Source Of Phenotypic Variation Research Articles

A pan-TE map highlights transposable elements underlying domestication and agronomic traits in Asian rice.

Transposable elements (TEs) are ubiquitous genomic components and hard to study due to being highly repetitive. Here we assembled 232 chromosome-level genomes based on long-read sequencing data. Coupling the 232 genomes with 15 existing assemblies, we developed a pan-TE map comprising both cultivated and wild Asian rice. We detected 177084 high-quality TE variations and inferred their derived state using outgroups. We found TEs were one source of phenotypic variation during rice domestication and differentiation. We identified 1246 genes whose expression variation was associated with TEs but not single-nucleotide polymorphisms (SNPs), such as OsRbohB, and validated OsRbohB's relative expression activity using a dual-Luciferase (LUC) reporter assays system. Our pan-TE map allowed us to detect multiple novel loci associated with agronomic traits. Collectively, our findings highlight the contributions of TEs to domestication, differentiation and agronomic traits in rice, and there is massive potential for gene cloning and molecular breeding by the high-quality Asian pan-TE map we generated.

Selfing revealed potential for higher yield performance than backcrossing among tomato segregating populations of Solanum lycopersicum × S. pimpinellifolium crosses under tropical humid climate

The objectives of this study were to assess and identify new source of phenotypic variability among F3 and BC1F2 tomato populations, and apply genotype by yield*trait (GYT) biplots for population and line selection based on multiple traits. Four diverse cultivated parents (‘CLN2498D’ [D] and ‘CLN2417H’ [H] from Ethiopia; ‘UC Dan INDIA’ [U] and ‘Tima’ [T] from Nigeria), and wild parent ‘LA2093’ [W] were used to generate 276 potential breeding lines. The lines were categorized into eight populations (‘pop_1_W/H1’, ‘pop_2_W/H2’, ‘pop_3_W/D1’, ‘pop_4_W/D2’, ‘pop_5_W/T1’, ‘pop_6_W/T2’, ‘pop_7_W/U1’, and ‘pop_8_W/U2’), and evaluated twice in the field using 19 × 15 alpha-lattice design with two replicates. Significant differences were observed among lines and populations for all yield enhancing traits. ‘Pop_1_W/H1’, ‘pop_4_W/D2’ and ‘pop_6_W/T2’ expressed the highest genetic divergence for plant height, number of leaves, total flower and fruit number, and fruit weight. GYT biplots revealed that all yield*trait interactions had a positive correlation with each other. F3 populations, ‘pop_5_W/T1’ and ‘pop_1_W/H1’ exhibited the best performance for majority of the yield*trait combinations. Hierarchical clustering on principal components (HCPC) revealed overlapping lines (70.58% of Cluster D lines) and (54.05% of Cluster U lines) from the two F3 populations. In BC1F2 population, 32.35% of the 34 original lines of Cluster D and 48.48% of Cluster T lines overlapped between Clusters D and T, while 18.18% of Cluster T lines and 8.82% of Cluster H lines were transgressive between Clusters T and H. Transgressive segregants ‘0210U1’, ‘0211U1’, and ‘0171T1’ of selfed population using multivariate analysis were believed to represent potential sources of novel genetic variation for future tomato breeding.

Temperature and hypoxia trigger developmental phenotypic plasticity of cardiorespiratory physiology and growth in the parthenogenetic marbled crayfish, Procambarus virginalis Lyko, 2017

