrotheria Our hypothesis was that genes which duplicated coincident with the evolution of increased body mass (IBM) and reduced intrinsic cancer risk (RICR) would be uniquely enriched in tumor suppressor pathways compared to genes that duplicated in other lineages. Therefore, we identified duplicated genes in each Afrotherian lineage (Table 1 and Figure 3A) and tested if they were enriched in Reactome pathways related to cancer biology (Figure 3B, Table 2). No pathways related to cancer biology were enriched in either the Pseudoungulata (67.36-fold IBM, 13.37-log2 RICR), but few genes were inferred to be duplicated in this lineage reducing power to detect enriched pathways. Consistent with our hypothesis, 18.18% of the pathways that were enriched in the Paenungulate stem-lineage (1.45-fold IBM, 1.17-log2 RICR), 63% of the pathways that were enriched in the Tethytherian stem-lineage (11.82-fold IBM, 7.84-log2 RICR), and 38.81% of the pathways that were enriched in the Proboscidean stem-lineage (1.06-fold IBM, 3.14-log2 RICR) were related to tumor suppression (Figure 3B, Table 2). Similarly, 21.28% and 38.00% of the pathways that were enriched in manatee (1.11-fold IBM, 0.89-log2 RICR) and aardvark (67.36-fold IBM, 1.49-log2 RICR), respectively, were related to tumor suppression. In contrast, only 2.86% of the pathways that were enriched in hyrax (1.6-fold IBM, 1.49-log2 RICR) were related to tumor suppression (Figure 3B, Table 2). Unexpectedly, however, lineages without major increases in body size or lifespan, or decreases in intrinsic cancer risk, were also enriched for tumor suppressor pathways. For example, 13.85%, 37.04%, and 22.00% of the pathways that were enriched in the stem-lineages of Afroinsectivoa and Afrosoricida, and in E. telfairi, respectively, were related to cancer biology (Figure 3B, Table 2). Figure 3 with 2 supplements see all Download asset Open asset Pervasive duplication of tumor suppressors in Atlantogenata. (A) Afrotherian phylogeny indicating the number of genes duplicated in each lineage, inferred by maximum likelihood with Bayesian posterior probability (BPP) ≥0.80. Branches are colored according to log2 change in body size. Inset, phylogeny with branch lengths proportional to gene expression changes per gene. (B) Upset plot of cancer related Reactome pathways enriched in each Afrotherian lineage; lineages in which the cancer pathway enrichment percentage is less than background are shown in gray. Note that Upset plots are Euler diagrams showing intersections between sets; lines indicate intersections in pathway terms between lineages connected by that line (for example, the line connecting the points for Aardvark and Tenrec indicate pathway indications for those two lineages), and empty sets are not shown. (C) Wordcloud of pathways enriched exclusively in the Proboscidean stem-lineage (purple), shared between Proboscidea and Tethytheria (blue), or shared between Proboscidea and any other lineage (green). Table 1 Genomes used in this study. SpeciesCommon NameGenomesHighest Quality GenomeReference(s)Choloepus hoffmanniHoffmans two-toed slothchoHof1,choHof-C_hoffmanni-2.0.1_HiCDudchenko et al., 2017choHof2,choHof-C_hoffmanni-2.0.1_HiCChrysochloris asiaticaCape golden molechrAsi1mchrAsi1mGCA_000296735.1Dasypus novemcinctusNine-banded armadillodasNov3dasNov3GCA_000208655.2Echinops telfairiLesser Hedgehog TenrecechTel2echTel2GCA_000313985.1Elephantulus edwardiiCape elephant shreweleEdw1meleEdw1mGCA_000299155.1Elephas maximusAsian elephanteleMaxDeleMaxDPalkopoulou et al., 2018Loxodonta africanaAfrican savanna elephantloxAfr3,loxAfr4ftp://ftp.broadinstitute.org/pub/assemblies/mammals/elephant/loxAfr4loxAfrC,loxAfr4Loxodonta cyclotisAfrican forest elephantloxCycFloxCycFPalkopoulou et al., 2018Mammut americanumAmerican mastodonmamAmeImamAmeIPalkopoulou et al., 2018Mammuthus columbiColumbian mammothmamColUmamColUPalkopoulou et al., 2018Mammuthus primigeniusWoolly mammothmamPriVmamPriVPalkopoulou et al., 2015Orycteropus aferAardvarkoryAfe1, oryAfe2oryAfe2Dudchenko et al., 2017Palaeoloxodon antiquusStraight tusked elephantpalAntNpalAntNPalkopoulou et al., 2018Procavia capensisRock hyraxproCap1, proCap2, proCap-Pcap_2.0_HiCproCap-Pcap_2.0_HiCDudchenko et al., 2017; Lindblad-Toh et al., 2011Trichechus manatus latirostrisManateetriMan1, triManLat2triManLat2Dudchenko et al., 2017; Foote et al., 2015 Table 2 Summary of reactome pathways in Atlantogenata. Number ofPercentageCancer pathways greater than simulated?GenesPathwaysCancer pathwaysSimulated cancer pathwaysAfroinsectivora366513.85%15.42%NoAfrosoricida792737.04%15.42%YesChrysochloris asiatica159110027.00%15.42%YesEchinops telfairi58710022.00%15.42%YesElephantidae612520.00%13.03%YesElephantulus edwardii210310022.00%15.42%YesElephas maximus943240.63%17.73%YesLoxodona126010.00%14.53%NoLoxodonta africana1004753.19%15.42%YesLoxodonta cyclotis763534.29%16.11%YesLoxodontini15120.00%13.82%NoMammut americanum52160.00%12.91%NoMammuthus5624.84%15.29%NoMammuthus columbi282626.92%12.88%YesMammuthus primigenius35160.00%12.28%NoOrycteropus afer50410038.00%15.42%YesPaenungulata282218.18%12.88%YesPalaeoloxodon antiquus3580.00%12.28%NoProboscidea1576738.81%9.52%YesProcavia capensis383352.86%15.42%NoPseudoungulata9100.00%14.90%NoTethytheria834663.04%18.52%YesTrichechus manatus4844721.28%15.42%Yes Our observation that gene duplicates in most lineages are enriched in cancer pathways suggest either that duplication of genes in cancer pathways is common in Afrotherians, or that there may be a systemic bias in the pathway enrichment analyses. For example, random gene sets may be generally enriched in pathway terms related to cancer biology. To explore this latter possibility, we generated 5000 randomly sampled gene sets of between 10 and 5000 genes, and tested for enriched Reactome pathways using ORA. We found that no cancer pathways were enriched (median hypergeometric p-value ≤0.05) among gene sets tested greater than 157 genes; however, in these smaller gene sets, 12–18% of enriched pathways were classified as cancer pathways. Without considering p-value thresholds, the percentage of enriched cancer pathways approaches ~15% (213/1381) in simulated sets. Thus, for larger gene sets, we used a simulated threshold of ~15% to determine if pathways related to cancer biology were enriched more than one would expect from sampling bias (Table 2). We directly compared our simulated and observed enrichment results by lineage and gene set size, and found that Afrosoricida, Cape golden mole, tenrec, Elephantidae, elephant shrew, Asian elephant, African Savannah elephant, African Forest elephant, Columbian mammoth, aardvark, Paenungulata, Proboscidea, Tethytheria, and manatee had enriched cancer pathway percentages above background with respect to their gene set sizes, that is expected enrichments based on random sampling of small gene sets (Table 2). Thus, we conclude that duplication of genes in cancer pathways is common in many Afrotherians but that the inference of enriched cancer pathway duplication is not different from