Footprints in the Sand: Deep Taxonomic Comparisons in Vertebrate Genomics to Unveil the Genetic Programs of Human Longevity

With the modern quality, quantity, and availability of genomic sequencing across species, as well as across the expanse of human populations, we can screen for shared signatures underlying longevity and lifespan. Knowledge of these mechanisms would be medically invaluable in combating aging and age-related diseases. The diversity of longevities across vertebrates is an opportunity to look for patterns of genetic variation that may signal how this life history property is regulated, and ultimately how it can be modulated. Variation in human longevity provides a unique window to look for cases of extreme lifespan within a population, as well as associations across populations for factors that influence capacity to live longer. Current large cohort studies support the use of population level analyses to identify key factors associating with human lifespan. These studies are powerful in concept, but have demonstrated limited ability to resolve signals from background variation. In parallel, the expanding catalog of sequencing and annotation from diverse species, some of which have evolved longevities well past a human lifespan, provides independent cases to look at the genomic signatures of longevity. Recent comparative genomic work has shown promise in finding shared mechanisms associating with longevity among distantly related vertebrate groups. Given the genetic constraints between vertebrates, we posit that a combination of approaches, of parallel meta-analysis of human longevity along with refined analysis of other vertebrate clades having exceptional longevity, will aid in resolving key regulators of enhanced lifespan that have proven to be elusive when analyzed in isolation.

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Towards a Socio-Economic Model for Southwest Asian Cereal Domestication

Agronomy ◽

10.3390/agronomy11122432 ◽

2021 ◽

Vol 11 (12) ◽

pp. 2432

Author(s):

Alexander Weide

Keyword(s):

Population Level ◽

Genetic Isolation ◽

Annual Plants ◽

Key Factors ◽

Genetic Constraints ◽

The Social ◽

Limited Food ◽

Selection For ◽

Social Units ◽

Extended Households

Mechanisms of selection for domestication traits in cereals and other annual plants are commonly explained from agro-technological and genetic perspectives. Since archaeobotanical data showed that domestication processes were slow and protracted, research focused on genetic constraints and hypothetical ‘non-selective’ management regimes to explain the low selection rates. I argue that these factors only partially explain the observed patterns and develop a model that contextualises the archaeobotanical data in their socio-economic settings. I propose that developments towards individual storage by small household units and the gradual increase in storage capacities with the development of extended households represent key factors for establishing the conditions for selection, as these practices isolated individually managed and stored cereal subpopulations and gradually reduced the need to replenish grain stocks with grains from unmanaged populations. This genetic isolation resulted in stronger and more persistent selection rates and facilitated the genetic fixation of domestication traits on a population level. Moreover, individual storage facilities within buildings reflect gradual developments towards households as the social units that mobilised agricultural labour, which negotiated new sharing principles over cultivated resources and drove the intensification of cultivation practices. In this sense, selection rates and the slow domestication process can be understood as a function of limited food sharing networks and increased labour-inputs into early arable environments—socio-economic processes that also unfolded gradually over a protracted period of time.

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Wastewater Surveillance of Antimicrobial Resistance in Human Populations: A Systematic Review

10.20944/preprints202010.0267.v1 ◽

2020 ◽

Author(s):

Kevin Chau ◽

Leanne Barker ◽

Natalie Sims ◽

Barbara Kasprzyk-Hordern ◽

Eric Budgell ◽

...

Keyword(s):

