Population-level consequences of inheritable somatic mutations and the evolution of mutation rates in plants

Mapping Intimacies ◽

10.1101/2020.09.29.318402 ◽

2020 ◽

Author(s):

Thomas Lesaffre

Keyword(s):

Life Expectancy ◽

Inbreeding Depression ◽

Life Histories ◽

Somatic Mutations ◽

Population Level ◽

Mutation Rates ◽

Deleterious Mutations

ABSTRACTInbreeding depression, that is the decrease in fitness of inbred relative to outbred individuals, was shown to increase strongly as life expectancy increases in plants. Because plants are thought to not have a separated germline, it was proposed that this pattern could be generated by somatic mutations accumulating during growth, since larger and more long-lived species have more opportunities for mutations to accumulate. A key determinant of the role of somatic mutations is the rate at which they occur, which likely differs between species because mutation rates may evolve differently in species with constrasting life-histories. In this paper, we study the evolution of the mutation rates in plants, and consider the population-level consequences of inheritable somatic mutations given this evolution. We show that despite substantially lower per year mutation rates, more long-lived species still tend to accumulate larger amounts of deleterious mutations because of higher per generation, leading to higher levels of inbreeding depression in these species. However, the magnitude of this increase depends strongly on how mutagenic meiosis is relative to growth.

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Population-level consequences of inheritable somatic mutations and the evolution of mutation rates in plants

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2021.1127 ◽

2021 ◽

Vol 288 (1958) ◽

pp. 20211127

Author(s):

Thomas Lesaffre

Keyword(s):

Life Expectancy ◽

Inbreeding Depression ◽

Life Histories ◽

Somatic Mutations ◽

Population Level ◽

Mutation Rates ◽

Deleterious Mutations

Inbreeding depression, that is the decrease in fitness of inbred relative to outbred individuals, was shown to increase strongly as life expectancy increases in plants. Because plants are thought to not have a separated germline, it was proposed that this pattern could be generated by somatic mutations accumulating during growth, since larger and more long-lived species have more opportunities for mutations to accumulate. A key determinant of the role of somatic mutations is the rate at which they occur, which probably differs between species because mutation rates may evolve differently in species with constrasting life histories. In this paper, I study the evolution of the mutation rates in plants, and consider the population-level consequences of inheritable somatic mutations given this evolution. I show that despite substantially lower somatic and meiotic mutation rates, more long-lived species still tend to accumulate larger amounts of deleterious mutations because of the increased number of opportunities they have to acquire mutations during growth, leading to higher levels of inbreeding depression in these species. However, the magnitude of this increase depends strongly on how mutagenic meiosis is relative to growth, to the point of being close to non-existent in some situations.

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Inbreeding depression and the maintenance of deleterious genes by mutation: model of a Drosophila chromosome

Genetics Research ◽

10.1017/s0016672300028007 ◽

1989 ◽

Vol 53 (2) ◽

pp. 119-128 ◽

Cited By ~ 8

Author(s):

John A. Sved ◽

Alan N. Wilton

Keyword(s):

Inbreeding Depression ◽

Gene Interaction ◽

Mutation Rates ◽

Deleterious Mutations ◽

Partial Dominance ◽

Mutation Model ◽

Recessive Genes ◽

Deleterious Genes ◽

Selective Interactions ◽

Lethal Genes

SummaryInbreeding experiments in Drosophila, particularly those carried out using the ‘balancer equilibration’ technique, have revealed high levels of inbreeding depression. It has been estimated that non-lethal chromosomes have a fitness of 20% or less in homozygous condition compared to chromosome heterozygotes. Deleterious recessive genes are, in principle, capable of explaining such inbreeding depression. In this paper we have asked quantitatively whether the observed high levels are consistent with what is known about numbers of loci and mutation rates. We find that accepted mutation rates are easily high enough, provided that the deleterious genes are fully recessive. Partial dominance, even to the extent of 10% or less, reverses this conclusion. These calculations have been made assuming the multiplicative model. However the arguments are potentially sensitive to certain types of selective interactions, and a model which proposes quadratic gene interaction allows for higher levels of partial dominance. We also test the effect of taking into account a further constraint. Crow and Mukai have argued from estimates of the persistence of new deleterious mutations affecting viability that heterozygotes have a reduction in fitness of around 1–2% per locus, similar to the estimate for lethal genes. Application of this additional constraint would markedly reduce the range of permissible selection coefficients. However we argue that the selective disadvantages in heterozygotes of most mutations affecting fitness are unlikely to be as high as estimated for mutations affecting viability.

