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• W2085124423 abstract "Technological advances in biology have begun to dramatically change the way we think about evolution, development, health and disease. The ability to sequence the genomes of many individuals within a population, and across multiple species, has opened the door to the possibility of answering some long-standing and perplexing questions about our own genetic heritage. One such question revolves around the nature of cellular hyperproliferation. This cellular behavior is used to effect wound healing in most animals, as well as, in some animals, the regeneration of lost body parts. Yet at the same time, cellular hyperproliferation is the fundamental pathological condition responsible for cancers in humans. Here, I will discuss why microevolution, macroevolution and developmental biology all have to be taken into consideration when interpreting studies of both normal and malignant hyperproliferation. I will also illustrate how a synthesis of evolutionary sciences and developmental biology through the study of diverse model organisms can inform our understanding of both health and disease. Technological advances in biology have begun to dramatically change the way we think about evolution, development, health and disease. The ability to sequence the genomes of many individuals within a population, and across multiple species, has opened the door to the possibility of answering some long-standing and perplexing questions about our own genetic heritage. One such question revolves around the nature of cellular hyperproliferation. This cellular behavior is used to effect wound healing in most animals, as well as, in some animals, the regeneration of lost body parts. Yet at the same time, cellular hyperproliferation is the fundamental pathological condition responsible for cancers in humans. Here, I will discuss why microevolution, macroevolution and developmental biology all have to be taken into consideration when interpreting studies of both normal and malignant hyperproliferation. I will also illustrate how a synthesis of evolutionary sciences and developmental biology through the study of diverse model organisms can inform our understanding of both health and disease. In the past 40 to 50 years, biologists working on a variety of organisms have provided the context to understanding human birth defects and disease. Just as biology is the foundation of medicine, evolution is the foundation of biology. Thus, evolutionary sciences are in a position to profoundly inform our understanding of human disease. Take cancer, for example: cancer does not respect ethnicity, or gender [1Howlader N, N.A., Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK (eds). (2011). SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD. Volume Based on November 2010 SEER data submission, posted to the SEER web site, 2011. (National Institutes of Health, National Cancer Institute), pp. Based on November 2010 SEER data submission, posted to the SEER web site, 2011.Google Scholar]. That all of us can be potentially fated to experience this disease speaks to the common thread of genetic ancestry shared by all humans. This in turn reflects a common gene toolkit that underlies the complex physiology and body plans of nearly all animals. In fact, our health and disease states are but the latest manifestations of the long and ongoing process of evolution — a combination of random mutation and drift, natural selection (Box 1), and in the particular case of humans, even social engineering.Box 1Overview of key evolutionary terms.Microevolution: changes in gene frequency within a population, which can generally be observed over short periods of time. Such changes may occur due to at least four different processes:Mutation: changes in DNA sequence, introduced during DNA replication (cell division).Natural and/or artificial selection: Natural genetic variants may sometimes be advantageous (positive selection), or deleterious (negative selection) to the survival and/or reproductive output of an individual, leading to changes in the frequency of genetic variants. This process is called natural selection. Selection applied by humans to plants and animals [71Allaby R.G. Fuller D.Q. Brown T.A. The genetic expectations of a protracted model for the origins of domesticated crops.Proc. Natl. Acad. Sci. 2008; 105: 13982-13986Crossref PubMed Scopus (193) Google Scholar, 72Diamond J. Location, location, location: The first farmers.Science. 