On the evolutionary developmental biology of the cell.

Organisms are complex assemblages of cells, cells that produce light, shoot harpoons, and secrete glue. Therefore, identifying the mechanisms that generate novelty at the level of the individual cell is essential for understanding how multicellular life evolves. For decades, the field of evolutionary developmental biology (Evo-Devo) has been developing a framework for connecting genetic variation that arises during embryonic development to the emergence of diverse adult forms. With increasing access to new single cell 'omics technologies and an array of techniques for manipulating gene expression, we can now extend these inquiries inward to the level of the individual cell. In this opinion, I argue that applying an Evo-Devo framework to single cells makes it possible to explore the natural history of cells, where this was once only possible at the organismal level.

One-line hybrid rice with high-efficiency synthetic apomixis and near-normal fertility.

KEY MESSAGE: High-frequency clonal seeds and near-normal fertility were obtained by engineering synthetic apomixis in hybrid rice. The one-line strategy, with the advantage of unnecessary seed production, is the final stage for the hybrid rice development and can be achieved through the fixation of heterosis via artificially inducing apomixis. Recently, synthetic apomixis has been generated in rice by combining MiMe (Mitosis instead of Meiosis) with either the ectopic expression of BABY BOOM (BBM1 or BBM4) or mutation of MATRILINEAL (MTL), resulting in over 95.00% of clonal seeds. However, the frequency of clonal seeds was only 29.20% when AtDD45 promoter was used to drive BBM1. In addition, achieving both a high frequency of clonal seeds and near-normal fertility simultaneously had been elusive in earlier strategies. In this study, using AtDD45 promoter to drive BBM1 expression in combination with the MiMe mutant resulted in the apomixis frequency as high as 98.70%. Even more, employing fusion promoters (AtMYB98_AtDD1_OsECA1-like1) to drive WUS expression in combination with pAtDD45:BBM1 and MiMe could produce clonal seeds at rates of up to 98.21%, the highest seed setting rate reached to 83.67%. Multiple-embryos were observed in clonal lines at a frequency ranging from 3.37% to 60.99%. Transmission of the high frequency of apomixis through skipped generations (atavism) was identified in two clonal lines, even though it remained stable in the majority of clonal lines. These findings significantly advance the pursuit of fixed heterosis in rice through synthetic apomixis, edging closer to its agricultural application.

From developmental to atavistic bet-hedging: How cancer cells pervert the exploitation of random single-cell phenotypic fluctuations.

Stochastic gene expression plays a leading developmental role through its contribution to cell differentiation. It is also proposed to promote phenotypic diversification in malignant cells. However, it remains unclear if these two forms of cellular bet-hedging are identical or rather display distinct features. Here we argue that bet-hedging phenomena in cancer cells are more similar to those occurring in unicellular organisms than to those of normal metazoan cells. We further propose that the atavistic bet-hedging strategies in cancer originate from a hijacking of the normal developmental bet-hedging of metazoans. Finally, we discuss the constraints that may shape the atavistic bet-hedging strategies of cancer cells.

Darwin and the White Shipwrecked Sailor: Beyond Blending Inheritance and the Jenkin Myth.

This paper revisits Fleeming Jenkin's anonymous review of Charles Darwin's Origin of Species, published in the North British Review in June 1867. This review is usually revered for its impact on Darwin's theory of descent with modification. Its classical interpretation states that Jenkin, a Professor of Engineering at the University of Edinburgh, made a compelling case against natural selection based on the fact of "blending inheritance" and the "swamping" of advantageous variations. Those themes, however, are strikingly absent from Jenkin's text. They were later read into Jenkin's text by scholars trying to explain how Darwinian selection was reconciled with Mendelian genes and the birth of the Modern Synthesis. While many scholars have tried to measure Jenkin's effect on Darwin, the value of the 1867 review remains unclear. This paper re-examines its content and concludes that Jenkin's "able review" was in fact written by an engineer whose competencies in biology were very low. Focusing on the figure of the shipwrecked white sailor isolated on an island inhabited by Black people, this paper also underlines the racial assumptions behind Jenkin's review. "Blending inheritance" is thus a theme linked to theoretical reworkings on the question of race and skin colors, taking its root in Galton's typology of heredity. Darwin was probably mostly unimpressed by Jenkin's review. The problems raised by the review were not so much "blending inheritance" and "swamping" but a conundrum of problems related to the effects of intercrossing on variation and reversion.

