Biology subjects

Rogers, J.

Publications and source records attributed to Rogers, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

DNA Origami Tension Sensors (DOTS) to study T cell receptor mechanics at membrane junctions

The T cell receptor (TCR) is thought to be a mechanosensor, meaning that it transmits mechanical force to its antigen and leverages the force to amplify the specificity and magnitude of TCR signaling. The past decade has witnessed the development of molecular probes which have revealed many aspects of receptor mechanotransduction. However, most force probes are immobilized on hard substrates, thus failing to reveal mechanics in the physiological context of cell membranes. In this report, we developed DNA origami tension sensors (DOTS) which bear force sensors on a DNA origami breadboard and allow mapping of TCR mechanotransduction at dynamic intermembrane junctions. We demonstrate that TCR-antigen bonds experience 5-10 pN forces, and the mechanical events are dependent on cell state, antigen mobility, antigen potency, antigen height and F-actin activity. We tethered DOTS onto a microparticle to mechanically screen antigen in high throughput using flow cytometry. Finally, DOTS were anchored onto live B cell membranes thus producing the first quantification of TCR mechanics at authentic immune cell-cell junctions.

biophysics↗

bioRxiv2023

Large-scale phylogenomics uncovers a complex evolutionary history and extensive ancestral gene flow in an African primate radiation

Understanding the drivers of speciation is fundamental in evolutionary biology, and recent studies highlight hybridization as a potential facilitator of adaptive radiations. Using whole-genome sequencing data from 22 species of guenons (tribe Cercopithecini), one of the worlds largest primate radiations, we show that rampant gene flow characterizes their evolutionary history, and identify ancient hybridization across deeply divergent lineages differing in ecology, morphology and karyotypes. Lineages experiencing gene flow tend to be more species-rich than non-admixed lineages. Mitochondrial transfers between distant lineages were likely facilitated by co-introgression of co-adapted nuclear variants. Although the genomic landscapes of introgression were largely lineage specific, we found that genes with immune functions were overrepresented in introgressing regions, in line with adaptive introgression, whereas genes involved in pigmentation and morphology may contribute to reproductive isolation. This study provides important insights into the prevalence, role and outcomes of ancestral hybridization in a large mammalian radiation.

evolutionary biology↗

bioRxiv2023

Genome-wide coancestry reveals details of ancient and recent male-driven reticulation in baboons

Baboons (genus Papio) are a morphologically and behaviorally diverse clade of catarrhine monkeys that have experienced hybridization between phenotypically and genetically distinct phylogenetic species. We used high coverage whole genome sequences from 225 wild baboons representing 19 geographic localities to investigate population genomics and inter-species gene flow. Our analyses provide an expanded picture of evolutionary reticulation among species and reveal novel patterns of population structure within and among species, including differential admixture among conspecific populations. We describe the first example of a baboon population with a genetic composition that is derived from three distinct lineages. The results reveal processes, both ancient and recent, that produced the observed mismatch between phylogenetic relationships based on matrilineal, patrilineal, and biparental inheritance. We also identified several candidate genes that may contribute to species-specific phenotypes. One-Sentence SummaryGenomic data for 225 baboons reveal novel sites of inter-species gene flow and local effects due to differences in admixture.

evolutionary biology↗

bioRxiv2023

Pelage Variation and Morphometrics of Closely Related Callithrix Marmoset Species and Their Hybrids

