Identifying the molecular underpinnings of the neural specializations that underlie human cognitive and behavioral traits has long been of considerable interest. Much research on human-specific ...changes in gene expression and epigenetic marks has focused on the prefrontal cortex, a brain structure distinguished by its role in executive functions. The cerebellum shows expansion in great apes and is gaining increasing attention for its role in motor skills and cognitive processing, including language. However, relatively few molecular studies of the cerebellum in a comparative evolutionary context have been conducted. Here, we identify human-specific methylation in the lateral cerebellum relative to the dorsolateral prefrontal cortex, in a comparative study with chimpanzees (Pan troglodytes) and rhesus macaques (Macaca mulatta). Specifically, we profiled genome-wide methylation levels in the three species for each of the two brain structures and identified human-specific differentially methylated genomic regions unique to each structure. We further identified which differentially methylated regions (DMRs) overlap likely regulatory elements and determined whether associated genes show corresponding species differences in gene expression. We found greater human-specific methylation in the cerebellum than the dorsolateral prefrontal cortex, with differentially methylated regions overlapping genes involved in several conditions or processes relevant to human neurobiology, including synaptic plasticity, lipid metabolism, neuroinflammation and neurodegeneration, and neurodevelopment, including developmental disorders. Moreover, our results show some overlap with those of previous studies focused on the neocortex, indicating that such results may be common to multiple brain structures. These findings further our understanding of the cerebellum in human brain evolution.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epigenetic age has emerged as an important biomarker of biological ageing. It has revealed that some tissues age faster than others, which is vital to understanding the complex phenomenon of ageing ...and developing effective interventions. Previous studies have demonstrated that humans exhibit heterogeneity in pace of epigenetic ageing among brain structures that are consistent with differences in structural and microanatomical deterioration. Here, we add comparative data on epigenetic brain ageing for chimpanzees, humans' closest relatives. Such comparisons can further our understanding of which aspects of human ageing are evolutionarily conserved or specific to our species, especially given that humans are distinguished by a long lifespan, large brain, and, potentially, more severe neurodegeneration with age. Specifically, we investigated epigenetic ageing of the dorsolateral prefrontal cortex and cerebellum, of humans and chimpanzees by generating genome-wide CpG methylation data and applying established epigenetic clock algorithms to produce estimates of biological age for these tissues. We found that both species exhibit relatively slow epigenetic ageing in the brain relative to blood. Between brain structures, humans show a faster rate of epigenetic ageing in the dorsolateral prefrontal cortex compared to the cerebellum, which is consistent with previous findings. Chimpanzees, in contrast, show comparable rates of epigenetic ageing in the two brain structures. Greater epigenetic change in the human dorsolateral prefrontal cortex compared to the cerebellum may reflect both the protracted development of this structure in humans and its greater age-related vulnerability to neurodegenerative pathology.
Chimpanzees have consistent individual differences in behaviour, also referred to as personality. Similar to human personality structure, five dimensions are commonly found in chimpanzee studies that ...show evidence for convergent and predictive validity (Dominance, Openness, Extraversion, Agreeableness, and Reactivity/Undependability). These dimensions are to some extent heritable, indicating a genetic component that explains part of the variation in personality scores, but are also influenced by environmental factors, such as the early social rearing background of the individuals. In this study, we investigated the role of epigenetic modification of the dopamine receptor D2 gene (DRD2) as a potential mechanism underlying personality variation in 51 captive chimpanzees. We used previously collected personality trait rating data and determined levels of DRD2 CpG methylation in peripheral blood samples for these same individuals. Results showed that DRD2 methylation is most strongly associated with Extraversion, and that varying methylation levels at specific DRD2 sites are associated with changes in Extraversion in nursery-reared, but not mother-reared, individuals. These results highlight the role of dopaminergic signalling in chimpanzee personality, and indicate that environmental factors, such as social experiences early in life, can have long-lasting behavioural effects, potentially through modification of the epigenome. These findings add to the growing evidence demonstrating the importance of the experience-dependent methylome for the development of complex social traits like personality.
