Clinical significance and mechanisms associated with segmental UPD

Whole chromosome uniparental disomy (UPD) has been well documented with mechanisms largely understood. However, the etiology of segmental limited UPD (segUPD) is not as clear. In a 10-year period of confirming (> 300) cases of whole chromosome UPD, we identified 86 segmental cases in both prenatal and postnatal samples. Thirty-two of these cases showed mosaic segmental UPD at 11p due to somatic selection associated with Beckwith–Wiedemann syndrome. This study focuses on apparent mechanisms associated with the remaining cases, many of which appear to represent corrections of genomic imbalance such as deletions and derivative chromosomes. In some cases, segmental UPD was associated with the generation of additional genomic imbalance while in others it apparently resulted in restoration of euploidy. Multiple tests utilizing noninvasive prenatal testing (NIPT), chorionic villus sampling (CVS) and amniotic fluid samples from the same pregnancy revealed temporal evidence of correction and a “hotspot” at 1p. Although in many cases the genomic imbalance was dosage “repaired” in the analyzed tissue, clinical effects could be sustained due to early developmental effects of the original imbalance or due to its continued existence in other tissues. In addition, if correction did not occur in the gametes there would be recurrence risks for the offspring of those individuals. Familial microarray allele patterns are presented that differentiate lack of gamete correction from somatic derived gonadal mosaicism. These results suggest that the incidence of segUPD mediated correction is underestimated and may explain the etiology of some clinical phenotypes which are undetected by routine microarray analysis and many exome sequencing studies.

The evolution of multicellularity and cancer: views and paradigms

Conceptually and mechanistically, the evolution of multicellularity required the integration of single cells into new functionally, reproductively and evolutionary stable multicellular individuals. As part of this process, a change in levels of selection occurred, with selection at the multicellular level overriding selection at the cell level. The stability of multicellular individuals is dependent on a combination of mechanisms that supress within-group evolution, by both reducing the occurrence of somatic mutations as well as supressing somatic selection. Nevertheless, mutations that, in a particular microenvironment, confer mutant lineages a fitness advantage relative to normal somatic cells do occur, and can result in cancer. This minireview highlights several views and paradigms that relate the evolution of multicellularity to cancer. As a phenomenon, cancer is generally understood as a failure of multicellular systems to suppress somatic evolution. However, as a disease, cancer is interpreted in different frameworks: (i) a breakdown of cooperative behaviors underlying the evolution of multicellularity, (ii) a disruption of molecular networks established during the emergence of multicellularity to impose constraints on single-celled units, or (iii) an atavistic state resulting from reactivating primitive programs that originated in the earliest unicellular species. A number of assumptions are common in all the views relating cancer as a disease to the evolution of multicellularity. For instance, cancer is considered a reversal to unicellularity, and cancer cells are thought to both resemble unicellular organisms and benefit from ancestral-like traits. Nevertheless, potential limitations of current paradigms should be acknowledged as different perspectives can provide novel insights with potential therapeutic implications.

Somatic Selection Distinguishes Oncogenes and Tumor Suppressor Genes

Motivation Functions of cancer driver genes vary substantially across tissues and organs. Distinguishing passenger genes (PGs), oncogenes (OGs) and tumor suppressor genes (TSGs) for each cancer type is critical for understanding tumor biology and identifying clinically actionable targets. Although many computational tools are available to predict putative cancer driver genes, resources for context-aware classifications of OGs and TSGs are limited. Results We show that the direction and magnitude of somatic selection of protein-coding mutations are significantly different for PGs, OGs and TSGs. Based on these patterns, we develop a new method (genes under selection in tumors, GUST) to discover OGs and TSGs in a cancer-type specific manner. GUST shows a high accuracy (92%) when evaluated via strict cross-validations. Its application to 10,172 tumor exomes found known and novel cancer drivers with high tissue-specificities. In 11 out of 13 OGs shared among multiple cancer types, we found functional domains selectively engaged in different cancers, suggesting differences in disease mechanisms. Availability An R implementation of the GUST algorithm is available at https://github.com/liliulab/gust. A database with pre-computed results is available at https://liliulab.shinyapps.io/gust. Supplementary information Supplementary data are available at Bioinformatics online.

Somatic selection of poorly differentiating variant stem cell clones could be a key to human ageing

Any replicating system in which heritable variants with differing replicative potentials can arise is subject to a Darwinian evolutionary process. The continually replicating adult tissue stem cells that control the integrity of many tissues of long-lived, multicellular, complex vertebrate organisms, including humans, constitute such a replicating system. Our suggestion is that somatic selection for mutations (or stable epigenetic changes) that cause an increased rate of adult tissue stem cell proliferation, and their long-term persistence, at the expense of normal differentiation, is a major key to the ageing process. Once an organism has passed the reproductive age, there is no longer any significant counterselection at the organismal level to this inevitable cellular level Darwinian process.Author ContributionsWFB conceived the project. WFB and DJMC wrote the manuscript.

A generalized theory of age-dependent carcinogenesis

The Multi-Stage Model of Carcinogenesis (MMC), developed in the 1950 s-70s, postulated carcinogenesis as a Darwinian somatic selection process. The cellular organization of tissues was then poorly understood, with almost nothing known about cancer drivers and stem cells. The MMC paradigm was later confirmed, and cancer incidence was explained as a function of mutation occurrence. However, the MMC has never been tested for its ability to account for the discrepancies in the number of driver mutations and the organization of the stem cell compartments underlying different cancers that still demonstrate nearly universal age-dependent incidence patterns. Here we demonstrate by Monte Carlo modeling the impact of key somatic evolutionary parameters on the MMC performance, revealing that two additional major mechanisms, aging-dependent somatic selection and life history-dependent evolution of species-specific tumor suppressor mechanisms, need to be incorporated into the MMC to make it capable of generalizing cancer incidence across tissues and species.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

The Dual Role of Evo-Devo Mechanisms and the Extended Evolutionary Synthesis

The distinction between mechanisms that generate biological variation and mechanisms that modify it has been important in contemporary Biology, especially since the establishment of the Evolutionary Synthesis (ES) in the first part of the twentieth century. In the ES, and in its subsequent legacy to evolutionary biology, the focus was directed at mechanisms that modify biological variation. In recent years, evo-devo (Evolutionary Developmental Biology) emerged as an area of knowledge that proposes to extend the ES in many forms. In this sense, given that evo-devo integrates different areas of Biology, different types of mechanisms can be found. In order to understand evo-devo mechanisms, as well as its relation with the ES, we analyzed the role that evo-devo mechanisms play with respect to biological variation. The main question in our analysis was: do evo-devo mechanisms have a function of generators and/or modifiers of biological variation? We focused on three evo-devo mechanisms: environmental induction, hypervariability/somatic selection and developmental bias. Our analysis showed a different characterization of the action of evo-devo mechanisms. This heterogeneity in the role of evo-devo mechanisms shows that, in general, the distinction is maintained but there is a mechanism that presents a dual role. Our analysis indicates that, at least with respect to mechanisms, evo-devo extends and departs from what was proposed in the evolutionary synthesis.