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The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology, and is urgent given severe threats these species are facing. Here, we present high coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human-specific. This study will open a wide range of research avenues for future primate genomic research.One-Sentence SummaryThe whole genome sequences of 233 primate species provide insight into the determinants of genetic diversity, phylogenomics, and human uniqueness.

INTRODUCTIONMillions of people have received genome and exome sequencing to date, a collective effort that has illuminated for the first time the vast catalog of small genetic differences that distinguish us as individuals within our species. However, the effects of most of these genetic variants remain unknown, limiting their clinical utility and actionability. New approaches that can accurately discern disease-causing from benign mutations and interpret genetic variants on a genome-wide scale would constitute a meaningful initial step towards realizing the potential of personalized genomic medicine.RATIONALEAs a result of the short evolutionary distance between humans and nonhuman primates, our proteins share near-perfect amino acid sequence identity. Hence, the effects of a protein-altering mutation found in one species are likely to be concordant in the other species. By systematically cataloging common variants of nonhuman primates, we aimed to annotate these variants as being unlikely to cause human disease as they are tolerated by natural selection in a closely related species. Once collected, the resulting resource may be applied to infer the effects of unobserved variants across the genome using machine learning.RESULTSFollowing the strategy outlined above we obtained whole-genome sequencing data for 809 individuals from 233 primate species and cataloged 4.3 million common missense variants. We confirmed that human missense variants seen in at least one nonhuman primate species were annotated as benign in the ClinVar clinical variant database in 99% of cases. By contrast, common variants from mammals and vertebrates outside the primate lineage were substantially less likely to be benign in the ClinVar database (71 to 87% benign), restricting this strategy to nonhuman primates. Overall, we reclassified more than 4 million human missense variants of previously unknown consequence as likely benign, resulting in a greater than 50-fold increase in the number of annotated missense variants compared to existing clinical databases.To infer the pathogenicity of the remaining missense variants in the human genome, we constructed PrimateAI-3D, a semisupervised 3D-convolutional neural network that operates on voxelized protein structures. We trained PrimateAI-3D to separate common primate variants from matched control variants in 3D space as a semisupervised learning task. We evaluated the trained PrimateAI-3D model alongside 15 other published machine learning methods on their ability to distinguish between benign and pathogenic variants in six different clinical benchmarks and demonstrated that PrimateAI-3D outperformed all other classifiers in each of the tasks.CONCLUSIONOur study addresses one of the key challenges in the variant interpretation field, namely, the lack of sufficient labeled data to effectively train large machine learning models. By generating the most comprehensive primate sequencing dataset to date and pairing this resource with a deep learning architecture that leverages 3D protein structures, we were able to achieve meaningful improvements in variant effect prediction across multiple clinical benchmarks. Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.

The pygmy marmoset, the smallest of the anthropoid primates, has a broad distribution in Western Amazonia. Recent studies using molecular and morphological data have identified two distinct species separated by the Napo and Solimoes-Amazonas rivers. However, reconciling this new biological evidence with current taxonomy, i.e., two subspecies, Cebuella pygmaea pygmaea (Spix, 1823) and Cebuella pygmaea niveiventris (Lonnberg, 1940), was problematic given the uncertainty as to whether Spix’s pygmy marmoset (Cebuella pygmaea pygmaea) was collected north or south of the Napo and Solimoes-Amazonas rivers, making it unclear to which of the two newly revealed species the name pygmaea would apply. Here, we present the first molecular data from Spix’s type specimen of Cebuella pygmaea, as well as novel mitochondrial genomes from modern pygmy marmosets sampled near the type locality (Tabatinga) on both sides of the river. With these data, we can confirm the correct names of the two species identified, i.e., C. pygmaea for animals north of the Napo and Solimoes-Amazonas rivers and C. niveiventris for animals south of these two rivers. Phylogenetic analyses of the novel genetic data placed into the context of cytochrome b gene sequences from across the range of pygmy marmosets further led us to re-evaluate the geographical distribution for the two Cebuella species. We dated the split of these two species to 2.54 million years ago. We discuss additional, more recent, subdivisions within each lineage, as well as potential contact zones between the two species in the headwaters of these rivers.

A South American anthropoid Although there are many primate lineages in the Old World, it is thought that the New World is home to just one group, the platyrrhine monkeys, which appear to have colonized the region during the Eocene. Seiffert et al. describe a new primate species on the basis of fossil molars found in the Peruvian Amazon that appears to belong to the Parapithecidae, a group of stem anthropoid primates best known from northern Africa (see the Perspective by Godinot). The fossils appear to be from a well-differentiated lineage, suggesting that this species had been evolving within South America for some time. It is likely that the ancestors of this new species arrived via a transatlantic rafting event when sea levels dropped at the Eocene–Oligocene transition ∼32 to 35 million years ago. Science , this issue p. 194 ; see also p. 136

