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1.  Phylogenetic relationships of Malaysia’s long-tailed macaques, Macaca fascicularis, based on cytochrome b sequences 
ZooKeys  2014;121-140.
Phylogenetic relationships among Malaysia’s long-tailed macaques have yet to be established, despite abundant genetic studies of the species worldwide. The aims of this study are to examine the phylogenetic relationships of Macaca fascicularis in Malaysia and to test its classification as a morphological subspecies. A total of 25 genetic samples of M. fascicularis yielding 383 bp of Cytochrome b (Cyt b) sequences were used in phylogenetic analysis along with one sample each of M. nemestrina and M. arctoides used as outgroups. Sequence character analysis reveals that Cyt b locus is a highly conserved region with only 23% parsimony informative character detected among ingroups. Further analysis indicates a clear separation between populations originating from different regions; the Malay Peninsula versus Borneo Insular, the East Coast versus West Coast of the Malay Peninsula, and the island versus mainland Malay Peninsula populations. Phylogenetic trees (NJ, MP and Bayesian) portray a consistent clustering paradigm as Borneo’s population was distinguished from Peninsula’s population (99% and 100% bootstrap value in NJ and MP respectively and 1.00 posterior probability in Bayesian trees). The East coast population was separated from other Peninsula populations (64% in NJ, 66% in MP and 0.53 posterior probability in Bayesian). West coast populations were divided into 2 clades: the North-South (47%/54% in NJ, 26/26% in MP and 1.00/0.80 posterior probability in Bayesian) and Island-Mainland (93% in NJ, 90% in MP and 1.00 posterior probability in Bayesian). The results confirm the previous morphological assignment of 2 subspecies, M. f. fascicularis and M. f. argentimembris, in the Malay Peninsula. These populations should be treated as separate genetic entities in order to conserve the genetic diversity of Malaysia’s M. fascicularis. These findings are crucial in aiding the conservation management and translocation process of M. fascicularis populations in Malaysia.
doi:10.3897/zookeys.407.6982
PMCID: PMC4042704  PMID: 24899832
Long-tailed macaque; Macaca fascicularis; Cytochrome b; phylogenetic relationships
2.  Human-specific epigenetic variation in the immunological Leukotriene B4 Receptor (LTB4R/BLT1) implicated in common inflammatory diseases 
Genome Medicine  2014;6(3):19.
Background
Common human diseases are caused by the complex interplay of genetic susceptibility as well as environmental factors. Due to the environment’s influence on the epigenome, and therefore genome function, as well as conversely the genome’s facilitative effect on the epigenome, analysis of this level of regulation may increase our knowledge of disease pathogenesis.
Methods
In order to identify human-specific epigenetic influences, we have performed a novel genome-wide DNA methylation analysis comparing human, chimpanzee and rhesus macaque.
Results
We have identified that the immunological Leukotriene B4 receptor (LTB4R, BLT1 receptor) is the most epigenetically divergent human gene in peripheral blood in comparison with other primates. This difference is due to the co-ordinated active state of human-specific hypomethylation in the promoter and human-specific increased gene body methylation. This gene is significant in innate immunity and the LTB4/LTB4R pathway is involved in the pathogenesis of the spectrum of human inflammatory diseases. This finding was confirmed by additional neutrophil-only DNA methylome and lymphoblastoid H3K4me3 chromatin comparative data. Additionally we show through functional analysis that this receptor has increased expression and a higher response to the LTB4 ligand in human versus rhesus macaque peripheral blood mononuclear cells. Genome-wide we also find human species-specific differentially methylated regions (human s-DMRs) are more prevalent in CpG island shores than within the islands themselves, and within the latter are associated with the CTCF motif.
Conclusions
This result further emphasises the exclusive nature of the human immunological system, its divergent adaptation even from very closely related primates, and the power of comparative epigenomics to identify and understand human uniqueness.
doi:10.1186/gm536
PMCID: PMC4062055  PMID: 24598577
3.  Molecular Evolutionary Characterization of a V1R Subfamily Unique to Strepsirrhine Primates 
Genome Biology and Evolution  2014;6(1):213-227.
Vomeronasal receptor genes have frequently been invoked as integral to the establishment and maintenance of species boundaries among mammals due to the elaborate one-to-one correspondence between semiochemical signals and neuronal sensory inputs. Here, we report the most extensive sample of vomeronasal receptor class 1 (V1R) sequences ever generated for a diverse yet phylogenetically coherent group of mammals, the tooth-combed primates (suborder Strepsirrhini). Phylogenetic analysis confirms our intensive sampling from a single V1R subfamily, apparently unique to the strepsirrhine primates. We designate this subfamily as V1Rstrep. The subfamily retains extensive repertoires of gene copies that descend from an ancestral gene duplication that appears to have occurred prior to the diversification of all lemuriform primates excluding the basal genus Daubentonia (the aye-aye). We refer to the descendent clades as V1Rstrep-α and V1Rstrep-β. Comparison of the two clades reveals different amino acid compositions corresponding to the predicted ligand-binding site and thus potentially to altered functional profiles between the two. In agreement with previous studies of the mouse lemur (genus, Microcebus), the majority of V1Rstrep gene copies appear to be intact and under strong positive selection, particularly within transmembrane regions. Finally, despite the surprisingly high number of gene copies identified in this study, it is nonetheless probable that V1R diversity remains underestimated in these nonmodel primates and that complete characterization will be limited until high-coverage assembled genomes are available.
doi:10.1093/gbe/evu006
PMCID: PMC3914689  PMID: 24398377
G-protein-coupled receptors; lemurs; positive selection; olfaction; chemosensory genes; gene family evolution
4.  The Origin of the RB1 Imprint 
PLoS ONE  2013;8(11):e81502.
