Biology subjects

Charvet, C. J.

Publications and source records attributed to Charvet, C. J..

8 recordsLinked to original sources

bioRxiv2025

Cat brains age like humans: Translating Time shows pet cats live to be natural models for human aging

Translating biological time across species is a powerful tool to identify new models of human aging and disease. Currently, it is not clear whether any animal reaches an age comparable to a human in their 80s. Most species seem to age differently compared with humans. Some preliminary observations suggest that cats may share common patterns of aging with humans. Cats could serve as a promising model for human aging. Here, we find corresponding ages between cats, humans and other species to test whether cats can live to the equivalent of a human in their 80s. We analyzed 3,754 observations across species from sudden and gradual changes in anatomy, physiology, and behavior. Some of these data are from clinical records, whereas others are from brain scans using high-resolution MRI (7T and 3T). We studied pet cats, research colony cats, and wildcats living in zoos to encapsulate species variation in the speed of development and aging. We found that cat and human brains atrophy with age, and that their age-related patterns in brain aging are sufficiently similar that we could use them to generate cross-species age alignments. We also found that human postnatal development is stretched compared with cats and mice. Interestingly, some pet cats that visit clinics are much older than those in colonies. Therefore, cats, and especially pet cats, are natural model systems of human aging. Our findings call for increased integration across veterinary and human medicine to understand aging.

neuroscience↗

bioRxiv2024

From circuits to lifespan: translating mouse and human timelines with neuroimaging based tractography

Age is a major predictor of developmental processes and disease risk, but humans and model systems (e.g., mice) differ substantially in the pace of development and aging. The timeline of human developmental circuits is well known. It is unclear how such timelines compare to those in mice. We lack age alignments across the lifespan of mice and humans. Here, we build upon our Translating Time resource, which is a tool that equates corresponding ages during development. We collected 477 time points (n=1,132 observations) from age-related changes in body, bone, dental, and brain processes to equate corresponding ages across humans and mice. We acquired high-resolution diffusion MR scans of mouse brains (n=12) at sequential stages of postnatal development (postnatal day 3, 4, 12, 21, 60) to trace the timeline of brain circuit maturation (e.g., olfactory association pathway, corpus callosum). We found heterogeneity in white matter pathway growth. The corpus callosum largely ceases to grow days after birth while the olfactory association pathway grows through P60. We found that a P3 mouse equates to a human at roughly GW24, and a P60 mouse equates to a human in teenage years. Therefore, white matter pathway maturation is extended in mice as it is in humans, but there are species-specific adaptations. For example, olfactory-related wiring is protracted in mice, which is linked to their reliance on olfaction. Our findings underscore the importance of translational tools to map common and species-specific biological processes from model systems to humans. Significance statementMice are essential models of human brain development, but we currently lack precise age alignments across their lifespan. Here, we equate corresponding ages across mice and humans. We utilize high-resolution diffusion mouse brain scans to track the growth of brain white matter pathways, and we use our cross-species age alignments to map the timeline of these growth patterns from mouse to humans. In mice, olfactory association pathway growth continues well into the equivalent of human teenage years. The protracted development of olfactory association pathways in mice aligns with their specialized sense of smell. The generation of translational tools bridges the gap between animal models and human biology while enhancing our understanding of developmental processes generating variation across species.

neuroscience↗

bioRxiv2022

Transcription, structure, and organoids translate time across the lifespan of humans and great apes