Antimicrobial Resistance ◽

Longitudinal Studies ◽

Study Design ◽

Meta Analysis ◽

Population Level ◽

Human Populations ◽

Grab Sampling ◽

Culture Independent ◽

Methodological Approaches ◽

The Impact

Wastewater-based surveillance of antimicrobial resistance (AMR) may facilitate convenient monitoring of population-level AMR prevalence without the healthcare-associated bias and data collection restrictions inherent to clinically oriented systems. However, differences in study design and methodology likely contribute to differences in outcomes and interpretation, limiting reproducibility, reliability and meta-analysis. We therefore systematically reviewed studies using wastewater for AMR surveillance in human populations to identify optimal practices to detect wastewater-human AMR correlations. We evaluated 7,063 records and 174 full-text methods in a two-stage screen; 20 studies were included. Risk of bias assessment divided studies into high-risk (n=3), low-risk (n=3) and unclear-risk (n=14). Most studies detected wastewater-human AMR correlations (n=15) but only six studies identified statistically significant associations, most via culture-independent approaches (n=5). Genomic approaches also facilitated higher-resolution AMR monitoring whereas culture-based studies primarily undertook observational comparisons of specific organisms and phenotypic AMR profiles. Studies identifying wastewater-human AMR correlations were consistently associated with sampling wastewater influent irrespective of other methodological approaches. For longitudinal studies, a timeframe of >=6 months was similarly associated. Most influent studies identifying wastewater-human AMR correlations used composite (n=5) or flow-proportional wastewater sampling methods (n=4); however, grab sampling was commonest overall (n=6) and generally appeared similarly effective.Wastewater-based surveillance of AMR in human populations appears relatively robust, with most included studies reporting a correlation despite high diversity in study design and methodology. Our review supports sampling of wastewater influent using composite sampling (at a minimum) as a standard. Impacts of other methodological approaches are less clear; however, a minimum timeframe of six months for longitudinal studies, and increased sampling coverage for culture-independent studies to enable adequate biostatistical analyses appear sensible. As this relatively new field grows, more studies with clear wastewater-based population-level AMR surveillance aims are needed to better determine the impact of confounding features and validate comprehensive “best practice” protocols.

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The Three Genetics (Nuclear DNA, Mitochondrial DNA, and Gut Microbiome) of Longevity in Humans Considered as Metaorganisms

BioMed Research International ◽

10.1155/2014/560340 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 12

Author(s):

Paolo Garagnani ◽

Chiara Pirazzini ◽

Cristina Giuliani ◽

Marco Candela ◽

Patrizia Brigidi ◽

...

Keyword(s):

Mitochondrial Dna ◽

Nuclear Dna ◽

Complex Dynamics ◽

Nuclear Genome ◽

Holistic Approach ◽

Human Longevity ◽

Human Lifespan ◽

Complex Interactions ◽

Age Related

Usually the genetics of human longevity is restricted to the nuclear genome (nDNA). However it is well known that the nDNA interacts with a physically and functionally separated genome, the mitochondrial DNA (mtDNA) that, even if limited in length and number of genes encoded, plays a major role in the ageing process. The complex interplay between nDNA/mtDNA and the environment is most likely involved in phenomena such as ageing and longevity. To this scenario we have to add another level of complexity represented by the microbiota, that is, the whole set of bacteria present in the different part of our body with their whole set of genes. In particular, several studies investigated the role of gut microbiota (GM) modifications in ageing and longevity and an age-related GM signature was found. In this view, human being must be considered as “metaorganism” and a more holistic approach is necessary to grasp the complex dynamics of the interaction between the environment and nDNA-mtDNA-GM of the host during ageing. In this review, the relationship between the three genetics and human longevity is addressed to point out that a comprehensive view will allow the researchers to properly address the complex interactions that occur during human lifespan.

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Population frequencies of vkorc1 c1173t polymorphism, which determining the organism sensitivity to warfarin, in forest nenets and nganasans of northern siberia

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.02.35-42 ◽

2020 ◽

pp. 35-42

Author(s):

Р.П. Тийс ◽

Л.П. Осипова ◽

Е.Н. Воронина ◽

М.Л. Филипенко

Keyword(s):