The human RB1 gene is imprinted due to a differentially methylated CpG island in intron 2. This CpG island is part of PPP1R26P1, a truncated retrocopy of PPP1R26, and serves as a promoter for an alternative RB1 transcript. We show here by in silico analyses that the parental PPP1R26 gene is present in the analysed members of Haplorrhini, which comprise Catarrhini (Old World Monkeys, Small apes, Great Apes and Human), Platyrrhini (New World Monkeys) and tarsier, and Strepsirrhini (galago). Interestingly, we detected the retrocopy, PPP1R26P1, in all Anthropoidea (Catarrhini and Platyrrhini) that we studied but not in tarsier or galago. Additional retrocopies are present in human and chimpanzee on chromosome 22, but their distinct composition indicates that they are the result of independent retrotransposition events. Chimpanzee and marmoset have further retrocopies on chromosome 8 and chromosome 4, respectively. To examine the origin of the RB1 imprint, we compared the methylation patterns of the parental PPP1R26 gene and its retrocopies in different primates (human, chimpanzee, orangutan, rhesus macaque, marmoset and galago). Methylation analysis by deep bisulfite sequencing showed that PPP1R26 is methylated whereas the retrocopy in RB1 intron 2 is differentially methylated in all primates studied. All other retrocopies are fully methylated, except for the additional retrocopy on marmoset chromosome 4, which is also differentially methylated. Using an informative SNP for the methylation analysis in marmoset, we could show that the differential methylation pattern of the retrocopy on chromosome 4 is allele-specific. We conclude that the epigenetic fate of a PPP1R26 retrocopy after integration depends on the DNA sequence and selective forces at the integration site.
doi:10.1371/journal.pone.0081502
PMCID: PMC3839921  PMID: 24282601
5.  An Alu-Based Phylogeny of Gibbons (Hylobatidae) 
Molecular Biology and Evolution  2012;29(11):3441-3450.
Gibbons (Hylobatidae) are small, arboreal apes indigenous to Southeast Asia that diverged from other apes ∼15–18 Ma. Extant lineages radiated rapidly 6–10 Ma and are organized into four genera (Hylobates, Hoolock, Symphalangus, and Nomascus) consisting of 12–19 species. The use of short interspersed elements (SINEs) as phylogenetic markers has seen recent popularity due to several desirable characteristics: the ancestral state of a locus is known to be the absence of an element, rare potentially homoplasious events are relatively easy to resolve, and samples can be quickly and inexpensively genotyped. During radiation of primates, one particular family of SINEs, the Alu family, has proliferated in primate genomes. Nomascus leucogenys (northern white-cheeked gibbon) sequences were analyzed for repetitive content with RepeatMasker using a custom library. The sequences containing Alu elements identified as members of a gibbon-specific subfamily were then compared with orthologous positions in other primate genomes. A primate phylogenetic panel consisting of 18 primate species, including 13 gibbon species representing all four extant genera, was assayed for all loci, and a total of 125 gibbon-specific Alu insertions were identified. The resulting amplification patterns were used to generate a phylogenetic tree. We demonstrate significant support for Symphalangus as the most basal lineage within the family. Our findings also place Nomascus as a derived lineage, sister to Hoolock, with the Nomascus–Hoolock clade sister to Hylobates. Further, our analysis groups N. leucogenys and Nomascus siki as sister taxa to the exclusion of the other Nomascus species assayed. This study represents the first use of SINEs to determine the genus level phylogenetic relationships within the family Hylobatidae. These relationships have been resolved with robust support at most internal nodes, demonstrating the utility of SINE-based phylogenetic analysis. We postulate that hybridization and rapid radiation may have contributed to the complex and contradictory findings of the previous studies. Our findings will aid in the conservation of these threatened primates and inform future studies of the biogeographical history and distribution of modern gibbon species.
doi:10.1093/molbev/mss149
PMCID: PMC3472497  PMID: 22683814
primate; ape; phylogeny; retrotransposon; SINE; mobile elements
6.  Discordance Between Spatial Distributions of Y-Chromosomal and Mitochondrial Haplotypes in African Green Monkeys (Chlorocebus spp.): A Result of Introgressive Hybridization or Cryptic Diversity? 