BackgroundHybrids are expected to show greater phenotypic variation than their parental species, yet how hybrid phenotype expression varies with genetic distances in closely-related parental species remains surprisingly understudied. Here we study pelage and morphometric trait variation in anthropogenic hybrids vailable at the end of the article between four species of Brazilian Callithrix marmosets, a relatively recent primate radiation. Marmoset species are distinguishable by pelage phenotype and morphological specializations for eating tree exudates. Here, we (1) describe qualitative phenotypic pelage differences between parental species and hybrids; (2) test whether significant quantitative differences exist between parental and hybrid morphometric phenotypes; and (3) determine which hybrid morphometic traits show heterosis, dysgenesis, trangression, or intermediacy relative to the parental trait. For morphometric traits, we investigated both cranial and post-cranial traits, particularly as most hybrid morphological studies focus on the former instead of the latter. Finally, we estimate mitogenomic distances between marmoset species from previously published data. ResultsMarmoset hybrid facial and overall body pelage variation reflected novel combinations of coloration and patterns present in parental species. In morphometric traits, C. jacchus and C. penicillata were the most similar to each other, while C. aurita was the most distinct, and C. geoffroyi trait measures fell between these other species. Only three traits in C. jacchus x C. penicillata hybrids showed heterosis. We observed heterosis and dysgenesis in several traits of C. penicillata x C. geoffroyi hybrids. Transgressive segregation was observed in hybrids of C. aurita and the other species. These hybrids were also C. aurita-like for a number of traits. Genetic distance was closest between C. jacchus and C. penicillata and farthest between C. aurita and the other species. ConclusionWe attributed significant morphometric differences between marmoset species to variable levels of morphological specialization for exudivory in these species. Our results suggest that intermediate or parental species-like hybrid traits relative to the parental trait values are more likely in crosses between species with relatively lesser genetic distance. More extreme phenotypic variation is more likely in parental species with greater genetic distance, with transgressive traits appearing in hybrids of the most genetically distant parental species. We further suggest that less developmental disturbances can be expected in hybrids of more recently diverged parental species, and that future studies of hybrid phenotypic variation should investigate selective pressures on Callithrix cranial and post-cranial morphological traits.

zoology↗

bioRxiv2022

Comparison of Mitogenomic and Mitochondrial Markers for the Phylogenetic and Evolutionary Study of Marmosets, with special focus on captive Callithrix jacchus

Marmosets, especially Callithrix jacchus, are becoming valuable, high-demand biomedical models but their supply outside of their native Brazil is limited. Thus, uncovering the ancestry and biogeographic origins of captive marmosets is an essential task to optimize their biomedical use. Such information facilitates assessing standing levels of captive marmoset genetic diversity, identifying hybrids, and maintaining genetic diversity of captive marmoset populations. Here, we present 16 newly sequenced mitochondrial genomes from marmosets with C. jacchus phenotypes from international biomedical and animal supply facilities. We combine these new data with publicly available sequences to compare usage of mitogenome and the mtDNA control region for determining the ancestry and diversity of captive marmosets. MtDNA control region and mitogenome haplotypes from all 16 newly sequenced marmosets grouped within C. jacchus phylogenetic clades. Overall, phylogenies based on mitogenomes rather than the control region showed better resolved branching patterns with stronger statistical support within C. jacchus clades. However, both mtDNA markers show that C. jacchus is the sister clade to the phylogenetic C. penicillata Caatinga biome clade. Callithrix jacchus mtDNA control region haplotypes showed the highest haplotype and nucleotide diversity, and were intermediate in terms of per sequence theta and polymorphic sites. The larger number of available Callithrix mtDNA control region sequences relative to mitogenomes was used to determine ancestral mtDNA haplotype biogeographic origins. However, biogeographic origins for many C. jacchus haplotypes including those from international captive facilities could not be determined, which we attributed to unknown provenance information from natural C. jacchus populations. Given our results, we encourage increased sampling and genomic sequencing efforts for natural C. jacchus populations in Brazil, and utilizing the mitogenome over other mtDNA markers for phylogenetic-based analyses. Further, combining marmoset mitogenomic data with phenotypic and nuclear genomic data will greatly enhance the biomedical use of marmosets.

genetics↗

bioRxiv2022

Hibernation shows no apparent effect on germline mutation rates in grizzly bears

A male mutation bias is observed across vertebrates, and, where data are available, this bias is accompanied by increased per-generation mutation rates with parental age. While continuing mitotic cell division in the male germline post-puberty has been proposed as the major cellular mechanism underlying both patterns, little direct evidence for this role has been found. Understanding the evolution of the per-generation mutation rate among species requires that we identify the molecular mechanisms that change between species. Here, we study the per-generation mutation rate in an extended pedigree of the brown (grizzly) bear, Ursus arctos horribilis. Brown bears hibernate for one-third of the year, a period during which spermatogenesis slows or stops altogether. The cessation of spermatogenesis is predicted to lessen the male mutation bias and to lower the per-generation mutation rate in this species. However, using whole-genome sequencing, we find that both male bias and per-generation mutation rates are the same as expected for a non-hibernating species. We also carry out a phylogenetic comparison of substitution rates along the lineage leading to brown bear and panda (a non-hibernating species) and find no slowing of the substitution rate in the hibernator. Our results contribute to accumulating evidence that suggests that male germline cell division is not the major determinant of mutation rates and mutation biases. The results also provide a quantitative basis for improved estimates of the timing of carnivore evolution.