background in some lineages, particularly in ancestral nodes with a small number of estimated duplicates. Tumor suppressor pathways enriched exclusively within Proboscideans While duplication of cancer associated genes is common in Afrotheria, the 157 genes that duplicated in the Proboscidean stem-lineage (Figure 3A) were uniquely enriched in 12 pathways related to cancer biology (Figure 3B). Among these uniquely enriched pathways (Figure 3C) were pathways related to the cell cycle, including ‘G0 and Early G1’, ‘G2/M Checkpoints’, and ‘Phosphorylation of the APC/C’, pathways related to DNA damage repair including ‘Global Genome Nucleotide Excision Repair (GG-NER)’, ‘HDR through Single Strand Annealing (SSA)’, ‘Gap-filling DNA repair synthesis and ligation in GG-NER’, ‘Recognition of DNA damage by PCNA-containing replication complex’, and ‘DNA Damage Recognition in GG-NER’, pathways related to telomere biology including ‘Extension of Telomeres’ and ‘Telomere Maintenance’, pathways related to the apoptosome including ‘Activation of caspases through apoptosome-mediated cleavage’, and pathways related to ‘mTORC1-mediated signaling’ and ‘mTOR signaling’, which play important roles in the biology of aging. Thus, duplication of genes with tumor suppressor functions is pervasive in Afrotherians, but genes in some pathways related to cancer biology and tumor suppression are uniquely duplicated in large-bodied (long-lived) Proboscideans (Figure 4A,B). Figure 4 Download asset Open asset Duplications in the African savannah elephant (Loxodonta africana) are enriched for TP53-related and other tumor suppressor processes. (A) Upset plot of cancer-related Reactome pathways in African savannah elephant, highlighting shared genes in each set, and the pathway class represented by the combinations (see Figure 3 for a description of Upset plots). (B) Inverted Upset plot from A showing the pathways shared by genes highlighted by WEBGESTALT in each pathway. (C) Cladogram of Afrotheria with sequenced genomes. Exemplar tumor suppressor duplicates are mapped onto lineages in which those genes are duplicated. Dots represent a duplication event of the color-coded genes. Note that we are unable to determine duplication status for some genes in Proboscideans because of assembly gaps in ancient genomes (indicated with skull and crossbones); these genes appear to be independently duplicated in extant species (African Forest, African Savanah, and Asian elephants) because they are missing from ancient genomes, biasing ancestral reconstructions of duplication status. (D) Gene expression levels of genes from panel C that have two or more expressed duplicates. Figure 4—source data 1 Data set used for manual coding gene potential associated with Figure 4C,D. https://cdn.elifesciences.org/articles/65041/elife-65041-fig4-data1-v2.zip Download elife-65041-fig4-data1-v2.zip Among the genes uniquely duplicated within Proboscideans are TP53, COX20, LAMTOR5, PRDX1, STK11, BRD7, MAD2L1, BUB3, UBE2D1, SOD1, LIF, MAPRE1, CNOT11, CASP9, CD14, and HMGB2 (Figure 4C). Two of these, TP53 and LIF, have been previously described (Abegglen et al., 2015; Sulak et al., 2016; Vazquez et al., 2018). These genes are significantly enriched in pathways involved in apoptosis, cell cycle regulation, and both upstream and downstream pathways involving TP53. The majority of these genes are expressed in African Elephant transcriptome data (Figure 4D), suggesting that they maintained functionality after duplication. Coordinated duplication of TP53-related genes in Proboscidea Prior studies found that the ‘master’ tumor suppressor TP53 duplicated multiple times in elephants (Abegglen et al., 2015; Sulak et al., 2016), motivating us to further study duplication of genes involved in TP53-related pathways in Proboscidea. We traced the evolution of genes in the TP53 pathway that appeared in one or more Reactome pathway enrichments for genes duplicated recently in the African Elephant, which has the most complete genome among Proboscideans and for which several RNA-Seq data sets are available. We found that the initial duplication of TP53 in Tethytheria, where body size expanded, was preceded by the duplication of GTF2F1 and STK11 in Paenungulata and was coincident with the duplication of BRD7. These three genes are involved in regulating the transcription of TP53 (Liang and Mills, 2013; Launonen, 2005; Drost et al., 2010; Burrows et al., 2010), and their duplication prior to that of TP53 may have facilitated re-functionalization of TP53 retroduplicates. Interestingly, STK11 is also tumor suppressor that mediates tumor suppression via p21-induced senescence (Launonen, 2005). The other genes that are duplicated in the pathway are downstream of TP53; these genes duplicated either coincident with TP53, as in the case of SIAH1, or subsequently in Proboscidea, Elephantidae, or extant elephants (Figure 4). These genes are expressed in RNA-Seq data (Figure 4D), suggesting that they are functional. While transcript abundance estimates inferred from RNA-Seq data can suggest that genes are functional, recent non-functional duplicates can still be transcribed. Therefore we inferred if each duplicate shown in Figure 4C/D encoded a putatively function protein by manually curation, specifically to identify premature stop codons and overall sequence conservation. Most genes in Figure 4C/D, such as STK11, CD14, SOD1, and BRD7, were well conserved and lacked premature stop codons. We also find that the STK11, CD14, and BRD7 genes in the manatee were also well conserved, suggesting that extant manatees may also have enhanced tumor suppression and an augmented stress response. However, some of the duplicate genes in the mantatee genome have premature stop codons suggesting they are not translated into functional proteins, including the additional copies of MAPRE1, BUB3, and COX20 as well as at least one of the duplicate copies of CNOT11, HMGB2, MAD2L1, LIF, and TP53. For TP53, we have previously shown that duplicate copies of genes containing premature stop codons may still serve a functional role in regulating its progenitor's function. Thus, some of the genes with premature stop codons, such as duplicate COX20 and MAD2L1 which are expressed in RNA-Seq data, may encode functional lncRNA transcripts or truncated proteins. Some copies, including for CASP9 and PRDX1, contained partial RBBH hits with no premature stop codons; however, they also lacked the totality of the coding sequence and thus may represent cases of pseudogenization, subfunctionalization, or neofunctionalization. Discussion Among the evolutionary, developmental, and life history constraints on the evolution of large bodies and long lifespans is an increased risk of developing cancer. While body size and lifespan are correlated with cancer risk within species, there is no correlation between species because large and long-lived organisms have evolved enhanced cancer suppression mechanisms. While this ultimate evolutionary explanation is straightforward (Peto, 2015), determining th