1997; 278: 1243-1244Crossref Scopus (54) Google Scholar] is called ‘artificial selection’, and can be illustrated by the remarkable gamut of physical and behavioral features displayed by the more than 350 breeds thus far obtained by pigeon breeders [73Stringham S.A. Mulroy E.E. Xing J. Record D. Guernsey M.W. Aldenhoven J.T. Osborne E.J. Shapiro M.D. Divergence, convergence, and the ancestry of feral populations in the domestic rock pigeon.Curr. Biol. 2012; 22: 302-308Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar].Genetic drift: As DNA mutates and phenotypic changes are introduced and selected, and variation in the population increases, random events eventually come into play to determine which genetic changes will be maintained (fixed), or lost from the population. This random sampling is called genetic drift, and leads over time to changes in the relative frequency of gene variants (alleles) in a given population. In contrast to natural selection, in which reproductive success makes alleles more or less common, changes introduced by genetic drift are independent of reproductive or adaptive pressures and thus need not be benign or malignant.Gene flow: Another force affecting microevolution is gene flow, i.e., the addition or removal of gene variation by either immigration or emigration of individuals to and from a population. Consequently, migrations can have marked effects on allele frequency by modulating the genetic variation of an established gene pool.Macroevolution: changes that occur at or above the level of species. While microevolution can be readily applied to the study of individual species and can be aimed prospectively to predict allele frequencies, and to some extent evolutionary outcomes within a population, microevolution alone is insufficient to explain large-scale changes across multiple populations and geological time scales. Retrospective studies aimed at understanding the origins of genes, genomes and by extension species and phyla are, instead, the domain of macroevolution. Although most, if not all, of the microevolutionary causes that drive variation within a species apply to macroevolution [74Mayr E. Animal Species and Evolution. Harvard University Press, Cambridge, MA1963Google Scholar], the fundamental difference between them is scale. Rather than looking within a species and within that species' lifetime, macroevolution focuses on the general forces driving the evolution of species across millions of years. Disciplines such as paleontology [75Cowen R. History of Life.3rd Edition. Blackwell Science, Inc., Malden, Massachussetts2000Google Scholar], comparative genomics [76Datta M.W. Suckow M.A. Twigger S. Pollard M. Jacob H. Tonellato P.J. Using comparative genomics to leverage animal models in the identification of cancer genes. Examples in prostate cancer.Cancer Genomics Proteomics. 2005; 2: 137-144Google Scholar, 77Desai T.A. Rodionov D.A. Gelfand M.S. Alm E.J. Rao C.V. Engineering transcription factors with novel DNA-binding specificity using comparative genomics.Nucleic Acids Res. 2009; 37: 2493-2503Crossref PubMed Scopus (38) Google Scholar, 78Wolfe K.H. Comparative genomics and genome evolution in yeasts.Phil. Trans. R. Soc. B. 2006; 361: 403-412Crossref PubMed Scopus (54) Google Scholar], evolutionary developmental biology [79Haag E.S. Lenski R.E. L'enfant terrible at 30: the maturation of evolutionary developmental biology.Development. 2011; 138: 2633-2637Crossref PubMed Scopus (19) Google Scholar], and more recently genomic phylostratigraphy [27Domazet-Lošo T. Tautz D. Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa.BMC Biol. 2010; 8: 66Crossref PubMed Scopus (185) Google Scholar, 80Domazet-Lošo T. Brajkovic J. Tautz D. A phylostratigraphy approach to uncover the genomic history of major adaptations in metazoan lineages.Trends Genet. 2007; 23: 533-539Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 81Domazet-Lošo T. Tautz D. An ancient evolutionary origin of genes associated with human genetic diseases.Mol. Biol. Evol. 2008; 25: 2699-2707Crossref PubMed Scopus (127) Google Scholar], contribute the lion's share of evidence for macroevolution. Microevolution: changes in gene frequency within a population, which can generally be observed over short periods of time. Such changes may occur due to at least four different processes: Mutation: changes in DNA sequence, introduced during DNA replication (cell division). Natural and/or artificial selection: Natural genetic variants may sometimes be advantageous (positive selection), or deleterious (negative selection) to the survival and/or reproductive output of an individual, leading to changes in the frequency of genetic variants. This process is called natural selection. Selection applied by humans to plants and animals [71Allaby R.G. Fuller D.Q. Brown T.A. The genetic expectations of a protracted model for the origins of domesticated crops.Proc. Natl. Acad. Sci. 2008; 105: 13982-13986Crossref PubMed Scopus (193) Google Scholar, 72Diamond J. Location, location, location: The first farmers.Science. 