Attempting to differentiate phenotypic variation caused by environmentally-induced alterations in gene expression from that caused by actual allelic differences can be experimentally difficult. Environmental variables must be carefully controlled and then interindividual genetic differences ruled out as sources of phenotypic variation. We investigated phenotypic variability of cardiorespiratory physiology as well as biometric traits in the parthenogenetically-reproducing marbled crayfish Procambarus virginalis Lyko, 2017, all offspring being genetically identical clones. Populations of P. virginalis were reared from eggs tank-bred at four different temperatures (16, 19, 22 and 25 °C) or two different oxygen levels (9.5 and 20 kPa). Then, at Stage 3 and 4 juvenile stages, physiological (heart rate, oxygen consumption) and morphological (carapace length, body mass) variables were measured. Heart rate and oxygen consumption measured at 23 °C showed only small effects of rearing temperature in Stage 3 juveniles, with larger effects evident in older, Stage 4 juveniles. Additionally, coefficients of variation were calculated to compare our data to previously published data on P. virginalis as well as sexually-reproducing crayfish. Comparison revealed that carapace length, body mass and heart rate (but not oxygen consumption) indeed showed lower, yet notable coefficients of variation in clonal crayfish. Yet, despite being genetically identical, significant variation in their morphology and physiology in response to different rearing conditions nonetheless occurred in marbled crayfish. This suggests that epigenetically induced phenotypic variation might play a significant role in asexual but also sexually reproducing species.

Epigenetic effects of climate change on insects.

Climate change has been causing severe modifications to the environment that are predicted to aggravate in the future, which create critical challenges for insects to cope. Populations can respond to the changes depending on the standing genetic variation. Additionally, they could potentially rely on epigenetic mechanisms as a source of phenotypic variation. These mechanisms can influence gene regulation and can respond to the external environment, being implicated in phenotypic plasticity. Thus, epigenetic variation could be advantageous in changing, unpredictable environments. However, little is known about causal relationships between epigenetic marks and insects' phenotypes, and whether the effects are truly beneficial to the fitness. Empirical studies are now urgent to better understand whether epigenetic variation can help or hinder insect populations facing climate change.

Investigating the outcomes of virus coinfection within and across host species.

Interactions between coinfecting pathogens have the potential to alter the course of infection and can act as a source of phenotypic variation in susceptibility between hosts. This phenotypic variation may influence the evolution of host-pathogen interactions within host species and interfere with patterns in the outcomes of infection across host species. Here, we examine experimental coinfections of two Cripaviruses-Cricket Paralysis Virus (CrPV), and Drosophila C Virus (DCV)-across a panel of 25 Drosophila melanogaster inbred lines and 47 Drosophilidae host species. We find that interactions between these viruses alter viral loads across D. melanogaster genotypes, with a ~3 fold increase in the viral load of DCV and a ~2.5 fold decrease in CrPV in coinfection compared to single infection, but we find little evidence of a host genetic basis for these effects. Across host species, we find no evidence of systematic changes in susceptibility during coinfection, with no interaction between DCV and CrPV detected in the majority of host species. These results suggest that phenotypic variation in coinfection interactions within host species can occur independently of natural host genetic variation in susceptibility, and that patterns of susceptibility across host species to single infections can be robust to the added complexity of coinfection.

Alternative splicing as a source of phenotypic diversity.

A major goal of evolutionary genetics is to understand the genetic processes that give rise to phenotypic diversity in multicellular organisms. Alternative splicing generates multiple transcripts from a single gene, enriching the diversity of proteins and phenotypic traits. It is well established that alternative splicing contributes to key innovations over long evolutionary timescales, such as brain development in bilaterians. However, recent developments in long-read sequencing and the generation of high-quality genome assemblies for diverse organisms has facilitated comparisons of splicing profiles between closely related species, providing insights into how alternative splicing evolves over shorter timescales. Although most splicing variants are probably non-functional, alternative splicing is nonetheless emerging as a dynamic, evolutionarily labile process that can facilitate adaptation and contribute to species divergence.

