Abstract
Genome-wide scans for positive selection have become important for genomic medicine, and many studies aim to find genomic regions affected by positive selection that are associated with risk allele variations among populations. Most such studies are designed to detect recent positive selection. However, we hypothesize that ancient positive selection is also important for adaptation to pathogens, and has affected current immune-mediated common diseases. Based on this hypothesis, we developed a novel linkage disequilibrium-based pipeline, which aims to detect regions associated with ancient positive selection across populations from single nucleotide polymorphism (SNP) data. By applying this pipeline to the genotypes in the International HapMap project database, we show that genes in the detected regions are enriched in pathways related to the immune system and infectious diseases. The detected regions also contain SNPs reported to be associated with cancers and metabolic diseases, obesity-related traits, type 2 diabetes, and allergic sensitization. These SNPs were further mapped to biological pathways to determine the associations between phenotypes and molecular functions. Assessments of candidate regions to identify functions associated with variations in incidence rates of these diseases are needed in the future.
Highlights
Genome-wide scans of positive selection are a recent advance in genomic medicine, and have become an important way to infer risk allele variations across populations and elucidate genetic mechanisms of human evolutionary adaptation to local environments, dietary patterns, and infectious diseases [1]
The allele of an single nucleotide polymorphism (SNP) in CYP3A5, a member of the CYP3A subfamily, shows large frequency differences between African Americans and non-Africans [9,10,11]; and the region that contains this gene shows a high degree of linkage disequilibrium (LD) that was affected by positive selection in Europeans [9, 12]
Because this allele is involved in CYP3A5 expression and metabolism of clinically important drugs, differences in genetic background may be associated with differential drug responses among populations [9,10,11]
Summary
Genome-wide scans of positive selection are a recent advance in genomic medicine, and have become an important way to infer risk allele variations across populations and elucidate genetic mechanisms of human evolutionary adaptation to local environments, dietary patterns, and infectious diseases [1]. The allele of an SNP in CYP3A5, a member of the CYP3A subfamily, shows large frequency differences between African Americans and non-Africans [9,10,11]; and the region that contains this gene shows a high degree of linkage disequilibrium (LD) that was affected by positive selection in Europeans [9, 12] Because this allele is involved in CYP3A5 expression and metabolism of clinically important drugs (e.g., the immunosuppressant tacrolimus [13] and the HIV protease inhibitor saquinavir [14]), differences in genetic background may be associated with differential drug responses among populations [9,10,11]. Other common complex diseases with risk allele frequencies that differ across human populations include cancers (e.g., breast cancer and prostate cancer), cardiovascular diseases, metabolic diseases (e.g., hypertension), neurodegenerative diseases (e.g., Alzheimer’s disease), and systemic autoimmune diseases (e.g., systemic lupus erythematosus and rheumatoid arthritis) [3, 15]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