Paradoxes of cancer: Survival at the brink.

The fundamental understanding of how Cancer initiates, persists and then progresses is evolving. High-resolution technologies, including single-cell mutation and gene expression measurements, are now attainable, providing an ever-increasing insight into the molecular details. However, this higher resolution has shown that somatic mutation theory itself cannot explain the extraordinary resistance of cancer to extinction. There is a need for a more Systems-based framework of understanding cancer complexity, which in particular explains the regulation of gene expression during cell-fate decisions. Cancer displays a series of paradoxes. Here we attempt to approach them from the view-point of adaptive exploration of gene regulatory networks at the edge of order and chaos, where cell-fate is changed by oscillations between alternative regulators of cellular senescence and reprogramming operating through self-organisation. On this background, the role of polyploidy in accessing the phylogenetically pre-programmed "oncofetal attractor" state, related to unicellularity, and the de-selection of unsuitable variants at the brink of cell survival is highlighted. The concepts of the embryological and atavistic theory of cancer, cancer cell "life-cycle", and cancer aneuploidy paradox are dissected under this lense. Finally, we challenge researchers to consider that cancer "defects" are mostly the adaptation tools of survival programs that have arisen during evolution and are intrinsic of cancer. Recognition of these features should help in the development of more successful anti-cancer treatments.

Distinguishing serial homologs from novel traits: Experimental limitations and ideas for improvements.

One of the central but yet unresolved problems in evolutionary biology concerns the origin of novel complex traits. One hypothesis is that complex traits derive from pre-existing gene regulatory networks (GRNs) reused and modified to specify a novel trait somewhere else in the body. This simple explanation encounters problems when the novel trait that emerges in a body is in a region that is known to harbor a latent or repressed trait that has been silent for millions of years. Is the novel trait merely a re-emerged de-repressed trait or a truly novel trait that emerged via a novel deployment of an old GRN? A couple of new studies sided on opposite sides of this question when investigating the origin of horns in dung beetles and helmets in treehoppers that develop in the first thoracic segment (T1) of their bodies, a segment known to harbor a pair of repressed/modified wings in close relatives. Here, I point to some key limitations of the experimental approaches used and highlight additional experiments that could be done in future to resolve the developmental origin of these and other traits.

Thyroid and endostyle development in cyclostomes provides new insights into the evolutionary history of vertebrates.

BACKGROUND: The endostyle is an epithelial exocrine gland found in non-vertebrate chordates (amphioxi and tunicates) and the larvae of modern lampreys. It is generally considered to be an evolutionary precursor of the thyroid gland of vertebrates. Transformation of the endostyle into the thyroid gland during the metamorphosis of lampreys is thus deemed to be a recapitulation of a past event in vertebrate evolution. In 1906, Stockard reported that the thyroid gland in hagfish, the sister cyclostome group of lampreys, develops through an endostyle-like primordium, strongly supporting the plesiomorphy of the lamprey endostyle. However, the findings in hagfish thyroid development were solely based on this single study, and these have not been confirmed by modern molecular, genetic, and morphological data pertaining to hagfish thyroid development over the last century. RESULTS: Here, we showed that the thyroid gland of hagfish undergoes direct development from the ventrorostral pharyngeal endoderm, where the previously described endostyle-like primordium was not found. The developmental pattern of the hagfish thyroid, including histological features and regulatory gene expression profiles, closely resembles that found in modern jawed vertebrates (gnathostomes). Meanwhile, as opposed to gnathostomes but similar to non-vertebrate chordates, lamprey and hagfish share a broad expression domain of Nkx2-1/2-4, a key regulatory gene, in the pharyngeal epithelium during early developmental stages. CONCLUSIONS: Based on the direct development of the thyroid gland both in hagfish and gnathostomes, and the shared expression profile of thyroid-related transcription factors in the cyclostomes, we challenge the plesiomorphic status of the lamprey endostyle and propose an alternative hypothesis where the lamprey endostyle could be obtained secondarily in crown lampreys.