Introgressive hybridization may cause substantial discordances among phylogenies based on different genetic markers. Such discordances have been found in diverse mammal species including primates. A recent study of mitochondrial DNA (mtDNA) revealed several poly- and paraphyletic relationships in African green monkeys (Chlorocebus), suggesting contemporary and/or ancient introgressive hybridization among almost all parapatric species of the genus. However, mtDNA analyses alone do not allow us to draw conclusions concerning introgression events. In this study we analyzed two Y chromosomal (Y-chr) markers for 30 African green monkey samples and compared the resulting genetic relationships to those based on published mtDNA data. In line with the results for mtDNA, we found no Y-chr evidence of hypothesized hybridization among Chlorocebus sabaeus and C. tantalus in the northern part of the contact zone in West Africa, and we found two distinct and distantly related Y-chr haplotypes within the range of C. tantalus, suggesting possible cryptic genetic diversity rather than ancient introgressive hybridization in this species. In contrast, Y-chr data revealed monophyletic relationships within Chlorocebus pygerythrus from East Africa, suggesting that mtDNA paraphylies found in this species are most likely to be the result of ancient introgressive hybridization and subsequent cytonuclear extinction of an earlier taxon. Our results accentuate the importance of analyzing sex chromosomal data in addition to mtDNA to obtain more information on the potential outcomes of hybridization with respect to genetic and species diversity. Analysis of more diverse nuclear marker sets is needed to obtain a more complete picture of the African green monkey evolution.
doi:10.1007/s10764-013-9717-5
PMCID: PMC3789887  PMID: 24098065
Ancient hybridization; Nuclear swamping; Old World monkeys; Outcomes of hybridization
7.  Genetic Diversity in Endangered Guizhou Snub-Nosed Monkeys (Rhinopithecus brelichi): Contrasting Results from Microsatellite and Mitochondrial DNA Data 
PLoS ONE  2013;8(8):e73647.
To evaluate the conservation status of a species or population it is necessary to gain insight into its ecological requirements, reproduction, genetic population structure, and overall genetic diversity. In our study we examined the genetic diversity of Rhinopithecus brelichi by analyzing microsatellite data and compared them with already existing data derived from mitochondrial DNA, which revealed that R. brelichi exhibits the lowest mitochondrial diversity of all so far studied Rhinopithecus species. In contrast, the genetic diversity of nuclear DNA is high and comparable to other Rhinopithecus species, i.e. the examined microsatellite loci are similarly highly polymorphic as in other species of the genus. An explanation for these differences in mitochondrial and nuclear genetic diversity could be a male biased dispersal. Females most likely stay within their natal band and males migrate between bands, thus mitochondrial DNA will not be exchanged between bands but nuclear DNA via males. A Bayesian Skyline Plot based on mitochondrial DNA sequences shows a strong decrease of the female effective population size (Nef) starting about 3,500 to 4,000 years ago, which concurs with the increasing human population in the area and respective expansion of agriculture. Given that we found no indication for a loss of nuclear DNA diversity in R. brelichi it seems that this factor does not represent the most prominent conservation threat for the long-term survival of the species. Conservation efforts should therefore focus more on immediate threats such as development of tourism and habitat destruction.
doi:10.1371/journal.pone.0073647
PMCID: PMC3756984  PMID: 24009761
8.  A Mitogenomic Phylogeny of Living Primates 
PLoS ONE  2013;8(7):e69504.
Primates, the mammalian order including our own species, comprise 480 species in 78 genera. Thus, they represent the third largest of the 18 orders of eutherian mammals. Although recent phylogenetic studies on primates are increasingly built on molecular datasets, most of these studies have focused on taxonomic subgroups within the order. Complete mitochondrial (mt) genomes have proven to be extremely useful in deciphering within-order relationships even up to deep nodes. Using 454 sequencing, we sequenced 32 new complete mt genomes adding 20 previously not represented genera to the phylogenetic reconstruction of the primate tree. With 13 new sequences, the number of complete mt genomes within the parvorder Platyrrhini was widely extended, resulting in a largely resolved branching pattern among New World monkey families. We added 10 new Strepsirrhini mt genomes to the 15 previously available ones, thus almost doubling the number of mt genomes within this clade. Our data allow precise date estimates of all nodes and offer new insights into primate evolution. One major result is a relatively young date for the most recent common ancestor of all living primates which was estimated to 66-69 million years ago, suggesting that the divergence of extant primates started close to the K/T-boundary. Although some relationships remain unclear, the large number of mt genomes used allowed us to reconstruct a robust primate phylogeny which is largely in agreement with previous publications. Finally, we show that mt genomes are a useful tool for resolving primate phylogenetic relationships on various taxonomic levels.
doi:10.1371/journal.pone.0069504
PMCID: PMC3713065  PMID: 23874967
9.  Relatively Recent Evolution of Pelage Coloration in Colobinae: Phylogeny and Phylogeography of Three Closely Related Langur Species 
PLoS ONE  2013;8(4):e61659.
To understand the evolutionary processes leading to the diversity of Asian colobines, we report here on a phylogenetic, phylogeographical and population genetic analysis of three closely related langurs, Trachypithecus francoisi, T. poliocephalus and T. leucocephalus, which are all characterized by different pelage coloration predominantly on the head and shoulders. Therefore, we sequenced a 395 bp long fragment of the mitochondrial control region from 178 T. francoisi, 54 T. leucocephalus and 19 T. poliocephalus individuals, representing all extant populations of these three species. We found 29 haplotypes in T. francoisi, 12 haplotypes in T. leucocephalus and three haplotypes in T. poliocephalus. T. leucocephalus and T. poliocephalus form monophyletic clades, which are both nested within T. francoisi, and diverged from T. francoisi recently, 0.46-0.27 (T. leucocephalus) and 0.50-0.25 million years ago (T. poliocephalus). Thus, T. francoisi appears as a polyphyletic group, while T. leucocephalus and T. poliocephalus are most likely independent descendents of T. francoisi that are both physically separated from T. francoisi populations by rivers, open sea or larger habitat gaps. Since T. francoisi populations show no variability in pelage coloration, pelage coloration in T. leucocephalus and T. poliocephalus is most likely the result of new genetic mutations after the split from T. francoisi and not of the fixation of different characters derived from an ancestral polymorphism. This case study highlights that morphological changes for example in pelage coloration can occur in isolated populations in relatively short time periods and it provides a solid basis for studies in related species. Nevertheless, to fully understand the evolutionary history of these three langur species, nuclear loci should be investigated as well.