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THE ROLE OF PHOSPHATIDYLINOSITOL-3-KINASE IN CARCINOGENESIS

Problems in oncology ◽

10.37469/0507-3758-2017-63-4-545-556 ◽

2017 ◽

Vol 63 (4) ◽

pp. 545-556

Author(s):

Natalya Oskina ◽

Aleksandr Shcherbakov ◽

Maksim Filipenko ◽

Nikolay Kushlinskiy ◽

L. Ovchinnikova

Keyword(s):

Genetic Disease ◽

Intracellular Signaling ◽

Somatic Mutations ◽

Pi3k Pathway ◽

Genetic Alterations ◽

Phosphatidylinositol 3 Kinase ◽

Intracellular Signaling Pathway ◽

Metabolic Activities ◽

Carcinogenic Process

Currently it is established that cancer is a genetic disease and that somatic mutations are the initiators of the carcinogenic process. The PI3K/AKT/mTOR pathway is an important intracellular signaling pathway regulating the cell growth and metabolic activities. Aberrant activation of the PI3K pathway is commonly observed in many different cancers. In this review we analyze the genetic alterations of PI3K pathway in a variety of human malignancies and discuss their possible implications for diagnosis and therapy.

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Hormones and Behavior

The Oxford Handbook of Evolutionary Psychology and Behavioral Endocrinology ◽

10.1093/oxfordhb/9780190649739.013.2 ◽

2019 ◽

pp. 11-26

Author(s):

Maren N. Vitousek ◽

Laura A. Schoenle

Keyword(s):

Life History ◽

Life Histories ◽

Life History Traits ◽

Developmental Plasticity ◽

Endocrine System ◽

Phenotypic Traits ◽

Social Environments ◽

Trade Offs ◽

And Behavior

Hormones mediate the expression of life history traits—phenotypic traits that contribute to lifetime fitness (i.e., reproductive timing, growth rate, number and size of offspring). The endocrine system shapes phenotype by organizing tissues during developmental periods and by activating changes in behavior, physiology, and morphology in response to varying physical and social environments. Because hormones can simultaneously regulate many traits (hormonal pleiotropy), they are important mediators of life history trade-offs among growth, reproduction, and survival. This chapter reviews the role of hormones in shaping life histories with an emphasis on developmental plasticity and reversible flexibility in endocrine and life history traits. It also discusses the advantages of studying hormone–behavior interactions from an evolutionary perspective. Recent research in evolutionary endocrinology has provided insight into the heritability of endocrine traits, how selection on hormone systems may influence the evolution of life histories, and the role of hormonal pleiotropy in driving or constraining evolution.

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The role of habitat configuration in shaping animal population processes: a framework to generate quantitative predictions

Oecologia ◽

10.1007/s00442-021-04967-y ◽

2021 ◽

Author(s):

Peng He ◽

Pierre-Olivier Montiglio ◽

Marius Somveille ◽

Mauricio Cantor ◽

Damien R. Farine

Keyword(s):

Population Level ◽

R Package ◽

Habitat Configuration ◽

Modelling Framework ◽

Alternative Habitat ◽

Animal Populations ◽

Research Questions ◽

Habitat Networks ◽

Animal Habitat

AbstractBy shaping where individuals move, habitat configuration can fundamentally structure animal populations. Yet, we currently lack a framework for generating quantitative predictions about the role of habitat configuration in modulating population outcomes. To address this gap, we propose a modelling framework inspired by studies using networks to characterize habitat connectivity. We first define animal habitat networks, explain how they can integrate information about the different configurational features of animal habitats, and highlight the need for a bottom–up generative model that can depict realistic variations in habitat potential connectivity. Second, we describe a model for simulating animal habitat networks (available in the R package AnimalHabitatNetwork), and demonstrate its ability to generate alternative habitat configurations based on empirical data, which forms the basis for exploring the consequences of alternative habitat structures. Finally, we lay out three key research questions and demonstrate how our framework can address them. By simulating the spread of a pathogen within a population, we show how transmission properties can be impacted by both local potential connectivity and landscape-level characteristics of habitats. Our study highlights the importance of considering the underlying habitat configuration in studies linking social structure with population-level outcomes.

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Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer

Journal of Translational Medicine ◽

10.1186/s12967-021-02842-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

M. Janusz Mezynski ◽

Angela M. Farrelly ◽

Mattia Cremona ◽

Aoife Carr ◽

Clare Morgan ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Lines ◽

Somatic Mutations ◽

Trastuzumab Resistance ◽

Her2 Positive ◽

Erbb Family ◽

Gastric Tumour ◽

Pi3k Signalling ◽

Trial Setting

Abstract Background Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Methods Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Results Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM–1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05). Conclusions PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.

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