Jeffrey Rogers

Non-human primates are an ideal model for interrogating the genetic basis of human lifespan and resilience due to their long lifespan compared to other model organisms, development of similar age-related chronic conditions, and genetic similarity. However, like humans, statistical methods for modeling survival suffer from the challenges of dealing with non-proportionality of hazards, large numbers of living individuals that must be censored, and loss-to-follow-up over studies that may last a decade or more. Here we overcome these challenges through the use of pseudo-observations of Restricted Mean Survival Time as a measure of resilience to the acute challenge of radiation exposure and chronic challenges of aging and a Western-style diet in rhesus macaques (Macaca mulatta) from the Wake Forest Non-Human Primate Radiation Late Effects Cohort. Our whole-exome analysis used Genome-wide Efficient Mixed Model Association (GEMMA) to identify variants associated with longevity, and a subsequent Gene Set Enrichment Analysis (GSEA) highlighted the cadherin and integrin signaling pathways as central to this resilience. As dysregulation of cell adhesion and extracellular matrix signaling is central to the development of fibrosis, we tested the functional relevance of these signals using a targeted Combined Annotation Dependent Depletion (CADD) score-weighted Sequence Kernel Association Test-Optimal (SKAT-O) analysis of GSEA leading-edge genes from both the cadherin and integrin pathways. This linked variant burden in PCDHGA5, PCDHGA3, PCDHGB2, PCDHA11, and PSENEN to the severity of myocardial fibrosis, and in IBSP, PDGFD, and LAMC2 to the severity of pulmonary fibrosis observed at necropsy. Critically, we note that the genetic variants are not caused by the radiation but rather create an underlying risk for disease that is then exacerbated by the acute and persistent stressors challenging these animals' intrinsic resilience. The success of this method in identifying biologically relevant genetic variants underlying survival in animals undergoing a strong challenge to their resilience highlights not only the role of genes predisposing animals to fibrosis in lifespan, but the overall utility of pseudo-observations in overcoming the limitations of survival analyses in humans and other long-lived species.

Complex ecological and evolutionary patterns shaped the rich biodiversity of the Neotropics. Understanding how diversity emerges and is maintained is key to anticipating potential biotic responses to current anthropogenic changes. Howler monkeys ( Alouatta ) are one of the most successful radiations inhabiting this region. However, 11 of the 16 taxa currently recognised are classified as threatened by the IUCN Red List, and the genus faces increasing threats from deforestation, habitat fragmentation, and hunting. Here, we present a genomic-wide analysis covering 11 of the 13 recognised Alouatta species. Our results indicate that most of this genus’ diversity in Amazonia originated in the last million years, driven by major biogeographic and ecological factors, such as geographical barriers (e.g., Amazonian rivers, and the Andes), as well as by ecological gradients, including savanna-forest mosaics and ecotonal zones. Historical biogeographic reconstructions support a trans-Andean origin for Alouatta . Based on integrative taxonomy, including genomic and morphological evidence from numerous specimens, we formally identify groups and provide descriptions for two new species. Our findings underscore the power of genome-wide data to uncover hidden diversity and to inform conservation strategies, particularly in rapidly transforming tropical ecosystems where undescribed species may already be at risk.

Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy primarily caused by mutations in OPA1 . We identified and defined a spontaneous nonhuman primate (NHP) model of ADOA using rhesus macaques heterozygous for a missense mutation ( OPA1 A8S). With ocular examinations, ophthalmic imaging, electroretinography, histopathology, immunohistochemistry, and transmission electron microscopy (TEM), we documented retinal nerve fiber layer (RNFL) thinning, retinal ganglion cell (RGC) loss and dysfunction, OPA1 mislocalization, and reduced axonal mitochondrial density in affected macaques. Our investigation revealed substantial phenotypic variability among affected macaques, shedding light on the pathogenesis of ADOA. The retinas were evaluated using techniques such as spectral-domain optical coherence tomography and fundus photography facilitating observation of structural changes in the retina and optic nerve. Thinning of the RNFL and optic nerve head degeneration, hallmark features of ADOA, were observed in affected macaques. Decreased RGC function in the OPA1 heterozygotes was demonstrated with pattern electroretinography. Histopathological analysis and immunohistochemical staining of postmortem retinal tissue suggested RGC loss in the papillomacular bundle, with reduced OPA1 and mitochondria in the RGC axons, indicating dysfunctional mitochondrial dynamics and reduced function consistent with ADOA. Ultrastructural changes were evident with TEM including dysmorphic mitochondria, axonal loss, myelin disruption, and hypertrophic astrocytic processes. The observed similar pattern of RGC loss and dysfunction coupled with phenotypic heterogeneity in our NHP model reflects the clinical variability observed in human ADOA patients indicating that therapeutic interventions in this foveate model will likely translate to the human condition.

Genetic mutations within select cells of a tissue, termed mosaic variants (MV), are being increasingly recognized for their role in human disease. This growing interest underscores the need for specialized tools to detect and analyze MVs. However, such detection methods still lack thorough evaluation, largely due to missing benchmarking datasets that are large, reliable, and reflective of the complexity of biological samples. To address this gap, we developed MosaicSim, a tool for simulating variants in realistic sequencing data. The TweakVar workflow is at the tool's core and represents a unique simulation pipeline that layers simulated MVs onto empirical whole genome sequencing data, generating a large, realistic ground truth dataset that combines the strengths of both simulation and biological data. To demonstrate the functionality of the workflow, we simulated 1,000 mosaic single nucleotide polymorphisms using TweakVar within whole genome sequencing files of different coverages. MVs were called with Illumina's DRAGEN and compared to the ground truth. Our results show 150×–445× coverage performed comparably, with a true-positive rate between 50.4% (300×) and 54.9% (150×) and no false-positives detected. Across all samples, increasing variant allele frequency had a significant positive effect on call success. Additionally, we observed that call rates for variants in lower complexity regions improved with increasing read depth. We did not find significant effects attributable to specific mutation patterns or mean read map quality. MosaicSim fills a critical unmet need by providing representative, customizable ground truth datasets for MV benchmarking, enabling systematic evaluation and optimization of variant calling methods.

