Dataset Information

Pathogenic Interleukin-10 Receptor Alpha Variants in Humans - Balancing Natural Selection and Clinical Implications.

ABSTRACT: Balancing natural selection is a process by which genetic variants arise in populations that are beneficial to heterozygous carriers, but pathogenic when homozygous. We systematically investigated the prevalence, structural, and functional consequences of pathogenic IL10RA variants that are associated with monogenic inflammatory bowel disease. We identify 36 non-synonymous and non-sense variants in the IL10RA gene. Since the majority of these IL10RA variants have not been functionally characterized, we performed a systematic screening of their impact on STAT3 phosphorylation upon IL-10 stimulation. Based on the geographic accumulation of confirmed pathogenic IL10RA variants in East Asia and in Northeast China, the distribution of infectious disorders worldwide, and the functional evidence of IL-10 signaling in the pathogenesis, we identify Schistosoma japonicum infection as plausible selection pressure driving variation in IL10RA. Consistent with this is a partially augmented IL-10 response in peripheral blood mononuclear cells from heterozygous variant carriers. A parasite-driven heterozygote advantage through reduced IL-10 signaling has implications for health care utilization in regions with high allele frequencies and potentially indicates pathogen eradication strategies that target IL-10 signaling.

SUBMITTER: Aschenbrenner D

PROVIDER: S-EPMC9892166 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pathogenic Interleukin-10 Receptor Alpha Variants in Humans - Balancing Natural Selection and Clinical Implications.

Aschenbrenner Dominik D Ye Ziqing Z Zhou Ying Y Hu Wenhui W Brooks Isabel I Williams Isabelle I Capitani Melania M Gartner Lisa L Kotlarz Daniel D Snapper Scott B SB Klein Christoph C Muise Aleixo M AM Marsden Brian D BD Huang Ying Y Uhlig Holm H HH

Journal of clinical immunology 20221112 2

Balancing natural selection is a process by which genetic variants arise in populations that are beneficial to heterozygous carriers, but pathogenic when homozygous. We systematically investigated the prevalence, structural, and functional consequences of pathogenic IL10RA variants that are associated with monogenic inflammatory bowel disease. We identify 36 non-synonymous and non-sense variants in the IL10RA gene. Since the majority of these IL10RA variants have not been functionally characteri ...[more]

PMID: 36370291

Similar Datasets

Project description:The review describes the main methods for assessing directional selection in human populations. These include bioinformatic analysis of DNA sequences via detection of linkage disequilibrium and of deviations from the random distribution of frequencies of genetic variants, demographic and anthropometric studies based on a search for a correlation between fertility and phenotypic traits, genome-wide association studies on fertility along with genetic loci and polygenic risk scores, and a comparison of allele frequencies between generations (in modern samples and in those obtained from burials). Each approach has its limitations and is applicable to different periods in the evolution of Homo sapiens. The main source of error in such studies is thought to be sample stratification, the small number of studies on nonwhite populations, the impossibility of a complete comparison of the associations found and functionally significant causative variants, and the difficulty with taking into account all nongenetic determinants of fertility in contemporary populations. The results obtained by various methods indicate that the direction of human adaptation to new food products has not changed during evolution since the Neolithic; many variants of immunity genes associated with inflammatory and autoimmune diseases in modern populations have undergone positive selection over the past 2-3 thousand years owing to the spread of bacterial and viral infections. For some genetic variants and polygenic traits, an alteration of the direction of natural selection in Europe has been documented, e. g., for those associated with an immune response and cognitive abilities. Examination of the correlation between fertility and educational attainment yields conflicting results. In modern populations, to a greater extent than previously, there is selection for variants of genes responsible for social adaptation and behavioral phenotypes. In particular, several articles have shown a positive correlation of fertility with polygenic risk scores of attention deficit/hyperactivity disorder.

Dataset Information

Pathogenic Interleukin-10 Receptor Alpha Variants in Humans - Balancing Natural Selection and Clinical Implications.

Publications

Pathogenic Interleukin-10 Receptor Alpha Variants in Humans - Balancing Natural Selection and Clinical Implications.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets