Comparing the selective landscape of TLR7 and TLR8 across primates reveals unique sites under positive selection in Alouatta.

Among primates, susceptibility to yellow fever (YFV), a single-stranded (ss) RNA virus, ranges from complete resistance to high susceptibility. Howler monkeys (genus Alouatta) are the most susceptible to YFV. In order to identify Alouatta-specific genetic factors that may be responsible for their susceptibility, we collected skin samples from howler monkey museum specimens of the species A. caraya and A. guariba clamitans. We compared the rate of nonsynonymous to synonymous (dN/dS) changes of Toll-like receptor (TLR) 7 and TLR8, the two genes responsible for detecting all ssRNA viruses, across the Primate order. Overall, we found that the TLR7 gene is under stronger purifying selection in howler monkeys compared to other New World and Old World primates, but TLR8 is under the same selective pressure. When we evaluated dN/dS at each codon, we found six codons under positive selection in Alouatta TLR8 and two codons under positive selection in TLR7. The changes in TLR7 are unique to A. guariba clamitans and are found in functionally important regions likely to affect detection of ssRNA viruses by TLR7/TLR8, as well as downstream signaling. These amino acid differences in A. guariba clamitans may play a role in YFV susceptibility. These results have implications for identifying genetic factors affecting YFV susceptibility in primates.

Positively selected variants in functionally important regions of TLR7 in Alouatta guariba clamitans with yellow fever virus exposure in Northern Argentina.

BACKGROUND: In 2007-2009, a major yellow fever virus (YFV) outbreak in Northern Argentina decimated the local howler monkey (Alouatta) population. AIMS: To evaluate whether the surviving howler monkeys possess advantageous genetic variants inherited from monkeys alive prior to the YFV outbreak, we explored the relationship between Toll-like receptor (TLR) 7 and TLR8 gene variation and YFV susceptibility. METHODS: We used samples from Alouatta individuals in Misiones, Argentina alive before the YFV outbreak, individuals that died during the outbreak, and individuals that survived the outbreak and are alive today. We measured genetic divergence between Alouatta YFV exposure groups and evaluated Alouatta-specific substitutions for functional consequences. RESULTS: We did not find different allele frequencies in the post-YFV exposure Alouatta group compared to the pre-exposure group. We identified three nonsynonymous variants in TLR7 in Alouatta guariba clamitans. Two of these substitutions are under positive selection in functionally important regions of the gene. DISCUSSION AND CONCLUSIONS: Our results did not indicate that surviving howler monkey spossess advantageous genetic variants at greater frequency than those alive before the YFV outbreak. However, the positively selected unique coding differences in A. guariba clamitans are in the region important in pathogen detection which may affect YFV resistance. Morework is necessary to fully explore this hypothesis.

EAR MITES, OTODECTES CYNOTIS, ON WILD FOXES (PSEUDALOPEX SPP.) IN CHILE.

We found the ear mite parasite (Otodectes cynotis; Acari: Psoroptidae) in two distant insular endangered fox populations in Chile. We identified O. cynotis in both the Darwin's fox (Pseudalopex fulvipes) from Chiloé and the Fuegian culpeo (Pseudalopex culpaeus lycoides) in Tierra del Fuego. These populations are approximately 2,000 km apart. Infestation rates were high for both endemic foxes: 76% (19/25) of Darwin's foxes were affected, and 73% (11/15) of Fuegian culpeos had ear mites. Two Darwin's foxes had abundant ear discharge, and one of these also exhibited secondary infections of Morganella morganii and Geotrichum sp. fungi. Mites were characterized molecularly as Otodectes spp. for the Fuegian culpeo samples. Genetic analyses of two mites found the O. cynotis genotype I, as well as what appeared to be a new allele sequence for O. cynotis. These results confirmed the hypothesis of a worldwide distribution species of ear mite. Introduced chilla foxes (Pseudalopex griseus; n=11) on Tierra del Fuego Island and domestic dogs (Canis lupus familiaris; n=379) from both islands were also sampled, but they showed no signs of infection. Our findings provided insight into the genetic diversity, the origins, and the possible impact of this globally distributed mite on endemic free-ranging populations of foxes.