Allopatric speciation, especially on large islands and archipelagos, is a significant driver of evolutionary diversification, as geographic isolation fosters the independent evolution of populations ^1,2 . In these isolated populations, lineage sorting and genetic drift dominate, accelerating allele fixation and reducing shared genetic variation ^3,4 . Here, we investigated how sea-level transgression during the Early Holocene triggered rapid speciation in large vertebrates by studying macaques isolated on Dangan Island (DGD), located just 30 km from present-day Hong Kong. Whole-genome sequencing revealed that ∼10,000 years of isolation drove the macaques’ evolution into a distinct species, as indicated by pronounced genomic divergence (mean F st > = 0.462 vs. mainland), 1.94 million lineage-specific variants, and complete ancestral differentiation with no evidence of post-isolation gene flow. A severe demographic collapse (effective population size, Ne ≈ 40) led to substantial genomic erosion (65.8% loss of genetic diversity). Paradoxically, this also enhanced resilience through drift-mediated genetic triage. Increased homozygosity exposed and purged lethal recessive alleles in lipid metabolism pathways (68% reduction in genetic load), while simultaneously fixing mildly deleterious variants—such as a splice-site mutation in SKAP2 —thereby generating a form of genomic “burden” alongside rapid immune adaptation via 251 fixed missense mutations. These findings demonstrate that island isolation can drive vertebrate speciation within a few thousand years, with genetic drift playing a dominant role in shaping genomic architecture. Accordingly, conservation strategies should prioritize monitoring loss-of-function (LoF) variants in essential pathways and prescreening for deleterious allele combinations between donors and recipients prior to implementing genetic rescue in small, drift-sensitive populations.

Complex traits arise from networks of coding and regulatory loci, making it difficult to resolve their genetic basis. Macroevolutionary studies leverage tens of millions of years of divergence across species to uncover fixed genomic changes invisible to within-species approaches, such as GWAS, offering a complementary framework for generating hypotheses in biomedical research. Here, we present the first phylogenetic protein-coding primate-wide genome–phenome map (P3GMap), spanning 200 curated traits across 224 primate species, which we release through the Primate Genome-Phenome Archive (PGA, https://pgarchive.github.io ). Using two complementary approaches, convergent amino acid substitutions and relative evolutionary rates, we linked protein-coding variation to complex phenotypes and identified thousands of candidate gene-trait associations, including lineage-specific signals related to diet, immunity, and lifespan. One sentence summary: Cross-species genome-phenome mapping in primates reveals thousands of protein-coding variants linked to the evolution of complex traits.

Age and sex have been found to be important determinants of the mutation rate per generation in mammals, but the mechanisms underlying these factors are still unclear. One approach to distinguishing between alternative mechanisms is to study species that reproduce at very young ages, as competing hypotheses make different predictions about patterns of mutation in these organisms. Here, we study the germline mutation rate in the gray short-tailed opossum, Monodelphis domestica, a laboratory model species that becomes reproductively mature at less than 6 mo of age. Whole-genome sequencing of 22 trios reveals one of the lowest mutation rates per generation found in mammals thus far (0.252 × 10−8 per base pair per generation at an average parental age of 313 d), which is expected given their early reproduction. We also examine the mutation spectrum and find fewer mutations at CpG sites in opossums than in humans, consistent with the lower CpG content in the opossum genome. We observe that two-thirds of mutations are inherited from the male parent in opossums, slightly lower than the degree of male bias observed in organisms that reproduce at much older ages. Nevertheless, the very young age at reproduction in opossums suggests that ongoing spermatogonial divisions in males after puberty are not the primary driver of the observed male mutation bias. These findings contribute to a growing body of evidence that the differences between male and female germline mutation may arise from mechanisms other than cell division postpuberty.

Genomic resources, such as draft genomes, are vital for biodiversity monitoring and conservation. For endangered species, they enable the development of tools like organellar genomes and molecular markers, which are crucial for population genetics. Advances in sequencing technologies now allow high‐throughput genotyping with detailed amplicon sequences, enhancing genetic variation studies. The northern muriqui ( Brachyteles hypoxanthus ), a critically endangered primate endemic to Brazil's Atlantic Forest, currently lacks both nuclear and mitochondrial genome data and species‐specific microsatellite markers for population genetic studies. We assembled a 2.52 Gb draft genome for B. hypoxanthus with 202,243 contigs (N50 = 29,134 bp), and BUSCO analyses indicated 52% completeness and 15.5% fragmented genes. The complete 16,635 bp mitochondrial genome retains the conserved mammalian structure with 22 tRNAs, 2 rRNAs, 13 CDS, and an origin of replication. Additionally, we designed 31 SSR primer pairs suitable for non‐invasive sampling and genotyping, alongside two mtDNA and two sex‐determination primers, configured into three multiplex PCR sets. These genomic resources, including the draft genome, complete mitochondrial genome, and microsatellite markers, provide essential tools for evolutionary analyses and the genetic monitoring of B. hypoxanthus populations, supporting its conservation.