There have been multiple published phylogenetic analyses of platyrrhine primates (New World monkeys) using both morphological and molecular data, but relatively few that have integrated both types of data into a total evidence approach. Here, we present phylogenetic analyses of recent and fossil platyrrhines, based on a total evidence data set of 418 morphological characters and 10.2 kilobases of DNA sequence data from 17 nuclear genes taken from previous studies, using undated and tip-dating approaches in a Bayesian framework. We compare the results of these analyses with molecular scaffold analyses using maximum parsimony and Bayesian approaches, and we use a formal information theoretic approach to identify unstable taxa. After a posteriori pruning of unstable taxa, the undated and tip-dating topologies appear congruent with recent molecular analyses and support largely similar relationships, with strong support for Stirtonia as a stem alouattine, Neosaimiri as a stem saimirine, Cebupithecia as a stem pitheciine, and Lagonimico as a stem callitrichid. Both analyses find three Greater Antillean subfossil platyrrhines (Xenothrix, Antillothrix, and Paralouatta) to form a clade that is related to Callicebus, congruent with a single dispersal event by the ancestor of this clade to the Greater Antilles. They also suggest that the fossil Proteropithecia may not be closely related to pitheciines, and that all known platyrrhines older than the Middle Miocene are stem taxa. Notably, the undated analysis found the Early Miocene Panamacebus (currently recognized as the oldest known cebid) to be unstable, and the tip-dating analysis placed it outside crown Platyrrhini. Our tip-dating analysis supports a late Oligocene or earliest Miocene (20.8-27.0 Ma) age for crown Platyrrhini, congruent with recent molecular clock analyses.

Phylogenies with estimates of divergence times are essential for investigating many evolutionary questions. In principle, “tip-dating” is arguably the most appropriate approach, with fossil and extant taxa analyzed together in a single analysis, and topology and divergence times estimated simultaneously. However, “node-dating” (as used in many molecular clock analyses), in which fossil evidence is used to calibrate the age of particular nodes a priori, will probably remain the dominant approach, due to various issues with analyzing morphological and molecular data together. Tip-dating may nevertheless play a key role in robustly identifying fossil taxa that can be used to inform node-dating calibrations. Here, we present tip-dating analyses of platyrrhine primates (so-called “New World monkeys”) based on a total evidence dataset of 418 morphological characters and 10.2 kb of DNA sequence data from 17 nuclear genes, combined from previous studies. The resultant analyses support a late Oligocene or early Miocene age for crown Platyrrhini (composite age estimate: 20.7-28.2 Ma). Other key findings include placement of the early Miocene putative cebidPanamacebusoutside crown Platyrrhini, equivocal support forProteropitheciabeing a pitheciine, and support for a clade comprising three subfossil platyrrhines from the Caribbean (Xenothrix,AntillothrixandParalouatta), related to Callicebinae. Based on these results and the available literature, we provide a list of 27 well-justified node calibrations for primate divergences, following best practices: 17 within Haplorhini, five within Strepsirrhini, one for crown Primates, and four for deeper divergences within Euarchontoglires. In each case, we provide a hard minimum bound, and for 23 of these we also provide a soft maximum bound and a suggested prior distribution. For each calibrated node, we provide the age of the oldest fossil of each daughter lineage that descends from it, which allows use of the “CladeAge” method for specifying priors on node ages.

The pygmy marmoset, the smallest of the anthropoid primates, has a broad distribution in Western Amazonia. Recent studies using molecular and morphological data have identified two distinct species separated by the Napo and Solimões-Amazonas rivers. However, reconciling this new biological evidence with current taxonomy, i.e., two subspecies, Cebuella pygmaea pygmaea (Spix, 1823) and Cebuella pygmaea niveiventris (Lönnberg, 1940), was problematic given the uncertainty as to whether Spix’s pygmy marmoset (Cebuella pygmaea pygmaea) was collected north or south of the Napo and Solimões-Amazonas rivers, making it unclear to which of the two newly revealed species the name pygmaea would apply. Here, we present the first molecular data from Spix’s type specimen of Cebuella pygmaea, as well as novel mitochondrial genomes from modern pygmy marmosets sampled near the type locality (Tabatinga) on both sides of the river. With these data, we can confirm the correct names of the two species identified, i.e., C. pygmaea for animals north of the Napo and Solimões-Amazonas rivers and C. niveiventris for animals south of these two rivers. Phylogenetic analyses of the novel genetic data placed into the context of cytochrome b gene sequences from across the range of pygmy marmosets further led us to re-evaluate the geographical distribution for the two Cebuella species. We dated the split of these two species to 2.54 million years ago. We discuss additional, more recent, subdivisions within each lineage, as well as potential contact zones between the two species in the headwaters of these rivers.