Women's Pregnancy Life History and Alzheimer's Risk: Can Immunoregulation Explain the Link?

BACKGROUND: Pregnancy is associated with improvement in immunoregulation that persists into the geriatric phase. Impaired immunoregulation is implicated in Alzheimer's disease (AD) pathogenesis. Hence, we investigate the relationship between pregnancy and AD. METHODS: Cross-sectional cohort of British women (N = 95). Cox proportional hazards modeling assessed the putative effects of cumulative months pregnant on AD risk and the mutually adjusted effects of counts of first and third trimesters on AD risk. RESULTS: Cumulative number of months pregnant, was associated with lower AD risk (ß = -1.90, exp(ß) = 0.15, P = .02). Cumulative number of first trimesters was associated with lower AD risk after adjusting for third trimesters (ß = -3.83, exp(ß) = 0.02, P < .01), while the latter predictor had no significant effect after adjusting for the former. CONCLUSIONS: Our observation that first trimesters (but not third trimesters) conferred protection against AD is more consistent with immunologic effects, which are driven by early gestation, than estrogenic exposures, which are greatest in late gestation. Results may justify future studies with immune biomarkers.

Correction: The Malagarasi River Does Not Form an Absolute Barrier to Chimpanzee Movement in Western Tanzania.

[This corrects the article DOI: 10.1371/journal.pone.0058965.].

Evolutionary trade-off between vocal tract and testes dimensions in howler monkeys.

Males often face a trade-off between investments in precopulatory and postcopulatory traits [1], particularly when male-male contest competition determines access to mates [2]. To date, studies of precopulatory strategies have largely focused on visual ornaments (e.g., coloration) or weapon morphology (e.g., antlers, horns, and canines). However, vocalizations can also play an important role in both male competition and female choice [3-5]. We investigated variation in vocal tract dimensions among male howler monkeys (Alouatta spp.), which produce loud roars using a highly specialized and greatly enlarged hyoid bone and larynx [6]. We examined the relative male investment in hyoids and testes among howler monkey species in relation to the level of male-male competition and analyzed the acoustic consequences of variation in hyoid morphology. Species characterized by single-male groups have large hyoids and small testes, suggesting high levels of vocally mediated competition. Larger hyoids lower formant frequencies, probably increasing the acoustic impression of male body size and playing a role analogous to investment in large body size or weaponry. Across species, as the number of males per group increases, testes volume also increases, indicating higher levels of postcopulatory sperm competition, while hyoid volume decreases. These results provide the first evidence of an evolutionary trade-off between investment in precopulatory vocal characteristics and postcopulatory sperm production.

Androgens in a female primate: Relationships with reproductive status, age, dominance rank, fetal sex and secondary sexual color.

A comprehensive understanding of the role of androgens in reproduction, behavior and morphology requires the examination of female, as well as male, hormone profiles. However, we know far less about the biological significance of androgens in females than in males. We investigated the relationships between fecal androgen (immunoreactive testosterone) levels and reproductive status, age, dominance rank, fetal sex and a secondary sexual trait (facial color) in semi-free-ranging female mandrills (Mandrillus sphinx), using samples collected from 19 reproductively mature females over 13months. Fecal androgens varied with reproductive status, being highest during gestation. Fecal androgens began to increase at 3months of gestation, and peaked at 5months. This pattern is more similar to that found in a platyrrhine than in other cercopithecine species, suggesting that such patterns are not necessarily phylogenetically constrained. Fecal androgens did not vary systematically with rank, in contrast to the relationship we have reported for male mandrills, and in line with sex differences in how rank is acquired and maintained. Offspring sex was unrelated to fecal androgens, either prior to conception or during gestation, contrasting with studies of other primate species. Mean facial color was positively related to mean fecal androgens across females, reflecting the same relationship in male mandrills. However, the relationship between color and androgens was negative within females. Future studies of the relationship between female androgens and social behavior, reproduction and secondary sexual traits will help to elucidate the factors underlying the similarities and differences found between the sexes and among studies.

