DNA methylation signatures of early-life adversity are exposure-dependent in wild baboons.

The early-life environment can profoundly shape the trajectory of an animal's life, even years or decades later. One mechanism proposed to contribute to these early-life effects is DNA methylation. However, the frequency and functional importance of DNA methylation in shaping early-life effects on adult outcomes is poorly understood, especially in natural populations. Here, we integrate prospectively collected data on fitness-associated variation in the early environment with DNA methylation estimates at 477,270 CpG sites in 256 wild baboons. We find highly heterogeneous relationships between the early-life environment and DNA methylation in adulthood: aspects of the environment linked to resource limitation (e.g., low-quality habitat, early-life drought) are associated with many more CpG sites than other types of environmental stressors (e.g., low maternal social status). Sites associated with early resource limitation are enriched in gene bodies and putative enhancers, suggesting they are functionally relevant. Indeed, by deploying a baboon-specific, massively parallel reporter assay, we show that a subset of windows containing these sites are capable of regulatory activity, and that, for 88% of early drought-associated sites in these regulatory windows, enhancer activity is DNA methylation-dependent. Together, our results support the idea that DNA methylation patterns contain a persistent signature of the early-life environment. However, they also indicate that not all environmental exposures leave an equivalent mark and suggest that socioenvironmental variation at the time of sampling is more likely to be functionally important. Thus, multiple mechanisms must converge to explain early-life effects on fitness-related traits.

Diet composition impacts eQTL discovery across multiple tissues in baboons.

Understanding how genetic variation impacts gene expression is a major goal of genomics; however, only a fraction of disease-associated loci have been demonstrated to impact gene expression when cells are in an unperturbed "steady state." In this issue of Cell Genomics, Lin et al.1 investigate how exposure to a particular cellular context (i.e., a high-cholesterol, high-fat diet) can enhance our ability to identify new regulatory variants through longitudinal sampling of three tissue types in the baboon.

Validation of genes for H-ARS severity prediction in leukemia patients - interspecies comparison, challenges, and promises.

PURPOSE: In a previous baboon-study, a total of 29 genes were identified for clinical outcome prediction of the hematologic, acute, radiation, syndrome (H-ARS) severity. Among them, four genes (FDXR, DDB2, POU2AF1, WNT3) appeared promising and were validated in five leukemia patients. Within this study, we sought further in-vivo validation in a larger number of whole-body irradiated patients. MATERIAL AND METHODS: Peripheral blood was drawn from 10 leukemia patients before and up to 3 days during a fractionated (2 Gy/day) total-body irradiation (TBI) with 2-12Gy. After RNA-isolation, gene expression (GE) was evaluated on 31 genes widely used in biodosimetry and H-ARS prediction employing qRT-PCR. A customized low-density-array (LDA) allowed simultanously analyzing all genes, the 96-well format further examined the four most promising genes. Fold-changes (FC) in GE relative to pre-irradiation were calculated. RESULTS: Five patients suffering from acute-lymphoblastic-leukemia (ALL) respectively non-Hodgkin-lymphoma (NHL) revealed sufficient RNA-amounts and corresponding lymphocyte and neutrophile counts for running qRT-PCR, while acute-myeloid-leukemia (AML) and one myelofibrosis patient could not supply enough RNA. Generally, 1-2µg total RNA was isolated, whereas up to 10-fold differences in RNA-quantities (associated suppressed GE-changes) were identified among pre-exposure and exposure samples. From 31 genes, 23 were expressed in at least one of the pre-exposure samples. Relative to pre-exposure, the number of expressed genes could halve at 48 and 72h after irradiation. Using the LDA, 13 genes were validated in human samples. The four most promising genes (vid. sup.) were either undetermined or too close to pre-exposure. However, they were measured using the more sensitive 96-well format, except WNT3, which wasn´t detectable. As in previous studies, an opposite regulation in GE for FDXR in leukemia patients (up-regulated) relative to baboons (down-regulated) was reconfirmed. Radiation-induced GE-changes of DDB2 (up-regulated) and POU2AF1 (down-regulated) behaved similarly in both species. Hence, 16 out of 23 genes of two species showed GE-changes in the same direction, and up-regulated FDXR as in human studies were revalidated. CONCLUSION: Identified genes for H-ARS severity prediction, previously detected in baboons, were validated in ALL but not in AML patients. Limitations related to leukemia type, associated reduced RNA amounts, suppressed GE changes, and methodological challenges must be considered as factors negatively affecting the total number of validated genes. Based on that, we propose additional controls including blood cell counts and preferably fluorescence-based RNA quantity measurements for selecting promising samples and using a more sensitive 96-well format for candidate genes with low baseline copy numbers.

