Epigenetic Age Acceleration and Chronological Age: Associations With Cognitive Performance in Daily Life.

DNA methylation-derived epigenetic clocks offer the opportunity to examine aspects of age acceleration (ie, the difference between an individual's biological age and chronological age), which vary among individuals and may better account for age-related changes in cognitive function than chronological age. Leveraging existing ambulatory cognitive assessments in daily life from a genetically diverse sample of 142 adults in midlife, we examined associations between 5 measures of epigenetic age acceleration and performance on tasks of processing speed and working memory. Covarying for chronological age, we used multilevel models to examine associations of epigenetic age acceleration (Horvath 1, Horvath 2, Hannum, PhenoAge, and GrimAge clocks) with both average level and variability of cognitive performance. Positive age acceleration (ie, epigenetic age greater than chronological age) was associated with poorer mean processing speed (Horvath 1 and 2) and working memory (GrimAge). Higher chronological age was also associated with poorer mean processing speed and working memory performance. Further, positive age acceleration was generally associated with greater intraindividual variability in working memory and processing speed tasks, whereas being chronologically older was associated with less intraindividual variability. Although further work is needed, our results indicate age acceleration effects have comparable or greater size as those for chronological age differences, suggesting that epigenetic age acceleration may account for additional risk and interindividual variation in cognitive performance above chronological age.

Getting it right: Teaching undergraduate biology to undermine racial essentialism.

How we teach human genetics matters for social equity. The biology curriculum appears to be a crucial locus of intervention for either reinforcing or undermining students' racial essentialist views. The Mendelian genetic models dominating textbooks, particularly in combination with racially inflected language sometimes used when teaching about monogenic disorders, can increase middle and high school students' racial essentialism and opposition to policies to increase equity. These findings are of particular concern given the increasing spread of racist misinformation online and the misappropriation of human genomics research by white supremacists, who take advantage of low levels of genetics literacy in the general public. Encouragingly, however, teaching updated information about the geographical distribution of human genetic variation and the complex, multifactorial basis of most human traits, reduces students' endorsement of racial essentialism. The genetics curriculum is therefore a key tool in combating misinformation and scientific racism. Here, we describe a framework and example teaching materials for teaching students key concepts in genetics, human evolutionary history, and human phenotypic variation at the undergraduate level. This framework can be flexibly applied in biology and anthropology classes and adjusted based on time availability. Our goal is to provide undergraduate-level instructors with varying levels of expertise with a set of evidence-informed tools for teaching human genetics to combat scientific racism, including an evolving set of instructional resources, as well as learning goals and pedagogical approaches. Resources can be found at https://noto.li/YIlhZ5. Additionally, we hope to generate conversation about integrating modern genetics into the undergraduate curriculum, in light of recent findings about the risks and opportunities associated with teaching genetics.

Multi-ancestry fine-mapping improves precision to identify causal genes in transcriptome-wide association studies.

Transcriptome-wide association studies (TWASs) are a powerful approach to identify genes whose expression is associated with complex disease risk. However, non-causal genes can exhibit association signals due to confounding by linkage disequilibrium (LD) patterns and eQTL pleiotropy at genomic risk regions, which necessitates fine-mapping of TWAS signals. Here, we present MA-FOCUS, a multi-ancestry framework for the improved identification of genes underlying traits of interest. We demonstrate that by leveraging differences in ancestry-specific patterns of LD and eQTL signals, MA-FOCUS consistently outperforms single-ancestry fine-mapping approaches with equivalent total sample sizes across multiple metrics. We perform TWASs for 15 blood traits using genome-wide summary statistics (average nEA = 511 k, nAA = 13 k) and lymphoblastoid cell line eQTL data from cohorts of primarily European and African continental ancestries. We recapitulate evidence demonstrating shared genetic architectures for eQTL and blood traits between the two ancestry groups and observe that gene-level effects correlate 20% more strongly across ancestries than SNP-level effects. Lastly, we perform fine-mapping using MA-FOCUS and find evidence that genes at TWAS risk regions are more likely to be shared across ancestries than they are to be ancestry specific. Using multiple lines of evidence to validate our findings, we find that gene sets produced by MA-FOCUS are more enriched in hematopoietic categories than alternative approaches (p = 2.36 × 10-15). Our work demonstrates that including and appropriately accounting for genetic diversity can drive more profound insights into the genetic architecture of complex traits.

Human genetic admixture through the lens of population genomics.