Population Level ◽

Indigenous Populations ◽

Human Populations ◽

Similar Distribution ◽

Taimyr Peninsula ◽

Key Factors ◽

Single Nucleotide ◽

Individual Level ◽

Vkorc1 Gene ◽

Similar Distribution Pattern

Полиморфизм C1173T гена VKORC1 является одним из ключевых факторов, определяющих как этнические, так и индивидуальные различия в чувствительности к антикоагулянту варфарину и его поддерживающей дозе у пациентов при лечении тромбозозависимых заболеваний. В связи с этим, на популяционном уровне проведено исследование полиморфизма VKORC1 C1173T среди коренных представителей лесных ненцев Ямало-Ненецкого автономного округа и нганасан полуострова Таймыр Красноярского края. Генотипирование однонуклеотидных замен в гене VKORC1 проводилось в режиме реального времени с использованием конкурирующих TaqMan-зондов. Выявлено, что вариант VKORC1 1173T встречается с высокой частотой в изученных популяциях: 67% у лесных ненцев и 94% у нганасан. Этот показатель существенно и статистически значимо выше, чем у европейцев, и имеет схожий характер распространения с таковым у азиатов Китая и Японии. Результаты нашего исследования расширяют знания о полиморфизме гена VKORC1 в человеческих популяциях, а также способствуют развитию персонализированной медицины по отношению к коренным жителям Сибири, так как генетический статус человека, имеющего вариант 1173T, может учитываться в целях достижения максимально безопасной и эффективной терапии варфарином при тромбозозависимых заболеваниях. Polymorphism C1173T of the VKORC1 gene is one of the key factors determining both ethnic and individual differences in the sensitivity to the anticoagulant warfarin and its maintenance dose in patients in the treatment of thrombosis-dependent diseases. In this regard, at the population level the VKORC1 C1173T polymorphism was studied in indigenous populations of the Forest Nenets (the Yamal-Nenets Autonomous Okrug) and Nganasans (the Taimyr Peninsula of the Krasnoyarsk region). Genotyping of C1173T single nucleotide substitution in the VKORC1 gene was carried out in real time using competing TaqMan probes. It was revealed that the variant VKORC1 1173T occurs with a high frequency in the studied populations: 67% in Forest Nenets and 94% in Nganasans. This indicator is significantly higher than that of Europeans, and has a similar distribution pattern with that of Asians. The results of our study expand knowledge about VKORC1 gene polymorphism in human populations, and also promote the development of personalized medicine in relation to indigenous people of Siberia, since the genetic status of a person with variant 1173T can be taken into account at an individual level in order to achieve the most safe and effective warfarin therapy of thrombosis-dependent diseases.

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THE LONGEVITY CONSORTIUM VISION

Innovation in Aging ◽

10.1093/geroni/igz038.758 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S208-S209

Author(s):

Daniel S Evans ◽

Steven R Cummings ◽

Nicholas Schork

Keyword(s):

Healthy Aging ◽

Human Longevity ◽

Cooperative Research ◽

Healthy Human ◽

Molecular Features ◽

Human Lifespan ◽

Age Related ◽

Show Evidence ◽

Funding Opportunities ◽

Multiple Chronic Diseases

Abstract Molecular factors and pathways promoting human longevity and healthy aging can potentially delay or prevent multiple chronic diseases and conditions, but identifying such factors that can be pharmacologically targeted requires an integrated multidisciplinary approach. We describe the design of the five research projects and three cores of the Longevity Consortium (LC) and how their cooperative research is designed to discover molecular factors and pathways that can predict healthy human aging and longevity, associate with extreme human lifespan, show relevance to chronic age-related conditions, respond to interventions to slow aging in mice, and show evidence for association with lifespan across species. A systems biology approach is undertaken to identify common molecular features across human traits and organisms, and a chemoinformatics approach to link molecular targets to candidate healthy aging interventions. The LC results are made publicly available and we provide funding opportunities to the scientific community to support pilot projects.

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Insights from evolutionarily relevant models for human ageing

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2019.0605 ◽

2020 ◽

Vol 375 (1811) ◽

pp. 20190605

Author(s):

Melissa Emery Thompson ◽

Alexandra G. Rosati ◽

Noah Snyder-Mackler

Keyword(s):