The Transcriptome and Proteome Networks of Malignant Tumours Reveal Atavistic Attractors of Polyploidy-Related Asexual Reproduction.

The expression of gametogenesis-related (GG) genes and proteins, as well as whole genome duplications (WGD), are the hallmarks of cancer related to poor prognosis. Currently, it is not clear if these hallmarks are random processes associated only with genome instability or are programmatically linked. Our goal was to elucidate this via a thorough bioinformatics analysis of 1474 GG genes in the context of WGD. We examined their association in protein-protein interaction and coexpression networks, and their phylostratigraphic profiles from publicly available patient tumour data. The results show that GG genes are upregulated in most WGD-enriched somatic cancers at the transcriptome level and reveal robust GG gene expression at the protein level, as well as the ability to associate into correlation networks and enrich the reproductive modules. GG gene phylostratigraphy displayed in WGD+ cancers an attractor of early eukaryotic origin for DNA recombination and meiosis, and one relative to oocyte maturation and embryogenesis from early multicellular organisms. The upregulation of cancer-testis genes emerging with mammalian placentation was also associated with WGD. In general, the results suggest the role of polyploidy for soma-germ transition accessing latent cancer attractors in the human genome network, which appear as pre-formed along the whole Evolution of Life.

Atavisms in the avian hindlimb and early developmental polarity of the limb.

BACKGROUND: The naturally occurring chicken mutant talpid2 (ta2 ), best known for its limb and craniofacial defects, has long served as a valuable tool for developmental biologists studying growth and patterning of craniofacial structures and the limb. The mutant provides a unique tool to examine the molecular and cellular processes regulating limb development. RESULTS: This mutant also provides unique insights into the evolution of developmental genetic programs. Previous work defined the appearance of atavistic dentition in ta2 embryos. Herein we describe the appearance of ancestral characters of the hindlimb in embryonic ta2 chicken embryos. CONCLUSION: As the ta2 phenotype arises as a result of mutation in C2CD3 and disrupted cilia function, this mutant provides genetic and developmental insight into the causes of asymmetry in the limb and also a model for the evolution of the avian hindlimb.

Whatever happened to reversion?

The idea of 'reversion' or 'atavism' has a peculiar history. For many authors in the late-nineteenth and early-twentieth centuries - including Darwin, Galton, Pearson, Weismann, and Spencer, among others - reversion was one of the central phenomena which a theory of heredity ought to explain. By only a few decades later, however, Fisher and others could look back upon reversion as a historical curiosity, a non-problem, or even an impediment to clear theorizing. I explore various reasons that reversion might have appeared to be a central problem for this first group of figures, focusing on their commitment to a variety of conceptual features of evolutionary theory; discuss why reversion might have then ceased to be an interesting phenomenon; and, finally, close with some more general thoughts about the death of scientific problems.

Generalized hypertrichosis syndromes in Mexico.

Hypertrichosis is a rare condition characterized by excessive hair in areas of the body that are not predominantly androgen dependent. We can identify three main syndromes with congenital generalized hypertrichosis terminalis described in Mexico. The first is X-linked generalized hypertrichosis, an ultra-rare disease, with few cases reported to date. The second is Cantú syndrome, also known as hypertrichotic osteochondrodysplasia, which has a wide spectrum of clinical manifestations and is caused by pathogenic variants in ABCC9 and KCNJ8. The third is congenital hypertrichosis terminalis with or without gingival hyperplasia, which displays other features and involves several associated genes. The first two syndromes were described by the Mexican geneticist José María Cantú, and the concept of atavistic genes was invoked to explain the emergence of this outstanding trait. By understanding the genetic and pathophysiological basis of hypertrichosis, we can offer effective treatment to patients and help solve esthetic problems related to hair growth.

Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors.