We critically review the use of the term "life history theory" in recent publications on evolutionary psychology, focusing on how the idea of a fast-slow continuum is deployed in that literature. We raise four issues: First, concerning plasticity, should we expect the effects of plasticity on the developmental response of a trait to mirror the effects of selection on the mean of that trait? We conclude that we should not. Do only plastic responses to harsh or unpredictable environments accelerate maturation, or are there plausible alternatives, such as nutrition? In many situations better nutrition is a plausible alternative. Second, how should we conceive of the harshness of an environment? It has several important dimensions. It could mean an increase in the mean mortality rate, a decrease in the mean growth rate or fertility rate, or increases in the variances of any of those rates. Our judgement of harshness will also be affected by the distribution of such effects across patches in space and through generations in time. The combination and distribution of effects make important differences to predictions. Third, where did the fast-slow idea come from, and how much does it explain? It was initially detected in comparisons across higher taxonomic levels, whose relevance to variation among individuals is unclear and where it fails to explain much of the variation. Fourth, what sorts of processes could generate the fast-slow pattern? Here we expand on insights mentioned earlier in passing to make clear how spatial population structure and class effects generate alternative predictions. We conclude with some thoughts on the nature of theories and research strategies and on how one might respond to empirical puzzles.

As shown throughout this book, urbanization moulds evolutionary processes in many biological systems. But what are its effects on the species that is itself the cause of this radical habitat modification? At least two major cultural transitions in history have involved urbanization: the transition to agriculture, and the continuing transition to modernity. Humans both endure and create the selective pressures associated with urbanization, a process of niche construction with complex evolutionary consequences. Urbanization modifies extrinsic mortality, nutrition, hygiene, demography, the toxicity of air, our microbiota, social interactions, and other factors known to shape selection on morphological, physiological, immunological, life-history, and behavioural traits. Today more than half of humanity lives in cities and is exposed to this new evolutionary context. This chapter presents the elements needed to understand the evolutionary potential of humans living in cities, focusing on traits affecting health. Urbanization can alter the expression of tradeoffs and the selection on traits in ways that change the prevalence of both infectious and non-communicable diseases. The chapter identifies several challenges for research. These include the difficulty of separating the effects of urbanization per se from those of modernization in general, and the need to better integrate eco-evolutionary feedbacks, culture, and learning into microevolutionary models to understand how urban life modifies selection on health. Finally, the chapter discusses why the application to humans of gene editing technologies, such as CRISPR-Cas9, is likely to interact with natural selection, an issue deserving closer attention from evolutionary biologists.

