TimiRGeN: R/Bioconductor package for time series microRNA-mRNA integration and analysis.

MOTIVATION: The analysis of longitudinal datasets and construction of gene regulatory networks (GRNs) provide a valuable means to disentangle the complexity of microRNA (miRNA)-mRNA interactions. However, there are no computational tools that can integrate, conduct functional analysis and generate detailed networks from longitudinal miRNA-mRNA datasets. RESULTS: We present TimiRGeN, an R package that uses time point-based differential expression results to identify miRNA-mRNA interactions influencing signaling pathways of interest. miRNA-mRNA interactions can be visualized in R or exported to PathVisio or Cytoscape. The output can be used for hypothesis generation and directing in vitro or further in silico work such as GRN construction. AVAILABILITY AND IMPLEMENTATION: TimiRGeN is available for download on Bioconductor (https://bioconductor.org/packages/TimiRGeN) and requires R v4.0.2 or newer and BiocManager v3.12 or newer. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A dynamic framework for the study of optimal birth intervals reveals the importance of sibling competition and mortality risks.

Human reproductive patterns have been well studied, but the mechanisms by which physiology, ecology and existing kin interact to affect the life history need quantification. Here, we create a model to investigate how age-specific interbirth intervals adapt to environmental and intrinsic mortality, and how birth patterns can be shaped by competition and help between siblings. The model provides a flexible framework for studying the processes underlying human reproductive scheduling. We developed a state-based optimality model to determine age-dependent and family-dependent sets of reproductive strategies, including the state of the mother and her offspring. We parameterized the model with realistic mortality curves derived from five human populations. Overall, optimal birth intervals increase until the age of 30 after which they remain relatively constant until the end of the reproductive lifespan. Offspring helping each other does not have much effect on birth intervals. Increasing infant and senescent mortality in different populations decreases interbirth intervals. We show that sibling competition and infant mortality interact to lengthen interbirth intervals. In lower-mortality populations, intense sibling competition pushes births further apart. Varying the adult risk of mortality alone has no effect on birth intervals between populations; competition between offspring drives the differences in birth intervals only when infant mortality is low. These results are relevant to understanding the demographic transition, because our model predicts that sibling competition becomes an important determinant of optimal interbirth intervals only when mortality is low, as in post-transition societies. We do not predict that these effects alone can select for menopause.

The plastic fly: the effect of sustained fluctuations in adult food supply on life-history traits.

Many adult traits in Drosophila melanogaster show phenotypic plasticity, and the effects of diet on traits such as lifespan and reproduction are well explored. Although plasticity in response to food is still present in older flies, it is unknown how sustained environmental variation affects life-history traits. Here, we explore how such life-long fluctuations of food supply affect weight and survival in groups of flies and affect weight, survival and reproduction in individual flies. In both experiments, we kept adults on constant high or low food and compared these to flies that experienced fluctuations of food either once or twice a week. For these 'yoyo' groups, the initial food level and the duration of the dietary variation differed during adulthood, creating four 'yoyo' fly groups. In groups of flies, survival and weight were affected by adult food. However, for individuals, survival and reproduction, but not weight, were affected by adult food, indicating that single and group housing of female flies affects life-history trajectories. Remarkably, both the manner and extent to which life-history traits varied in relation to food depended on whether flies initially experienced high or low food after eclosion. We therefore conclude that the expression of life-history traits in adult life is affected not only by adult plasticity, but also by early adult life experiences. This is an important but often overlooked factor in studies of life-history evolution and may explain variation in life-history experiments.

Modelling the checkpoint response to telomere uncapping in budding yeast.