Shifts between cooperation and antagonism driven by individual variation: a systematic synthesis review

The outcomes of interspecific and intraspecific ecological interactions can be considered to fall along continua from cooperative (mutually beneficial) to antagonistic (detrimental to one or both parties). Furthermore, the position of an interaction outcome along the continuum, for example whether a symbiont provides net costs or benefits to its host, or whether two conspecifics cooperatively forage or compete for food, is often not fixed but can change over time or across contexts. In this systematic review, we investigate the role of intraspecific trait variation (‘ITV') in one or both interacting parties in determining the cooperative‐antagonistic outcome of inter‐ and intraspecific ecological interactions. Based on a literature collection of 96 empirical and theoretical publications meeting our inclusion criteria, we give an overview of the types of interaction continua involved; traits related to outcome variance; and mechanisms as well as constraints on shifts in interactions outcomes. We propose that ITV can lead to shifts in interaction outcomes via two interrelated mechanisms. First,trait frequency effectsoccur when there are changes in a population's composition of traits linked to cooperation or antagonism (e.g. aggressive personality types, cheater phenotypes etc.), leading to net shifts in interaction outcomes. Second,systemic variance effectsoccur where the level of ITV in a trait in a population (as opposed to the mean value) is the factor that influences the cooperative‐antagonistic outcome. Heritable trait differences and phenotypic plasticity are sources of phenotypic variation among individuals, and both the degree of heritability and plasticity of the trait involved may determine whether shifts between cooperation and antagonism are likely to be short‐term (i.e. context‐dependent) or lead to more persistent shifts (e.g. mutualism breakdown). To guide future research, we describe knowledge gaps and divergences between empirical and theoretical literature, highlighting the value of applying evidence synthesis methods in ecology and evolution.

Development and optimization of an in vivo electrocardiogram recording method and analysis program for adult zebrafish.

ABSTRACTClinically pertinent electrocardiogram (ECG) data from model systems, such as zebrafish, are crucial for illuminating factors contributing to human cardiac electrophysiological abnormalities and disease. Current zebrafish ECG collection strategies have not adequately addressed the consistent acquisition of high-quality traces or sources of phenotypic variation that could obscure data interpretation. Thus, we developed a novel platform to ensure high-quality recording of in vivo subdermal adult zebrafish ECGs and zebrafish ECG reading GUI (zERG), a program to acquire measurements from traces that commercial software cannot examine owing to erroneous peak calling. We evaluate normal ECG trait variation, revealing highly reproducible intervals and wave amplitude variation largely driven by recording artifacts, and identify sex and body size as potential confounders to PR, QRS and QT intervals. With this framework, we characterize the effect of the class I anti-arrhythmic drug flecainide acetate on adults, provide support for the impact of a Long QT syndrome model, and establish power calculations for this and other studies. These results highlight our pipeline as a robust approach to evaluate zebrafish models of human cardiac electrophysiological phenotypes.

Genetic and plastic rewiring of food webs under climate change

Climate change is altering ecological and evolutionary processes across biological scales. These simultaneous effects of climate change pose a major challenge for predicting the future state of populations, communities and ecosystems. This challenge is further exacerbated by the current lack of integration of research focused on these different scales.We propose that integrating the fields of quantitative genetics and food web ecology will reveal new insights on how climate change may reorganize biodiversity across levels of organization. This is because quantitative genetics links the genotypes of individuals to population‐level phenotypic variation due to genetic (G), environmental (E) and gene‐by‐environment (G × E) factors. Food web ecology, on the other hand, links population‐level phenotypes to the structure and dynamics of communities and ecosystems.We synthesize data and theory across these fields and find evidence that genetic (G) and plastic (E and G × E) phenotypic variation within populations will change in magnitude under new climates in predictable ways. We then show how changes in these sources of phenotypic variation can rewire food webs by altering the number and strength of species interactions, with consequences for ecosystem resilience. We also find evidence suggesting there are predictable asymmetries in genetic and plastic trait variation across trophic levels, which set the pace for phenotypic change and food web responses to climate change. Advances in genomics now make it possible to partition G, E and G × E phenotypic variation in natural populations, allowing tests of the hypotheses we propose.By synthesizing advances in quantitative genetics and food web ecology, we provide testable predictions for how the structure and dynamics of biodiversity will respond to climate change.

