The genomics of exceptional longevity in rockfishes refine genetic foundations of human lifespan variation

2021 ◽  
Author(s):  
Stephen Treaster ◽  
Joris Deelen ◽  
Jacob Daane ◽  
Joanne Murabito ◽  
David Karasik ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Genetic Regulation ◽  
Time Frame ◽  
Genomic Variation ◽  
Human Longevity ◽  
Evolutionary Time ◽  
Aryl Hydrocarbon ◽  
Human Lifespan ◽  
Heritable Trait ◽  
Lifespan Variation

Abstract Longevity is a defining, heritable trait that varies dramatically between species. To resolve the genetic regulation of this trait, we have mined genomic variation in rockfishes, ranging in longevity from 11 to over 205 years. Shifts in rockfish longevity occurred multiple times independently, and in a short evolutionary time frame, thus empowering convergence analyses. Our analyses reveal a common network of genes under convergent restricted evolution in long-lived lineages, encompassing established aging regulators such as insulin-signaling, yet also identify flavonoid (aryl-hydrocarbon) metabolism as a novel pathway modulating longevity. Further, these genes were used to refine human longevity GWAS, identifying the aryl-hydrocarbon metabolism pathway to be significantly associated with the 99th percentile of human longevity, independently validating its importance and conservation. This evolutionary intersection highlights a novel, conserved genetic architecture that associates with the evolution of longevity across vertebrates and provides actionable targets for research into lifespan and healthspan modulation.

scholarly journals Germline burden of rare damaging variants negatively affects human healthspan and lifespan

2019 ◽  
Author(s):  
Anastasia V. Shindyapina ◽  
Aleksandr A. Zenin ◽  
Andrei E. Tarkhov ◽  
Peter O. Fedichev ◽  
Vadim N. Gladyshev
Keyword(s):  
Association Studies ◽  
Twin Studies ◽  
Cumulative Effect ◽  
Human Longevity ◽  
Order Effects ◽  
Genome Wide Association Studies ◽  
Mortality And Morbidity ◽  
Human Lifespan ◽  
Lifespan Variation ◽  
Lifespan Variability

Genome-wide association studies often explore links between particular genes and phenotypes of interest. Known genetic variants, however, are responsible for only a small fraction of human lifespan variation evident from genetic twin studies. To account for the missing longevity variance, we hypothesized that the cumulative effect of deleterious variants may affect human longevity. Here, we report that the burden of rarest protein-truncating variants (PTVs) negatively impacts both human healthspan and lifespan in two large independent cohorts. Longer-living subjects have both fewer rarest PTVs and less damaging PTVs. In contrast, we show that the burden of frequent PTVs and rare non-PTVs is less deleterious, lacking association with longevity. The combined effect of rare PTVs is similar to that of known variants associated with longer lifespan and accounts for 1 − 2 years of lifespan variability. We further find that somatic accumulation of PTVs accounts for a minute fraction of mortality and morbidity acceleration and hence provides little support for its causal role in aging. Thus, damaging mutations, germline and somatic, can only contribute to aging as a result of higher-order effects including interactions of multiple forms of damage.

scholarly journals Genetic architecture of reciprocal social behavior in toddlers: Implications for heterogeneity in the early origins of autism spectrum disorder

2020 ◽  
Vol 32 (4) ◽  
pp. 1190-1205
Author(s):  
Natasha Marrus ◽  
Julia D. Grant ◽  
Brooke Harris-Olenak ◽  
Jordan Albright ◽  
Drew Bolster ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Genetic Architecture ◽  
Ethnically Diverse ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Genetic Influences ◽  
Heritable Trait ◽  
Birth Registries

AbstractImpairment in reciprocal social behavior (RSB), an essential component of early social competence, clinically defines autism spectrum disorder (ASD). However, the behavioral and genetic architecture of RSB in toddlerhood, when ASD first emerges, has not been fully characterized. We analyzed data from a quantitative video-referenced rating of RSB (vrRSB) in two toddler samples: a community-based volunteer research registry (n = 1,563) and an ethnically diverse, longitudinal twin sample ascertained from two state birth registries (n = 714). Variation in RSB was continuously distributed, temporally stable, significantly associated with ASD risk at age 18 months, and only modestly explained by sociodemographic and medical factors (r2 = 9.4%). Five latent RSB factors were identified and corresponded to aspects of social communication or restricted repetitive behaviors, the two core ASD symptom domains. Quantitative genetic analyses indicated substantial heritability for all factors at age 24 months (h2 ≥ .61). Genetic influences strongly overlapped across all factors, with a social motivation factor showing evidence of newly-emerging genetic influences between the ages of 18 and 24 months. RSB constitutes a heritable, trait-like competency whose factorial and genetic structure is generalized across diverse populations, demonstrating its role as an early, enduring dimension of inherited variation in human social behavior. Substantially overlapping RSB domains, measurable when core ASD features arise and consolidate, may serve as markers of specific pathways to autism and anchors to inform determinants of autism's heterogeneity.