A key issue in both molecular and evolutionary biology has been to define the roles of genes and phenotypes in the adaptation of organisms to environmental changes. The dominant view has been that an organism's metabolic adaptations are driven by gene expression and that gene mutations, independent of the starting phenotype, are responsible for the evolution of new metabolic phenotypes. We propose an alternate hypothesis, in which the phenotype and genotype together determine metabolic adaptation both in the lifetime of the organism and in the evolutionary selection of adaptive metabolic traits. We tested this hypothesis by flux-balance and metabolic-control analysis of the relative roles of the starting phenotype and gene expression in regulating the metabolic adaptations during the Crabtree effect in yeast, when they are switched from a low- to high-glucose environment. Critical for successful short-term adaptation was the ability of the glycogen/trehalose shunt to balance the glycolytic pathway. The role of later gene expression of new isoforms of glycolytic enzymes, rather than flux control, was to provide additional homeostatic mechanisms allowing an increase in the amount and efficiency of adenosine triphosphate and product formation while maintaining glycolytic balance. We further showed that homeostatic mechanisms, by allowing increased phenotypic plasticity, could have played an important role in guiding the evolution of the Crabtree effect. Although our findings are specific to Crabtree yeast, they are likely to be broadly found because of the well-recognized similarities in glucose metabolism across kingdoms and phyla from yeast to humans.

