Biology subjects

Harrison, G. F.

Publications and source records attributed to Harrison, G. F..

5 recordsLinked to original sources

bioRxiv2025

No evidence for disassortative mating based on HLA genotype in a natural fertility population

Studies dating back several decades have suggested that humans prefer potential mates with dissimilar HLA genotypes. Evidence for actualized disassortative mating based on the human-specific MHC remains inconclusive. For instance, cosmopolitan populations have often exhibited the opposite trend whereby assortative mating at the MHC is observed, indicating that social stratification may overwhelm potential biological mate preferences. However, small-scale, endogamous populations-whose social structures more closely resemble those throughout most of human evolution-have been largely overlooked. Here, we assess HLA dissimilarity among Himba pastoralists from Namibia, where socially accepted concurrency allows individuals to maintain both arranged marital and self-selected ("love match") partnerships. This provides a rare opportunity to directly test HLA similarity across contrasting partnership types (arranged vs chosen) within the same social system (n = 249 observed partnerships). We find no difference in HLA dissimilarity (neither at the genotype nor protein divergence level) between partnership types, nor in their fitness benefits to potential offspring as assessed via computationally predicted pathogen binding affinities. The effects of the partnership types likewise do not differ from a random, background distribution of 18,487 possible unrelated pairings. Finally, we detect extensive haplotype sharing across the HLA region, suggesting that episodes of fluctuating positive selection may be a stronger force maintaining HLA polymorphism than disassortative mating, even in an evolutionarily relevant social context.

evolutionary biology↗

bioRxiv2021

Allele imputation for the Killer cell Immunoglobulin-like Receptor KIR3DL1/S1

Highly polymorphic interactions of KIR3DL1 and KIR3DS1 with HLA class I ligands modulates the effector functions of natural killer (NK) cells and some T cells. This genetically determined diversity affects severity of infections, immune-mediated diseases, and some cancers, and impacts the course of cancer treatment, including transplantation. KIR3DL1 is an inhibitory receptor, and KIR3DS1 is an activating receptor encoded by the KIR3DL1/S1 gene that has more than 200 diverse and divergent alleles. Determination of KIR3DL1/S1 genotypes for medical application is hampered by complex sequence and structural variation that distinguishes individuals and populations, requiring targeted approaches to generate and analyze high-resolution allele data. To overcome these obstacles, we developed and optimized a model for imputing KIR3DL1/S1 alleles at high-resolution from whole-genome SNP data, and designed to represent a substantial component of human genetic diversity. We show that our Global model is effective at imputing KIR3DL1/S1 alleles with an accuracy ranging from 89% in Africans to 97% in East Asians, with mean specificity of 99.8% and sensitivity of 99% for named alleles >1% frequency. We used the established algorithm of the HIBAG program, in a modification named Pulling Out Natural killer cell Genomics (PONG). Because HIBAG was designed to impute HLA alleles also from whole-genome SNP data, PONG allows combinatorial diversity of KIR3DL1/S1 and HLA-A and B to be analyzed using complementary techniques on a single data source. The use of PONG thus negates the need for targeted sequencing data in very large-scale association studies where such methods might not be tractable. All code, imputation models, test data and documentation are available at https://github.com/NormanLabUCD/PONG. Author SummaryNatural killer (NK) cells are cytotoxic lymphocytes that identify and kill infected or malignant cells and guide immune responses. The effector functions of NK cells are modulated through polymorphic interactions of KIR3DL1/S1 on their surface with the human leukocyte antigens (HLA) that are found on most other cell types in the body. KIR3DL1/S1 is highly polymorphic and differentiated across human populations, affecting susceptibility and course of multiple immune-mediated diseases and their treatments. Genotyping KIR3DL1/S1 for direct medical application or research has been encumbered by the complex sequence and structural variation, which requires targeted approaches and extensive domain expertise to generate and validate high-resolution allele calls. We therefore developed Pulling Out Natural Killer Cell Genomics (PONG) to impute KIR3DL1/S1 alleles from whole genome SNP data, and which we implemented as an open-source R package. We assessed imputation performance using data from five broad population groups that represent a substantial portion of human genetic diversity. We can impute KIR3DL1/S1 alleles with an accuracy ranging from 89% in Africans and South Asians to 97% in East Asians. Globally, imputation of KIR3DL1/S1 alleles having frequency >1% has a mean sensitivity of 94% and specificity of 99.8%. Thus, the PONG method both enables highly sensitive individual-level calling and makes large scale medical genetic studies of KIR3DL1/S1 possible.

