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Population Genetics in the Human Microbiome.
Garud, NR, Pollard, KS
Trends in genetics : TIG. 2020;(1):53-67
Abstract
While the human microbiome's structure and function have been extensively studied, its within-species genetic diversity is less well understood. However, genetic mutations in the microbiome can confer biomedically relevant traits, such as the ability to extract nutrients from food, metabolize drugs, evade antibiotics, and communicate with the host immune system. The population genetic processes by which these traits evolve are complex, in part due to interacting ecological and evolutionary forces in the microbiome. Advances in metagenomic sequencing, coupled with bioinformatics tools and population genetic models, facilitate quantification of microbiome genetic variation and inferences about how this diversity arises, evolves, and correlates with traits of both microbes and hosts. In this review, we explore the population genetic forces (mutation, recombination, drift, and selection) that shape microbiome genetic diversity within and between hosts, as well as efforts towards predictive models that leverage microbiome genetics.
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Fine-mapping inflammatory bowel disease loci to single-variant resolution.
Huang, H, Fang, M, Jostins, L, Umićević Mirkov, M, Boucher, G, Anderson, CA, Andersen, V, Cleynen, I, Cortes, A, Crins, F, et al
Nature. 2017;(7662):173-178
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Abstract
Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.
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Sequence variation and structural conservation allows development of novel function and immune evasion in parasite surface protein families.
Higgins, MK, Carrington, M
Protein science : a publication of the Protein Society. 2014;(4):354-65
Abstract
Trypanosoma and Plasmodium species are unicellular, eukaryotic pathogens that have evolved the capacity to survive and proliferate within a human host, causing sleeping sickness and malaria, respectively. They have very different survival strategies. African trypanosomes divide in blood and extracellular spaces, whereas Plasmodium species invade and proliferate within host cells. Interaction with host macromolecules is central to establishment and maintenance of an infection by both parasites. Proteins that mediate these interactions are under selection pressure to bind host ligands without compromising immune avoidance strategies. In both parasites, the expansion of genes encoding a small number of protein folds has established large protein families. This has permitted both diversification to form novel ligand binding sites and variation in sequence that contributes to avoidance of immune recognition. In this review we consider two such parasite surface protein families, one from each species. In each case, known structures demonstrate how extensive sequence variation around a conserved molecular architecture provides an adaptable protein scaffold that the parasites can mobilise to mediate interactions with their hosts.
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Adaptive interactions between HLA and HIV-1: highly divergent selection imposed by HLA class I molecules with common supertype motifs.
John, M, Heckerman, D, James, I, Park, LP, Carlson, JM, Chopra, A, Gaudieri, S, Nolan, D, Haas, DW, Riddler, SA, et al
Journal of immunology (Baltimore, Md. : 1950). 2010;(8):4368-77
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Abstract
Currently, 1.1 million individuals in the United States are living with HIV-1 infection. Although this is a relatively small proportion of the global pandemic, the remarkable mix of ancestries in the United States, drawn together over the past two centuries of continuous population migrations, provides an important and unique perspective on adaptive interactions between HIV-1 and human genetic diversity. HIV-1 is a rapidly adaptable organism and mutates within or near immune epitopes that are determined by the HLA class I genotype of the infected host. We characterized HLA-associated polymorphisms across the full HIV-1 proteome in a large, ethnically diverse national United States cohort of HIV-1-infected individuals. We found a striking divergence in the immunoselection patterns associated with HLA variants that have very similar or identical peptide-binding specificities but are differentially distributed among racial/ethnic groups. Although their similarity in peptide binding functionally clusters these HLA variants into supertypes, their differences at sites within the peptide-binding groove contribute to race-specific selection effects on circulating HIV-1 viruses. This suggests that the interactions between the HLA/HIV peptide complex and the TCR vary significantly within HLA supertype groups, which, in turn, influences HIV-1 evolution.
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Molecular epidemiology of human respiratory syncytial virus in Uruguay: 1985-2001--a review.
Arbiza, J, Delfraro, A, Frabasile, S
Memorias do Instituto Oswaldo Cruz. 2005;(3):221-30
Abstract
The variability of the G glycoprotein from human respiratory syncytial viruses (HRSV) (groups A and B) isolated during 17 consecutive epidemics in Montevideo, Uruguay have been analyzed. Several annual epidemics were studied, where strains from groups A and B circulated together throughout the epidemics with predominance of one of them. Usually, group A predominates, but in some epidemics group B is more frequently detected. To analyse the antigenic diversity of the strains, extracts of cells infected with different viruses of group A were tested with a panel of anti-G monoclonal antibodies (MAbs). The genetic variability of both groups was analyzed by sequencing the C-terminal third of the G protein gene. The sequences obtained together with previously published sequences were used to perform phylogenetic analyses. The data from Uruguayan isolates, together with those from the rest of the world provide information regarding worldwide strain circulation. Phylogenetic analyses of HRSV from groups A and B show a model of evolution analogous to the one proposed for influenza B viruses providing information that would be beneficial for future immunization programs and to design safe vaccines.