This paper surveys some of the important insights that molecular evolution has contributed to evolutionary medicine; they include phage therapy, cancer biology, helminth manipulation of the host immune system, quality control of gametes, and pathogen outbreaks. Molecular evolution has helped to revolutionize our understanding of cancer, of autoimmune disease, and of the origin, spread, and pathogenesis of emerging diseases, where it has suggested new therapies, illuminated mechanisms, and revealed historical processes: all have practical therapeutic implications. While much has been accomplished, much remains to be done.

This paper surveys some of the important insights that molecular evolution has contributed to evolutionary medicine; they include phage therapy, cancer biology, helminth manipulation of the host immune system, quality control of gametes, and pathogen outbreaks. Molecular evolution has helped to revolutionize our understanding of cancer, of autoimmune disease, and of the origin, spread, and pathogenesis of emerging diseases, where it has suggested new therapies, illuminated mechanisms, and revealed historical processes: all have practical therapeutic implications. While much has been accomplished, much remains to be done.

IMPORTANCE Surgical removal of adenoids and tonsils to treat obstructed breathing or recurrent middle-ear infections remain common pediatric procedures; however, little is known about their long-term health consequences despite the fact that these lymphatic organs play important roles in the development and function of the immune system. OBJECTIVE To estimate long-term disease risks associated with adenoidectomy, tonsillectomy, and adenotonsillectomy in childhood. DESIGN, SETTING, AND PARTICIPANTS A population-based cohort study of up to 1189 061 children born in Denmark between 1979 and 1999 and evaluated in linked national registers up to 2009, covering at least the first 10 and up to 30 years of their life, was carried out. Participants in the case and control groups were selected such that their health did not differ significantly prior to surgery. EXPOSURES Participants were classified as exposed if adenoids or tonsils were removed within the first 9 years of life. MAIN OUTCOMES AND MEASURES The incidence of disease (defined by International Classification of Diseases, Eighth Revision [ICD-8] and Tenth Revision [ICD-10] diagnoses) up to age 30 years was examined using stratified Cox proportional hazard regressions that adjusted for 18 covariates, including parental disease history, pregnancy complications, birth weight, Apgar score, sex, socioeconomic markers, and region of Denmark born. RESULTS A total of up to 1 189 061 children were included in this study (48% female); 17 460 underwent adenoidectomy. 11 830 tonsillectomy, and 31 377 adenotonsillectomy; 1157 684 were in the control group. Adenoidectomy and tonsillectomy were associated with a 2- to 3-fold increase in diseases of the upper respiratory tract (relative risk [RR], 1.99; 95% CI, 1.51-2.63 and RR, 2.72; 95% CI, 1.54-4.80; respectively). Smaller increases in risks for infectious and allergic diseases were also found: adenotonsillectomy was associated with a 17% increased risk of infectious diseases (RR, 1.17; 95% CI, 1.10-1.25) corresponding to an absolute risk increase of 2.14% because these diseases are relatively common (12%) in the population. In contrast, the long-term risks for conditions that these surgeries aim to treat often did not differ significantly and were sometimes lower or higher. CONCLUSIONS AND RELEVANCE In this study of almost 1.2 million children, of whom 17 460 had adenoidectomy. 11830 tonsillectomy, and 31 377 adenotonsillectomy, surgeries were associated with increased long-term risks of respiratory, infectious, and allergic diseases. Although rigorous controls for confounding were used where such data were available, it is possible these effects could not be fully accounted for, Our results suggest it is important to consider long-term risks when making decisions to perform tonsillectomy or adenoidectomy.