Humans have unique cognitive capacities that, compared with apes, are not only simply expressed as a higher level of general intelligence, but also as a quantitative difference in sociocognitive ...skills. Humans’ closest living relatives, bonobos (Pan paniscus), and chimpanzees (Pan troglodytes), show key between-species differences in social cognition despite their close phylogenetic relatedness, with bonobos arguably showing greater similarities to humans. To better understand the evolution of these traits, we investigate the neurochemical mechanisms underlying sociocognitive skills by focusing on variation in genes encoding proteins with well-documented roles in mammalian social cognition: the receptors for vasopressin (AVPR1A), oxytocin (OXTR), serotonin (HTR1A), and dopamine (DRD2). Although these genes have been well studied in humans, little is known about variation in these genes that may underlie differences in social behavior and cognition in apes. We comparatively analyzed sequence data for 33 bonobos and 57 chimpanzees, together with orthologous sequence data for other apes. In all four genes, we describe genetic variants that alter the amino acid sequence of the respective receptors, raising the possibility that ligand binding or signal transduction may be impacted. Overall, bonobos show 57% more fixed substitutions than chimpanzees compared with the ancestral Pan lineage. Chimpanzees, show 31% more polymorphic coding variation, in line with their larger historical effective population size estimates and current wider distribution. An extensive literature review comparing allelic changes in Pan with known human behavioral variants revealed evidence of homologous evolution in bonobos and humans (OXTR rs4686301(T) and rs237897(A)), while humans and chimpanzees shared OXTR rs2228485(A), DRD2 rs6277(A), and DRD2 rs11214613(A) to the exclusion of bonobos. Our results offer the first in-depth comparison of neurochemical receptor gene variation in Pan and put forward new variants for future behavior–genotype association studies in apes, which can increase our understanding of the evolution of social cognition in modern humans.
Recent research has revealed clock‐like patterns of epigenetic change across the life span in humans. Models describing these epigenetic changes have been dubbed “epigenetic clocks,” and they can not ...only predict chronological age but also reveal biological age, which measures physiological homeostasis and deterioration over the life span. Comparative studies of the epigenetic clocks of different primate species are likely to provide insights into the evolution of life history schedules, as well as shed light on the physiological and genetic bases of aging and aging‐related diseases. Chronological age estimation using clock‐based calculators may also offer biological anthropologists a useful tool for applying to forensic and demographic studies.
Age-associated epigenetic change in chimpanzees and humans Guevara, Elaine E.; Lawler, Richard R.; Staes, Nicky ...
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
11/2020, Letnik:
375, Številka:
1811
Journal Article
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Methylation levels have been shown to change with age at sites across the human genome. Change at some of these sites is so consistent across individuals that it can be used as an ‘epigenetic clock’ ...to predict an individual's chronological age to within a few years. Here, we examined how the pattern of epigenetic ageing in chimpanzees compares with humans. We profiled genome-wide blood methylation levels by microarray for 113 samples from 83 chimpanzees aged 1–58 years (26 chimpanzees were sampled at multiple ages during their lifespan). Many sites (greater than 65 000) showed significant change in methylation with age and around one-third (32%) of these overlap with sites showing significant age-related change in humans. At over 80% of sites showing age-related change in both species, chimpanzees displayed a significantly faster rate of age-related change in methylation than humans. We also built a chimpanzee-specific epigenetic clock that predicted age in our test dataset with a median absolute deviation from known age of only 2.4 years. However, our chimpanzee clock showed little overlap with previously constructed human clocks. Methylation at CpGs comprising our chimpanzee clock showed moderate heritability. Although the use of a human microarray for profiling chimpanzees biases our results towards regions with shared genomic sequence between the species, nevertheless, our results indicate that there is considerable conservation in epigenetic ageing between chimpanzees and humans, but also substantial divergence in both rate and genomic distribution of ageing-associated sites.
This article is part of the theme issue ‘Evolution of the primate ageing process'.