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 interspecies gene flow. Our analyses provide an expanded picture of evolutionary reticulation among species and reveal 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.

Universal gut microbial relationships in the gut microbiome of wild baboons.

Ecological relationships between bacteria mediate the services that gut microbiomes provide to their hosts. Knowing the overall direction and strength of these relationships is essential to learn how ecology scales up to affect microbiome assembly, dynamics, and host health. However, whether bacterial relationships are generalizable across hosts or personalized to individual hosts is debated. Here, we apply a robust, multinomial logistic-normal modeling framework to extensive time series data (5534 samples from 56 baboon hosts over 13 years) to infer thousands of correlations in bacterial abundance in individual baboons and test the degree to which bacterial abundance correlations are 'universal'. We also compare these patterns to two human data sets. We find that, most bacterial correlations are weak, negative, and universal across hosts, such that shared correlation patterns dominate over host-specific correlations by almost twofold. Further, taxon pairs that had inconsistent correlation signs (either positive or negative) in different hosts always had weak correlations within hosts. From the host perspective, host pairs with the most similar bacterial correlation patterns also had similar microbiome taxonomic compositions and tended to be genetic relatives. Compared to humans, universality in baboons was similar to that in human infants, and stronger than one data set from human adults. Bacterial families that showed universal correlations in human infants were often universal in baboons. Together, our work contributes new tools for analyzing the universality of bacterial associations across hosts, with implications for microbiome personalization, community assembly, and stability, and for designing microbiome interventions to improve host health.

Communities of bacteria living in the guts of humans and other animals perform essential services for their hosts such as digesting food, degrading toxins, or fighting viruses and other bacteria that cause disease. These services emerge from so-called 'ecological' relationships between different species of bacteria. One species, for example, may break down a molecule in human food into another compound that is, in turn, digested by another species into a small molecule that the human gut can absorb and use. The bacteria involved in such a process may become more or less common together in their host. In other situations, some bacteria may have opposing roles to each other, meaning that if one species becomes more abundant it may reduce the level of the other. However, it is not known if relationships between different bacteria are consistent across hosts (i.e., universal) or unique to each host (personalized). In other words, if a pair of bacteria increase and decrease in abundance together in one host, do they do the same in other hosts? Microbes often swap genes with each other to gain new traits; as each host harbors a distinctive set of gut microbes, it may be possible for microbial relationships to change depending on the bacterial species present in a specific environment. To investigate, Roche et al. studied the bacteria in thousands of samples of feces collected from 56 baboons over a 13-year period. These samples came from a long-term research project in Amboseli, Kenya which has been studying a population of wild baboons continuously since 1971. Roche et al. measured the abundance of hundreds of gut bacteria in the feces to understand the relationships between pairs. This revealed that connections between species were largely universal rather than personalized to each baboon. Furthermore, the pairs of bacteria with the strongest positive or negative associations had the most consistent relationships across the baboons. Microbial relationships that have strong effects on the microbiome's composition might therefore be especially universal. Further analyses measuring gut bacteria in human babies also found that relationships between pairs of bacteria were largely universal. Hence, individual species of bacteria may fill similar ecological roles in each host across humans and other primates, and perhaps also in other mammals. These findings suggest that it may be possible to leverage the ecological relationships between bacteria to develop universal therapies for human diseases associated with gut bacteria, such as inflammatory bowel disease or Clostridium difficile infection.

Combinatorial targeting of epigenome-modifying enzymes with decitabine and RN-1 synergistically increases HbF.

Increased fetal hemoglobin (HbF) levels reduce the symptoms of sickle cell disease (SCD) and increase the lifespan of patients. Because curative strategies for bone marrow transplantation and gene therapy technologies remain unavailable to a large number of patients, the development of a safe and effective pharmacological therapy that increases HbF offers the greatest potential for disease intervention. Although hydroxyurea increases HbF, a substantial proportion of patients fail to demonstrate an adequate response. Pharmacological inhibitors of DNA methyltransferase (DNMT1) and lysine-specific demethylase 1A (LSD1), 2 epigenome-modifying enzymes associated with the multiprotein corepressor complex recruited to the repressed γ-globin gene, are powerful in vivo inducers of HbF. The hematological side effects of these inhibitors limit feasible clinical exposures. We evaluated whether administering these drugs in combination could reduce the dose and/or time of exposure to any single agent to minimize adverse effects, while achieving additive or synergistic increases in HbF. The DNMT1 inhibitor decitabine (0.5 mg/kg per day) and the LSD1 inhibitor RN-1 (0.25 mg/kg per day) administered in combination 2 days per week produced synergistic increases in F-cells, F-reticulocytes, and γ-globin messenger RNA in healthy baboons. Large increases in HbF and F-cells were observed in healthy, nonanemic, and anemic (phlebotomized) baboons. Combinatorial therapy targeting epigenome-modifying enzymes could thus be a useful strategy for producing larger increases in HbF to modify the clinical course of SCD.