The Industrial Revolution and the accompanying nutritional, epidemiological and demographic transitions have profoundly changed human ecology and biology, leading to major shifts in life history traits, which include age and size at maturity, age-specific fertility and lifespan. Mismatch between past adaptations and the current environment means that gene variants linked to higher fitness in the past may now, through antagonistic pleiotropic effects, predispose post-transition populations to non-communicable diseases, such as Alzheimer disease, cancer and coronary artery disease. Increasing evidence suggests that the transition to modernity has also altered the direction and intensity of natural selection acting on many traits, with important implications for public and global health.

Traditional genome-wide scans for positive selection have mainly uncovered selective sweeps associated with monogenic traits. While selection on quantitative traits is much more common, very few signals have been detected because of their polygenic nature. We searched for positive selection signals underlying coronary artery disease (CAD) in worldwide populations, using novel approaches to quantify relationships between polygenic selection signals and CAD genetic risk. We identified new candidate adaptive loci that appear to have been directly modified by disease pressures given their significant associations with CAD genetic risk. These candidates were all uniquely and consistently associated with many different male and female reproductive traits suggesting selection may have also targeted these because of their direct effects on fitness. We found that CAD loci are significantly enriched for lifetime reproductive success relative to the rest of the human genome, with evidence that the relationship between CAD and lifetime reproductive success is antagonistic. This supports the presence of antagonistic-pleiotropic tradeoffs on CAD loci and provides a novel explanation for the maintenance and high prevalence of CAD in modern humans. Lastly, we found that positive selection more often targeted CAD gene regulatory variants using HapMap3 lymphoblastoid cell lines, which further highlights the unique biological significance of candidate adaptive loci underlying CAD. Our study provides a novel approach for detecting selection on polygenic traits and evidence that modern human genomes have evolved in response to CAD-induced selection pressures and other early-life traits sharing pleiotropic links with CAD.