Analysis of full-length mitochondrial DNA D-loop sequences from Macaca fascicularis of different geographical origin reveals novel haplotypes.

BACKGROUND: Cynomolgus macaques are indigenous to Asia occupying a range of geographical areas. A non-indigenous population established on Mauritius approximately 500 years ago. Mauritian cynomolgus macaques are recognised as having low genetic diversity compared to Indonesian macaques, from which they originated. As cynomolgus macaques are widely used as a biomedical model, there have been many studies of their genetic relationships. However, population diversity and relationships have only been assessed through analysis of either the hypervariable region I or II separately within the D-loop region of the mitochondrial genome in these macaques. METHODS: Using sequencing, we defined haplotypes encompassing the full D-loop sequence for Mauritian and Indonesian cynomolgus macaques. RESULTS: We evaluated the haplotype relationships by constructing a median-joining network based on full-length D-loop sequences, which has not been reported previously. CONCLUSION: Our data allow a complete D-loop haplotype, including a hereto unreported polymorphic region, to be defined to aid the resolution of populations of cynomolgus macaques and which highlights the value in analysing both D-loop hypervariable regions in concert.

Evidence for varying social strategies across the day in chacma baboons.

Strong social bonds can make an important contribution to individual fitness, but we still have only a limited understanding of the temporal period relevant to the adjustment of social relationships. While there is growing recognition of the importance of strong bonds that persist for years, social relationships can also vary over weeks and months, suggesting that social strategies may be optimized over shorter timescales. Using biological market theory as a framework, we explore whether temporal variation in the benefits of social relationships might be sufficient to generate daily adjustments of social strategies in wild baboons. Data on grooming, one measure of social relationships, were collected from 60 chacma baboons (Papio ursinus) across two troops over a six month period. Our analyses suggest that social strategies can show diurnal variation, with subordinates preferentially grooming more dominant individuals earlier in the day compared with later in the day. These findings indicate that group-living animals may optimize certain elements of their social strategies over relatively short time periods.

Limited genetic diversity in the critically endangered Mexican howler monkey (Alouatta palliata mexicana) in the Selva Zoque, Mexico.

The Mexican howler monkey (Alouatta palliata mexicana) is a critically endangered primate, which is paleoendemic to Mexico. However, despite the potential significance of genetic data for its management and conservation, there have been no population genetic studies of this subspecies. To examine genetic diversity in the key remaining forest refuge for A. p. mexicana, the Selva Zoque, we amplified full-length mitochondrial control region sequences (1,100 bp) from 45 individuals and found 7 very similar haplotypes. Haplotype diversity (h = 0.486) and nucleotide diversity (π = 0.0007) were extremely low compared to other Neotropical primates. Neutrality tests, used to evaluate demographic effects (Tajima's D = -1.48, p = 0.05; Fu's F s = -3.33, p = 0.02), and mismatch distribution (sum of squares deviation = 0.006, p = 0.38; raggedness index = 0.12, p = 0.33) were consistent with a recent and mild population expansion and genetic diversity appears to be historically low in this taxon. Future studies should use a combination of mitochondrial and nuclear markers to fully evaluate genetic diversity and to better understand demographic history in A. p. mexicana. These studies should be undertaken throughout its geographic range in order to evaluate population structure and identify management units for conservation. Due to the limited distribution and population size of A. p. mexicana, future conservation strategies may need to consider genetic management. However, a more detailed knowledge of the population genetics of the subspecies is urgently recommended to maximise the conservation impact of these strategies.

Cumulative estrogen exposure, number of menstrual cycles, and Alzheimer's risk in a cohort of British women.