How the neural structures supporting human cognition develop and arose in evolution is an enduring question of interest. Yet, we still lack appropriate procedures to align ages across primates, and this lacuna has hindered progress in understanding the evolution of biological programs. We generated a dataset of unprecedented size consisting of 573 time points from abrupt and gradual changes in behavior, anatomy, and transcription across human and 8 non-human primate species. We included time points from diverse human populations to capture within-species variation in the generation of cross-species age alignments. We also extracted corresponding ages from organoids. The identification of corresponding ages across the lifespan of 8 primate species, including apes (e.g., orangutans, gorillas) and monkeys (i.e., marmosets, macaques) reveal that some biological pathways are extended in humans compared with some non-human primates. Particularly, the human lifespan is unusually extended relative to studied nonhuman primates demonstrating that very old age is a phase of life in humans that does not map to other studied primate species. More generally, our work prompts a reevaluation in the choice of a model system to understand aging given very old age in humans is a period of life with a clear counterpart in great apes. Significance StatementWhat is special about the duration of human development and aging has been an enduring source of interest. A significant hurdle in identifying which biological programs are unusually extended in humans is the lack of standardized approaches with which to align ages across species. We harnessed temporal variation in behavior, transcription, and anatomy to align ages across the lifespan of primates. These data reveal which biological programs are conserved, and which are modified. Harnessing time points across scales of study guides the choice of model systems to understand disease progression, and can be used to enhance care of great apes, many of which are critically endangered.

neuroscience↗

bioRxiv2021

Tracing cortical circuits in humans and non-human primates from high resolution connectomic, transcriptomic, and temporal dimensions

The neural circuits that support human cognition are a topic of enduring interest. Yet, the lack of tools available to map human brain circuits has precluded our ability to trace the human and non-human primate connectome. We harnessed high-resolution connectomic, anatomic, and transcriptomic data to investigate the evolution and development of frontal cortex circuitry. We applied machine learning to RNA sequencing data to find corresponding ages between humans and macaques and to compare the development of circuits across species. We transcriptionally defined neural circuits by testing for associations between gene expression and white matter maturation. We then considered transcriptional and structural growth to test whether frontal cortex circuit maturation is unusually extended in humans relative to other species. We also considered gene expression and high-resolution diffusion MR tractography of adult brains to test for cross-species variation in frontal cortex circuits. We found that frontal cortex circuitry development is extended in primates, and concomitant with an expansion in cortico-cortical pathways compared with mice in adulthood. Importantly, we found that these parameters varied relatively little across humans and studied primates. These data identify a surprising collection of conserved features in frontal cortex circuits across humans and Old World monkeys. Our work demonstrates that integrating transcriptional and connectomic data across temporal dimensions is a robust approach to trace the evolution of brain connectomics in primates. Significance StatementWe lack appropriate tools to visualize the human brain connectome. We develop new approaches to study connections in the human and non-human primate brains. The integration of transcription with structure offers an unprecedented opportunity to study circuitry evolution. Our integrative approach finds corresponding ages across species and transcriptionally defines neural circuits. We used this information to test for variation in circuit maturation across species and found a surprising constellation of similar features in frontal cortex neural circuits across humans and primates. Integrating across scales of biological organization expands the repertoire of tools available to study connections in primates, which opens new avenues to study connections in health and diseases of the human brain.

neuroscience↗

bioRxiv2020

Cutting across structural and transcriptomic scales translates time across the lifespan and resolves frontal cortex development in human evolution

How the unique capacities of human cognition arose in evolution is a question of enduring interest. It is still unclear which developmental programs are responsible for the emergence of the human brain. The inability to determine corresponding ages between humans and apes has hampered progress in detecting developmental programs leading to the emergence of the human brain. I harness temporal variation in anatomical, behavioral, and transcriptional variation to determine corresponding ages from fetal to postnatal development and aging, between humans and chimpanzees. This multi-dimensional approach results in 137 corresponding time points across the lifespan, from embryonic day 44 to [~]55 years of age, in humans and their equivalent ages in chimpanzees. I used these data to test whether developmental programs, such as the timeline of prefrontal cortex maturation, previously claimed to differ between humans and chimpanzees, do so once variation in developmental schedules is controlled for. I compared the maturation of frontal cortex projections from structural magnetic resonance (MR) scans and from temporal variation in the expression of genes used to track long-range projecting neurons (i.e., supragranular-enirhced genes) in chimpanzees and humans. Contrary to what has been suggested, the timetable of prefrontal cortex maturation is not unusually extended in humans. This dataset, which is the largest with which to determine corresponding ages across humans and chimpanzees, provides a rigorous approach to control for variation in developmental schedules and to identify developmental programs responsible for unique features of the human brain.