Tumors of distinct tissues of origin and genetic makeup display common hallmark cellular phenotypes, including sustained proliferation, suppression of cell death, and altered metabolism. These phenotypic commonalities have been proposed to stem from disruption of conserved regulatory mechanisms evolved during the transition to multicellularity to control fundamental cellular processes such as growth and replication. Dating the evolutionary emergence of human genes through phylostratigraphy uncovered close association between gene age and expression level in RNA sequencing data from The Cancer Genome Atlas for seven solid cancers. Genes conserved with unicellular organisms were strongly up-regulated, whereas genes of metazoan origin were primarily inactivated. These patterns were most consistent for processes known to be important in cancer, implicating both selection and active regulation during malignant transformation. The coordinated expression of strongly interacting multicellularity and unicellularity processes was lost in tumors. This separation of unicellular and multicellular functions appeared to be mediated by 12 highly connected genes, marking them as important general drivers of tumorigenesis. Our findings suggest common principles closely tied to the evolutionary history of genes underlie convergent changes at the cellular process level across a range of solid cancers. We propose altered activity of genes at the interfaces between multicellular and unicellular regions of human gene regulatory networks activate primitive transcriptional programs, driving common hallmark features of cancer. Manipulation of cross-talk between biological processes of different evolutionary origins may thus present powerful and broadly applicable treatment strategies for cancer.

[Unusual neoplasm in the scrotum].

A clinical case of scrotal atavism in the form of bone plate, which simulated neoplasm of scrotal organs and has not been previously described, is presented in the article. In our opinion, the tumor is a vestige of Bakulyum, an organ, which disappeared in Homo sapiens. The patient was successfully operated in the outpatient surgical department with good functional and long-term results. After 1-year follow-up, there were no complaints or recurrence. The patient had normal sexual function.

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

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

The Systemic-Evolutionary Theory of the Origin of Cancer (SETOC): A New Interpretative Model of Cancer as a Complex Biological System.

The Systemic-Evolutionary Theory of Cancer (SETOC) is a recently proposed theory based on two important concepts: (i) Evolution, understood as a process of cooperation and symbiosis (Margulian-like), and (ii) The system, in terms of the integration of the various cellular components, so that the whole is greater than the sum of the parts, as in any complex system. The SETOC posits that cancer is generated by the de-emergence of the "eukaryotic cell system" and by the re-emergence of cellular subsystems such as archaea-like (genetic information) and/or prokaryotic-like (mitochondria) subsystems, featuring uncoordinated behaviors. One of the consequences is a sort of "cellular regression" towards ancestral or atavistic biological functions or behaviors similar to those of protists or unicellular organisms in general. This de-emergence is caused by the progressive breakdown of the endosymbiotic cellular subsystem integration (mainly, information = nucleus and energy = mitochondria) as a consequence of long-term injuries. Known cancer-promoting factors, including inflammation, chronic fibrosis, and chronic degenerative processes, cause prolonged damage that leads to the breakdown or failure of this form of integration/endosymbiosis. In normal cells, the cellular "subsystems" must be fully integrated in order to maintain the differentiated state, and this integration is ensured by a constant energy intake. In contrast, when organ or tissue damage occurs, the constant energy intake declines, leading, over time, to energy shortage, failure of endosymbiosis, and the de-differentiated state observed in dysplasia and cancer.

Loss in the making: absence of pelvic fins and presence of paedomorphic pelvic girdles in a Late Devonian antiarch placoderm (jawed stem-gnathostome).

Within jawed vertebrates, pelvic appendages have been modified or lost repeatedly, including in the most phylogenetically basal, extinct, antiarch placoderms. One Early Devonian basal antiarch, Parayunnanolepis, possessed pelvic girdles, suggesting the presence of pelvic appendages at the origin of jawed vertebrates; their absence in more derived antiarchs implies a secondary loss. Recently, paired female genital plates were identified in the Late Devonian antiarch, Bothriolepis canadensis, in the position of pelvic girdles in other placoderms. We studied these putative genital plates along an ontogenetic series of B. canadensis; ontogenetic changes in their morphology, histology and elemental composition suggest they represent endoskeletal pelvic girdles composed of perichondral and endochondral bone. We suggest that pelvic fins of derived antiarchs were lost, while pelvic girdles were retained, but reduced, relative to Parayunnanolepis This indicates developmental plasticity and evolutionary lability in pelvic appendages, shortly after these elements evolved at the origin of jawed vertebrates.