scholarly journals On Using Local Ancestry to Characterize the Genetic Architecture of Human Phenotypes: Genetic Regulation of Gene Expression in Multiethnic or Admixed Populations as a Model

2018 ◽  
Author(s):  
Yizhen Zhong ◽  
Minoli Perera ◽  
Eric R. Gamazon
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Type I ◽  
Eqtl Mapping ◽  
Entire Genome ◽  
Local Ancestry ◽  
Heritability Estimation

AbstractBackgroundUnderstanding the nature of the genetic regulation of gene expression promises to advance our understanding of the genetic basis of disease. However, the methodological impact of use of local ancestry on high-dimensional omics analyses, including most prominently expression quantitative trait loci (eQTL) mapping and trait heritability estimation, in admixed populations remains critically underexplored.ResultsHere we develop a statistical framework that characterizes the relationships among the determinants of the genetic architecture of an important class of molecular traits. We estimate the trait variance explained by ancestry using local admixture relatedness between individuals. Using National Institute of General Medical Sciences (NIGMS) and Genotype-Tissue Expression (GTEx) datasets, we show that use of local ancestry can substantially improve eQTL mapping and heritability estimation and characterize the sparse versus polygenic component of gene expression in admixed and multiethnic populations respectively. Using simulations of diverse genetic architectures to estimate trait heritability and the level of confounding, we show improved accuracy given individual-level data and evaluate a summary statistics based approach. Furthermore, we provide a computationally efficient approach to local ancestry analysis in eQTL mapping while increasing control of type I and type II error over traditional approaches.ConclusionOur study has important methodological implications on genetic analysis of omics traits across a range of genomic contexts, from a single variant to a prioritized region to the entire genome. Our findings highlight the importance of using local ancestry to better characterize the heritability of complex traits and to more accurately map genetic associations.

Aryl Hydrocarbon Receptor and Its Diverse Ligands and Functions: An Exposome Receptor

2021 ◽  
Vol 62 (1) ◽  
Author(s):  
Lucie Larigot ◽  
Louise Benoit ◽  
Meriem Koual ◽  
Céline Tomkiewicz ◽  
Robert Barouki ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Bacterial Infections ◽  
Critical Role ◽  
Time Frame ◽  
Receptor Activation ◽  
Annual Review ◽  
Publication Date ◽  
Pharmacological Characterization ◽  
Cancer Pathways ◽  
Aryl Hydrocarbon

The aryl hydrocarbon receptor (AhR) is a transcriptional factor that regulates multiple functions following its activation by a variety of ligands, including xenobiotics, natural products, microbiome metabolites, and endogenous molecules. Because of this diversity, the AhR constitutes an exposome receptor. One of its main functions is to regulate several lines of defense against chemical insults and bacterial infections. Indeed, in addition to its well-established detoxication function, it has several functions at physiological barriers, and it plays a critical role in immunomodulation. The AhR is also involved in the development of several organs and their homeostatic maintenance. Its activity depends on the type of ligand and on the time frame of the receptor activation, which can be either sustained or transient, leading in some cases to opposite modes of regulations as illustrated in the regulation of different cancer pathways. The development of selective modulators and their pharmacological characterization are important areas of research. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Macroevolutionary consequences of sexual conflict

2018 ◽  
Vol 14 (6) ◽  
pp. 20180186
Author(s):  
Jo S. Hermansen ◽  
Jostein Starrfelt ◽  
Kjetil L. Voje ◽  
Nils C. Stenseth
Keyword(s):  
Sexual Selection ◽  
Genetic Architecture ◽  
Time Frame ◽  
Sexual Conflicts ◽  
Males And Females ◽  
Selection For ◽  
Evolutionary Consequences ◽  
Future Work ◽  
Shared Genetic

