RESUMEN
Cancer is a disease that stems from a fundamental liability inherent to multicellular life forms in which an individual cell is capable of reneging on the interests of the collective organism. Although cancer is commonly described as an evolutionary process, a less appreciated aspect of tumorigenesis may be the constraints imposed by the organism's developmental programs. Recent work from single-cell transcriptomic analyses across a range of cancer types has revealed the recurrence, plasticity, and co-option of distinct cellular states among cancer cell populations. Here, we note that across diverse cancer types, the observed cell states are proximate within the developmental hierarchy of the cell of origin. We thus posit a model by which cancer cell states are directly constrained by the organism's "developmental map." According to this model, a population of cancer cells traverses the developmental map, thereby generating a heterogeneous set of states whose interactions underpin emergent tumor behavior.
Asunto(s)
Modelos Biológicos , Neoplasias , Animales , Humanos , Carcinogénesis/patología , Carcinogénesis/genética , Neoplasias/patología , Neoplasias/genética , Neoplasias/metabolismo , Análisis de la Célula Individual , Transcriptoma/genética , Células Madre Neoplásicas/patologíaRESUMEN
Joint morphogenesis is a complex process known to require the interaction of developmental cascades and mechanical loading, yet many details of this interaction are incompletely understood. While prior work has established populational patterns of joint morphological (co)variance, exploring how these patterns manifest within the individual provides information on the deployment of morphogenic processes as either systemic or local influences on joint shape. To better identify the patterns of variance-generating morphogenic processes, this study investigates the degree to which individual joint shapes deviate from population averages systematically across the body. Using three-dimensional landmark data from 200 adult skeletons, we ranked individuals based on their distances from morphological centroids for eight major joints. Spearman correlations assessed associations between ranks across various articular pairings, testing hypotheses regarding systemic versus localized variance. Results reveal low coordination between deviations observed in conarticular surfaces, functional analogs, and same-bone surfaces; however strong associations exist between antimeres, suggesting the left-right deployment of variance-generating morphogenic patterns is highly consistent. These results support a model of localized rather than systemic processes driving variation in joint shape. While more remains to be elucidated about the specifics of articular surface morphogenesis, these findings advance our understanding of the systems of variance generation at play during development and growth of our definitive joint morphology.
RESUMEN
Human craniofacial shape is highly variable yet highly heritable with genetic variants interacting through multiple layers of development. Here, we hypothesize that Mendelian phenotypes represent the extremes of a phenotypic spectrum and, using achondroplasia as an example, we introduce a syndrome-informed phenotyping approach to identify genomic loci associated with achondroplasia-like facial variation in the normal population. We compared three-dimensional facial scans from 43 individuals with achondroplasia and 8246 controls to calculate achondroplasia-like facial scores. Multivariate GWAS of the control scores revealed a polygenic basis for normal facial variation along an achondroplasia-specific shape axis, identifying genes primarily involved in skeletal development. Jointly modeling these genes in two independent control samples showed craniofacial effects approximating the characteristic achondroplasia phenotype. These findings suggest that both complex and Mendelian genetic variation act on the same developmentally determined axes of facial variation, providing new insights into the genetic intersection of complex traits and Mendelian disorders.
RESUMEN
Los constreñimientos del desarrollo se ubican en la intersección entre evolución y desarrollo, lo que los convierte en uno de los focos cruciales de investigación en la EvoDevo. Desafortunadamente, tanto el concepto mismo de constreñimiento como sus referencias fácticas han estado rodeados de confusión y controversia, lo que ha impedido un mayor avance en su estudio. En este artículo, tras revisar varios de los textos clásicos sobre constreñimientos, identifico algunas de las fuentes de confusión en torno al tema. Llamo la atención sobre la utilidad de recuperar la taxonomía que divide a los constreñimientos en universales y locales, lo cual brinda enorme claridad en la comprensión de la naturaleza misma del fenómeno. Resalto la necesidad de evitar algunas aproximaciones ortodoxas recurrentes en su estudio, al tiempo que defiendo su importancia como factores del desarrollo con implicaciones evolutivas.
Developmental constraints are located on the interface between evolution and development, which make them a crucial focus of research in EvoDevo. Unfortunately, the concept of constraint and its factual references have been surrounded by confusion and controversy, which have limited the advancement of their study. In this paper, after reviewing some traditional literature on the subject, I identify some specific sources of confusion. I propose to recover the classical taxonomical division of constraints that divide them into universal and local, which brings clarity to the understanding of their nature. I highlight the need of avoiding some recurrent orthodox approaches on the topic, as well as defending their importance as developmental factors that have evolutionary implications.
