Biology subjects

Majic, P.

Publications and source records attributed to Majic, P..

4 recordsLinked to original sources

bioRxiv2026

Cell-lineage selection interacts with development and life history to shape the rates and identity of heritable mutations

Mutation rates determine the supply of heritable variation and are central to evolutionary theory, yet they are usually treated as properties of molecular mutational processes. We hypothesised that mutation rates are also shaped by selection among cell lineages within organisms and that the strength of this process depends on developmental and life-history traits. To test the extent of this idea, we combined mathematical modelling with experiments in Drosophila melanogaster and treated mutation rates as emergent properties of interactions among molecular mutagenesis, development, life history, and cell-lineage selection. The model predicts that even modest effects of mutations on cellular fitness can substantially alter the probability that mutations are transmitted, and that these effects depend strongly on developmental architecture, germline dynamics, and time to reproduction. In Drosophila, we experimentally demonstrate biased transmission of a mutation affecting cellular proliferation and show that this bias changes over the reproductive lifespan of the individual. Extending the model genome-wide reveals that the cellular distribution of fitness effects and its interaction with developmental parameters influence both the estimated mutation rate and the composition of transmitted mutations, producing transmission biases that favour mutations with particular cellular fitness effects. These results suggest that developmental and life-history parameters determine how cellular fitness effects translate into transmission bias; therefore, estimates of heritable mutational input can vary from species to species even under constant molecular mutagenesis. By filtering mutations before they enter populations, developmental and life-history evolution can modify both the rate and the nature of heritable variation and thereby influence evolutionary trajectories.

evolutionary biology↗

bioRxiv2025

The evolution of mutation rates in the light of development and cell-lineage selection

Mutation rates drive the pace and potential of evolutionary change. However, to better understand the evolutionary implications of mutation rates, there is a need to uncover the causes of their diversification. In multicellular organisms, all mutations first arise in a single cell in a developmental context. Whether a mutation enters a populations gene pool can therefore depend on developmental events that affect the likelihood of mutant cell lineages of producing gametes. For this reason, the evolution of mutation rates in populations is governed not only by changes in the rates at which mutations occur at the molecular level, but also by changes in developmental features of organisms and how mutations impact cellular fitness during development. We present a theoretical framework that, supported by empirical data from mammals and experiments on the fruit fly, demonstrate how generational mutation rates can be shaped by changes in developmental parameters and intraorganismal selective processes even when molecular mutation rates are presumed constant. Our model highlights how the diversity of mutation rates observed across animals may be the byproduct of organismal development rather than the result of direct selection against mutator alleles. As such, development not only introduces phenotypic biases, it also shapes the rates and trajectories of genetic diversity and is thus at the core of evolutionary theory.

evolutionary biology↗

bioRxiv2021

The adaptive potential of non-heritable somatic mutations

Non-heritable somatic mutations are typically associated with deleterious effects such as in cancer and senescence, so their role in adaptive evolution has received little attention. However, most somatic mutations are harmless and some even confer a fitness advantage to the organism carrying them. We hypothesized that heritable, germline genotypes that are likely to express an advantageous phenotype via non-heritable somatic mutation will have a selective advantage over other germline genotypes, and this advantage will channel evolving populations toward more fit germline genotypes, thus promoting adaptation. We tested this hypothesis by simulating evolving populations of developing organisms with an impermeable germline-soma separation navigating a minimal fitness landscape. The simulations revealed the conditions under which non-heritable somatic mutations promote adaptation. Specifically, this can occur when the somatic mutation supply is high, when only very few cells with the advantageous somatic mutation are required to increase organismal fitness, and when the somatic mutation also confers a selective advantage to cells with that mutation. We therefore provide proof-of-principle that non-heritable somatic mutations can promote adaptive evolution via a process we call somatic genotypic exploration. We discuss the biological plausibility of this phenomenon, as well as its evolutionary implications. SignificanceThe immensity of non-heritable genetic diversity arising in the soma has been largely disregarded in evolutionary theory as a source of adaptation. Here, we introduce a model in which non-heritable somatic mutations arising during development confer an organismal fitness advantage. Analysis of this model shows how such mutations channel evolving populations toward adaptive germline genotypes. This is most likely to occur when somatic mutations confer a fitness benefit at both the cellular and organismal levels, evoking a synergistic form of multi-level selection that contrasts with the antagonistic forms typically associated with somatic mutations in cancer and senescence. As such, our study invites a new view of somatic genetic diversity in evolutionary theory as a potential source of adaptation.

evolutionary biology↗

bioRxiv2019

Enhancers facilitate the birth of de novo genes and their functional integration into regulatory networks

Regulatory networks control the spatiotemporal gene expression patterns that give rise to and define the individual cell types of multicellular organisms. In eumetazoa, distal regulatory elements called enhancers play a key role in determining the structure of such networks, particularly the wiring diagram of \"who regulates whom.\" Mutations that affect enhancer activity can therefore rewire regulatory networks, potentially causing changes in gene expression that are adaptive. Here, we use whole-tissue and single-cell transcriptomic and chromatin accessibility data from mouse to show that enhancers play an additional role in the evolution of regulatory networks: They facilitate network growth by creating transcriptionally active regions of open chromatin that are conducive to de novo gene evolution. Specifically, our comparative transcriptomic analysis with three other mammalian species shows that young, mouse-specific intergenic open reading frames are preferentially located near enhancers, whereas older open reading frames are not. Mouse-specific intergenic open reading frames that are proximal to enhancers are more highly and stably transcribed than those that are not proximal to enhancers or promoters, and they are transcribed in a limited diversity of cellular contexts. Furthermore, we report several instances of mouse-specific intergenic open reading frames that are proximal to promoters that show evidence of being repurposed enhancers. We also show that open reading frames gradually acquire specific interactions with enhancers over macro-evolutionary timescales, helping integrate new genes into existing regulatory networks. Taken together, our results highlight a dual role of enhancers in expanding and rewiring gene regulatory networks.

evolutionary biology↗