Over the past 50 years, geneticists have made great strides in understanding how our species' evolutionary history gave rise to current patterns of human genetic diversity classically summarized by Lewontin in his 1972 paper, 'The Apportionment of Human Diversity'. One evolutionary process that requires special attention in both population genetics and statistical genetics is admixture: gene flow between two or more previously separated source populations to form a new admixed population. The admixture process introduces ancestry-based structure into patterns of genetic variation within and between populations, which in turn influences the inference of demographic histories, identification of genetic targets of selection and prediction of complex traits. In this review, we outline some challenges for admixture population genetics, including limitations of applying methods designed for populations without recent admixture to the study of admixed populations. We highlight recent studies and methodological advances that aim to overcome such challenges, leveraging genomic signatures of admixture that occurred in the past tens of generations to gain insights into human history, natural selection and complex trait architecture. This article is part of the theme issue 'Celebrating 50 years since Lewontin's apportionment of human diversity'.

Hunter-gatherer genomes reveal diverse demographic trajectories during the rise of farming in Eastern Africa.

The fate of hunting and gathering populations following the rise of agriculture and pastoralism remains a topic of debate in the study of human prehistory. Studies of ancient and modern genomes have found that autochthonous groups were largely replaced by expanding farmer populations with varying levels of gene flow, a characterization that is influenced by the almost universal focus on the European Neolithic.1-5 We sought to understand the demographic impact of an ongoing cultural transition to farming in Southwest Ethiopia, one of the last regions in Africa to experience such shifts.6 Importantly, Southwest Ethiopia is home to several of the world's remaining hunter-gatherer groups, including the Chabu people, who are currently transitioning away from their traditional mode of subsistence.7 We generated genome-wide data from the Chabu and four neighboring populations, the Majang, Shekkacho, Bench, and Sheko, to characterize their genetic ancestry and estimate their effective population sizes over the last 60 generations. We show that the Chabu are a distinct population closely related to ancient people who occupied Southwest Ethiopia >4,500 years ago. Furthermore, the Chabu are undergoing a severe population bottleneck, which began approximately 1,400 years ago. By analyzing eleven Eastern African populations, we find evidence for divergent demographic trajectories among hunter-gatherer-descendant groups. Our results illustrate that although foragers respond to encroaching agriculture and pastoralism with multiple strategies, including cultural adoption of agropastoralism, gene flow, and economic specialization, they often face population decline.

Epigenome-wide association study of posttraumatic stress disorder identifies novel loci in U.S. military veterans.

Posttraumatic stress disorder (PTSD) is a chronic and disabling psychiatric disorder prevalent in military veterans. Epigenetic mechanisms have been implicated in the etiology of PTSD, with DNA methylation being the most studied to identify novel molecular biomarkers associated with this disorder. We performed one of the largest single-sample epigenome-wide association studies (EWAS) of PTSD to date. Our sample included 1135 male European-American U.S. veterans who participated in the National Health and Resilience in Veterans Study (NHRVS). DNA was collected from saliva samples and the Illumina HumanMethylation EPIC BeadChip was used for the methylation analysis. PTSD was assessed using the PTSD Checklist. An EWAS was conducted using linear regression adjusted for age, cell-type proportions, first 10 principal components, and smoking status. After Bonferroni correction, we identified six genome-wide significant (GWS) CpG sites associated with past-month PTSD and three CpGs with lifetime PTSD (prange = 10-10-10-8). These CpG sites map to genes involved in immune function, transcription regulation, axonal guidance, cell signaling, and protein binding. Among these, SENP7, which is involved in transcription regulation and has been linked to risk-taking behavior and alcohol consumption in genome-wide association studies, replicated in an independent veteran cohort and was downregulated in medial orbitofrontal cortex of PTSD postmortem brain tissue. These findings suggest potential epigenetic biomarkers of PTSD that may help inform the pathophysiology of this disorder in veterans and other trauma-affected populations.

Integrative genomic analyses identify susceptibility genes underlying COVID-19 hospitalization.

Despite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of genes and pathways that contribute to COVID-19. Here, we integrate a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, splicing, and protein levels (n = 18,502). We identify 27 genes related to inflammation and coagulation pathways whose genetically predicted expression was associated with COVID-19 hospitalization. We functionally characterize the 27 genes using phenome- and laboratory-wide association scans in Vanderbilt Biobank (n = 85,460) and identified coagulation-related clinical symptoms, immunologic, and blood-cell-related biomarkers. We replicate these findings across trans-ethnic studies and observed consistent effects in individuals of diverse ancestral backgrounds in Vanderbilt Biobank, pan-UK Biobank, and Biobank Japan. Our study highlights and reconfirms putative causal genes impacting COVID-19 severity and symptomology through the host inflammatory response.

Inferring archaic introgression from hominin genetic data.

Questions surrounding the timing, extent, and evolutionary consequences of archaic admixture into human populations have a long history in evolutionary anthropology. More recently, advances in human genetics, particularly in the field of ancient DNA, have shed new light on the question of whether or not Homo sapiens interbred with other hominin groups. By the late 1990s, published genetic work had largely concluded that archaic groups made no lasting genetic contribution to modern humans; less than a decade later, this conclusion was reversed following the successful DNA sequencing of an ancient Neanderthal. This reversal of consensus is noteworthy, but the reasoning behind it is not widely understood across all academic communities. There remains a communication gap between population geneticists and paleoanthropologists. In this review, we endeavor to bridge this gap by outlining how technological advancements, new statistical methods, and notable controversies ultimately led to the current consensus.