1997; 278: 1243-1244Crossref Scopus (54) Google Scholar] is called ‘artificial selection’, and can be illustrated by the remarkable gamut of physical and behavioral features displayed by the more than 350 breeds thus far obtained by pigeon breeders [73Stringham S.A. Mulroy E.E. Xing J. Record D. Guernsey M.W. Aldenhoven J.T. Osborne E.J. Shapiro M.D. Divergence, convergence, and the ancestry of feral populations in the domestic rock pigeon.Curr. Biol. 2012; 22: 302-308Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar]. Genetic drift: As DNA mutates and phenotypic changes are introduced and selected, and variation in the population increases, random events eventually come into play to determine which genetic changes will be maintained (fixed), or lost from the population. This random sampling is called genetic drift, and leads over time to changes in the relative frequency of gene variants (alleles) in a given population. In contrast to natural selection, in which reproductive success makes alleles more or less common, changes introduced by genetic drift are independent of reproductive or adaptive pressures and thus need not be benign or malignant. Gene flow: Another force affecting microevolution is gene flow, i.e., the addition or removal of gene variation by either immigration or emigration of individuals to and from a population. Consequently, migrations can have marked effects on allele frequency by modulating the genetic variation of an established gene pool. Macroevolution: changes that occur at or above the level of species. While microevolution can be readily applied to the study of individual species and can be aimed prospectively to predict allele frequencies, and to some extent evolutionary outcomes within a population, microevolution alone is insufficient to explain large-scale changes across multiple populations and geological time scales. Retrospective studies aimed at understanding the origins of genes, genomes and by extension species and phyla are, instead, the domain of macroevolution. Although most, if not all, of the microevolutionary causes that drive variation within a species apply to macroevolution [74Mayr E. Animal Species and Evolution. Harvard University Press, Cambridge, MA1963Google Scholar], the fundamental difference between them is scale. Rather than looking within a species and within that species' lifetime, macroevolution focuses on the general forces driving the evolution of species across millions of years. Disciplines such as paleontology [75Cowen R. History of Life.3rd Edition. Blackwell Science, Inc., Malden, Massachussetts2000Google Scholar], comparative genomics [76Datta M.W. Suckow M.A. Twigger S. Pollard M. Jacob H. Tonellato P.J. Using comparative genomics to leverage animal models in the identification of cancer genes. Examples in prostate cancer.Cancer Genomics Proteomics. 2005; 2: 137-144Google Scholar, 77Desai T.A. Rodionov D.A. Gelfand M.S. Alm E.J. Rao C.V. Engineering transcription factors with novel DNA-binding specificity using comparative genomics.Nucleic Acids Res. 2009; 37: 2493-2503Crossref PubMed Scopus (38) Google Scholar, 78Wolfe K.H. Comparative genomics and genome evolution in yeasts.Phil. Trans. R. Soc. B. 2006; 361: 403-412Crossref PubMed Scopus (54) Google Scholar], evolutionary developmental biology [79Haag E.S. Lenski R.E. L'enfant terrible at 30: the maturation of evolutionary developmental biology.Development. 2011; 138: 2633-2637Crossref PubMed Scopus (19) Google Scholar], and more recently genomic phylostratigraphy [27Domazet-Lošo T. Tautz D. Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa.BMC Biol. 2010; 8: 66Crossref PubMed Scopus (185) Google Scholar, 80Domazet-Lošo T. Brajkovic J. Tautz D. A phylostratigraphy approach to uncover the genomic history of major adaptations in metazoan lineages.Trends Genet. 2007; 23: 533-539Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 81Domazet-Lošo T. Tautz D. An ancient evolutionary origin of genes associated with human genetic diseases.Mol. Biol. Evol. 2008; 25: 2699-2707Crossref PubMed Scopus (127) Google Scholar], contribute the lion's share of evidence for macroevolution. Whether extant or extinct, all organisms share a common attribute: variation. Such variation represents the collective genetic history of each population and, in turn, reflects the evolutionary forces that shaped both the species and the individuals within each population. Therefore, one must attempt to understand the extent by which historical evolutionary processes, such as selection and drift, have affected the mechanistic intricacies of our extant physiological and pathological states. For example, recent findings for a role in the regeneration of lost body parts for proteins generally associated with human cancers [2Oviedo N.J. Pearson B.J. Levin M. Sánchez Alvarado A. Planarian PTEN homologs regulate stem cells and regeneration through TOR signaling.Dis. Model Mech. 2008; 1 (discussion 141): 131-143Crossref PubMed Scopus (71) Google Scholar, 3Pajcini K.V. Corbel S.Y. Sage J. Pomerantz J.H. Blau H.M. Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle.Cell Stem Cell. 2010; 7: 198-213Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 4Pearson B.J. Sánchez Alvarado A. A planarian p53 homolog regulates proliferation and self-renewal in adult stem cell lineages.Development. 