The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Vincent J Lynch - One of the best experts on this subject based on the ideXlab platform.

  • an ancient fecundability associated polymorphism creates a gata2 binding site in a distal enhancer of hla f
    American Journal of Human Genetics, 2018
    Co-Authors: Katelyn M Mika, Francesco J Demayo, Vincent J Lynch
    Abstract:

    Variation in female reproductive traits, such as fertility, fecundity, and fecundability, are heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits have been challenging. Here, we explore the functional significance and evolutionary history of a G/A polymorphism at SNP rs2523393, which is an eQTL for HLA-F and is significantly associated with fecundability (the probability of being pregnant within a single menstrual cycle). We replicated the association between the rs2523393 genotype and HLA-F expression by using GTEx data and demonstrate that HLA-F is upregulated in the endometrium during the window of implantation and by progesterone in decidual stromal cells. Next, we show that the rs2523393 A allele creates a GATA2 binding site in a progesterone-responsive distal enhancer that loops to the HLA-F promoter. Remarkably, we found that the A allele is derived in the human lineage and that the G/A polymorphism arose before the divergence of modern and archaic humans and segregates at intermediate to high frequencies across human populations. Remarkably, the derived A allele is has also been identified in a GWAS as a risk allele for multiple sclerosis. These data suggest that the polymorphism is maintained by Antagonistic Pleiotropy and a reproduction-health tradeoff in human evolution.

  • an ancient fecundability associated polymorphism switches a repressor into an enhancer of endometrial tap2 expression
    American Journal of Human Genetics, 2016
    Co-Authors: Katelyn M Mika, Vincent J Lynch
    Abstract:

    Variation in female reproductive traits, such as fertility, fecundity, and fecundability, is heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits has been challenging. Here, we explore the functional significance and evolutionary history of a T/C polymorphism of SNP rs2071473, which we have previously shown is an eQTL for TAP2 and significantly associated with fecundability (time to pregnancy). We replicated the association between the rs2071473 genotype and TAP2 expression by using GTEx data and demonstrated that TAP2 is expressed by decidual stromal cells at the maternal-fetal interface. Next, we showed that rs2071473 is located within a progesterone-responsive cis-regulatory element that functions as a repressor with the T allele and an enhancer with the C allele. Remarkably, we found that this polymorphism arose before the divergence of modern and archaic humans, segregates at intermediate to high frequencies across human populations, and has genetic signatures of long-term balancing selection. This variant has also previously been identified in genome-wide association studies of immune-related disease, suggesting that both alleles are maintained as a result of Antagonistic Pleiotropy.

  • an ancient fecundability associated polymorphism switches a repressor into an enhancer of endometrial tap2 expression
    bioRxiv, 2016
    Co-Authors: Katelyn M Mika, Vincent J Lynch
    Abstract:

    Variation in female reproductive traits such as fertility, fecundity, and fecundability are heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits has been challenging. Here we explore the functional significance and evolutionary history of a C/T polymorphism of SNP rs2071473, which we have previously shown is an eQTL for TAP2 and significantly associated with fecundability (time to pregnancy). We replicated the association between rs2071473 genotype and TAP2 expression using GTEx data and demonstrate that TAP2 is expressed by decidual stromal cells at the maternal-fetal interface. Next, we show that rs2071473 is located within a progesterone responsive cis-regulatory element that functions as a repressor with the T allele and an enhancer with the C allele. Remarkably, we found this polymorphism arose before the divergence of modern and archaic humans, is segregating at intermediate to high frequencies across human populations, and has genetic signatures of long-term balancing selection. This variant has also previously been identified in GWA studies of immune related disease, suggesting both alleles are maintained due to Antagonistic Pleiotropy.

Arcadi Navarro - One of the best experts on this subject based on the ideXlab platform.

  • reply to retesting the influences of mutation accumulation and Antagonistic Pleiotropy on human senescence and disease
    Nature Ecology and Evolution, 2019
    Co-Authors: Juan Antonio Rodriguez, Urko M Marigorta, David A Hughes, Nino Spataro, Elena Bosch, Xavier Farre, Gerard Muntane, Arcadi Navarro
    Abstract:

    This work was supported by Ministerio de Ciencia e Innovacion, Spain (with project grants BFU2015-68649-P, BFU2016-77961-P and PGC2018-101927-B-I00, MINECO/AEI/FEDER, UE), the Spanish National Institute of Bioinformatics (PT17/0009/0020), Direccio General de Recerca, Generalitat de Catalunya (2017SGR702, 2017SGR880) and the “Unidad de Excelencia Maria de Maeztu”, funded by the MINECO (ref: MDM-2014-0370).

  • Antagonistic Pleiotropy and mutation accumulation influence human senescence and disease
    Nature Ecology and Evolution, 2017
    Co-Authors: Juan Antonio Rodriguez, Urko M Marigorta, David A Hughes, Nino Spataro, Elena Bosch, Arcadi Navarro
    Abstract:

    Senescence has long been a public health challenge as well as a fascinating evolutionary problem. There is neither a universally accepted theory for its ultimate causes, nor a consensus about what may be its impact on human health. Here we test the predictions of two evolutionary explanations of senescence-mutation accumulation and Antagonistic Pleiotropy-which postulate that genetic variants with harmful effects in old ages can be tolerated, or even favoured, by natural selection at early ages. Using data from genome-wide association studies (GWAS), we study the effects of genetic variants associated with diseases appearing at different periods in life, when they are expected to have different impacts on fitness. Data fit theoretical expectations. Namely, we observe higher risk allele frequencies combined with large effect sizes for late-onset diseases, and detect a significant excess of early-late Antagonistically pleiotropic variants that, strikingly, tend to be harboured by genes related to ageing. Beyond providing systematic, genome-wide evidence for evolutionary theories of senescence in our species and contributing to the long-standing question of whether senescence is the result of adaptation, our approach reveals relationships between previously unrelated pathologies, potentially contributing to tackling the problem of an ageing population.