evolutionary biology↗

bioRxiv2021

Human generation times across the past 250,000 years

The generation times of our recent ancestors can tell us about both the biology and social organization of prehistoric humans, placing human evolution on an absolute timescale. We present a method for predicting historic male and female generation times based on changes in the mutation spectrum. Our analyses of whole-genome data reveal an average generation time of 26.9 years across the past 250,000 years, with fathers consistently older (30.7 years) than mothers (23.2 years). Shifts in sex-averaged generation times have been driven primarily by changes to the age of paternity rather than maternity, though we report a disproportionate increase in female generation times over the past several thousand years. We also find a large difference in generation times among populations, with samples from current African populations showing longer ancestral generation times than non-Africans for over a hundred thousand years, reaching back to a time when all humans occupied Africa.

evolutionary biology↗

bioRxiv2021

High-altitude adaptation and incipient speciation in geladas

Survival at high altitude requires adapting to extreme conditions such as environmental hypoxia. To understand high-altitude adaptations in a primate, we assembled the genome of the gelada (Theropithecus gelada), an endemic Ethiopian monkey, and complemented it with population resequencing, hematological, and morphometric data. Unexpectedly, we identified a novel karyotype that may contribute to reproductive isolation between gelada populations. We also identified genomic elements including protein-coding sequences and gene families that exhibit accelerated changes in geladas and may contribute to high-altitude adaptation. Our findings lend insight into mechanisms of speciation and adaptation while providing promising avenues for functional hypoxia research.

genomics↗

bioRxiv2021

Comparative Molecular Genomic Analyses of a Spontaneous Rhesus Macaque Model of Mismatch Repair-Deficient Colorectal Cancer

Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C<G, p.Tyr343Ter). Our study incorporated a detailed molecular characterization of rhesus CRC for cross-comparison with human MMRd CRC. We performed PCR-based MSI testing, transcriptomic analysis, and reduced-representation bisulfite sequencing (RRBS) of rhesus CRC (n=41 samples) using next-generation sequencing (NGS). Systems biology pipelines were used for gene set enrichment analysis (GSEA) for pathway discovery, consensus molecular subtyping (CMS), and somatic mutation profiling. Overall, the majority of rhesus tumors displayed high levels of MSI (MSI-high) and differential gene expression profiles that were consistent with known deregulated pathways in human CRC. DNA methylation analysis exposed differentially methylated patterns among MSI-H, MSI-L (MSI-low)/MSS (MS-stable) and LS tumors with MLH1 predominantly inactivated among sporadic MSI-H CRCs. The findings from this study support the use of rhesus macaques as the preferred animal model to study carcinogenesis, develop immunotherapies and vaccines, and implement chemoprevention approaches pertinent to sporadic MSI-H and LS CRC in humans.

cancer biology↗

bioRxiv2021

Age-Related Changes in the Rhesus Macaque Eye

PurposeTo assess age-related changes in the rhesus macaque eye and evaluate them to corresponding human age-related eye disease. MethodsData from eye exams and imaging tests including intraocular pressure (IOP), lens thickness, axial length, and retinal optical coherence tomography (OCT) images were evaluated from 142 individuals and statistically analyzed for age-related changes. Quantitative autofluorescence (qAF) was measured as was the presence of macular lesions as related to age. ResultsAges of the 142 rhesus macaques ranged from 0.7 to 29 years (mean=16.4 years, stdev=7.5 years). Anterior segment measurements such as IOP, lens thickness, and axial length were acquired. Advanced retinal imaging in the form of optical coherence tomography and qAF were obtained. Quantitative assessments were made and variations by age groups were analyzed to compare with established age-related changes in human eyes. Quantitative analysis of data revealed age-related increase in intraocular pressure, ocular biometry (lens thickness and axial length), and presence of macular lesions. Age-related changes in thicknesses of retinal layers on OCT were observed and quantified. Age was correlated with increased qAF. ConclusionsThe rhesus macaque has age-related ocular changes similar to humans. IOP increases with age while retinal ganglion cell layer thickness decreases. Macular lesions develop in some aged animals. Our findings support the concept that rhesus macaques may be useful for the study of important age-related diseases such as glaucoma, macular diseases, and cone disorders, and for development of therapies for these diseases.