Joint attention (JA) is an important milestone in human infant development and is predictive of the onset of language later in life. Clinically, it has been reported that children at risk for or with ...a diagnosis of autism spectrum disorder (ASD) perform more poorly on measures of JA compared to neurotypical controls. JA is not unique to humans but has also been reported in great apes and to a lesser extent in more distantly related monkeys. Further, individual differences in JA among chimpanzees are associated with polymorphisms in the vasopressin and oxytocin genes, AVPR1A and OXTR. Here, we tested whether individual variation in DNA methylation of OXTR and AVPR1A were associated with performance on JA tasks in chimpanzees. We found that individual differences in JA performance was associated with AVPR1A methylation, but not OXTR methylation in the chimpanzees. The collective results provide further evidence of the role of AVPR1A in JA abilities in chimpanzees. The results further suggest that methylation values for AVPR1A may be useful biomarkers for identifying individuals at risk for ASD or related neurodevelopmental disorders associated with impairments in JA abilities.
Lay Summary
This study examines how chimpanzee performance on joint attention tasks relate to the methylation of two genes associated with autism spectrum disorder (ASD). We found that chimpanzees that performed better on one task had lower methylation of the vasopressin receptor gene (AVPR1A). This indicates that AVPR1A methylation may be a promising ASD biomarker for predicting whether a given individual is at risk for developing impairments in nonverbal social communication.
While low serotonergic activity is often associated with psychological disorders such as depression, anxiety, mood, and personality disorders, variations in serotonin also contribute to normal ...personality differences. In this study, we investigated the role of blood DNA methylation levels at individual CpG sites of two key serotonergic genes (serotonin receptor gene 1A, HTR1A; serotonin transporter gene, SLC6A4) in predicting the personalities of captive chimpanzees. We found associations between methylation at 9/48 CpG sites with four personality dimensions: Dominance, Reactivity/Dependability, Agreeableness, and Openness. Directionality of effects were CpG location-dependent and confirmed a role of serotonergic methylation in reducing anxiety (Dominance) and aggression-related personality (Reactivity/Undependability) while simultaneously promoting prosocial (Agreeableness) and exploratory personalities (Openness). Although early-life adversity has been shown to impact serotonergic methylation patterns in other species, here, atypical early social rearing experiences only had a modest impact on CpG methylation levels in this chimpanzee sample. The precise environmental factors impacting serotonergic methylation in chimpanzees remain to be identified. Nevertheless, our study suggests a role in shaping natural variation in animal personalities. The results of this study offer a basis for future hypothesis-driven testing in additional populations and species to better understand the impact of ecology and evolution on complex behavioral traits.
While humans exhibit a significant degree of neuropathological changes associated with deficits in cognitive and memory functions during aging, non‐human primates (NHP) present with more variable ...expressions of pathological alterations among individuals and species. As such, NHP with long life expectancy in captivity offer an opportunity to study brain senescence in the absence of the typical cellular pathology caused by age‐related neurodegenerative illnesses commonly seen in humans. Age‐related changes at neuronal population, single cell, and synaptic levels have been well documented in macaques and marmosets, while age‐related and Alzheimer's disease‐like neuropathology has been characterized in additional species including lemurs as well as great apes. We present a comparative overview of existing neuropathologic observations across the primate order, including classic age‐related changes such as cell loss, amyloid deposition, amyloid angiopathy, and tau accumulation. We also review existing cellular and ultrastructural data on neuronal changes, such as dendritic attrition and spine alterations, synaptic loss and pathology, and axonal and myelin pathology, and discuss their repercussions on cellular and systems function and cognition.
The use of non‐human primates (NHP) as models in aging and neurodegeneration research provide a unique and highly valuable source with direct translation to humans. Great apes show Alzheimer's disease (AD) pathology features. Amyloid‐β deposition (a, b), tau pretangles (c), neurofibrillary tangles (d) and neuritic clusters of dystrophic neurites (e), in a 33‐year‐old female chimpanzee brain. APP/Aβ amyloid plaques (f) in a 55‐year‐old female Western lowland gorilla (scale bars = 25 µm). Further investigation incorporating suitable NHP models and advanced therapeutic interventions would be pivotal to understand the clinical manifestation of AD and address the progressive decline in cognition seen during normal aging and in AD.
Highlights
Non‐human primates (NHP) show white matter damage and decreased arborization of dendritic trees and loss of spines.
NHP species present extracellular plaques and vascular amyloid, whereas tauopathy is highly variable.
NHP show abnormal changes in glia and microglia associated with AD‐like pathologies.
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