The effect of estrogen on Alzheimer's Disease (AD) risk has received substantial research and media attention, especially in terms of hormone replacement therapy. But reproductive history is also an important modifier of estrogenic exposure, and deserves further investigation. Importantly, there is wide variation in reproductive patterns that modifies estrogen exposure during the reproductive span, which previous AD studies have not incorporated into their calculations. We measured degree of Alzheimer's-type dementia in a cohort of elderly British women, and collected detailed reproductive and medical history information, which we used to estimate number of months with estrogen exposure and number of months with menstrual cycles. Using Cox proportional-hazards models, we find that longer duration of estrogen exposure may have a protective effect against AD risk, such that for every additional month with estrogen, women experienced on average a 0.5% decrease in AD risk (N=89, p=0.02). More menstrual cycles may also have a protective effect against AD risk, although this result was of borderline statistical significance (p<0.10). These results build upon previous methodologies by taking into account a variety of parameters including oral contraceptive use, breastfeeding, post-partum anovulation, abortions, and miscarriages. Additionally, Cox models revealed that longer reproductive span, age>21 at first birth, and more months in lifetime spent pregnant had protective effects against AD risk.

Maternal breastfeeding history and Alzheimer's disease risk.

The effect of early and midlife factors on later-life cognitive function has attracted scientific and public interest in recent years, especially with respect to hormonal risk factors for dementia. There is substantial evidence for reproductive history affecting Alzheimer's disease (AD) etiology. Here, we demonstrate how breastfeeding history affects women's risk of AD. Reproductive history data was collected, and AD diagnostic interviews were performed, for a cohort of elderly British women. Using Cox proportional-hazard models, we find that longer breastfeeding duration corresponded to reduced risk of AD (p < 0.01, n = 81). Women who breastfed had lower AD risk than women who did not breastfeed (p = 0.017, n = 81). Breastfeeding practices are an important modifier of cumulative endogenous hormone exposure for mothers. Ovarian hormone deprivation and/or insulin sensitivity benefits of breastfeeding may be responsible for the observed reduction in AD risk. Future studies concerning hormone effects on AD risk should consider how reproductive history leads to variation in endogenous hormone exposure and how this may influence the relationship between hormones and AD.

Testing for post-copulatory selection for major histocompatibility complex genotype in a semi-free-ranging primate population.

A large body of evidence suggests that major histocompatibility complex (MHC) genotype influences mate choice. However, few studies have investigated MHC-mediated post-copulatory mate choice under natural, or even semi-natural, conditions. We set out to explore this question in a large semi-free-ranging population of mandrills (Mandrillus sphinx) using MHC-DRB genotypes for 127 parent-offspring triads. First, we showed that offspring MHC heterozygosity correlates positively with parental MHC dissimilarity suggesting that mating among MHC dissimilar mates is efficient in increasing offspring MHC diversity. Second, we compared the haplotypes of the parental dyad with those of the offspring to test whether post-copulatory sexual selection favored offspring with two different MHC haplotypes, more diverse gamete combinations, or greater within-haplotype diversity. Limited statistical power meant that we could only detect medium or large effect sizes. Nevertheless, we found no evidence for selection for heterozygous offspring when parents share a haplotype (large effect size), genetic dissimilarity between parental haplotypes (we could detect an odds ratio of ≥1.86), or within-haplotype diversity (medium-large effect). These findings suggest that comparing parental and offspring haplotypes may be a useful approach to test for post-copulatory selection when matings cannot be observed, as is the case in many study systems. However, it will be extremely difficult to determine conclusively whether post-copulatory selection mechanisms for MHC genotype exist, particularly if the effect sizes are small, due to the difficulty in obtaining a sufficiently large sample.

The malagarasi river does not form an absolute barrier to chimpanzee movement in Western Tanzania.