Intralocus sexual conflicts arise whenever the fitness optima for a trait expressed in both males and females differ between the sexes and shared genetic architecture constrains the sexes from evolving independently towards their respective optima. Such sexual conflicts are commonplace in nature, yet their long-term evolutionary consequences remain unexplored. Using a Bayesian phylogenetic comparative framework, we studied the macroevolutionary dynamics of intersexual trait integration in stalk-eyed flies (Diopsidae) spanning a time frame of more than 25 Myr. We report that increased intensity of sexual selection on male eyestalks is associated with reduced intersexual eyestalk integration, as well as sex-specific rates of eyestalk evolution. Despite this, lineages where males have been under strong sexual selection for millions of years still exhibit high levels of intersexual trait integration. This low level of decoupling between the sexes may indicate that exaggerated female eyestalks are in fact adaptive—or alternatively, that there are strong constraints on reducing trait integration between the sexes. Future work should seek to clarify the relative roles of constraints and selection in contributing to the varying levels of intersexual trait integration in stalk-eyed flies, and in this way clarify whether sexual conflicts can act as constraints on adaptive evolution even on macroevolutionary time scales.

scholarly journals The Interplay Between Stress Related Genes and Its Role in Human Longevity: Insights for Translational Studies

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 671-671
Author(s):  
Anatoliy Yashin ◽  
Deqing Wu ◽  
Konstantin Arbeev ◽  
Olivia Bagley ◽  
Igor Akushevich ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cellular Stress ◽  
Experimental Studies ◽  
Laboratory Animals ◽  
Human Longevity ◽  
Proliferating Cells ◽  
Human Data ◽  
Human Lifespan ◽  
Stress Signals ◽  
Lifespan Variability

Abstract Human lifespan is a multifactorial trait resulted from complicated interplay among many genetic and environmental factors. Despite substantial progress in clarifying many aspects of lifespan’ variability the mechanism of its multifactorial regulation remains unclear. In this paper we investigate the role of genes from integrated stress response (ISR) pathway in such regulation. Experimental studies showed that persistent cellular stress may result in cellular senescence (for proliferating cells), or in apoptosis (for post-mitotic cells) which may affect health and lifespan in laboratory animals. These studies also showed which ISR genes are likely to interplay to produce joint effects on these traits. Note that in humans, the interplay between these genes does not necessarily influence these traits. This is because biological mechanisms regulating these traits in laboratory animals and humans may differ. This means that, when possible, the experimentally detected connections promising for human applications, should be verified using available human data before their testing in expensive clinical trials. In this paper we used HRS data to test connection between SNPs from the EIF2AK4 gene that senses cellular stress signals and the DDIT3 gene from the apoptosis regulation part of the ISR. We found genome wide significant associations between interacting SNPs from these genes and longevity. This result shows that available human data may be successfully used for making important steps in translation of experimental research findings towards their application in humans. Following this strategy may increase efficiency of clinical trials aiming to find appropriate medications to promote human health and longevity.

scholarly journals Rapid emergence of clonal interference during malaria parasite cultivation

2020 ◽  
Author(s):  
Catherine Jett ◽  
Aliou Dia ◽  
ian H. cheeseman
Keyword(s):  
Growth Rate ◽  
Malaria Parasite ◽  
Time Frame ◽  
Genomic Variation ◽  
Clonal Interference ◽  
Long Term Culture ◽  
Parasite Plasmodium Falciparum ◽  
Cell Genome

Abstract Laboratory cultivation of the malaria parasite Plasmodium falciparum has underpinned nearly all advances in malariology in the past 30 years. When freshly isolated clinical isolates are adapted to in vitro culture mutations rapidly fix increasing the parasite growth rate and stability. While the dynamics of culture adaptation are increasingly well characterized, we know little about the extent of genomic variation that arises and spreads during long term culture. To address this we cloned the 3D7 reference strain and maintained a culture for ~84 asexual cycles (167 days). Growth rate of the culture population increased 1.14-fold over this timeframe. We used single cell genome sequencing of parasites at cycles 21 and 84 to measure the accumulation of diversity in vitro . This parasite population showed strong signals of adaptation across this time frame. By cycle 84 two dominant clades had arisen and were segregating with the dynamics of clonal interference. This highlights the continual process of adaptation in malaria parasites, even in parasites which have been extensively adapted to long term culture.

scholarly journals Polygenic basis and biomedical consequences of telomere length variation

2021 ◽  
Vol 53 (10) ◽  
pp. 1425-1433
Author(s):  
Veryan Codd ◽  
Qingning Wang ◽  
Elias Allara ◽  
Crispin Musicha ◽  
Stephen Kaptoge ◽  
...  
Keyword(s):  
Telomere Length ◽  
Genetic Architecture ◽  
Cellular Proliferation ◽  
Genetic Regulation ◽  
Biological Traits ◽  
Length Variation ◽  
Leukocyte Telomere Length ◽  
Naturally Occurring ◽  
Bone Marrow Function ◽  
Genetically Determined

AbstractTelomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.

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