2010; 137: 213-221Crossref PubMed Scopus (139) Google Scholar] have prompted a re-examination of the evolutionary origins of the functions of these molecules. Resolving the perplexing fact that, despite possessing a common gene toolkit, origin organisms, such as planarians, flies, nematodes and many other species, do not seem to display the same frequency or evidence of cancer [5Pearson B.J. Sánchez Alvarado A. Regeneration, stem cells, and the evolution of tumor suppression.Cold Spring Harb. Symp. Quant. Biol. 2008; 73: 565-572Crossref PubMed Scopus (59) Google Scholar] should be of great importance in understanding the causes/origins and mechanisms of this disease. As more and more data are being accumulated on the genomics of cancers [6Beroukhim R. Mermel C.H. Porter D. Wei G. Raychaudhuri S. Donovan J. Barretina J. Boehm J.S. Dobson J. Urashima M. et al.The landscape of somatic copy-number alteration across human cancers.Nature. 2010; 463: 899-905Crossref PubMed Scopus (2693) Google Scholar, 7Greaves M. Maley C.C. Clonal evolution in cancer.Nature. 2012; 481: 306-313Crossref PubMed Scopus (1981) Google Scholar], the functions of so-called ‘cancer genes’ in diverse, less studied animal species might provide not only new insights on how the functions of such genes may have naturally evolved, but also shed light on our mechanistic understanding of the disease itself. In this review, I will attempt to illustrate the need for simultaneously considering the roles of microevolution, macroevolution (Box 1), development, and social engineering on biological systems when interrogating the causes and mechanisms of disease, particularly those driven by excessive cellular proliferation such as cancer. I will also suggest that by simultaneously considering the retrospective nature of evolutionary developmental biology and the prospective forces of microevolution and population genetics, it becomes possible to investigate the complexities of present-day human cancers, and re-examine basic concepts, such as tumor suppression, as well as the model organisms currently being used to study this and other human disorders. Based on a population of 6 billion people and a mutation rate of 2 × 10−8 per base pair, Kruglyak and Nickerson [8Kruglyak L. Nickerson D.A. Variation is the spice of life.Nat. Genet. 2001; 27: 234-236Crossref PubMed Scopus (685) Google Scholar] calculated that, in the most recent human generation, every possible mutation that is compatible with life will have occurred an average of 240 times. This rapid rate of change in the allele frequencies of a population is known as microevolution (Box 1) [9Dobzhansky T. Genetics and the Origin of Species.3rd Edition. Columbia University Press, New York1951Google Scholar]. That microevolutionary principles can help explain the incidence, pathology and characteristics of many human diseases has not gone unnoticed by the medical community [10Nowell P.C. The clonal evolution of tumor cell populations.Science. 1976; 194: 23-28Crossref PubMed Scopus (4861) Google Scholar, 11Hogardt M. Heesemann J. Adaptation of Pseudomonas aeruginosa during persistence in the cystic fibrosis lung.Int. J. Med. Microbiol. 2010; 300: 557-562Crossref PubMed Scopus (171) Google Scholar, 12Zhao Y. Epstein R.J. Unexpected functional similarities between gatekeeper tumour suppressor genes and proto-oncogenes revealed by systems biology.J. Hum. Genet. 2011; 56: 369-376Crossref PubMed Scopus (3) Google Scholar]. This is particularly evident in studies in which population genetics have been applied to uncover the causes of disease susceptibility in human populations [13Bellamy R. Genetics and pulmonary medicine bullet †3: Genetic susceptibility to tuberculosis in human populations.Thorax. 1998; 53: 588-593Crossref PubMed Scopus (66) Google Scholar, 14Cirulli E.T. Goldstein D.B. Uncovering the roles of rare variants in common disease through whole-genome sequencing.Nat. Rev. Genet. 2010; 11: 415-425Crossref PubMed Scopus (877) Google Scholar, 15Dietrich W.F. Using mouse genetics to understand infectious disease pathogenesis.Genome Res. 2001; 11: 325-331Crossref PubMed Scopus (13) Google Scholar, 16Iwasa Y. Michor F. Komarova N.L. Nowak M.A. Population genetics of tumor suppressor genes.J. Theor. Biol. 2005; 233: 15-23Crossref PubMed Scopus (47) Google Scholar, 17Lipsitch M. Bacterial population genetics and disease.Science. 2001; 292: 59-60Crossref PubMed Scopus (9) Google Scholar, 18Pollex R.L. Hegele R.A. Copy number variation in the human genome and its implications for cardiovascular disease.Circulation. 2007; 115: 3130-3138Crossref PubMed Scopus (61) Google Scholar]. One intriguing and insightful application of microevolutionary principles to the study of cancer was recently put forward by Greaves and Malley [7Greaves M. Maley C.C. Clonal evolution in cancer.Nature. 