The Malagarasi River has long been thought to be a barrier to chimpanzee movements in western Tanzania. This potential geographic boundary could affect chimpanzee ranging behavior, population connectivity and pathogen transmission, and thus has implications for conservation strategies and government policy. Indeed, based on mitochondrial DNA sequence comparisons it was recently argued that chimpanzees from communities to the north and to the south of the Malagarasi are surprisingly distantly related, suggesting that the river prevents gene flow. To investigate this, we conducted a survey along the Malagarasi River. We found a ford comprised of rocks that researchers could cross on foot. On a trail leading to this ford, we collected 13 fresh fecal samples containing chimpanzee DNA, two of which tested positive for SIVcpz. We also found chimpanzee feces within the riverbed. Taken together, this evidence suggests that the Malagarasi River is not an absolute barrier to chimpanzee movements and communities from the areas to the north and south should be considered a single population. These results have important consequences for our understanding of gene flow, disease dynamics and conservation management.

Hygiene and the world distribution of Alzheimer's disease: Epidemiological evidence for a relationship between microbial environment and age-adjusted disease burden.

BACKGROUND AND OBJECTIVES: Alzheimer's disease (AD) shares certain etiological features with autoimmunity. Prevalence of autoimmunity varies between populations in accordance with variation in environmental microbial diversity. Exposure to microorganisms may improve individuals' immunoregulation in ways that protect against autoimmunity, and we suggest that this may also be the case for AD. Here, we investigate whether differences in microbial diversity can explain patterns of age-adjusted AD rates between countries. METHODOLOGY: We use regression models to test whether pathogen prevalence, as a proxy for microbial diversity, across 192 countries can explain a significant amount of the variation in age-standardized AD disability-adjusted life-year (DALY) rates. We also review and assess the relationship between pathogen prevalence and AD rates in different world populations. RESULTS: Based on our analyses, it appears that hygiene is positively associated with AD risk. Countries with greater degree of sanitation and lower degree of pathogen prevalence have higher age-adjusted AD DALY rates. Countries with greater degree of urbanization and wealth exhibit higher age-adjusted AD DALY rates. CONCLUSIONS AND IMPLICATIONS: Variation in hygiene may partly explain global patterns in AD rates. Microorganism exposure may be inversely related to AD risk. These results may help predict AD burden in developing countries where microbial diversity is rapidly diminishing. Epidemiological forecasting is important for preparing for future healthcare needs and research prioritization.

Maternal effects and the endocrine regulation of mandrill growth.

Maternal effects can influence offspring growth and development, and thus fitness. However, the physiological factors mediating these effects in nonhuman primates are not well understood. We investigated the impact of maternal effects on variation in three important components of the endocrine regulation of growth in male and female mandrills (Mandrillus sphinx), from birth to 9 years of age. Using a mixed longitudinal set (N = 252) of plasma samples, we measured concentrations of insulin-like growth factor-I (IGF-I), growth hormone binding protein (GHBP), and free testosterone (free T). We evaluated the relationship of ontogenetic patterns of changes in hormone concentration to patterns of growth in body mass and body length, and determined that these endocrine factors play a significant role in growth of both young (infant and juvenile) and adolescent male mandrills, but only in growth of young female mandrills. We also use mixed models analysis to determine the relative contribution of the effects of maternal rank, parity, and age on variation in hormone and binding protein concentrations. Our results suggest that all of these maternal effects account for significant variation in hormone and binding protein concentrations in all male age groups. Of the maternal effects measured, maternal rank was the most frequently identified significant maternal effect on variation in hormone and binding protein concentrations. We suggest that these endocrine factors provide mechanisms that contribute to the maternal effects on offspring growth previously noted in this population.

Terrestrial nest-building by wild chimpanzees (Pan troglodytes): implications for the tree-to-ground sleep transition in early hominins.