A Comprehensive Overview of Baboon Phylogenetic History.

Baboons (genus Papio) are an intriguing study system to investigate complex evolutionary processes and the evolution of social systems. An increasing number of studies over the last 20 years has shown that considerable incongruences exist between phylogenies based on morphology, mitochondrial, and nuclear sequence data of modern baboons, and hybridization and introgression have been suggested as the main drivers of these patterns. Baboons, therefore, present an excellent opportunity to study these phenomena and their impact on speciation. Advances both in geographic and genomic coverage provide increasing details on the complexity of the phylogeography of baboons. Here, we compile the georeferenced genetic data of baboons and review the current knowledge on baboon phylogeny, discuss the evolutionary processes that may have shaped the patterns that we observe today, and propose future avenues for research.

Protocol for a high titer of BaEV-Rless pseudotyped lentiviral vector: Focus on syncytium formation and detachment.

The development of hematopoietic stem cell (HSCs) gene therapy for DNA repair disorders, such as Fanconi anemia and Bloom syndrome, is challenging because of the induction of HSCs apoptosis by cytokine stimulation. Although the Baboon envelope pseudotyped lentiviral vector (BaEV-Rless-LV) has been reported as a non-stimulatory gene transfer tool, the virus titer of BaEV-Rless-LV is too low for use in clinical applications. Transfected 293 T cells with helper plasmids, including the BaEV-Rless plasmid, showed morphological changes, such as syncytium formation and detachment. To establish a novel protocol for producing a high titer of BaEV-Rless-LV, we optimized three aspects of a basic virus production protocol by focusing on modifying culture conditions and the use of reagents: the virus titer increased 3-fold when the amount of BaEV-Rless plasmid was increased 1.2-fold; the highest titer was obtained when the viral supernatant was harvested at 48-h post-transfection, despite complete syncytium formation and detachment of the 293 T cells; and the use of poly-L-lysine-coated culture plates to enhance the adhesion and proliferation of 293 T cells and prevent detachment doubled the titer. Collectively, our novel protocol resulted in a 10-fold titer increase compared to the basic protocol and may be useful in clinical applications for treating DNA repair disorders.

Production of CRISPRi-engineered primary human mammary epithelial cells with baboon envelope pseudotyped lentiviral vectors.

Primary human mammary epithelial cells (pHMECs) are known to be remarkably difficult to engineer genetically. Here, we present a protocol for efficient transduction of pHMECs using a baboon retroviral envelope glycoprotein for pseudotyping of lentiviral vectors (BaEV-LVs). We describe the preparation of the BaEV-LVs, the isolation of pHMECs from breast samples, and the subsequent transduction of pHMECs. We also detail the use of CRISPRi technology to efficiently silence gene expression in pHMECs, which can then be used for functional assays. For complete details on the use and execution of this protocol, please refer to Richart et al. (2022).1.

Selection against admixture and gene regulatory divergence in a long-term primate field study.

Genetic admixture is central to primate evolution. We combined 50 years of field observations of immigration and group demography with genomic data from ~9 generations of hybrid baboons to investigate the consequences of admixture in the wild. Despite no obvious fitness costs to hybrids, we found signatures of selection against admixture similar to those described for archaic hominins. These patterns were concentrated near genes where ancestry is strongly associated with gene expression. Our analyses also show that introgression is partially predictable across the genome. This study demonstrates the value of integrating genomic and field data for revealing how "genomic signatures of selection" (e.g., reduced introgression in low-recombination regions) manifest in nature; moreover, it underscores the importance of other primates as living models for human evolution.

Genomic variation in baboons from central Mozambique unveils complex evolutionary relationships with other Papio species.