The Impact of Age at First Lambing on Milk Yield and Lactation Length in a Population of Istrian Sheep under Semi-Intensive Management.

Simple SummaryThe impact of age at first lambing on dairy traits has been poorly investigated in sheep, especially in semi-intensive husbandry systems. Insufficient information on this issue, especially scientifically proven, leads to many speculations among breeders. The aim of this study was to examine the impact of age at first lambing on days in milk, daily milk yield, and total milk yield. The study was conducted on field data routinely collected in a population of Istrian sheep bred under selection. It was determined that the prolongation of the first mating of lamb ewes to the second year of life is not beneficial to milk production. In conclusion, ewes reared under semi-intensive dairy orientated systems could be successfully bred in their first year of life in order to reduce their unproductive non-milking phase. This study aimed to examine the impact of ewe’s age at first lambing (AFL) on days in milk (DIM), average daily milk yield (DMY), and total milk yield (TMY). Symmetrical bimodal distribution of AFL enabled classification of maidens in those mated in the first (47%) or second year of life (53%). After accounting for all available sources of phenotypic variability with the linear mixed model for repeated records, it was estimated that AFL had a statistically significant effect only on DIM (p < 0.001). The litter size had a significant effect only on TMY (p < 0.001), while the effect of the parity was significant for all the examined traits (p < 0.001). The results of the study suggest that prolongation of age at first mating to the second year of life is not justified in dairy-orientated sheep farms. However, more evidence on this issue is needed for generalization, especially considering some other traits that can impact profitability of dual-purpose sheep farms (reproduction traits, growth rate of lambs, etc.).

Zea mays RNA-seq estimated transcript abundances are strongly affected by read mapping bias

BackgroundGenetic variation for gene expression is a source of phenotypic variation for natural and agricultural species. The common approach to map and to quantify gene expression from genetically distinct individuals is to assign their RNA-seq reads to a single reference genome. However, RNA-seq reads from alleles dissimilar to this reference genome may fail to map correctly, causing transcript levels to be underestimated. Presently, the extent of this mapping problem is not clear, particularly in highly diverse species. We investigated if mapping bias occurred and if chromosomal features associated with mapping bias. Zea mays presents a model species to assess these questions, given it has genotypically distinct and well-studied genetic lines.ResultsIn Zea mays, the inbred B73 genome is the standard reference genome and template for RNA-seq read assignments. In the absence of mapping bias, B73 and a second inbred line, Mo17, would each have an approximately equal number of regulatory alleles that increase gene expression. Remarkably, Mo17 had 2–4 times fewer such positively acting alleles than did B73 when RNA-seq reads were aligned to the B73 reference genome. Reciprocally, over one-half of the B73 alleles that increased gene expression were not detected when reads were aligned to the Mo17 genome template. Genes at dissimilar chromosomal ends were strongly affected by mapping bias, and genes at more similar pericentromeric regions were less affected. Biased transcript estimates were higher in untranslated regions and lower in splice junctions. Bias occurred across software and alignment parameters.ConclusionsMapping bias very strongly affects gene transcript abundance estimates in maize, and bias varies across chromosomal features. Individual genome or transcriptome templates are likely necessary for accurate transcript estimation across genetically variable individuals in maize and other species.

The Role of cis- and trans-Acting RNA Regulatory Elements in Leukemia.

Simple SummaryAlterations in primary RNA motifs and aberrant expression levels of non-coding RNA molecules have emerged as biomarkers of disease development and progression. Advances in antisense oligonucleotide (ASO) techniques and pharmacologic discoveries in targeting of RNA structures and RNA–protein interactions with small molecules open a new area in RNA therapeutics that may help in developing a next generation of anti-cancer drugs.RNA molecules are a source of phenotypic diversity and an operating system that connects multiple genetic and metabolic processes in the cell. A dysregulated RNA network is a common feature of cancer. Aberrant expression of long non-coding RNA (lncRNA), micro RNA (miRNA), and circular RNA (circRNA) in tumors compared to their normal counterparts, as well as the recurrent mutations in functional regulatory cis-acting RNA motifs have emerged as biomarkers of disease development and progression, opening avenues for the design of novel therapeutic approaches. This review looks at the progress, challenges and future prospects of targeting cis-acting and trans-acting RNA elements for leukemia diagnosis and treatment.