W e are happy to announce the transition in the Editor-in-Chief of Evolution, Medicine and Public Health (EMPH) from Stephen Stearns to Charles Nunn. It occurred on 1 January 2017. As part of this transition, we anticipate some turnover in the editorial board, for it coincides with the terms of our first group of Associate Editors. We thank all members of the editorial board for helping to grow the journal and for ensuring a rigorous review process that quickly delivers high-quality feedback to authors of submitted manuscripts. We also thank the many authors for submitting their best work to EMPH, and the referees for their constructive reviews. Finally, we thank the editorial and production team at Oxford University Press (OUP) for their efforts to keep us all moving forward in our service to the journal and the academic community, and for keeping the EMPH website populated with fresh and professionally formatted papers. OUP waived publication fees from 2012 through 2015. When we began to charge publishing fees in 2016, we saw a predictable decline in submissions, yet we continued to attract an outstanding set of manuscripts for consideration. In addition, our acceptance rate in 2016 held steady at about 56%. All of the accepted papers are Open Access and thus available free-of-charge on the EMPH website. We were also happy to see an impressively diverse set of Research Articles, Reviews, Commentaries, and Clinical Briefs published in 2016. The areas of medical science in which evolutionary thinking is already strong—cancer, antibiotic resistance and the hygiene hypothesis—are all areas that we would like to see better represented in the journal. However, their relative scarcity is actually testament to the success of evolutionary thinking in those areas—reviewers and editors at more established journals now accept the importance of evolutionary perspectives in these areas, leading to fewer submissions to EMPH. Thus, our inability to attract the best papers in some areas is actually a signal that the broader purpose of EMPH and the International Society for Evolution, Medicine and Public Health (ISEPMH) is succeeding. Nunn’s goals as Editor-in-Chief are to increase the number of submissions while maintaining the high quality of articles accepted for publication, and to ensure that EMPH continues to cover the breadth of topics in evolutionary medicine. Working with OUP, we shall continue offering a world-class publishing venue—i.e. constructive reviews delivered quickly, with efficient movement of accepted papers into publication by the production department. EMPH is emerging as the “go-to” journal for topnotch research in evolutionary medicine, with an international following. To continue this growth, it is important for members of ISEMPH to submit their best work to EMPH, to participate actively as reviewers, to engage with our published articles and to cite them in forthcoming papers. Good science properly applied reduces suffering and saves lives. That’s what we want to publish.

Evolutionary medicine is a research frontier whose promise has only partially been realized. Here I discuss the advances that have built its foundation and point to where progress is most needed.

BACKGROUND Surgical removal of the adenoids and tonsils are common pediatric procedures, with conventional wisdom suggesting their absence has little impact on health or disease. However, little is known about long-term health consequences beyond the perioperative risks. Such ignorance is significant, for these lymphatic organs play important roles in both the development and the function of the immune system. METHODS We tested the long-term consequences of surgery in the population of Denmark by examining risk for 28 diseases with ̴1 million individuals followed from birth up to 30 years of age depending on whether any of three common surgeries (adenoidectomy, tonsillectomy, adenotonsillectomy) occurred in the first 9 years of life. To weigh costs and benefits, we also compared the absolute risks for these diseases to the risks for the conditions that these surgeries aimed to treat. We obtained robust results by using stratified Cox regressions with statistically well-powered samples of cases (with surgery) and controls (without surgery) whose general health was no different prior to surgery. We adjusted our estimates of risk for diseases occurring before surgery, stratified for sex (and other effects) and for 18 covariates, including parental disease history and birth metrics. RESULTS We found significantly elevated relative risks for many diseases, with effects on respiratory, allergic and infectious disorders after removal of adenoids and tonsils being most pronounced. For some of these diseases, absolute risk increases were considerable. In comparison, many risks for conditions that surgeries aimed to treat were either not significantly different or significantly higher following surgery up to 30 years of age. This suggests that any immediate benefits of these surgeries may not continue longer-term, while resulting in slightly compromised early adult health due to significantly increased risk of many non-target diseases. CONCLUSIONS Our results indicate that surgical removal of tonsils and adenoids early in life are associated with longer-term health risks. They underline the importance of these organs and tissues for normal immune functioning and early immune development, and suggest that these longer-term disease risks may outweigh the short-term benefits of these surgeries.

Elephants have significantly reduced their risk of cancer by duplicating an important gene called TP53.

Although fitness is central to the evolutionary process, metrics vary by timescale. Different timescales may give rise to different estimates of selection, especially during demographic transitions caused by rapid environmental and socioeconomic change. In this study, we used a dataset of a human population in Finland from 1775 to 1950 to compare two fitness metrics and their estimates of selection pressures, before and during a demographic transition. Both metrics, lifetime reproductive success and an annual metric of individual performance, declined while selection on the ages at first and last reproduction remained nearly constant, favouring individuals with wider reproductive windows. The ability to partition the annual metric into contributions from reproduction and survival revealed the short-term effects of a famine and the reversal of selection pressure via the survival component of annual fitness. Although the metrics generally agreed, the annual metric detected the effects of environmental variation and demographic change occurring within a generation.