BACKGROUND: Gorongosa National Park in Mozambique hosts a large population of baboons, numbering over 200 troops. Gorongosa baboons have been tentatively identified as part of Papio ursinus on the basis of previous limited morphological analysis and a handful of mitochondrial DNA sequences. However, a recent morphological and morphometric analysis of Gorongosa baboons pinpointed the occurrence of several traits intermediate between P. ursinus and P. cynocephalus, leaving open the possibility of past and/or ongoing gene flow in the baboon population of Gorongosa National Park. In order to investigate the evolutionary history of baboons in Gorongosa, we generated high and low coverage whole genome sequence data of Gorongosa baboons and compared it to available Papio genomes. RESULTS: We confirmed that P. ursinus is the species closest to Gorongosa baboons. However, the Gorongosa baboon genomes share more derived alleles with P. cynocephalus than P. ursinus does, but no recent gene flow between P. ursinus and P. cynocephalus was detected when available Papio genomes were analyzed. Our results, based on the analysis of autosomal, mitochondrial and Y chromosome data, suggest complex, possibly male-biased, gene flow between Gorongosa baboons and P. cynocephalus, hinting to direct or indirect contributions from baboons belonging to the "northern" Papio clade, and signal the presence of population structure within P. ursinus. CONCLUSIONS: The analysis of genome data generated from baboon samples collected in central Mozambique highlighted a complex set of evolutionary relationships with other baboons. Our results provided new insights in the population dynamics that have shaped baboon diversity.

High-Resolution Estimates of Crossover and Noncrossover Recombination from a Captive Baboon Colony.

Homologous recombination has been extensively studied in humans and a handful of model organisms. Much less is known about recombination in other species, including nonhuman primates. Here, we present a study of crossovers (COs) and noncrossover (NCO) recombination in olive baboons (Papio anubis) from two pedigrees containing a total of 20 paternal and 17 maternal meioses, and compare these results to linkage disequilibrium (LD) based recombination estimates from 36 unrelated olive baboons. We demonstrate how COs, combined with LD-based recombination estimates, can be used to identify genome assembly errors. We also quantify sex-specific differences in recombination rates, including elevated male CO and reduced female CO rates near telomeres. Finally, we add to the increasing body of evidence suggesting that while most NCO recombination tracts in mammals are short (e.g., <500 bp), there is a non-negligible fraction of longer (e.g., >1 kb) NCO tracts. For NCO tracts shorter than 10 kb, we fit a mixture of two (truncated) geometric distributions model to the NCO tract length distribution and estimate that >99% of all NCO tracts are very short (mean 24 bp), but the remaining tracts can be quite long (mean 4.3 kb). A single geometric distribution model for NCO tract lengths is incompatible with the data, suggesting that LD-based methods for estimating NCO recombination rates that make this assumption may need to be modified.

Circulating miRNAs associated with bone mineral density in healthy adult baboons.

MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and circulate in the blood, making them attractive biomarkers of disease state for tissues like bone that are challenging to interrogate directly. Here, we report on five miRNAs-miR-197-3p, miR-320a, miR-320b, miR-331-5p, and miR-423-5p-associated with bone mineral density (BMD) in 147 healthy adult baboons. These baboons ranged in age from 15 to 25 years (45-75 human equivalent years) and 65% were female with a broad range of BMD values including a minority of osteopenic animals. miRNAs were generated via RNA sequencing from buffy coats collected at necropsy and areal BMD (aBMD) measured postmortem via dual-energy X-ray absorptiometry (DXA) of the lumbar vertebrae. Differential expression analysis controlled for the underlying pedigree structure of these animals to account for genetic variation which may drive miRNA abundance and aBMD values. While many of these miRNAs have been associated with the risk of osteoporosis in humans, this finding is of interest because the cohort represents a model of normal aging and bone metabolism rather than a disease cohort. The replication of miRNA associations with osteoporosis or other bone metabolic disorders in animals with healthy aBMD suggests an overlap in normal variation and disease states. We suggest that these miRNAs are involved in the regulation of cellular proliferation, apoptosis, and protein composition in the extracellular matrix throughout life; and age-related dysregulation of these systems may lead to disease. These miRNAs may be early indicators of progression to disease in advance of clinically detectible osteoporosis.

Gut microbiome heritability is nearly universal but environmentally contingent.

Relatives have more similar gut microbiomes than nonrelatives, but the degree to which this similarity results from shared genotypes versus shared environments has been controversial. Here, we leveraged 16,234 gut microbiome profiles, collected over 14 years from 585 wild baboons, to reveal that host genetic effects on the gut microbiome are nearly universal. Controlling for diet, age, and socioecological variation, 97% of microbiome phenotypes were significantly heritable, including several reported as heritable in humans. Heritability was typically low (mean = 0.068) but was systematically greater in the dry season, with low diet diversity, and in older hosts. We show that longitudinal profiles and large sample sizes are crucial to quantifying microbiome heritability, and indicate scope for selection on microbiome characteristics as a host phenotype.