doi:10.1371/journal.pone.0061659
PMCID: PMC3629164  PMID: 23613895
11.  Correction: Mitochondrial Genome Sequences Effectively Reveal the Phylogeny of Hylobates Gibbons 
PLoS ONE  2013;8(2):10.1371/annotation/9ca325c6-7a42-4cfd-9085-125571708b5c.
doi:10.1371/annotation/9ca325c6-7a42-4cfd-9085-125571708b5c
PMCID: PMC3894298
12.  Human-specific CpG “beacons” identify loci associated with human-specific traits and disease 
Epigenetics  2012;7(10):1188-1199.
Regulatory change has long been hypothesized to drive the delineation of the human phenotype from other closely related primates. Here we provide evidence that CpG dinucleotides play a special role in this process. CpGs enable epigenome variability via DNA methylation, and this epigenetic mark functions as a regulatory mechanism. Therefore, species-specific CpGs may influence species-specific regulation. We report non-polymorphic species-specific CpG dinucleotides (termed “CpG beacons”) as a distinct genomic feature associated with CpG island (CGI) evolution, human traits and disease. Using an inter-primate comparison, we identified 21 extreme CpG beacon clusters (≥ 20/kb peaks, empirical p < 1.0 × 10−3) in humans, which include associations with four monogenic developmental and neurological disease related genes (Benjamini-Hochberg corrected p = 6.03 × 10−3). We also demonstrate that beacon-mediated CpG density gain in CGIs correlates with reduced methylation in these species in orthologous CGIs over time, via human, chimpanzee and macaque MeDIP-seq. Therefore mapping into both the genomic and epigenomic space the identified CpG beacon clusters define points of intersection where a substantial two-way interaction between genetic sequence and epigenetic state has occurred. Taken together, our data support a model for CpG beacons to contribute to CGI evolution from genesis to tissue-specific to constitutively active CGIs.
doi:10.4161/epi.22127
PMCID: PMC3469460  PMID: 22968434
epigenetics; epigenomics; CpG islands; gene regulation; evolution; human disease
13.  Large-scale MHC class II genotyping of a wild lemur population by next generation sequencing 
Immunogenetics  2012;64:895-913.
The critical role of major histocompatibility complex (MHC) genes in disease resistance, along with their putative function in sexual selection, reproduction and chemical ecology, make them an important genetic system in evolutionary ecology. Studying selective pressures acting on MHC genes in the wild nevertheless requires population-wide genotyping, which has long been challenging because of their extensive polymorphism. Here, we report on large-scale genotyping of the MHC class II loci of the grey mouse lemur (Microcebus murinus) from a wild population in western Madagascar. The second exons from MHC-DRB and -DQB of 772 and 672 individuals were sequenced, respectively, using a 454 sequencing platform, generating more than 800,000 reads. Sequence analysis, through a stepwise variant validation procedure, allowed reliable typing of more than 600 individuals. The quality of our genotyping was evaluated through three independent methods, namely genotyping the same individuals by both cloning and 454 sequencing, running duplicates, and comparing parent–offspring dyads; each displaying very high accuracy. A total of 61 (including 20 new) and 60 (including 53 new) alleles were detected at DRB and DQB genes, respectively. Both loci were non-duplicated, in tight linkage disequilibrium and in Hardy–Weinberg equilibrium, despite the fact that sequence analysis revealed clear evidence of historical selection. Our results highlight the potential of 454 sequencing technology in attempts to investigate patterns of selection shaping MHC variation in contemporary populations. The power of this approach will nevertheless be conditional upon strict quality control of the genotyping data.
doi:10.1007/s00251-012-0649-6
PMCID: PMC3496554  PMID: 22948859
MHC; Genetic diversity; Next generation (454) sequencing; Microcebus murinus; Positive selection
14.  Correction: An Alu-Based Phylogeny of Lemurs (Infraorder: Lemuriformes) 
PLoS ONE  2012;7(8):10.1371/annotation/378aaec2-599e-4cd4-8941-3a14c208b757.
doi:10.1371/annotation/378aaec2-599e-4cd4-8941-3a14c208b757
PMCID: PMC3439493
15.  An Alu-Based Phylogeny of Lemurs (Infraorder: Lemuriformes) 
PLoS ONE  2012;7(8):e44035.