The Seagrass Methylome Is Associated With Variation in Photosynthetic Performance Among Clonal Shoots.

Evolutionary theory predicts that clonal organisms are more susceptible to extinction than sexually reproducing organisms, due to low genetic variation and slow rates of evolution. In agreement, conservation management considers genetic variation as the ultimate measure of a population’s ability to survive over time. However, clonal plants are among the oldest living organisms on our planet. Here, we test the hypothesis that clonal seagrass meadows display epigenetic variation that complements genetic variation as a source of phenotypic variation. In a clonal meadow of the seagrass Zostera marina, we characterized DNA methylation among 42 shoots. We also sequenced the whole genome of 10 shoots to correlate methylation patterns with photosynthetic performance under exposure to and recovery from 27°C, while controlling for somatic mutations. Here, we show for the first time that clonal seagrass shoots display DNA methylation variation that is independent from underlying genetic variation, and associated with variation in photosynthetic performance under experimental conditions. It remains unknown to what degree this association could be influenced by epigenetic responses to transplantation-related stress, given that the methylomes showed a strong shift under acclimation to laboratory conditions. The lack of untreated control samples in the heat stress experiment did not allow us to distinguish methylome shifts induced by acclimation from such induced by heat stress. Notwithstanding, the co-variation in DNA methylation and photosynthetic performance may be linked via gene expression because methylation patterns varied in functionally relevant genes involved in photosynthesis, and in the repair and prevention of heat-induced protein damage. While genotypic diversity has been shown to enhance stress resilience in seagrass meadows, we suggest that epigenetic variation plays a similar role in meadows dominated by a single genotype. Consequently, conservation management of clonal plants should consider epigenetic variation as indicator of resilience and stability.

Paternal effects in a wild-type zebrafish implicate a role of sperm-derived small RNAs.

While the importance of maternal effects has long been appreciated, a growing body of evidence now points to the paternal environment having an important influence on offspring phenotype. Indeed, research on rodent models suggests that paternal stress leaves an imprint on the behaviour and physiology of offspring via nongenetic information carried in the spermatozoa; however, fish have been understudied with regard to these sperm-mediated effects. Here, we investigated whether the zebrafish was subjected to heritable influences of paternal stress by exposing males to stressors (conspecific-derived alarm cue, chasing and bright light) before mating and assessing the behavioural and endocrine responses of their offspring, including their behavioural response to conspecific-derived alarm cue. We found that after males are exposed to stress, their larval offspring show weakened responses to stressors. Small RNA sequencing subsequently revealed that the levels of several small noncoding RNAs, including microRNAs, PIWI-interacting RNAs and tRNA-derived small RNAs, were altered in the spermatozoa of stressed fathers, suggesting that stress-induced alterations to the spermatozoal RNA landscape may contribute to shaping offspring phenotype. The work demonstrates that paternal stress should not be overlooked as a source of phenotypic variation and that spermatozoal small RNAs may be important intergenerational messengers in fish.