Primate innate immune responses to bacterial and viral pathogens reveals an evolutionary trade-off between strength and specificity.

Despite their close genetic relatedness, apes and African and Asian monkeys (AAMs) differ in their susceptibility to severe bacterial and viral infections that are important causes of human disease. Such differences between humans and other primates are thought to be a result, at least in part, of interspecies differences in immune response to infection. However, because of the lack of comparative functional data across species, it remains unclear in what ways the immune systems of humans and other primates differ. Here, we report the whole-genome transcriptomic responses of ape species (human and chimpanzee) and AAMs (rhesus macaque and baboon) to bacterial and viral stimulation. We find stark differences in the responsiveness of these groups, with apes mounting a markedly stronger early transcriptional response to both viral and bacterial stimulation, altering the transcription of ∼40% more genes than AAMs. Additionally, we find that genes involved in the regulation of inflammatory and interferon responses show the most divergent early transcriptional responses across primates and that this divergence is attenuated over time. Finally, we find that relative to AAMs, apes engage a much less specific immune response to different classes of pathogens during the early hours of infection, up-regulating genes typical of anti-viral and anti-bacterial responses regardless of the nature of the stimulus. Overall, these findings suggest apes exhibit increased sensitivity to bacterial and viral immune stimulation, activating a broader array of defense molecules that may be beneficial for early pathogen killing at the potential cost of increased energy expenditure and tissue damage.

Genome-wide ancestry and introgression in a Zambian baboon hybrid zone.

Hybridization in nature offers unique insights into the process of natural selection in incipient species and their hybrids. In order to evaluate the patterns and targets of selection, we examine a recently discovered baboon hybrid zone in the Kafue River Valley of Zambia, where Kinda baboons (Papio kindae) and grey-footed chacma baboons (P. ursinus griseipes) coexist with hybridization. We genotyped baboons at 14,962 variable genome-wide autosomal markers using double-digest RADseq. We compared ancestry patterns from this genome-wide data set to previously reported ancestry from mitochondrial-DNA and Y-chromosome sources. We also fit a Bayesian genomic cline model to scan for genes with extreme patterns of introgression. We show that the Kinda baboon Y chromosome has penetrated the species boundary to a greater extent than either mitochondrial DNA or the autosomal chromosomes. We also find evidence for overall restricted introgression in the JAK/STAT signalling pathway. Echoing results in other species including humans, we find evidence for enhanced and/or directional introgression of immune-related genes or pathways including the toll-like receptor pathway, the blood coagulation pathway, and the LY96 gene. Finally we show enhanced introgression and excess chacma baboon ancestry in the sperm tail gene ODF2. Together, our results elucidate the dynamics of introgressive hybridization in a primate system while identifying genes and pathways possibly under selection.

New mitogenomic lineages in Papio baboons and their phylogeographic implications.

OBJECTIVES: Incomplete and/or biased sampling either on a taxonomic or geographic level can lead to delusive phylogenetic and phylogeographic inferences. However, a complete taxonomic and geographical sampling is often and for various reasons impossible, particularly for widespread taxa such as baboons (Papio spp.). Previous studies on baboon phylogeography identified several sampling gaps, some of which we fill by investigating additional material including samples from museum specimens. MATERIALS AND METHODS: We generated 10 new mitochondrial genomes either via conventional PCR and subsequent Sanger sequencing from two blood samples or via high-throughput shotgun sequencing from degraded DNA extracted from eight museum specimens. Phylogenetic relationships and divergence times among baboon lineages were determined using maximum-likelihood and Bayesian inferences. RESULTS: We identified new mitochondrial lineages in baboons from Central Africa (Chad, the Central African Republic), from the Mahale, and the Udzungwa Mountains (Tanzania), with the latter likely representing a case of mitochondrial capture from sympatric kipunjis (Rungwecebus kipunji). We also found that the mitochondrial clades of olive baboons found in Ivory Coast and Tanzania extend into Niger and the Democratic Republic of Congo, respectively. Moreover, an olive baboon from Sierra Leone carries a mitochondrial haplotype usually found in Guinea baboons, suggesting gene flow between these two species. DISCUSSION: The extension of the geographic sampling by including samples from areas difficult to visit or from populations that are most likely extirpated has improved the geographic and temporal resolution of the mitochondrial phylogeny of baboons considerably. Our study also shows the great value of museum material for genetic analyses even when DNA is highly degraded.

