title: Selected heterozygosity at cis-regulatory sequences increases the expression homogeneity of a cell population in humans.
abstract: Examples of heterozygote advantage in humans are scarce and limited to protein-coding sequences. Here, we attempt a genome-wide functional inference of advantageous heterozygosity at cis-regulatory regions.
  
  
  
  The single-nucleotide polymorphisms bearing the signatures of balancing selection are enriched in active cis-regulatory regions of immune cells and epithelial cells, the latter of which provide barrier function and innate immunity. Examples associated with ancient trans-specific balancing selection are also discovered. Allelic imbalance in chromatin accessibility and divergence in transcription factor motif sequences indicate that these balanced polymorphisms cause distinct regulatory variation. However, a majority of these variants show no association with the expression level of the target gene. Instead, single-cell experimental data for gene expression and chromatin accessibility demonstrate that heterozygous sequences can lower cell-to-cell variability in proportion to selection strengths. This negative correlation is more pronounced for highly expressed genes and consistently observed when using different data and methods. Based on mathematical modeling, we hypothesize that extrinsic noise from fluctuations in transcription factor activity may be amplified in homozygotes, whereas it is buffered in heterozygotes. While high expression levels are coupled with intrinsic noise reduction, regulatory heterozygosity can contribute to the suppression of extrinsic noise.
  
  
  
  This mechanism may confer a selective advantage by increasing cell population homogeneity and thereby enhancing the collective action of the cells, especially of those involved in the defense systems in humans.
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, Republic of Korea.
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Sung
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 44919, Republic of Korea.
authors.forename: Juneil
authors.initials: J
authors.lastname: Jang
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, Republic of Korea.
authors.forename: Kang Seon
authors.initials: KS
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 44919, Republic of Korea.|Department of Physics, Ulsan National Institute of Science and Technology, Ulsan, 44919, Republic of Korea.|Mathematical Bioscience Institute, The Ohio State University, Columbus, Ohio, 43210, USA.
authors.forename: Cheol-Min
authors.initials: CM
authors.lastname: Ghim
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, Republic of Korea. jungkyoon@gmail.com.
authors.forename: Jung Kyoon
authors.initials: JK
authors.lastname: Choi
mesh_terms: D000465:Algorithms; D000483:Alleles; D022981:Allelic Imbalance; D001665:Binding Sites; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008954:Models, Biological; D059372:Nucleotide Motifs; D009928:Organ Specificity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002843:Chromatin; D014157:Transcription Factors