2012; 481: 306-313Crossref PubMed Scopus (1981) Google Scholar]. They describe how the inherent complexity of ‘tissue ecosystems’ in humans provides fertile ground for the appearance of genetic variation in otherwise clonally identical populations of cells. This variation effectively leads to rapid rates of change in allele frequencies in the different cell populations. In the case of cancers, increase in variation results in the production of subclones which themselves are subjected to microevolutionary processes resulting in complex lineage and branching evolutionary trajectories (Figure 1A). In other words, it appears as if the ontogeny of some forms of human cancers can be explained using microevolutionary principles. At this level of analysis, the appearance of cellular diversity in tumors is not dissimilar to the appearance of variation in animal populations (Figure 1B). Consider, for example, the wing pattern variation observed in Heliconius — a butterfly endemic to the tropics of South America — which is associated with different genomic rearrangements that lock together distinct genetic elements involved in wing-pattern formation [19Joron M. Frezal L. Jones R.T. Chamberlain N.L. Lee S.F. Haag C.R. Whibley A. Becuwe M. Baxter S.W. Ferguson L. et al.Chromosomal rearrangements maintain a polymorphic supergene controlling butterfly mimicry.Nature. 2011; 477: 203-206Crossref PubMed Scopus (362) Google Scholar]. Such rearrangements have allowed Heliconius to generate adaptive wing patterns according to geographic ecosystem variation [20Jones R.T. Salazar P.A. ffrench-Constant R.H. Jiggins C.D. Joron M. Evolution of a mimicry supergene from a multilocus architecture.Proc. Biol. Sci. 2012; 279: 316-325Crossref PubMed Scopus (31) Google Scholar]. Thus, understanding first principles of how variation is introduced into a population of either cells or animals that allow measurements of mutation, selection, genetic drift and flow can, in principle, inform essential aspects of cancer biology, such as the sequence of events that lead to the progression of a tumor, or whether a given mutation does or does not provide a proliferative (reproductive) advantage to a cancerous cell, and most importantly, help predict the outcomes of artificial selection (therapeutic intervention) such as resistance to chemotherapy. Studies of macroevolutionary transitions (Box 1) can illuminate the emergence of species and variation across and within taxa. When new attributes such as multicellularity emerge allowing organisms to venture into new environments, adaptive radiations follow, provided they encounter little or no competition [21Gavrilets S. Vose A. Dynamic patterns of adaptive radiation.Proc. Natl. Acad. Sci. USA. 2005; 102: 18040-18045Crossref PubMed Scopus (314) Google Scholar, 22Schluter D. The Ecology of Adaptive Radiation. Oxford University Press, Oxford2002Google Scholar]. Interestingly, multicellularity has been associated with the evolutionary appearance of genes known to be involved in tumor formation in humans. It has been proposed that cancer in humans is an evolutionary legacy [23Greaves M. Cancer: The Evolutionary Legacy. Oxford University Press, Oxford2004Google Scholar, 24Weinberg R.A. The Biology of Cancer. Garland Science, Oxford2008Google Scholar]. Yet, studies on whether tumors can form in basal animals have not been extensive [25Leroi A.M. Koufopanou V. Burt A. Cancer selection.Nat. Rev. Cancer. 2003; 3: 226-231Crossref PubMed Scopus (144) Google Scholar, 26Squires D.F. Neoplasia in a Coral?.Science. 1965; 148: 503-505Crossref PubMed Scopus (49) Google Scholar]. Moreover, given the remarkable differences between the molecular nature of tumor suppressors in invertebrates, such as Drosophila melanogaster, and vertebrates, such as humans and mice [5Pearson B.J. Sánchez Alvarado A. Regeneration, stem cells, and the evolution of tumor suppression.Cold Spring Harb. Symp. Quant. Biol. 2008; 73: 565-572Crossref PubMed Scopus (59) Google Scholar], the formal possibility remains that genes responsible for cancer may have emerged independently through convergent evolution. Recent phylostratigraphic tracking — a statistical approach for reconstructing macroevolutionary trends — of genes that when mutated are thought to participate in tumor formation and development, however, is beginning to provide robust macroevolutionary evidence for the ancient origins of cancer [27Domazet-Lošo T. Tautz D. Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa.BMC Biol. 2010; 8: 66Crossref PubMed Scopus (185) Google Scholar]. Comparison of the human cancer genes deposited in four databases (COSMIC [28Forbes S.A. Bhamra G. Bamford S. Dawson E. Kok C. Clements J. Menzies A. Teague J.W. Futreal P.A. Stratton M.R. The Catalogue of somatic mutations in cancer (COSMIC).Curr. Protoc. Hum. Genet. 