The Santa Rosa fossil locality in eastern Perú produced the first Paleogene vertebrate fauna from the Amazon Basin, including the oldest known monkeys from South America. This diverse paleofauna was originally assigned an Eocene age based largely on the stage of evolution of the site’s caviomorph rodents and marsupials. Here, we present detrital zircon dates that indicate that the maximum composite age of Santa Rosa is 29.6 ± 0.08 Ma (Lower Oligocene), although several zircons from Santa Rosa date to the Upper Oligocene. The first appearance datum for Caviomorpha in South America is purported to be the CTA-27 site in the Contamana region of Perú, which is hypothesized to be ∼41 Ma (Middle Eocene) in age. However, the presence of the same caviomorph species and/or genera at both CTA-27 and at Santa Rosa is now difficult to reconcile with a >11-My age difference. To further test the Middle Eocene age estimate for CTA-27, we ran multiple Bayesian tip-dating analyses of Caviomorpha, treating the ages of all Paleogene species from Perú as unknown. These analyses produced mean age estimates for Santa Rosa that closely approximate the maximum 29.6 ± 0.08 Ma composite date provided by detrital zircons, but predict that CTA-27 is much younger than currently thought (∼30 Ma). We conclude that the ∼41 Ma age proposed for CTA-27 is incorrect, and that there are currently no compelling Eocene records of either rodents or primates in the known fossil record of South America.

Background The rich rodent assemblages from the Eocene–Oligocene deposits of the Jebel Qatrani Formation (Fayum Depression, Egypt) have important implications for our understanding of the origin and paleobiogeography of Hystricognathi, a diverse clade that is now represented by the Afro-Asiatic Hystricidae, New World Caviomorpha, and African Phiomorpha. Methods Here we present previously undescribed material of the enigmatic hystricognath clade Phiocricetomyinae, from two stratigraphic levels in the lower sequence of the Jebel Qatrani Formation—a new genus and species (Qatranimys safroutus) from the latest Eocene Locality 41 (~34 Ma, the oldest and most productive quarry in the formation) and additional material of Talahphiomys lavocati from that species’ type locality, early Oligocene Quarry E (~31–33.2 Ma). Results The multiple specimens of Qatranimys safroutus from L-41 document almost the entire lower and upper dentition, as well as mandibular fragments and the first cranial remains known for a derived phiocricetomyine. Specimens from Quarry E allow us to expand comparisons with specimens from Libya (late Eocene of Dur at-Talah and early Oligocene of Zallah Oasis) that have been placed in T. lavocati, and we show that the Dur at-Talah and Zallah specimens do not pertain to this species. These observations leave the Fayum Quarry E as the only locality where T. lavocati occurs.

In most group-living mammals, reproductive success declines with increasing age and increases with increasing rank. Such effects have mainly been studied in matrilineal and in "age positive" hierarchies, which are stable and in which high ranking females often outperform low ranking ones. These relationships are less well-understood in age-inversed dominance hierarchies, in which a female's rank changes over time. We analyzed demographic data of 2 wild, unprovisioned groups of gray langurs (Semnopithecus schistaceus) near Ramnagar, Nepal covering periods of 5 years each. Female rank was unstable and age-inversed. We measured reproductive success via birth rates (57 births), infant survival (proportion of infants surviving to 2 years) and number of offspring surviving to 2 years of age (successful births) for 3 age and 3 rank classes. We found that old females performed significantly worse than expected (birth rate P = 0.04; successful births P = 0.03). The same was true for low ranking females (P = 0.04, and P < 0.01, respectively). Infant survival was highest for young and middle-aged as well as for high and middle ranking females. Overall, the results for these unstable hierarchies were rather similar to those for stable hierarchies of other mammals, particularly several nonhuman primates. Compared to a provisioned population of a closely related species, the wild and unprovisioned population examined (i) showed stronger age effects, while (ii) female reproductive success was equally affected by rank. Future comparative studies are needed to examine whether captive or provisioned populations deviate predictably from wild populations.

The Middle Pleistocene represents a period of critical importance in human evolution, marked by encephalisation and dental reduction, and increasing diversification of temporally and spatially distributed hominin lineages in Africa, Asia and Europe. New specimens, especially from areas less well represented in the fossil record, can inform the debate on morphological changes to the skeleton and teeth and the phylogenetic course of human evolution during this period. The mandible from the cave of Mala Balanica, Serbia has recently been re-dated to at least 400 ka, and its well-preserved dentition presents an excellent opportunity to characterize molar crown morphology at this time period, and re-examine claims for a lack of Neandertal affinities in the specimen. In this study we employ microtomography to image the internal structure of the mandibular molars (focusing on the morphology of the enamel-dentine junction, or EDJ) of the BH-1 specimen and a comparative sample (n = 141) of Homo erectus sensu lato, Homo neanderthalensis, Pleistocene Homo sapiens, and recent H. sapiens. We quantitatively assess EDJ morphology using 3D geometric morphometrics and examine the expression of discrete dental traits at the dentine surface. We also compare third molar enamel thickness in BH-1 to those of H. neanderthalensis and both Pleistocene and recent H. sapiens, and document previously unreported morphology of the BH-1 premolar and molar roots. Our results highlight the reliability of the EDJ surface for classifying hominin taxa, indicate a primitive dental morphology for BH-1 molars, and confirm a general lack of derived Neandertal features for the Balanica individual. The plesiomorphic character of BH-1 is consistent with several competing models of Middle Pleistocene hominin evolution and provides an important regional and temporal example for reconstructing morphological changes in the mandible and teeth during this time period.