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Title: Architecture of polymorphisms in the human genome reveals functionally important and positively selected variants in immune response and drug transporter genes
Authors: Jin, Y 
Wang, J 
Bachtiar, M 
Chong, S.S 
Lee, C.G.L 
Keywords: ABC transporter
cytochrome P450
RNA splicing factor
transcription factor
amino acid sequence
conserved sequence
drug response
drug transporter gene
frameshift mutation
gene deletion
gene expression regulation
gene frequency
gene structure
gene targeting
genetic code
genetic conservation
genetic variability
genotype environment interaction
human genome
immune response
indel mutation
major histocompatibility complex
natural selection
population differentiation
positive selection
protein function
protein structure
purifying selection
regulator gene
single nucleotide polymorphism
amino acid substitution
genetic selection
human genome
innate immunity
regulatory sequence
RNA splicing
single nucleotide polymorphism
Amino Acid Substitution
Genome, Human
Immunity, Innate
INDEL Mutation
Polymorphism, Single Nucleotide
Regulatory Sequences, Nucleic Acid
RNA Splicing
Selection, Genetic
Issue Date: 2018
Citation: Jin, Y, Wang, J, Bachtiar, M, Chong, S.S, Lee, C.G.L (2018). Architecture of polymorphisms in the human genome reveals functionally important and positively selected variants in immune response and drug transporter genes. Human Genomics 12 (1) : 43. ScholarBank@NUS Repository.
Abstract: Background: Genetic polymorphisms can contribute to phenotypic differences amongst individuals, including disease risk and drug response. Characterization of genetic polymorphisms that modulate gene expression and/or protein function may facilitate the identification of the causal variants. Here, we present the architecture of genetic polymorphisms in the human genome focusing on those predicted to be potentially functional/under natural selection and the pathways that they reside. Results: In the human genome, polymorphisms that directly affect protein sequences and potentially affect function are the most constrained variants with the lowest single-nucleotide variant (SNV) density, least population differentiation and most significant enrichment of rare alleles. SNVs which potentially alter various regulatory sites, e.g. splicing regulatory elements, are also generally under negative selection. Interestingly, genes that regulate the expression of transcription/splicing factors and histones are conserved as a higher proportion of these genes is non-polymorphic, contain ultra-conserved elements (UCEs) and/or has no nonsynonymous SNVs (nsSNVs)/coding INDELs. On the other hand, major histocompatibility complex (MHC) genes are the most polymorphic with SNVs potentially affecting the binding of transcription/splicing factors and microRNAs (miRNA) exhibiting recent positive selection (RPS). The drug transporter genes carry the most number of potentially deleterious nsSNVs and exhibit signatures of RPS and/or population differentiation. These observations suggest that genes that interact with the environment are highly polymorphic and targeted by RPS. Conclusions: In conclusion, selective constraints are observed in coding regions, master regulator genes, and potentially functional SNVs. In contrast, genes that modulate response to the environment are highly polymorphic and under positive selection. © 2018 The Author(s).
Source Title: Human Genomics
ISSN: 1473-9542
DOI: 10.1186/s40246-018-0175-1
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