Integrative analyses identify susceptibility genes underlying COVID-19 hospitalization.

Despite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of genes and pathways that contribute to COVID-19. Here, we integrated a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, splicing, and protein levels (n=18,502). We identified 27 genes related to inflammation and coagulation pathways whose genetically predicted expression was associated with COVID-19 hospitalization. We functionally characterized the 27 genes using phenome- and laboratory-wide association scans in Vanderbilt Biobank (BioVU; n=85,460) and identified coagulation-related clinical symptoms, immunologic, and blood-cell-related biomarkers. We replicated these findings across trans-ethnic studies and observed consistent effects in individuals of diverse ancestral backgrounds in BioVU, pan-UK Biobank, and Biobank Japan. Our study highlights putative causal genes impacting COVID-19 severity and symptomology through the host inflammatory response.

Ancient European dog genomes reveal continuity since the Early Neolithic.

Europe has played a major role in dog evolution, harbouring the oldest uncontested Palaeolithic remains and having been the centre of modern dog breed creation. Here we sequence the genomes of an Early and End Neolithic dog from Germany, including a sample associated with an early European farming community. Both dogs demonstrate continuity with each other and predominantly share ancestry with modern European dogs, contradicting a previously suggested Late Neolithic population replacement. We find no genetic evidence to support the recent hypothesis proposing dual origins of dog domestication. By calibrating the mutation rate using our oldest dog, we narrow the timing of dog domestication to 20,000-40,000 years ago. Interestingly, we do not observe the extreme copy number expansion of the AMY2B gene characteristic of modern dogs that has previously been proposed as an adaptation to a starch-rich diet driven by the widespread adoption of agriculture in the Neolithic.

Trends in DNA Methylation with Age Replicate Across Diverse Human Populations.

Aging 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 rain forest and the ≠Khomani San of the South African Kalahari Desert. We identified 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 confirmed that an age-associated site in the promoter of 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 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.

Early farmers from across Europe directly descended from Neolithic Aegeans.

Farming and sedentism first appeared in southwestern Asia during the early Holocene and later spread to neighboring regions, including Europe, along multiple dispersal routes. Conspicuous uncertainties remain about the relative roles of migration, cultural diffusion, and admixture with local foragers in the early Neolithization of Europe. Here we present paleogenomic data for five Neolithic individuals from northern Greece and northwestern Turkey spanning the time and region of the earliest spread of farming into Europe. We use a novel approach to recalibrate raw reads and call genotypes from ancient DNA and observe striking genetic similarity both among Aegean early farmers and with those from across Europe. Our study demonstrates a direct genetic link between Mediterranean and Central European early farmers and those of Greece and Anatolia, extending the European Neolithic migratory chain all the way back to southwestern Asia.

Past climate change on Sky Islands drives novelty in a core developmental gene network and its phenotype.

BACKGROUND: A fundamental and enduring problem in evolutionary biology is to understand how populations differentiate in the wild, yet little is known about what role organismal development plays in this process. Organismal development integrates environmental inputs with the action of gene regulatory networks to generate the phenotype. Core developmental gene networks have been highly conserved for millions of years across all animals, and therefore, organismal development may bias variation available for selection to work on. Biased variation may facilitate repeatable phenotypic responses when exposed to similar environmental inputs and ecological changes. To gain a more complete understanding of population differentiation in the wild, we integrated evolutionary developmental biology with population genetics, morphology, paleoecology and ecology. This integration was made possible by studying how populations of the ant species Monomorium emersoni respond to climatic and ecological changes across five 'Sky Islands' in Arizona, which are mountain ranges separated by vast 'seas' of desert. Sky Islands represent a replicated natural experiment allowing us to determine how repeatable is the response of M. emersoni populations to climate and ecological changes at the phenotypic, developmental, and gene network levels. RESULTS: We show that a core developmental gene network and its phenotype has kept pace with ecological and climate change on each Sky Island over the last ~90,000 years before present (BP). This response has produced two types of evolutionary change within an ant species: one type is unpredictable and contingent on the pattern of isolation of Sky lsland populations by climate warming, resulting in slight changes in gene expression, organ growth, and morphology. The other type is predictable and deterministic, resulting in the repeated evolution of a novel wingless queen phenotype and its underlying gene network in response to habitat changes induced by climate warming. CONCLUSION: Our findings reveal dynamics of developmental gene network evolution in wild populations. This holds important implications: (1) for understanding how phenotypic novelty is generated in the wild; (2) for providing a possible bridge between micro- and macroevolution; and (3) for understanding how development mediates the response of organisms to past, and potentially, future climate change.