Lemurs (infraorder: Lemuriformes) are a radiation of strepsirrhine primates endemic to the island of Madagascar. As of 2012, 101 lemur species, divided among five families, have been described. Genetic and morphological evidence indicates all species are descended from a common ancestor that arrived in Madagascar ∼55–60 million years ago (mya). Phylogenetic relationships in this species-rich infraorder have been the subject of debate. Here we use Alu elements, a family of primate-specific Short INterspersed Elements (SINEs), to construct a phylogeny of infraorder Lemuriformes. Alu elements are particularly useful SINEs for the purpose of phylogeny reconstruction because they are identical by descent and confounding events between loci are easily resolved by sequencing. The genome of the grey mouse lemur (Microcebus murinus) was computationally assayed for synapomorphic Alu elements. Those that were identified as Lemuriformes-specific were analyzed against other available primate genomes for orthologous sequence in which to design primers for PCR (polymerase chain reaction) verification. A primate phylogenetic panel of 24 species, including 22 lemur species from all five families, was examined for the presence/absence of 138 Alu elements via PCR to establish relationships among species. Of these, 111 were phylogenetically informative. A phylogenetic tree was generated based on the results of this analysis. We demonstrate strong support for the monophyly of Lemuriformes to the exclusion of other primates, with Daubentoniidae, the aye-aye, as the basal lineage within the infraorder. Our results also suggest Lepilemuridae as a sister lineage to Cheirogaleidae, and Indriidae as sister to Lemuridae. Among the Cheirogaleidae, we show strong support for Microcebus and Mirza as sister genera, with Cheirogaleus the sister lineage to both. Our results also support the monophyly of the Lemuridae. Within Lemuridae we place Lemur and Hapalemur together to the exclusion of Eulemur and Varecia, with Varecia the sister lineage to the other three genera.
doi:10.1371/journal.pone.0044035
PMCID: PMC3429421  PMID: 22937148
16.  A comparative analysis of Y chromosome and mtDNA phylogenies of the Hylobates gibbons 
Background
The evolutionary relationships of closely related species have long been of interest to biologists since these species experienced different evolutionary processes in a relatively short period of time. Comparison of phylogenies inferred from DNA sequences with differing inheritance patterns, such as mitochondrial, autosomal, and X and Y chromosomal loci, can provide more comprehensive inferences of the evolutionary histories of species. Gibbons, especially the genus Hylobates, are particularly intriguing as they consist of multiple closely related species which emerged rapidly and live in close geographic proximity. Our current understanding of relationships among Hylobates species is largely based on data from the maternally-inherited mitochondrial DNAs (mtDNAs).
Results
To infer the paternal histories of gibbon taxa, we sequenced multiple Y chromosomal loci from 26 gibbons representing 10 species. As expected, we find levels of sequence variation some five times lower than observed for the mitochondrial genome (mtgenome). Although our Y chromosome phylogenetic tree shows relatively low resolution compared to the mtgenome tree, our results are consistent with the monophyly of gibbon genera suggested by the mtgenome tree. In a comparison of the molecular dating of divergences and on the branching patterns of phylogeny trees between mtgenome and Y chromosome data, we found: 1) the inferred divergence estimates were more recent for the Y chromosome than for the mtgenome, 2) the species H. lar and H. pileatus are monophyletic in the mtgenome phylogeny, respectively, but a H. pileatus individual falls into the H. lar Y chromosome clade.
Conclusions
Based on the ~6.4 kb of Y chromosomal DNA sequence data generated for each of the 26 individuals in this study, we provide molecular inferences on gibbon and particularly on Hylobates evolution complementary to those from mtDNA data. Overall, our results illustrate the utility of comparative studies of loci with different inheritance patterns for investigating potential sex specific processes on the evolutionary histories of closely related taxa, and emphasize the need for further sampling of gibbons of known provenance.
doi:10.1186/1471-2148-12-150
PMCID: PMC3444420  PMID: 22909292
Y chromosome phylogeny; Phylogenetic relationships; Divergence times; Mitochondrial genome; Gene flow
17.  Evolutionary History of the Odd-Nosed Monkeys and the Phylogenetic Position of the Newly Described Myanmar Snub-Nosed Monkey Rhinopithecus strykeri 
PLoS ONE  2012;7(5):e37418.
Odd-nosed monkeys represent one of the two major groups of Asian colobines. Our knowledge about this primate group is still limited as it is highlighted by the recent discovery of a new species in Northern Myanmar. Although a common origin of the group is now widely accepted, the phylogenetic relationships among its genera and species, and the biogeographic processes leading to their current distribution are largely unknown. To address these issues, we have analyzed complete mitochondrial genomes and 12 nuclear loci, including one X chromosomal, six Y chromosomal and five autosomal loci, from all ten odd-nosed monkey species. The gene tree topologies and divergence age estimates derived from different markers were highly similar, but differed in placing various species or haplogroups within the genera Rhinopithecus and Pygathrix. Based on our data, Rhinopithecus represent the most basal lineage, and Nasalis and Simias form closely related sister taxa, suggesting a Northern origin of odd-nosed monkeys and a later invasion into Indochina and Sundaland. According to our divergence age estimates, the lineages leading to the genera Rhinopithecus, Pygathrix and Nasalis+Simias originated in the late Miocene, while differentiation events within these genera and also the split between Nasalis and Simias occurred in the Pleistocene. Observed gene tree discordances between mitochondrial and nuclear datasets, and paraphylies in the mitochondrial dataset for some species of the genera Rhinopithecus and Pygathrix suggest secondary gene flow after the taxa initially diverged. Most likely such events were triggered by dramatic changes in geology and climate within the region. Overall, our study provides the most comprehensive view on odd-nosed monkey evolution and emphasizes that data from differentially inherited markers are crucial to better understand evolutionary relationships and to trace secondary gene flow.
doi:10.1371/journal.pone.0037418
PMCID: PMC3353941  PMID: 22616004
18.  Phylogenetic Relationships among the Colobine Monkeys Revisited: New Insights from Analyses of Complete mt Genomes and 44 Nuclear Non-Coding Markers 
PLoS ONE  2012;7(4):e36274.
