The physiological functions of natural killer (NK) cells in human immunity and reproduction depend upon diverse interactions between killer cell immunoglobulin-like receptors (KIRs) and their HLA ...class I ligands: HLA-A, HLA-B, and HLA-C. The genomic regions containing the KIR and HLA class I genes are unlinked, structurally complex, and highly polymorphic. They are also strongly associated with a wide spectrum of diseases, including infections, autoimmune disorders, cancers, and pregnancy disorders, as well as the efficacy of transplantation and other immunotherapies. To facilitate study of these extraordinary genes, we developed a method that captures, sequences, and analyzes the 13 KIR genes and HLA-A, HLA-B, and HLA-C from genomic DNA. We also devised a bioinformatics pipeline that attributes sequencing reads to specific KIR genes, determines copy number by read depth, and calls high-resolution genotypes for each KIR gene. We validated this method by using DNA from well-characterized cell lines, comparing it to established methods of HLA and KIR genotyping, and determining KIR genotypes from 1000 Genomes sequence data. This identified 116 previously uncharacterized KIR alleles, which were all demonstrated to be authentic by sequencing from source DNA via standard methods. Analysis of just two KIR genes showed that 22% of the 1000 Genomes individuals have a previously uncharacterized allele or a structural variant. The method we describe is suited to the large-scale analyses that are needed for characterizing human populations and defining the precise HLA and KIR factors associated with disease. The methods are applicable to other highly polymorphic genes.
Natural killer (NK) cells have diverse roles in hominid immunity and reproduction. Modulating these functions are the interactions between major histocompatibility complex (MHC) class I molecules ...that are ligands for two NK cell surface receptor types. Diverse killer cell immunoglobulin-like receptors (KIR) bind specific motifs encoded within the polymorphic MHC class I cell surface glycoproteins, while, in more conserved interactions, CD94:NKG2A receptors recognize MHC-E with bound peptides derived from MHC class I leader sequences. The hominid lineage presents a choreographed co-evolution of KIR with their MHC class I ligands.
, and
are present in all great apes with species-specific haplotypic variation in gene content. The Bw4 epitope recognized by lineage II KIR is restricted to MHC-B but also present on some gorilla and human MHC-A. Common to great apes, but rare in humans, are MHC-B possessing a C1 epitope recognized by lineage III KIR.
arose from duplication of
and is fixed in all great apes except orangutan, where it exists on approximately 50% of haplotypes and all allotypes are C1-bearing. Recent study showed that gorillas possess yet another intermediate
organization compared to humans. Like orangutans, but unlike the
species, duplication of
occurred. However,
is fixed, and the MHC-C C2 epitope (absent in orangutans) emerges. The evolution of MHC-C drove expansion of its cognate lineage III KIR. Recently, position -21 of the MHC-B leader sequence has been shown to be critical in determining NK cell educational outcome. In humans, methionine (-21M) results in CD94:NKG2A-focused education whereas threonine (-21T) produces KIR-focused education. This is another dynamic position among hominids. Orangutans have exclusively -21M, consistent with their intermediate stage in lineage III KIR-focused evolution. Gorillas have both -21M and -21T, like humans, but they are unequally encoded by their duplicated
genes. Chimpanzees have near-fixed -21T, indicative of KIR-focused NK education. Harmonious with this observation, chimpanzee KIR exhibit strong binding and, compared to humans, smaller differences between binding levels of activating and inhibitory KIR. Consistent between these MHC-NK cell receptor systems over the course of hominid evolution is the evolution of polymorphism favoring the more novel and dynamic KIR system.
The gastrointestinal tract harbors large and diverse populations of bacteria that vary among individuals and within individuals over time. Numerous internal and external factors can influence the ...contents of these microbial communities, including diet, geography, physiology, and the extent of contact among hosts. To investigate the contributions of such factors to the variation and changes in gut microbial communities, we analyzed the distal gut microbiota of individual chimpanzees from two communities in Gombe National Park, Tanzania. These samples, which were derived from 35 chimpanzees, many of whom have been monitored for multiple years, provide an unusually comprehensive longitudinal depth for individuals of known genetic relationships. Although the composition of the great-ape microbiota has been shown to codiversify with host species, indicating that host genetics and phylogeny have played a major role in its differentiation over evolutionary timescales, the geneaological relationships of individual chimpanzees did not coincide with the similarity in their gut microbial communities. However, the inhabitants from adjacent chimpanzee communities could be distinguished based on the contents of their gut microbiota. Despite the broad similarity of community members, as would be expected from shared diet or interactions, long-term immigrants to a community often harbored the most distinctive gut microbiota, suggesting that individuals retain hallmarks of their previous gut microbial communities for extended periods. This pattern was reinforced in several chimpanzees sampled over long temporal scales, in which the major constituents of the gut microbiota were maintained for nearly a decade.