One of the DNA damage-response mechanisms in budding yeast is temporary cell-cycle arrest while DNA repair takes place. The DNA damage response requires the coordinated interaction between DNA repair and checkpoint pathways. Telomeres of budding yeast are capped by the Cdc13 complex. In the temperature-sensitive cdc13-1 strain, telomeres are unprotected over a specific temperature range leading to activation of the DNA damage response and subsequently cell-cycle arrest. Inactivation of cdc13-1 results in the generation of long regions of single-stranded DNA (ssDNA) and is affected by the activity of various checkpoint proteins and nucleases. This paper describes a mathematical model of how uncapped telomeres in budding yeast initiate the checkpoint pathway leading to cell-cycle arrest. The model was encoded in the Systems Biology Markup Language (SBML) and simulated using the stochastic simulation system Biology of Ageing e-Science Integration and Simulation (BASIS). Each simulation follows the time course of one mother cell keeping track of the number of cell divisions, the level of activity of each of the checkpoint proteins, the activity of nucleases and the amount of ssDNA generated. The model can be used to carry out a variety of in silico experiments in which different genes are knocked out and the results of simulation are compared to experimental data. Possible extensions to the model are also discussed.

Evolution of the human menopause.

Menopause is an evolutionary puzzle since an early end to reproduction seems contrary to maximising Darwinian fitness. Several theories have been proposed to explain why menopause might have evolved, all based on unusual aspects of the human life history. One theory is that menopause follows from the extreme altriciality of human babies, coupled with the difficulty in giving birth due to the large neonatal brain size and the growing risk of child-bearing at older ages. There may be little advantage for an older mother in running the increased risk of a further pregnancy when existing offspring depend critically on her survival. An alternative theory is that within kin groups menopause enhances fitness by producing post-reproductive grandmothers who can assist their adult daughters. Such theories need careful quantitative assessment to see whether the fitness benefits are sufficient to outweigh the costs, particularly in circumstances of relatively high background mortality typical of ancestral environments. We show that individual theories fail this test, but that a combined model incorporating both hypotheses can explain why menopause may have evolved.

Calorie restriction and aging: a life-history analysis.

The disposable soma theory suggests that aging occurs because natural selection favors a strategy in which fewer resources are invested in somatic maintenance than are necessary for indefinite survival. However, laboratory rodents on calorie-restricted diets have extended life spans and retarded aging. One hypothesis is that this is an adaptive response involving a shift of resources during short periods of famine away from reproduction and toward increased somatic maintenance. The potential benefit is that the animal gains an increased chance of survival with a reduced intrinsic rate of senescence, thereby permitting reproductive value to be preserved for when the famine is over. We describe a mathematical life-history model of dynamic resource allocation that tests this idea. Senescence is modeled as a change in state that depends on the resources allocated to maintenance. Individuals are assumed to allocate the available resources to maximize the total number of descendants. The model shows that the evolutionary hypothesis is plausible and identifies two factors, both likely to exist, that favor this conclusion. These factors are that survival of juveniles is reduced during periods of famine and that the organism needs to pay an energetic "overhead" before any litter of offspring can be produced. If neither of these conditions holds, there is no evolutionary advantage to be gained from switching extra resources to maintenance. The model provides a basis to evaluate whether the life-extending effects of calorie-restriction might apply in other species, including humans.

Evolution, stress, and longevity.

The disposable soma theory suggests that longevity is determined through the setting of longevity assurance mechanisms so as to provide an optimal compromise between investments in somatic maintenance (including stress resistance) and in reproduction. A corollary is that species with low extrinsic mortality are predicted to invest relatively more effort in maintenance, resulting in slower intrinsic ageing, than species with high extrinsic mortality. We tested this prediction in a comparative study of stress resistance in primary skin fibroblasts and confirmed that cells from long-lived species are indeed more resistant to a variant of stressors. A widely studied example of within-species variation in lifespan is the rodent calorie restriction model. Food-restricted animals show elevations in a range of stress response mechanisms, and it has been suggested that this is an outcome of natural selection for life history plasticity. We have developed a theoretical model for dynamic optimisation of the allocation of effort to maintenance and reproduction in response to fluctuations in food availability. The model supports the suggestion that the response to calorie restriction may be an evolutionary adaptation, raising interesting questions about the hierarchy of genetic control of multiple stress response systems. The model identifies ecological factors likely to support such an adaptation that may be relevant in considering the likely relevance of a similar response to calorie restriction in other species. Comparative and theoretical studies support the role of somatic maintenance and stress response systems in controlling the rate of ageing.