Background
Phylogenetic relationships among Asian and African colobine genera have been disputed and are not yet well established. In the present study, we revisit the contentious relationships within the Asian and African Colobinae by analyzing 44 nuclear non-coding genes (>23 kb) and mitochondrial (mt) genome sequences from 14 colobine and 4 non-colobine primates.
Principal Findings
The combined nuclear gene and the mt genome as well as the combined nuclear and mt gene analyses yielded different phylogenetic relationships among colobine genera with the exception of a monophyletic ‘odd-nosed’ group consisting of Rhinopithecus, Pygathrix and Nasalis, and a monophyletic African group consisting of Colobus and Piliocolobus. The combined nuclear data analyses supported a sister-grouping between Semnopithecus and Trachypithecus, and between Presbytis and the odd-nosed monkey group, as well as a sister-taxon association of Pygathrix and Rhinopithecus within the odd-nosed monkey group. In contrast, mt genome data analyses revealed that Semnopithecus diverged earliest among the Asian colobines and that the odd-nosed monkey group is sister to a Presbytis and Trachypithecus clade, as well as a close association of Pygathrix with Nasalis. The relationships among these genera inferred from the analyses of combined nuclear and mt genes, however, varied with the tree-building methods used. Another remarkable finding of the present study is that all of our analyses rejected the recently proposed African colobine paraphyly and hybridization hypothesis and supported reciprocal monophyly of the African and Asian groups.
Significance
The phylogenetic utility of large-scale new non-coding genes was assessed using the Colobinae as a model, We found that these markers were useful for distinguishing nodes resulting from rapid radiation episodes such as the Asian colobine radiation. None of these markers here have previously been used for colobine phylogenetic reconstruction, increasing the spectrum of molecular markers available to mammalian systematics.
doi:10.1371/journal.pone.0036274
PMCID: PMC3338693  PMID: 22558416
19.  Genetic signatures of a demographic collapse in a large-bodied forest dwelling primate (Mandrillus leucophaeus) 
Ecology and Evolution  2012;2(3):550-561.
It is difficult to predict how current climate change will affect wildlife species adapted to a tropical rainforest environment. Understanding how population dynamics fluctuated in such species throughout periods of past climatic change can provide insight into this issue. The drill (Mandrillus leucophaeus) is a large-bodied rainforest adapted mammal found in West Central Africa. In the middle of this endangered monkey's geographic range is Lake Barombi Mbo, which has a well-documented palynological record of environmental change that dates to the Late Pleistocene. We used a Bayesian coalescent-based framework to analyze 2,076 base pairs of mitochondrial DNA across wild drill populations to infer past changes in female effective population size since the Late Pleistocene. Our results suggest that the drill underwent a nearly 15-fold demographic collapse in female effective population size that was most prominent during the Mid Holocene (approximately 3-5 Ka). This time period coincides with a period of increased dryness and seasonality across Africa and a dramatic reduction in forest coverage at Lake Barombi Mbo. We believe that these changes in climate and forest coverage were the driving forces behind the drill population decline. Furthermore, the warm temperatures and increased aridity of the Mid Holocene are potentially analogous to current and future conditions faced by many tropical rainforest communities. In order to prevent future declines in population size in rainforest-adapted species such as the drill, large tracts of forest should be protected to both preserve habitat and prevent forest loss through aridification.
doi:10.1002/ece3.98
PMCID: PMC3399144  PMID: 22822434
Bayesian Skyline Plot; bottleneck; climate change; Cross-Sanaga-Bioko forests; drill; Mandrillus
20.  Acoustic structure of male loud-calls support molecular phylogeny of Sumatran and Javanese leaf monkeys (genus Presbytis) 
Background
The degree to which loud-calls in nonhuman primates can be used as a reliable taxonomic tool is the subject of ongoing debate. A recent study on crested gibbons showed that these species can be well distinguished by their songs; even at the population level the authors found reliable differences. Although there are some further studies on geographic and phylogenetic differences in loud-calls of nonhuman primate species, it is unclear to what extent loud-calls of other species have a similar close relation between acoustic structure, phylogenetic relatedness and geographic distance. We therefore conducted a field survey in 19 locations on Sumatra, Java and the Mentawai islands to record male loud-calls of wild surilis (Presbytis), a genus of Asian leaf monkeys (Colobinae) with disputed taxanomy, and compared the structure of their loud-calls with a molecular genetic analysis.