In sexually reproducing animals, male and female reproductive strategies often conflict 1. In some species, males use aggression to overcome female choice 2, 3, but debate persists over the extent to ...which this strategy is successful. Previous studies of male aggression toward females among wild chimpanzees have yielded contradictory results about the relationship between aggression and mating behavior 4–11. Critically, however, copulation frequency in primates is not always predictive of reproductive success 12. We analyzed a 17-year sample of behavioral and genetic data from the Kasekela chimpanzee (Pan troglodytes schweinfurthii) community in Gombe National Park, Tanzania, to test the hypothesis that male aggression toward females increases male reproductive success. We examined the effect of male aggression toward females during ovarian cycling, including periods when the females were sexually receptive (swollen) and periods when they were not. We found that, after controlling for confounding factors, male aggression during a female’s swollen periods was positively correlated with copulation frequency. However, aggression toward swollen females was not predictive of paternity. Instead, aggression by high-ranking males toward females during their nonswollen periods was positively associated with likelihood of paternity. This indicates that long-term patterns of intimidation allow high-ranking males to increase their reproductive success, supporting the sexual coercion hypothesis. To our knowledge, this is the first study to present genetic evidence of sexual coercion as an adaptive strategy in a social mammal.
•Aggression toward sexually receptive females correlated with male mating success•Aggression toward non-sexually receptive females was associated with paternity•The effect of aggression on paternity was strongest for high-ranking males•This represents the first genetic evidence of long-term sexual coercion in mammals
In a study of wild chimpanzees, Feldblum et al. present the first evidence of the genetic effects of male-female aggression in mammals. Aggression toward sexually receptive females increased male mating success, but only aggression toward non-sexually receptive females increased male paternity odds. This effect was strongest for high-ranking males.
Coalitionary aggression occurs when at least two individuals jointly direct aggression at one or more conspecific targets. Scientists have long argued that this common form of cooperation has ...positive fitness consequences. Nevertheless, despite evidence that social bond strength (which is thought to promote coalition formation) is correlated with fitness in primates, cetaceans, and ungulates, few studies have directly examined whether coalitionary aggression improves reproductive success. We tested the hypothesis that among free-ranging chimpanzees (Pan troglodytes schweinfurthii), participation in coalitionary aggression increases reproductive output. Using 14 years of genetic and behavioral data from Gombe National Park, Tanzania, we found that coalitionary aggression increased a male's chances of (A) siring offspring, compared to other males of similar dominance rank, and (B) ascending in rank, a correlate of future reproductive output. Because male chimpanzees form coalitions with many others within a complex network, we used social network analysis to identify the types of connections correlated with these fitness benefits. The beneficiaries of coalitionary aggression were males with the highest "betweenness"—that is, those who tended to have coalition partners who themselves did not form coalitions with each other. This suggests that beyond simply recognizing third-party relationships, chimpanzees may use this knowledge to choose coalition partners. If so, this is a significant step forward in our knowledge of the adaptive value of social intelligence. Regardless of mechanism, however, this is the first evidence of genetic benefits of coalitionary aggression in this species, and therefore has important implications for understanding the evolution of cooperation.
Competition for fertile females determines male reproductive success in many species. The priority of access model predicts that male dominance rank determines access to females, but this model has ...been difficult to test in wild populations, particularly in promiscuous mating systems. Tests of the model have produced variable results, probably because of the differing socioecological circumstances of individual species and populations. We tested the predictions of the priority of access model in the chimpanzees of Gombe National Park, Tanzania. Chimpanzees are an interesting species in which to test the model because of their fission–fusion grouping patterns, promiscuous mating system and alternative male mating strategies. We determined paternity for 34 offspring over a 22-year period and found that the priority of access model was generally predictive of male reproductive success. However, we found that younger males had higher success per male than older males, and low-ranking males sired more offspring than predicted. Low-ranking males sired offspring with younger, less desirable females and by engaging in consortships more often than high-ranking fathers. Although alpha males never sired offspring with related females, inbreeding avoidance of high-ranking male relatives did not completely explain the success of low-ranking males. While our work confirms that male rank typically predicts male chimpanzee reproductive success, other factors are also important; mate choice and alternative male strategies can give low-ranking males access to females more often than would be predicted by the model. Furthermore, the success of younger males suggests that they are more successful in sperm competition.