Identifying a Diagnostic Window for the Use of Gene Expression Profiling to Predict Acute Radiation Syndrome.

In the event of a mass casualty radiological or nuclear scenario, it is important to distinguish between the unexposed (worried well), low-dose exposed individuals and those developing the hematological acute radiation syndrome (HARS) within the first three days postirradiation. In previous baboon studies, we identified altered gene expression changes after irradiation, which were predictive for the later developing HARS severity. Similar changes in the expression of four of these genes were observed using an in vitro human whole blood model. However, these studies have provided only limited information on the time frame of the changes after exposure in relationship to the development of HARS. In this study we analyzed the time-dependent changes in mRNA expression after in vitro irradiation of whole blood. Changes in the expression of informative mRNAs (FDXR, DBB2, POU2AF1 and WNT3) were determined in the blood of eight healthy donors (6 males, 2 females) after irradiation at 0 (control), 0.5, 2 and 4 Gy using qRT-PCR. FDXR expression was significantly upregulated (P < 0.001) 4 h after ≥0.5 Gy irradiation, with an 18-40-fold peak attained 4-12 h postirradiation which remained elevated (4-9-fold) at 72 h. DDB2 expression was upregulated after 4 h (fold change, 5-8, P < 0.001 at ≥ 0.5 Gy) and remained upregulated (3-4-fold) until 72 h (P < 0.001). The earliest time points showing a significant downregulation of POU2AF1 and WNT3 were 4 h (fold change = 0.4, P = 0.001, at 4 Gy) and 8 h (fold change = 0.3-0.5, P < 0.001, 2-4 Gy), respectively. These results indicate that the diagnostic window for detecting HARS-predictive changes in gene expression may be opened as early as 2 h for most (75%) and at 4 h postirradiation for all individuals examined. Depending on the RNA species studied this may continue for at least three days postirradiation.

A comparison of humans and baboons suggests germline mutation rates do not track cell divisions.

In humans, most germline mutations are inherited from the father. This observation has been widely interpreted as reflecting the replication errors that accrue during spermatogenesis. If so, the male bias in mutation should be substantially lower in a closely related species with similar rates of spermatogonial stem cell divisions but a shorter mean age of reproduction. To test this hypothesis, we resequenced two 3-4 generation nuclear families (totaling 29 individuals) of olive baboons (Papio anubis), who reproduce at approximately 10 years of age on average, and analyzed the data in parallel with three 3-generation human pedigrees (26 individuals). We estimated a mutation rate per generation in baboons of 0.57×10-8 per base pair, approximately half that of humans. Strikingly, however, the degree of male bias in germline mutations is approximately 4:1, similar to that of humans-indeed, a similar male bias is seen across mammals that reproduce months, years, or decades after birth. These results mirror the finding in humans that the male mutation bias is stable with parental ages and cast further doubt on the assumption that germline mutations track cell divisions. Our mutation rate estimates for baboons raise a further puzzle, suggesting a divergence time between apes and Old World monkeys of 65 million years, too old to be consistent with the fossil record; reconciling them now requires not only a slowdown of the mutation rate per generation in humans but also in baboons.

Baboon bearing resemblance in pigmentation pattern to Siamese cat carries a missense mutation in the tyrosinase gene.

An infant hamadryas baboon exhibiting an albino phenotype-white body hair and red eyes-was born to parents with wild-type body color. Pigmentation on some parts of its body surfaced during childhood and progressed with age. This baboon in adulthood has gray hair on parts of its body, such as the tail, distal portion of the legs, and face, with the remainder being white. This pigmentation pattern resembles that of the Siamese cat and the Himalayan variants of the mouse and the mink. The distinguishing phenotypes in these animals are known to be caused by a temperature-sensitive activity of tyrosinase, an enzyme essential for biosynthesis of melanin. We sequenced all the five exons of the tyrosinase (TYR) gene of this albino baboon, which were amplified by PCR, and found a base substitution leading to alteration of the 365th amino acid from Ala to Thr. Tyrosinase requires copper as a cofactor for its enzyme function. It has two copper-binding sites, the second of which contains His residues in positions 363 and 367 that are critical to its function. Thus, p.(Ala365Thr) due to a mutation in the TYR gene is a likely candidate for the cause of the albino phenotype in this baboon.