Individual Characteristics ◽

Ageing Process ◽

Model Organisms ◽

Small Scale ◽

Human Populations ◽

Ageing Population ◽

Human Lifespan ◽

Age Related ◽

The Social ◽

Human Ageing

As the world confronts the health challenges of an ageing population, there has been dramatically increased interest in the science of ageing. This research has overwhelmingly focused on age-related disease, particularly in industrialized human populations and short-lived laboratory animal models. However, it has become clear that humans and long-lived primates age differently than many typical model organisms, and that many of the diseases causing death and disability in the developed world are greatly exacerbated by modern lifestyles. As such, research on how the human ageing process evolved is vital to understanding the origins of prolonged human lifespan and factors increasing vulnerability to degenerative disease. In this issue, we highlight emerging comparative research on primates, highlighting the physical, physiological, behavioural and cognitive processes of ageing. This work comprises data and theory on non-human primates, as well as under-represented data on humans living in small-scale societies, which help elucidate how environment shapes senescence. Component papers address (i) the critical processes that comprise senescence in long-lived primates; (ii) the social, ecological or individual characteristics that predict variation in the pace of ageing; and (iii) the complicated relationship between ageing trajectories and disease outcomes. Collectively, this work provides essential comparative, evolutionary data on ageing and demonstrates its unique potential to inform our understanding of the human ageing process. This article is part of the theme issue ‘Evolution of the primate ageing process’.

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The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity

Genes ◽

10.3390/genes10030222 ◽

2019 ◽

Vol 10 (3) ◽

pp. 222 ◽

Cited By ~ 22

Author(s):

Paolo Abondio ◽

Marco Sazzini ◽

Paolo Garagnani ◽

Alessio Boattini ◽

Daniela Monti ◽

...

Keyword(s):

Evolutionary Dynamics ◽

Human Longevity ◽

Human Populations ◽

Worldwide Distribution ◽

Age Related ◽

Gene Environment ◽

Genome Wide ◽

History Of ◽

Extreme Longevity ◽

Adaptive Role

Human longevity is a complex phenotype resulting from the combinations of context-dependent gene-environment interactions that require analysis as a dynamic process in a cohesive ecological and evolutionary framework. Genome-wide association (GWAS) and whole-genome sequencing (WGS) studies on centenarians pointed toward the inclusion of the apolipoprotein E (APOE) polymorphisms ε2 and ε4, as implicated in the attainment of extreme longevity, which refers to their effect in age-related Alzheimer’s disease (AD) and cardiovascular disease (CVD). In this case, the available literature on APOE and its involvement in longevity is described according to an anthropological and population genetics perspective. This aims to highlight the evolutionary history of this gene, how its participation in several biological pathways relates to human longevity, and which evolutionary dynamics may have shaped the distribution of APOE haplotypes across the globe. Its potential adaptive role will be described along with implications for the study of longevity in different human groups. This review also presents an updated overview of the worldwide distribution of APOE alleles based on modern day data from public databases and ancient DNA samples retrieved from literature in the attempt to understand the spatial and temporal frame in which present-day patterns of APOE variation evolved.

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Trends in DNA methylation with age replicate across diverse human populations

10.1101/073171 ◽

2016 ◽

Author(s):

Shyamalika Gopalan ◽

Oana Carja ◽

Maud Fagny ◽

Etienne Patin ◽

Justin W. Myrick ◽

...

Keyword(s):

Dna Methylation ◽

Meta Analysis ◽

Chronological Age ◽

Human Populations ◽

Strongly Correlated ◽

Hunter Gatherers ◽

Cpg Sites ◽

Age Related ◽

Genome Wide ◽

Methylation Patterns

AbstractAging is associated with widespread changes in genome-wide patterns of DNA methylation. Thousands of CpG sites whose tissue-specific methylation levels are strongly correlated with chronological age have been previously identified. However, the majority of these studies have focused primarily on cosmopolitan populations living in the developed world; it is not known if age-related patterns of DNA methylation at these loci are similar across a broad range of human genetic and ecological diversity. We investigated genome-wide methylation patterns using saliva and whole blood derived DNA from two traditionally hunting and gathering African populations: the Baka of the western Central African rainforest and the ≠Khomani San of the South African Kalahari Desert. We identify hundreds of CpG sites whose methylation levels are significantly associated with age, thousands that are significant in a meta-analysis, and replicate trends previously reported in populations of non-African descent. We confirm that an age-associated site in the gene ELOVL2 shows a remarkably congruent relationship with aging in humans, despite extensive genetic and environmental variation across populations. We also demonstrate that genotype state at methylation quantitative trait loci (meQTLs) can affect methylation trends at some known age-associated CpG sites. Our study explores the relationship between CpG methylation and chronological age in populations of African hunter-gatherers, who rely on different diets across diverse ecologies. While many age-related CpG sites replicate across populations, we show that considering common genetic variation at meQTLs further improves our ability to detect previously identified age associations.

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