Results
The acoustic analysis of 100 surili male loud-calls from 68 wild animals confirms the differentiation of P.potenziani, P.comata, P.thomasi and P.melalophos. In a more detailed acoustic analysis of subspecies of P.melalophos, a further separation of the southern P.m.mitrata confirms the proposed paraphyly of this group. In concordance with their geographic distribution we found the highest correlation between call structure and genetic similarity, and lesser significant correlations between call structure and geographic distance, and genetic similarity and geographic distance.
Conclusions
In this study we show, that as in crested gibbons, the acoustic structure of surili loud-calls is a reliable tool to distinguish between species and to verify phylogenetic relatedness and migration backgrounds of respective taxa. Since vocal production in other nonhuman primates show similar constraints, it is likely that an acoustic analysis of call structure can help to clarify taxonomic and phylogenetic relationships.
doi:10.1186/1471-2148-12-16
PMCID: PMC3295661  PMID: 22305415
21.  Mitochondrial evidence for multiple radiations in the evolutionary history of small apes 
Background
Gibbons or small apes inhabit tropical and subtropical rain forests in Southeast Asia and adjacent regions, and are, next to great apes, our closest living relatives. With up to 16 species, gibbons form the most diverse group of living hominoids, but the number of taxa, their phylogenetic relationships and their phylogeography is controversial. To further the discussion of these issues we analyzed the complete mitochondrial cytochrome b gene from 85 individuals representing all gibbon species, including most subspecies.
Results
Based on phylogenetic tree reconstructions, several monophyletic clades were detected, corresponding to genera, species and subspecies. A significantly supported branching pattern was obtained for members of the genus Nomascus but not for the genus Hylobates. The phylogenetic relationships among the four genera were also not well resolved. Nevertheless, the new data permitted the estimation of divergence ages for all taxa for the first time and showed that most lineages emerged during four short time periods. In the first, between ~6.7 and ~8.3 mya, the four gibbon genera diverged from each other. In the second (~3.0 - ~3.9 mya) and in the third period (~1.3 - ~1.8 mya), Hylobates and Hoolock differentiated. Finally, between ~0.5 and ~1.1 mya, Hylobates lar diverged into subspecies. In contrast, differentiation of Nomascus into species and subspecies was a continuous and prolonged process lasting from ~4.2 until ~0.4 mya.
Conclusions
Although relationships among gibbon taxa on various levels remain unresolved, the present study provides a more complete view of the evolutionary and biogeographic history of the hylobatid family, and a more solid genetic basis for the taxonomic classification of the surviving taxa. We also show that mtDNA constitutes a useful marker for the accurate identification of individual gibbons, a tool which is urgently required to locate hunting hotspots and select individuals for captive breeding programs. Further studies including nuclear sequence data are necessary to completely understand the phylogeny and phylogeography of gibbons.
doi:10.1186/1471-2148-10-74
PMCID: PMC2841658  PMID: 20226039
22.  A Novel System of Polymorphic and Diverse NK Cell Receptors in Primates 
PLoS Genetics  2009;5(10):e1000688.
There are two main classes of natural killer (NK) cell receptors in mammals, the killer cell immunoglobulin-like receptors (KIR) and the structurally unrelated killer cell lectin-like receptors (KLR). While KIR represent the most diverse group of NK receptors in all primates studied to date, including humans, apes, and Old and New World monkeys, KLR represent the functional equivalent in rodents. Here, we report a first digression from this rule in lemurs, where the KLR (CD94/NKG2) rather than KIR constitute the most diverse group of NK cell receptors. We demonstrate that natural selection contributed to such diversification in lemurs and particularly targeted KLR residues interacting with the peptide presented by MHC class I ligands. We further show that lemurs lack a strict ortholog or functional equivalent of MHC-E, the ligands of non-polymorphic KLR in “higher” primates. Our data support the existence of a hitherto unknown system of polymorphic and diverse NK cell receptors in primates and of combinatorial diversity as a novel mechanism to increase NK cell receptor repertoire.
Author Summary
Most receptors of natural killer (NK) cells interact with highly polymorphic major histocompatibility complex (MHC) class I molecules and thereby regulate the activity of NK cells against infected or malignant target cells. Whereas humans, apes, and Old and New World monkeys use the family of killer cell immunoglobulin-like receptors (KIR) as highly diverse NK cell receptors, this function is performed in rodents by the diverse family of lectin-like receptors Ly49. When did this functional separation occur in evolution? We followed this by investigating lemurs, primates that are distantly related to humans. We show here that lemurs employ the CD94/NKG2 family as their highly diversified NK cell receptors. The CD94/NKG2 receptors also belong to the lectin-like receptor family, but are rather conserved in “higher” primates and rodents. We could further demonstrate that lemurs have a single Ly49 gene like other primates but lack functional KIR genes of the KIR3DL lineage and show major deviations in their MHC class I genomic organisation. Thus, lemurs have evolved a “third way” of polymorphic and diverse NK cell receptors. In addition, the multiplied lemur CD94/NKG2 receptors can be freely combined, thereby forming diverse receptors. This is, therefore, the first description of some combinatorial diversity of NK cell receptors.
doi:10.1371/journal.pgen.1000688
PMCID: PMC2757895  PMID: 19834558
23.  Mitochondrial phylogeography of baboons (Papio spp.) – Indication for introgressive hybridization? 
Background
Baboons of the genus Papio are distributed over wide ranges of Africa and even colonized parts of the Arabian Peninsula. Traditionally, five phenotypically distinct species are recognized, but recent molecular studies were not able to resolve their phylogenetic relationships. Moreover, these studies revealed para- and polyphyletic (hereafter paraphyletic) mitochondrial clades for baboons from eastern Africa, and it was hypothesized that introgressive hybridization might have contributed substantially to their evolutionary history. To further elucidate the phylogenetic relationships among baboons, we extended earlier studies by analysing the complete mitochondrial cytochrome b gene and the 'Brown region' from 67 specimens collected at 53 sites, which represent all species and which cover most of the baboons' range.