systems biology↗

bioRxiv2021

Construction of a new chromosome-scale, long-read reference genome assembly of the Syrian hamster, Mesocricetus auratus

BackgroundThe Syrian hamster (Mesocricetus auratus) has been suggested as a useful mammalian model for a variety of diseases and infections, including infection with respiratory viruses such as SARS-CoV-2. The MesAur1.0 genome assembly was generated in 2013 using whole-genome shotgun sequencing with short-read sequence data. Current more advanced sequencing technologies and assembly methods now permit the generation of near-complete genome assemblies with higher quality and greater continuity. FindingsHere, we report an improved assembly of the M. auratus genome (BCM_Maur_2.0) using Oxford Nanopore Technologies long-read sequencing to produce a chromosome-scale assembly. The total length of the new assembly is 2.46 Gbp, similar to the 2.50 Gbp length of a previous assembly of this genome, MesAur1.0. BCM_Maur_2.0 exhibits significantly improved continuity with a scaffold N50 that is 6.7 times greater than MesAur1.0. Furthermore, 21,616 protein coding genes and 10,459 noncoding genes are annotated in BCM_Maur_2.0 compared to 20,495 protein coding genes and 4,168 noncoding genes in MesAur1.0. This new assembly also improves the unresolved regions as measured by nucleotide ambiguities, where approximately 17.11% of bases in MesAur1.0 were unresolved compared to BCM_Maur_2.0 in which the number of unresolved bases is reduced to 3.00%. ConclusionsAccess to a more complete reference genome with improved accuracy and continuity will facilitate more detailed, comprehensive, and meaningful research results for a wide variety of future studies using Syrian hamsters as models.

genomics↗

bioRxiv2021

Retinal organoids derived from rhesus macaque iPSCs undergo accelerated differentiation compared to human stem cells

PurposeTo compare the timing and efficiency of the development of non-human primate (NHP) derived retinal organoids in comparison to those derived from human embryonic stem cells. MethodsHuman embryonic stem cells (hESCs) and induced-pluripotent stem cells (rhiPSCs) derived from non-human primates (Macaca mulatta) were differentiated into retinal organoids by using an established differentiation protocol. Briefly, embryoid bodies were formed from pluripotent stem cells and induced into a neural lineage with neural induction media with the addition of BMP4. Thereafter, self-formation of optic vesicles was allowed to form in a 2D culture in retinal differentiation media (RDM). Optic vesicles were then manually harvested and cultured in suspension in 3D-RDM media until analysis. Differences in the timing of differentiation and efficiency of retinal organoid development were assessed by light microscopy, electron microscopy, immunocytochemistry, and single-cell transcriptomics. ResultsGeneration of retinal organoids was achieved from both human and several NHP pluripotent stem cells lines. All rhiPSC lines resulted in retinal differentiation with the formation of optic vesicle-like structures similar to what has been observed in hESC retinal organoids. NHP retinal organoids had laminated structure and were composed of mature retinal cell types including cone and rod photoreceptors. Single cell RNA sequencing was conducted at two time points, which allowed identification of cell types and characterization of developmental trajectory in the developing organoid. Important differences between rhesus and human cells were measured regarding the timing and efficiency of retinal organoid differentiation. While the culture of NHP-derived iPSCs is relatively difficult compared to human stem cells, the generation of retinal organoids is feasible and may be less time consuming due to an intrinsically faster timing of retinal differentiation. ConclusionsRetinal organoids produced from iPSCs derived from Rhesus monkey using established protocols differentiate through the stages of organoid development faster than those derived from human stem cells. The production of NHP retinal organoids may be advantageous to reduce experimental time and cost for basic biology studies in retinogenesis as well as for preclinical trials in NHPs studying retinal allograft transplantation.