neuroscience↗

bioRxiv2020

The Genetic Architecture of DNA Replication Timing in Human Pluripotent Stem Cells

DNA replication follows a strict spatiotemporal program that intersects with chromatin structure and gene regulation. However, the genetic basis of the mammalian DNA replication timing program is poorly understood1-3. To systematically identify genetic regulators of DNA replication timing, we exploited inter-individual variation in 457 human pluripotent stem cell lines from 349 individuals. We show that the human genomes replication program is broadly encoded in DNA and identify 1,617 cis-acting replication timing quantitative trait loci (rtQTLs4) - base-pair-resolution sequence determinants of replication initiation. rtQTLs function individually, or in combinations of proximal and distal regulators, to affect replication timing. Analysis of rtQTL locations reveals a histone code for replication initiation, composed of bivalent histone H3 trimethylation marks on a background of histone hyperacetylation. The H3 trimethylation marks are individually repressive yet synergize to promote early replication. We further identify novel positive and negative regulators of DNA replication timing, the former comprised of pluripotency-related transcription factors while the latter involve boundary elements. Human replication timing is controlled by a multi-layered mechanism that operates on target DNA sequences, is composed of dozens of effectors working combinatorially, and follows principles analogous to transcription regulation: a histone code, activators and repressors, and a promoter-enhancer logic.

genomics↗

bioRxiv2019

Brain wiring and supragranular-enriched genes linked to protracted human frontal cortex development.

The human frontal cortex is unusually large compared with many other species. The expansion of the human frontal cortex is accompanied by both connectivity and transcriptional changes. Yet, the developmental origins generating variation in frontal cortex circuitry across species remain unresolved. Nineteen genes, which encode filaments, synapse, and voltage-gated channels (e.g., NEFH, SYT2, VAMP1) are especially enriched in the supragranular layers of the cerebral cortex in humans relative to mice. The increased expression of these genes suggests enhanced cortico-cortical projections emerging from layer III in humans. We confirm that the expression of these supragranular-enriched genes is preferentially expressed in frontal cortex layer III in humans relative to mice. We demonstrate a concomitant expansion in cortico-cortical pathways projecting within the frontal cortex white matter in humans with diffusion MR tractography. To identify developmental sources of such variation, we compare frontal cortical white matter growth and developmental trajectories of transcriptional profiles of supragranular-enriched genes in humans and mice. We also use temporal changes in gene expression during postnatal development to control for variation in developmental schedules across species. The growth of the frontal cortex white matter and transcriptional profiles of supragranular genes are both protracted in humans relative to the timing of other transformations. These findings demonstrate that an expansion of projections emerging from the human frontal cortex is achieved by extending the duration of cortical circuitry development. Integrating RNA sequencing with neuroimaging level phenotypes is an effective strategy to assess deviations in developmental programs leading to variation in connections across species.

neuroscience↗

bioRxiv2019

High angular resolution diffusion MRI reveals conserved and deviant programs in the paths that guide human cortical circuitry

Diffusion MR tractography represents a novel opportunity to investigate conserved and deviant developmental programs between humans and other species such as mice. To that end, we acquired high angular resolution diffusion MR scans of mice (embryonic day [E] 10.5 to post-natal week [PW] 4) and human brains (gestational week [GW] 17 to 30) at successive stages of fetal development to investigate potential evolutionary changes in radial organization and emerging pathways between humans and mice. We compare radial glial development as well as commissural development (e.g., corpus callosum), primarily because our findings can be integrated with previous work. We also compare corpus callosal growth trajectories across primates (i.e., humans, rhesus macaques) and rodents (i.e., mice). One major finding is that the developing cortex of humans is predominated by pathways likely associated with a radial glial organization at GW 17-20, which is not as evident in age-matched mice (E 16.5, 17.5). Another finding is that, early in development, the corpus callosum follows a similar developmental timetable in primates (i.e., macaques, humans) as in mice. However, the corpus callosum grows for an extended period of time in primates compared with rodents. Taken together, these findings highlight deviant developmental programs underlying the emergence of cortical pathways in the human brain.

neuroscience↗