2008; Chapter 10 (Unit 10 11)PubMed Google Scholar], Entrez section in CancerGenes, CancerGenes proper [29Higgins M.E. Claremont M. Major J.E. Sander C. Lash A.E. CancerGenes: a gene selection resource for cancer genome projects.Nucleic Acids Res. 2007; 35: D721-D726Crossref PubMed Scopus (145) Google Scholar] and Network of Cancer Genes [30Syed A.S. D'Antonio M. Ciccarelli F.D. Network of Cancer Genes: a web resource to analyze duplicability, orthology and network properties of cancer genes.Nucleic Acids Res. 2010; 38: D670-675Crossref PubMed Scopus (23) Google Scholar]) against the genome sequences of organisms arranged according to their phylogenetic relationships uncovered a clear, statistically significant relationship between the likely point of emergence of metazoans and the appearance of genes we presently associate with cancer [27Domazet-Lošo T. Tautz D. Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa.BMC Biol. 2010; 8: 66Crossref PubMed Scopus (185) Google Scholar]. It is remarkable that in the transition between Holozoa (represented by the unicellular choanoflagelates) and early metazoans (represented by poriferans), there is a statistically significant overrepresentation of the genes found in the four cancer databases (Figure 2). Whether these genes are involved in tumor suppression and/or formation in these organisms remains largely unknown, but as we will see below, evidence from functional studies of invertebrates, such as the planarian Schmidtea mediterranea, are beginning to illuminate this question [2Oviedo N.J. Pearson B.J. Levin M. Sánchez Alvarado A. Planarian PTEN homologs regulate stem cells and regeneration through TOR signaling.Dis. Model Mech. 2008; 1 (discussion 141): 131-143Crossref PubMed Scopus (71) Google Scholar, 4Pearson B.J. Sánchez Alvarado A. A planarian p53 homolog regulates proliferation and self-renewal in adult stem cell lineages.Development. 2010; 137: 213-221Crossref PubMed Scopus (139) Google Scholar]. If, as the macroevolutionary evidence suggests, the genes that cause cancer today have an ancient evolutionary origin, it becomes clear that our present reliance on about a handful of model systems from only two branches of the animal tree of life (Deuterostomes and Ecdysozoans) may be severely limiting our ability to mechanistically understand cancer and many other human diseases. While microevolution can tell us much about relatively rapid changes within a population, and macroevolution illuminates the slow changes at or above the species level, developmental biology allows us to understand individuals. From the very moment an egg is fertilized, through its gastrulation, growth, maturity and death, development provides the context in which genes and the environment interact to produce all individuals in any given population. Hence, nowhere are the intertwined threads of microevolution, macroevolution and the environment more saliently displayed than during development. Evolutionary and developmental biologists follow development to understand the history, function and malfunctions of the individual. This approach, however, took nearly a hundred years to mature. Confronted with a myriad of developmental strategies used by embryos to become fully grown animals (Figure 3A), developmental biologists in the late 19th century such as August Weismann [31Weismann A. The Germ-plasm: a Theory of Heredity. Charles Scribne'rs Sons, New York, New York1893Google Scholar] and T.H. Morgan [32Morgan T.H. The origin of five mutations in eye color in Drosophila and their modes of inheritance.Science. 1911; 33: 534-537Crossref PubMed Scopus (36) Google Scholar] postulated that biological diversity arises from changes in gene functions, while evolutionary biologists like Bateson would argue that the selection of variation [33Bateson W.A. Materials for the Study of Variation, Treated with Especial Regard to Discontinuty in the Origin of Species. Macmillan & Company, London1894Google Scholar] was, in fact, truly responsible for the diversity found in biological systems [34Hall B.K. Betrayed by Balanoglossus: William Bateson's rejection of evolutionary embryology as the basis for understanding evolution.J. Exp. Zool. B Mol. Dev. Evol. 2005; 304: 1-17Crossref PubMed Scopus (9) Google Scholar]. Such explanatory disparities arose from analyzing the same problem (heritable variation) from different levels of analysis (genes vs. adaptations), and yielded many unproductive debates [35Morgan T.H. Evolution and Adaptation. The MacMillan Company, New York, New york1903Google Scholar]. Resolving this quandary would require first a synthesis of meiosis, recombination and genetics, and the advent of molecular biology (Figure 3B). This integrative approach, in turn, has allow" @default.
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• W2085124423 date "2012-09-01" @default.
• W2085124423 modified "2023-10-12" @default.
• W2085124423 title "Cellular Hyperproliferation and Cancer as Evolutionary Variables" @default.
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