The malaria parasite Plasmodium falciparum causes substantial human mortality, primarily in equatorial Africa. Enriched in affected African populations, the B*53 variant of HLA-B, a cell surface ...protein that presents peptide antigens to cytotoxic lymphocytes, confers protection against severe malaria. Gorilla, chimpanzee, and bonobo are humans' closest living relatives. These African apes have HLA-B orthologs and are infected by parasites in the same subgenus (Laverania) as P. falciparum, but the consequences of these infections are unclear. Laverania parasites infect bonobos (Pan paniscus) at only one (TL2) of many sites sampled across their range. TL2 spans the Lomami River and has genetically divergent subpopulations of bonobos on each side. Papa-B, the bonobo ortholog of HLA-B, includes variants having a B*53-like (B07) peptide-binding supertype profile. Here we show that B07 Papa-B occur at high frequency in TL2 bonobos and that malaria appears to have independently selected for different B07 alleles in the two subpopulations.
The most polymorphic part of the human genome, the
encodes over 160 proteins of diverse function. Half of them, including the
and
genes, are directly involved in immune responses. Consequently, the
...region strongly associates with numerous diseases and clinical therapies. Notoriously, the
region has been intractable to high-throughput analysis at complete sequence resolution, and current reference haplotypes are inadequate for large-scale studies. To address these challenges, we developed a method that specifically captures and sequences the 4.8-Mbp
region from genomic DNA. For 95
homozygous cell lines we assembled, de novo, a set of high-fidelity contigs and a sequence scaffold, representing a mean 98% of the target region. Included are six alternative
reference sequences of the human genome that we completed and refined. Characterization of the sequence and structural diversity of the
region shows the approach accurately determines the sequences of the highly polymorphic
and
genes and the complex structural diversity of complement factor
It has also uncovered extensive and unexpected diversity in other
genes; an example is
, which encodes a lung mucin and exhibits more coding sequence alleles than any
or
gene studied here. More than 60% of the coding sequence alleles analyzed were previously uncharacterized. We have created a substantial database of robust reference
haplotype sequences that will enable future population scale studies of this complicated and clinically important region of the human genome.
Major histocompatibility complex (MHC) class I molecules determine immune responses to viral infections. These polymorphic cell-surface glycoproteins bind peptide antigens, forming ligands for ...cytotoxic T and natural killer cell receptors. Under pressure from rapidly evolving viruses, hominoid MHC class I molecules also evolve rapidly, becoming diverse and species-specific. Little is known of the impact of infectious disease epidemics on MHC class I variant distributions in human populations, a context in which the chimpanzee is the superior animal model. Population dynamics of the chimpanzees inhabiting Gombe National Park, Tanzania have been studied for over 50 years. This population is infected with SIVcpz, the precursor of human HIV-1. Because HLA-B is the most polymorphic human MHC class I molecule and correlates strongly with HIV-1 progression, we determined sequences for its ortholog, Patr-B, in 125 Gombe chimpanzees. Eleven Patr-B variants were defined, as were their frequencies in Gombe's three communities, changes in frequency with time, and effect of SIVcpz infection. The growing populations of the northern and central communities, where SIVcpz is less prevalent, have stable distributions comprising a majority of low-frequency Patr-B variants and a few high-frequency variants. Driving the latter to high frequency has been the fecundity of immigrants to the northern community, whereas in the central community, it has been the fecundity of socially dominant individuals. In the declining population of the southern community, where greater SIVcpz prevalence is associated with mortality and emigration, Patr-B variant distributions have been changing. Enriched in this community are Patr-B variants that engage with natural killer cell receptors. Elevated among SIVcpz-infected chimpanzees, the Patr-B*06:03 variant has striking structural and functional similarities to HLA-B*57, the human allotype most strongly associated with delayed HIV-1 progression. Like HLA-B*57, Patr-B*06:03 correlates with reduced viral load, as assessed by detection of SIVcpz RNA in feces.
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