Results
Based on phylogenetic tree reconstructions seven well supported major haplogroups were detected, which reflect geographic populations and discordance between mitochondrial phylogeny and baboon morphology. Our divergence age estimates indicate an initial separation into southern and northern baboon clades 2.09 (1.54–2.71) million years ago (mya). We found deep divergences between haplogroups within several species (~2 mya, northern and southern yellow baboons, western and eastern olive baboons and northern and southern chacma baboons), but also recent divergence ages among species (< 0.7 mya, yellow, olive and hamadryas baboons in eastern Africa).
Conclusion
Our study confirms earlier findings for eastern Africa, but shows that baboon species from other parts of the continent are also mitochondrially paraphyletic. The phylogenetic patterns suggest a complex evolutionary history with multiple phases of isolation and reconnection of populations. Most likely all these biogeographic events were triggered by multiple cycles of expansion and retreat of savannah biomes during Pleistocene glacial and inter-glacial periods. During contact phases of populations reticulate events (i.e. introgressive hybridization) were highly likely, similar to ongoing hybridization, which is observed between East African baboon populations. Defining the extent of the introgressive hybridization will require further molecular studies that incorporate additional sampling sites and nuclear loci.
doi:10.1186/1471-2148-9-83
PMCID: PMC2681462  PMID: 19389236
24.  A Chromosomal Inversion Unique to the Northern White-Cheeked Gibbon 
PLoS ONE  2009;4(3):e4999.
The gibbon family belongs to the superfamily Hominoidea and includes 15 species divided into four genera. Each genus possesses a distinct karyotype with chromosome numbers varying from 38 to 52. This diversity is the result of numerous chromosomal changes that have accumulated during the evolution of the gibbon lineage, a quite unique feature in comparison with other hominoids and most of the other primates. Some gibbon species and subspecies rank among the most endangered primates in the world. Breeding programs can be extremely challenging and hybridization plays an important role within the factors responsible for the decline of captive gibbons. With less than 500 individuals left in the wild, the northern white-cheeked gibbon (Nomascus leucogenys leucogenys, NLE) is the most endangered primate in a successful captive breeding program. We present here the analysis of an inversion that we show being specific for the northern white-cheeked gibbon and can be used as one of the criteria to distinguish this subspecies from other gibbon taxa. The availability of the sequence spanning for one of the breakpoints of the inversion allows detecting it by a simple PCR test also on low quality DNA. Our results demonstrate the important role of genomics in providing tools for conservation efforts.
doi:10.1371/journal.pone.0004999
PMCID: PMC2656618  PMID: 19319194
25.  Is the New Primate Genus Rungwecebus a Baboon? 
PLoS ONE  2009;4(3):e4859.
Background
In 2005, a new primate species from Tanzania, the kipunji, was described and recognized as a member of the mangabey genus Lophocebus. However, molecular investigations based upon a number of papionins, including a limited sample of baboons of mainly unknown geographic origin, identified the kipunji as a sister taxon to Papio and not as a member of Lophocebus. Accordingly, the kipunji was separated into its own monotypic genus, Rungwecebus.
Methodology/Principal Findings
We compare available mitochondrial and nuclear sequence data from the voucher specimen of Rungwecebus to other papionin lineages, including a set of geographically proximal (parapatric) baboon samples. Based on mitochondrial sequence data the kipunji clusters with baboon lineages that lie nearest to it geographically, i.e. populations of yellow and chacma baboons from south-eastern Africa, and thus does not represent a sister taxon to Papio. Nuclear data support a Papio+Rungwecebus clade, but it remains questionable whether Rungwecebus represents a sister taxon to Papio, or whether it is nested within the genus as depicted by the mitochondrial phylogeny.
Conclusions/Significance
Our study clearly supports a close relationship between Rungwecebus and Papio and might indicate that the kipunji is congeneric with baboon species. However, due to its morphological and ecological uniqueness Rungwecebus more likely represents a sister lineage to Papio and experienced later introgressive hybridization. Presumably, male (proto-)kipunjis reproduced with sympatric female baboons. Subsequent backcrossing of the hybrids with kipunjis would have resulted in a population with a nuclear kipunji genome, but which retained the yellow/chacma baboon mitochondrial genome. Since only one kipunji specimen was studied, it remains unclear whether all members of the new genus have been impacted by intergeneric introgression or rather only some populations. Further studies with additional Rungwecebus samples are necessary to elucidate the complete evolutionary history of this newly-described primate genus.
doi:10.1371/journal.pone.0004859
PMCID: PMC2654078  PMID: 19295908

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