Nest-building is a great ape universal and arboreal nesting in chimpanzees and bonobos suggests that the common ancestor of Pan and Homo also nested in trees. It has been proposed that arboreal nest-building remained the prevailing pattern until Homo erectus, a fully terrestrial biped, emerged. We investigated the unusual occurrence of ground-nesting in chimpanzees (Pan troglodytes), which may inform on factors influencing the tree-to-ground sleep transition in the hominin lineage. We used a novel genetic approach to examine ground-nesting in unhabituated chimpanzees at Seringbara in the Nimba Mountains, Guinea. Previous research showed that ground-nesting at Seringbara was not ecologically determined. Here, we tested a possible mate-guarding function of ground-nesting by analyzing DNA from shed hairs collected from ground nests and tree nests found in close proximity. We examined whether or not ground-nesting was a group-level behavioral pattern and whether or not it occurred in more than one community. We used multiple genetic markers to identify sex and to examine variation in mitochondrial DNA control region (HV1, HV2) sequences. Ground-nesting was a male-biased behavior and males constructed more elaborate ("night") nests than simple ("day") nests on the ground. The mate-guarding hypothesis was not supported, as ground and associated tree nests were built either by maternally-related males or possibly by the same individuals. Ground-nesting was widespread and likely habitual in two communities. We suggest that terrestrial nest-building may have already occurred in arboreally-adapted early hominins before the emergence of H. erectus.

Molecules and mating: positive selection and reproductive behaviour in primates.

Sexual reproduction is generally thought to be more costly than asexual reproduction. However, it does have the advantage of accelerating rates of adaptation through processes such as recombination and positive selection. Comparative studies of the human and nonhuman primate genomes have demonstrated that positive selection has played an important role in the evolutionary history of humans and other primates. To date, many dozens of genes, thought to be affected by positive selection, have been identified. In this chapter, we will focus on genes that are associated with mating behaviours and reproductive processes, concentrating on genes that are most likely to enhance reproductive success and that also show evidence of positive selection. The genes encode phenotypic features that potentially influence mate choice decisions or impact the evolution and function of genes involved in the perception and regulation of, and the response to, phenotypic signals. We will also consider genes that influence precopulatory behavioural traits in humans and nonhuman primates, such as social bonding and aggression. The evolution of post-copulatory strategies such as sperm competition and selective abortion may also evolve in the presence of intense competition and these adaptations will also be considered. Although behaviour may not be solely determined by genes, the evidence suggests that the genes discussed in this chapter have some influence on human and nonhuman primate behaviour and that positive selection on these genes results in some degree of population differentiation and diversity.

The selfish grandma gene: the roles of the x-chromosome and paternity uncertainty in the evolution of grandmothering behavior and longevity.

When considering inclusive fitness, it is expected that individuals will provide more care towards those with whom they are more closely related. Thus, if a selfish X-linked genetic element influenced care giving, we would expect care giving to vary with X-relatedness. Recent studies have shown that X-chromosome inheritance patterns may influence selection of traits affecting behavior and life-history. Sexually antagonistic (SA) zygotic drive could encourage individuals to help those with whom they are more likely to share genetic material at the expense of other relatives. We reanalyze previously reported data in light of this new idea. We also evaluate the effects of paternity uncertainty on SA-zygotic drive. Our evidence suggests that human paternal discrepancy is relatively low. Using published models, we find the effects of paternal discrepancy do not override opportunity for selection based on X-relatedness. Based on these results, longevity and grandmothering behaviors, including favoritism, may be more heavily influenced by selection on the X-chromosome than by paternity uncertainty.

Odour signals major histocompatibility complex genotype in an Old World monkey.

The major histocompatibility complex (MHC) is an extraordinarily diverse cluster of genes that play a key role in the immune system. MHC gene products are also found in various body secretions, leading to the suggestion that MHC genotypes are linked to unique individual odourtypes that animals use to assess the suitability of other individuals as potential mates or social partners. We investigated the relationship between chemical odour profiles and genotype in a large, naturally reproducing population of mandrills, using gas chromatography-mass spectrometry and MHC genotyping. Odour profiles were not linked to the possession of particular MHC supertypes. Sex influenced some measures of odour diversity and dominance rank influenced some measures of odour diversity in males, but not in females. Odour similarity was strongly related to similarity at the MHC, and, in some cases, to pedigree relatedness. Our results suggest that odour provides both a cue of individual genetic quality and information against which the receiver can compare its own genotype to assess genetic similarity. These findings provide a potential mechanism underlying mate choice for genetic diversity and MHC similarity as well as kin selection.