Allele-specific expression is widespread in Bos indicus muscle and affects meat quality candidate genes

Differences between the expression of the two alleles of a gene are known as allele-specific expression (ASE), a common event in the transcriptome of mammals. Despite ASE being a source of phenotypic variation, its occurrence and effects on genetic prediction of economically relevant traits are still unexplored in bovines. Furthermore, as ASE events are likely driven by cis-regulatory mutations, scanning them throughout the bovine genome represents a significant step to elucidate the mechanisms underlying gene expression regulation. To address this question in a Bos indicus population, we built the ASE profile of the skeletal muscle tissue of 190 Nelore steers, using RNA sequencing data and SNPs genotypes from the Illumina BovineHD BeadChip (770 K bp). After quality control, 820 SNPs showed at least one sample with ASE. These SNPs were widespread among all autosomal chromosomes, being 32.01% found in 3′UTR and 31.41% in coding regions. We observed a considerable variation of ASE profile among individuals, which highlighted the need for biological replicates in ASE studies. Functional analysis revealed that ASE genes play critical biological functions in the development and maintenance of muscle tissue. Additionally, some of these genes were previously reported as associated with beef production and quality traits in livestock, thus indicating a possible source of bias on genomic predictions for these traits.

Comparative genetic and epigenetic diversity in pairs of sympatric, closely related plants with contrasting distribution ranges in south-eastern Iberian mountains.

Genetic diversity defines the evolutionary potential of a species, yet mounting evidence suggests that epigenetic diversity could also contribute to adaptation. Elucidating the complex interplay between genetic and epigenetic variation in wild populations remains a challenge for evolutionary biologists, and the intriguing possibility that epigenetic diversity could compensate for the loss of genetic diversity is one aspect that remains basically unexplored in wild plants. This hypothesis is addressed in this paper by comparing the extent and patterns of genetic and epigenetic diversity of phylogenetically closely related but ecologically disparate species. Seven pairs of congeneric species from Cazorla mountains in south-eastern Spain were studied, each pair consisting of one endemic, restricted-range species associated to stressful environments, and one widespread species occupying more favourable habitats. The prediction was tested that endemic species should have lower genetic diversity due to population fragmentation, and higher epigenetic diversity induced by environmental stress, than their widespread congeners. Genetic (DNA sequence variants) and epigenetic (DNA cytosine methylation variants) diversities and their possible co-variation were assessed in three populations of each focal species using amplified fragment length polymorphism (AFLP) and methylation-sensitive AFLP (MSAP). All species and populations exhibited moderate to high levels of genetic polymorphism irrespective of their ecological characteristics. Epigenetic diversity was greater than genetic diversity in all cases. Only in endemic species were the two variables positively related, but the difference between epigenetic and genetic diversity was greater at populations with low genetic polymorphism. Results revealed that the relationship between genetic and epigenetic diversity can be more complex than envisaged by the simple hypothesis addressed in this study, and highlight the need of additional research on the actual role of epigenetic variation as a source of phenotypic diversity before a realistic understanding of the evolutionary relevance of epigenetic phenomena in plant adaptation can be achieved.

Supply and larval traits at metamorphosis of a coastal marine invertebrate with a bi-phasic life cycle under contrasting oceanographic conditions

Patterns of larval supply and larval condition at metamorphosis play key roles in the structure and dynamics of marine populations. Hence, biological and environmental conditions driving the dispersion of larval individuals, shape early life phenotypes, and influence their survival and post-settlement success. We performed a study over two consecutive years at Ria de Aveiro (Portugal), a coastal lagoon influenced by upwelling regimens in the North-eastern Atlantic. This study assessed the effect of contrasting oceanographic conditions on larval supply and larval traits at metamorphosis of the green crab Carcinus maenas. Crab megalopae were daily sampled and monitored in the laboratory until metamorphosis. Environmental conditions experienced by larvae in the field were estimated considering their expected planktonic larval duration, which was calculated for each individual using the size at metamorphosis and the average water temperature during larval development. Presence/absence, megalopa supply, and larval size were posteriorly modelled using generalized linear mixed models. The analysis of the two consecutive years showed haphazard patterns, revealing that both larval supply and phenotypic traits changed during and between supply seasons. The lunar cycle and environmental conditions were identified as drivers of the presence and supply of megalopae. Settlement events with weak upwelling index were influenced by sea temperature, while intense and constant upwelling events conditioned megalopa supply and performance at metamorphosis. In 2013, megalopae invaded the coastal lagoon in a more advanced physiological stage than in 2012 and/or under better nutritional conditions, probably due to stronger and more constant upwelling events during their pelagic larval life. Our results show that oceanographic processes stimulating upwelling and secondary production are sources of phenotypic variation at settlement, influencing both early benthic performance and adult population dynamics of marine organisms with bi-phasic life cycles.