Rare events in earth history include the LB1 human skeleton from Flores, Indonesia, as a developmental singularity, not a unique taxon.

The original centrally defining features of "Homo floresiensis" are based on bones represented only in the single specimen LB1. Initial published values of 380-mL endocranial volume and 1.06-m stature are markedly lower than later attempts to confirm them, and facial asymmetry originally unreported, then denied, has been established by our group and later confirmed independently. Of nearly 200 syndromes in which microcephaly is one sign, more than half include asymmetry as another sign and more than one-fourth also explicitly include short stature. The original diagnosis of the putative new species noted and dismissed just three developmental abnormalities. Subsequent independent attempts at diagnosis (Laron Syndrome, Majewski osteodysplastic primordial dwarfism type II, cretinism) have been hampered a priori by selectively restricted access to specimens, and disparaged a posteriori using data previously unpublished, without acknowledging that all of the independent diagnoses corroborate the patent abnormal singularity of LB1. In this report we establish in detail that even in the absence of a particular syndromic diagnosis, the originally defining features of LB1 do not establish either the uniqueness or normality necessary to meet the formal criteria for a type specimen of a new species. In a companion paper we present a new syndromic diagnosis for LB1.

Evolved developmental homeostasis disturbed in LB1 from Flores, Indonesia, denotes Down syndrome and not diagnostic traits of the invalid species Homo floresiensis.

Human skeletons from Liang Bua Cave, Flores, Indonesia, are coeval with only Homo sapiens populations worldwide and no other previously known hominins. We report here for the first time to our knowledge the occipitofrontal circumference of specimen LB1. This datum makes it possible to link the 430-mL endocranial volume of LB1 reported by us previously, later confirmed independently by other investigators, not only with other human skeletal samples past and present but also with a large body of clinical data routinely collected on patients with developmental disorders. Our analyses show that the brain size of LB1 is in the range predicted for an individual with Down syndrome (DS) in a normal small-bodied population from the geographic region that includes Flores. Among additional diagnostic signs of DS and other skeletal dysplasiae are abnormally short femora combined with disproportionate flat feet. Liang Bua Cave femora, known only for LB1, match interlimb proportions for DS. Predictions based on corrected LB1 femur lengths show a stature normal for other H. sapiens populations in the region.

Observed changes in first metatarsal and medial cuneiform positions after first metatarsophalangeal joint arthrodesis.

The first intermetatarsal angle (IMA) is known to decrease after first metatarsophalangeal joint arthrodesis, although the exact mechanism by which this decrease occurs is not known. We measured the first IMA and obliquity of the medial cuneiform on anteroposterior weightbearing preoperative and postoperative radiographs in 86 feet and analyzed the statistical correlation between the IMA and the medial cuneiform angle. A change in the first IMA after first metatarsophalangeal joint fusion showed a strong positive correlation with a change in cuneiform obliquity (p < .0001). This finding was consistent in the direction and magnitude in each of 3 clinical subgroups: normal, p = .087; moderate deformity, p = .011; and severe deformity, p = .10. A comparison of the preoperative IMA and cuneiform obliquity revealed a trend toward a positive relationship but did not reach statistical significance (p = .08). The preoperative association between the IMA and medial cuneiform obliquity was not significant in any clinical subgroup, and the postoperative association between the IMA and cuneiform obliquity was not significant (p = .65). Clinical subgroup analysis showed no significant association between the IMA and the normal (p = .73) and moderately (p = .69) deformed feet, although the postoperative association between the IMA and cuneiform obliquity in the severely deformed group was significantly (p = .034) positive. A linear relationship between the reduction of the first IMA and medial cuneiform obliquity after metatarsophalangeal joint fusion was observed. Our findings suggest that frontal plane rotation influences cuneiform obliquity.