Disease-Related Genes from Population Genetic Aspect and Their Functional Significance

Abstract

Numerous disease-and trait-related genes have been identified owing to advances of modern genomic technologies. Atopic dermatitis (AD) is the most common and complex disease, and filaggrin gene (FLG) was identified as a strong genetic component. Numerous variations of FLG were identified and European and Asian patients harbor each distinct mutation profiles. Excess non-synonymous variants over synonymous variants of FLG in general populations indicate that positive selection may have a substantial role in shaping the mutation profiles. In various disorders, population history is important particularly considering population-specific mutations. Recently, genomes of archaic humans such as Nean-derthals and Denisovans had been sequenced and provided new evidence that 1-6% of modern Eurasian genome were introgressed by archaic humans. The introgres-sions had key roles in several immunological pathways including acquired and innate immunity. For example, parts of human leucocyte antigen (HLA) alleles were derived from archaic humans, which provided advantages for survival for ancestry of modern humans after the out-of-Africa expansion. A growing body of evidence supports the importance of variants in noncoding regions on human complex traits and natural selection. Thus, we introduce a topic on understanding of gene regulatory network recently demonstrated by ENCODE project, which provides clues of seeking functional impact of SNPs identified by genome-wide association study. SNPs located on DNase I hypersensitive sites are associated with disease causality through modulating transcriptional regulatory mechanisms. The allele-specific gene regulation is the key to understand the pathophysiology of common diseases.