Does phenotypic plasticity initiate developmental bias?

The generation of variation is paramount for the action of natural selection. Although biologists are now moving beyond the idea that random mutation provides the sole source of variation for adaptive evolution, we still assume that variation occurs randomly. In this review, we discuss an alternative view for how phenotypic plasticity, which has become well accepted as a source of phenotypic variation within evolutionary biology, can generate nonrandom variation. Although phenotypic plasticity is often defined as a property of a genotype, we argue that it needs to be considered more explicitly as a property of developmental systems involving more than the genotype. We provide examples of where plasticity could be initiating developmental bias, either through direct active responses to similar stimuli across populations or as the result of programmed variation within developmental systems. Such biased variation can echo past adaptations that reflect the evolutionary history of a lineage but can also serve to initiate evolution when environments change. Such adaptive programs can remain latent for millions of years and allow development to harbor an array of complex adaptations that can initiate new bouts of evolution. Specifically, we address how ideas such as the flexible stem hypothesis and cryptic genetic variation overlap, how modularity among traits can direct the outcomes of plasticity, and how the structure of developmental signaling pathways is limited to a few outcomes. We highlight key questions throughout and conclude by providing suggestions for future research that can address how plasticity initiates and harbors developmental bias.

Stochastic modeling of phenotypic switching and chemoresistance in cancer cell populations

Phenotypic heterogeneity in cancer cells is widely observed and is often linked to drug resistance. In several cases, such heterogeneity in drug sensitivity of tumors is driven by stochastic and reversible acquisition of a drug tolerant phenotype by individual cells even in an isogenic population. Accumulating evidence further suggests that cell-fate transitions such as the epithelial to mesenchymal transition (EMT) are associated with drug resistance. In this study, we analyze stochastic models of phenotypic switching to provide a framework for analyzing cell-fate transitions such as EMT as a source of phenotypic variability in drug sensitivity. Motivated by our cell-culture based experimental observations connecting phenotypic switching in EMT and drug resistance, we analyze a coarse-grained model of phenotypic switching between two states in the presence of cytotoxic stress from chemotherapy. We derive analytical results for time-dependent probability distributions that provide insights into the rates of phenotypic switching and characterize initial phenotypic heterogeneity of cancer cells. The results obtained can also shed light on fundamental questions relating to adaptation and selection scenarios in tumor response to cytotoxic therapy.

Utjecaj redoslijeda janjenja i veličine legla na svojstva mliječnosti istarske ovce

The aim of the study was to determine the influence of parity and litter size on dairy traits in Istrian ewes. The following traits were analysed: lactation milk yield (LMY), daily milk yield (DMY), fat yield (FY), fat content (FC), protein yield (PY), protein content (PC), lactose yield (LY), and lactose content (LC). Lactation records (n=6481) collected on 2786 ewes were analyzed using a statistical model adjusted for unbalanced data structure accounting for all the available sources of phenotypic variability. Parity had a statistically significant effect on all the investigated traits (P<0.01, P<0.001). LMY DMY, PY and LY peaked in third, FY, FC, and PC in fourth, and LC in second lactation. The estimated differences between parities with maximum and minimum production for LMY, FY, PY, and LY were 21.6 kg, 1.1 kg, 1.25 kg, and 0.98 kg, respectively. Litter size had a significant effect on all the investigated traits (P<0.01, P<0.001) except the FC (P<0.05). Multiple litters led to higher yields but to lower contents of dry matter components in the milk. The results of the study should contribute to better understanding of the phenotypic variability of some economically very important dairy traits in ewes.