immunology↗

bioRxiv2020

Genetically Determined Strength of Natural Killer Cells is Enhanced by Adaptive HLA class I Admixture in East Asians

Human natural killer (NK) cells are essential for controlling infection, cancer and fetal development. NK cell functions are modulated by interactions between polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR) and polymorphic HLA-A, -B and -C ligands expressed on tissue cells. All HLA-C alleles encode a KIR ligand and contribute to reproduction and immunity. In contrast, only some HLA-A and -B alleles encode KIR ligands and they focus on immunity. By high-resolution analysis of KIR and HLA-A, -B and -C genes, we show that the Chinese Southern Han are significantly enriched for interactions between inhibitory KIR and HLA-A and -B. This enrichment has had substantial input through population admixture with neighboring populations, who contributed HLA class I haplotypes expressing the KIR ligands B*46:01 and B*58:01, which subsequently rose to high frequency by natural selection. Consequently, over 80% of Southern Han HLA haplotypes encode more than one KIR ligand. Complementing the high number of KIR ligands, the Chinese Southern Han KIR locus combines a high frequency of genes expressing potent inhibitory KIR, with a low frequency of those expressing activating KIR. The Southern Han centromeric KIR region encodes strong, conserved, inhibitory HLA-C specific receptors, and the telomeric region provides a high number and diversity of inhibitory HLA-A and -B specific receptors. In all these characteristics, the Southern Han represent other East Asians, whose NK cell repertoires are thus enhanced in quantity, diversity and effector strength, likely through natural selection for resistance to endemic viral infections.

immunology↗

bioRxiv2018

Natural selection contributed to immunological differences between human hunter-gatherers and agriculturalists

The shift from a hunter-gatherer (HG) to an agricultural (AG) mode of subsistence is believed to have been associated with profound changes in the burden and diversity of pathogens across human populations. Yet, the extent to which the advent of agriculture may have impacted the evolution of the human immune system remains unknown. Here we present a comparative study of variation in the transcriptional responses of peripheral blood mononuclear cells to bacterial and viral stimuli between Batwa rainforest hunter-gatherers and Bakiga agriculturalists from Uganda. We observed increased divergence between hunter-gatherers and agriculturalists in the transcriptional response to viruses compared to that for bacterial stimuli. We demonstrate that a significant fraction of these transcriptional differences are under genetic control, and we show that positive natural selection has helped to shape population differences in immune regulation. Across the set of genetic variants underlying inter-population immune response differences, however, the signatures of positive selection were disproportionately observed in the rainforest hunter-gatherers. This result is counter to expectations based on the popularized notion that shifts in pathogen exposure due to the advent of agriculture imposed radically heightened selective pressures in agriculturalist populations.

evolutionary biology↗

bioRxiv2018

Polygenic adaptation and convergent evolution across both growth and cardiac genetic pathways in African and Asian rainforest hunter-gatherers

Different human populations facing similar environmental challenges have sometimes evolved convergent biological adaptations, for example hypoxia resistance at high altitudes and depigmented skin in northern latitudes on separate continents. The pygmy phenotype (small adult body size), a characteristic of hunter-gatherer populations inhabiting both African and Asian tropical rainforests, is often highlighted as another case of convergent adaptation in humans. However, the degree to which phenotypic convergence in this polygenic trait is due to convergent vs. population-specific genetic changes is unknown. To address this question, we analyzed high-coverage sequence data from the protein-coding portion of the genomes (exomes) of two pairs of populations, Batwa rainforest hunter-gatherers and neighboring Bakiga agriculturalists from Uganda, and Andamanese rainforest hunter-gatherers (Jarawa and Onge) and Brahmin agriculturalists from India. We observed signatures of convergent positive selection between the Batwa and Andamanese rainforest hunter-gatherers across the set of genes with annotated growth factor binding functions (p < 0.001). Unexpectedly, for the rainforest groups we also observed convergent and population-specific signatures of positive selection in pathways related to cardiac development (e.g. cardiac muscle tissue development; p = 0.001). We hypothesize that the growth hormone sub-responsiveness likely underlying the pygmy phenotype may have led to compensatory changes in cardiac pathways, in which this hormone also plays an essential role. Importantly, in the agriculturalist populations we did not observe similar patterns of positive selection on sets of genes associated with either growth or cardiac development, indicating that our results most likely reflect a history of convergent adaptation to the similar ecology of rainforest hunter-gatherers rather than a more common or general evolutionary pattern for human populations.

genomics↗