cell biology↗

bioRxiv2021

SVhound: Detection of future Structural Variation hotspots

Recent population studies are ever growing in size of samples to investigate the diversity of a given population or species. These studies reveal ever new polymorphism that lead to important insights into the mechanisms of evolution, but are also important for the interpretation of these variations. Nevertheless, while the full catalog of variations across entire species remains unknown, we can predict which regions harbor additional variations that remain hidden and investigate their properties, thereby enhancing the analysis for potentially missed variants. To achieve this we implemented SVhound (https://github.com/lfpaulin/SVhound), which based on a population level SVs dataset can predict regions that harbor novel SV alleles. We tested SVhound using subsets of the 1000 genomes project data and showed that its correlation (average correlation of 2,800 tests r=0.7136) is high to the full data set. Next, we utilized SVhound to investigate potentially missed or understudied regions across 1KGP and CCDG that included multiple genes. Lastly we show the applicability for SVhound also on a small and novel SV call set for rhesus macaque (Macaca mulatta) and discuss the impact and choice of parameters for SVhound. Overall SVhound is a unique method to identify potential regions that harbor hidden diversity in model and non model organisms and can also be potentially used to ensure high quality of SV call sets.

genomics↗

bioRxiv2021

De novo mutations in domestic cat are consistent with an effect of reproductive longevity on both the rate and spectrum of mutations

The mutation rate is a fundamental evolutionary parameter with direct and appreciable effects on the health and function of individuals. Here, we examine this important parameter in the domestic cat, a beloved companion animal as well as a valuable biomedical model. We estimate a mutation rate of 0.86 x 10-8 per bp per generation for the domestic cat (at an average parental age of 3.8 years). We find evidence for a significant paternal age effect, with more mutations transmitted by older sires. Our analyses suggest that the cat and the human have accrued similar numbers of mutations in the germline before reaching sexual maturity. The per-generation mutation rate in the cat is 28% lower than what has been observed in humans, but is consistent with the shorter generation time in the cat. Using a model of reproductive longevity, which takes into account differences in the reproductive age and time to sexual maturity, we are able to explain much of the difference in per-generation rates between species. We further apply our reproductive longevity model in a novel analysis of mutation spectra and find that the spectrum for the cat resembles the human mutation spectrum at a younger age of reproduction. Together, these results implicate changes in life-history as a driver of mutation rate evolution between species. As the first direct observation of the paternal age effect outside of rodents and primates, our results also suggest a phenomenon that may be universal among mammals.

evolutionary biology↗

bioRxiv2021

Variation in predicted COVID-19 risk among lemurs and lorises

The novel coronavirus SARS-CoV-2, which in humans leads to the disease COVID-19, has caused global disruption and more than 1.5 million fatalities since it first emerged in late 2019. As we write, infection rates are currently at their highest point globally and are rising extremely rapidly in some areas due to more infectious variants. The primary viral target is the cellular receptor angiotensin-converting enzyme-2 (ACE2). Recent sequence analyses of the ACE2 gene predicts that many nonhuman primates are also likely to be highly susceptible to infection. However, the anticipated risk is not equal across the Order. Furthermore, some taxonomic groups show high ACE2 amino acid conservation, while others exhibit high variability at this locus. As an example of the latter, analyses of strepsirrhine primate ACE2 sequences to date indicate large variation among lemurs and lorises compared to other primate clades despite low sampling effort. Here, we report ACE2 gene and protein sequences for 71 individual strepsirrhines, spanning 51 species and 19 genera. Our study reinforces previous results and finds additional variability in other strepsirrhine species, and suggests several clades of lemurs have high potential susceptibility to SARS-CoV-2 infection. Troublingly, some species, including the rare and Endangered aye-aye (Daubentonia madagascariensis), as well as those in the genera Avahi and Propithecus, may be at high risk. Given that lemurs are endemic to Madagascar and among the primates at highest risk of extinction globally, further understanding of the potential threat of COVID-19 to their health should be a conservation priority. All feasible actions should be taken to limit their exposure to SARS-CoV-2.

genetics↗

bioRxiv2020

Infant Inhibited Temperament in Primates Predicts Adult Behavior, is Heritable, and is Associated with Anxiety Relevant Genetic Variation