Stefano Giaimo - One of the best experts on this subject based on the ideXlab platform.

  • are some conventional measures of the rate of ageing consistent with Antagonistic Pleiotropy
    Journal of Theoretical Biology, 2013
    Co-Authors: Stefano Giaimo
    Abstract:

    Abstract Several measures of the rate of ageing have been proposed in the literature. But are they all equally good? In this work, three of these measures are considered: ω G and the parameter b for the Gompertz model, and ω W for the Weibull model. It is shown that ω G and ω W may fail to detect genuine changes in the rate of ageing when this rate varies in response to the fixation of Antagonistic–pleiotropic mutations with effects on survival, while the parameter b never fails to detect such changes. It is suggested that ω G and ω W are inconsistent with the Antagonistic Pleiotropy model for the evolution of ageing. Hence, they should not be used to test any prediction that this model is supposed to entail about the evolution of the rate of ageing, notably, Williams' prediction according to which the higher the level of environmental mortality, the higher the evolutionarily favoured rate of ageing.

  • Is cellular senescence an example of Antagonistic Pleiotropy?
    Aging Cell, 2012
    Co-Authors: Stefano Giaimo, Fabrizio D'adda Di Fagagna
    Abstract:

    It is generally accepted that the permanent arrest of cell division known as cellular senescence contributes to aging by an Antagonistic Pleiotropy mechanism: cellular senescence would act beneficially early in life by suppressing cancer, but detrimentally later on by causing frailty and, paradoxically, cancer. In this review, we show that there is room to rethink this common view. We propose a critical appraisal of the arguments commonly brought in support of it, and we qualitatively analyse published results that are of relevance to understand whether or not cellular senescence-associated genes really act in an Antagonistic-pleiotropic manner in humans.

Alberto Velando - One of the best experts on this subject based on the ideXlab platform.

  • a benign juvenile environment reduces the strength of Antagonistic Pleiotropy and genetic variation in the rate of senescence
    Journal of Animal Ecology, 2016
    Co-Authors: Sinyeon Kim, Neil B Metcalfe, Alberto Velando
    Abstract:

    The environment can play an important role in the evolution of senescence because the optimal allocation between somatic maintenance and reproduction depends on external factors influencing life expectancy. The aims of this study were to experimentally test whether environmental conditions during early life can shape senescence schedules, and if so, to examine whether variation among individuals or genotypes with respect to the degree of ageing differs across environments. We tested life-history plasticity and quantified genetic effects on the pattern of senescence across different environments within a reaction norm framework by using an experiment on the three-spined stickleback (Gasterosteus aculeatus, Linnaeus) in which F1 families originating from a wild annual population experienced different temperature regimes. Male sticklebacks that had experienced a more benign environment earlier in life subsequently reduced their investment in carotenoid-based sexual signals early in the breeding season, and consequently senesced at a slower rate later in the season, compared to those that had developed under harsher conditions. This plasticity of ageing was genetically determined. Both Antagonistic Pleiotropy and genetic variation in the rate of senescence were evident only in the individuals raised in the harsher environment. The experimental demonstration of genotype-by-environment interactions influencing the rate of reproductive senescence provides interesting insights into the role of the environment in the evolution of life histories. The results suggest that benign conditions weaken the scope for senescence to evolve and that the dependence on the environment may maintain genetic variation under selection.

M P Harris - One of the best experts on this subject based on the ideXlab platform.

  • reproductive senescence in a long lived seabird rates of decline in late life performance are associated with varying costs of early reproduction
    The American Naturalist, 2008
    Co-Authors: Thomas E Reed, Loeske E B Kruuk, Sarah Wanless, Morten Frederiksen, Emma J A Cunningham, M P Harris
    Abstract:

    Evolutionary theories of senescence predict that rates of decline in performance parameters should be shaped by early-life trade-offs between reproduction and somatic maintenance. Here we investigate factors influencing the rate of reproductive senescence in a long-lived seabird, the common guillemot Uria aalge, using data collected over a 23-year period. In the last 3 years of life, individual guillemots had significantly reduced breeding success and were less likely to hold a site or attempt to breed. Females senesced at a significantly faster rate than males. At the individual level, high levels of reproductive output earlier in life were associated with increased senescence later in life. This trade-off between early- and late-life reproduction was evident independent of the fact that as birds age, they breed later in the season. The rate of senescence was additionally dependent on environmental conditions experienced earlier in life, with evidence that harsh conditions amplified later declines in breeding success. Overall, individuals with intermediate levels of early-life productivity lived longer. These results provide support for the Antagonistic-Pleiotropy and disposable-soma theories of senescence and demonstrate for the first time in a wild bird population that increased rates of senescence in reproductive performance are associated with varying costs of reproduction early in life.