An anxious or inhibited temperament (IT) early in life is a major risk factor for the later development of stress-related psychopathology. Starting in infancy, nonhuman primates, like humans, begin to reveal their temperament when exposed to novel situations. Here, in Study 1 we demonstrate this infant IT predicts adult behavior. Specifically, in over 600 monkeys, we found that individuals scored as inhibited during infancy were more likely to refuse treats offered by potentially-threatening human experimenters as adults. In Study 2, using a sample of over 4000 monkeys from a large multi-generational family pedigree, we demonstrate that infant IT is partially heritable. The data revealed infant IT to reflect a co-inherited substrate that manifests across multiple latent variables. Finally, in Study 3 we performed whole-genome sequencing in 106 monkeys to identify IT-associated single-nucleotide variations (SNVs). Results demonstrated a genome-wide significant SNV near CTNNA2, suggesting a molecular target worthy of additional investigation. Moreover, we observed lower p-values in genes implicated in human association studies of neuroticism and depression. Together, these data demonstrate the utility of our model of infant inhibited temperament in the rhesus monkey to facilitate discovery of genes that are relevant to the long-term inherited risk to develop anxiety and depressive disorders.

genetics↗

bioRxiv2020

Place cells in head-fixed mice navigating a floating real-world environment

The hippocampal place cell system in rodents has provided a major paradigm for the scientific investigation of memory function and dysfunction. Place cells have been observed in area CA1 of the hippocampus of both freely moving animals, and of head-fixed animals navigating in virtual reality environments. However, spatial coding in virtual reality preparations has been observed to be impaired. Here we show that the use of a real-world environment system for head-fixed mice, consisting of a track floating on air, provides some advantages over virtual reality systems for the study of spatial memory. We imaged the hippocampus of head-fixed mice injected with the genetically encoded calcium indicator GCaMP6s while they navigated circularly constrained or open environments on the floating platform. We observed consistent place tuning in a substantial fraction of cells with place fields remapping when animals entered a different environment. When animals re-entered the same environment, place fields typically remapped over a time period of multiple days, faster than in freely moving preparations, but comparable with virtual reality. Spatial information rates were within the range observed in freely moving mice. Manifold analysis indicated that spatial information could be extracted from a low-dimensional subspace of the neural population dynamics. This is the first demonstration of place cells in head-fixed mice navigating on an air-lifted real-world platform, validating its use for the study of brain circuits involved in memory and affected by neurodegenerative disorders.

neuroscience↗

bioRxiv2020

Advanced Retinal Imaging and Ocular Parameters of the Rhesus Macaque Eye

PurposeTo determine the normal ocular biometric and perform advanced retinal imaging and functional assessment of a non-human primate used commonly in scientific research, the rhesus macaque. MethodsWe performed ocular phenotyping on rhesus macaques at the California National Primate Research Center. This consisted of anterior and posterior segment eye examination by ophthalmologists, advanced retinal imaging, and functional retinal electrophysiology. ResultsFull eye exams were performed on 142 animals consisting of pupillary light reflex, tonometry, external exam and photography, anterior slit lamp examination, and posterior segment examination by indirect ophthalmoscopy. Ages of the rhesus macaques ranged from 0.7 to 29 years (mean=16.4 years, stdev=7.5 years). Anterior segment measurements such as intraocular pressure (n=142), corneal thickness (n=84), lens thickness (n=114), and axial length (n=114) were acquired. Advanced retinal imaging in the form of fundus photography (n=78), optical coherence tomography (n=60), and quantitative autofluorescence (n=44) were obtained. Electroretinography (n=75) was used to assay retinal function. Quantitative analyses of macular structure, retinal layer segmentation, and rod and cone photoreceptor electrical responses are reported. Quantitative assessments were made and variations between genders and age groups were analyzed to compare with established sex and age-related changes in human eyes. ConclusionsThe rhesus macaque has ocular structure and function very similar to that of the human eye. Age-related ocular changes between rhesus and humans are similar. In particular, macular structure and function are very similar to humans making this species particularly useful for the study of macular biology and development of therapies for inherited and age-related macular degenerations as well as cone photoreceptor disorders.

physiology↗