TY - JOUR
T1 - Impact of Zygosity on Bimodal Phenotype Distributions
AU - Holst-Hansen, Thomas
AU - Abad, Elena
AU - Muntasell, Aura
AU - López-Botet, Miguel
AU - Jensen, Mogens H
AU - Trusina, Ala
AU - Garcia-Ojalvo, Jordi
N1 - Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.
PY - 2017/7/11
Y1 - 2017/7/11
N2 - Allele number, or zygosity, is a clear determinant of gene expression in diploid cells. However, the relationship between the number of copies of a gene and its expression can be hard to anticipate, especially when the gene in question is embedded in a regulatory circuit that contains feedback. Here, we study this question making use of the natural genetic variability of human populations, which allows us to compare the expression profiles of a receptor protein in natural killer cells among donors infected with human cytomegalovirus with one or two copies of the allele. Crucially, the distribution of gene expression in many of the donors is bimodal, which indicates the presence of a positive feedback loop somewhere in the regulatory environment of the gene. Three separate gene-circuit models differing in the location of the positive feedback loop with respect to the gene can all reproduce the homozygous data. However, when the resulting fitted models are applied to the hemizygous donors, one model (the one with the positive feedback located at the level of gene transcription) is superior in describing the experimentally observed gene-expression profile. In that way, our work shows that zygosity can help us relate the structure and function of gene regulatory networks.
AB - Allele number, or zygosity, is a clear determinant of gene expression in diploid cells. However, the relationship between the number of copies of a gene and its expression can be hard to anticipate, especially when the gene in question is embedded in a regulatory circuit that contains feedback. Here, we study this question making use of the natural genetic variability of human populations, which allows us to compare the expression profiles of a receptor protein in natural killer cells among donors infected with human cytomegalovirus with one or two copies of the allele. Crucially, the distribution of gene expression in many of the donors is bimodal, which indicates the presence of a positive feedback loop somewhere in the regulatory environment of the gene. Three separate gene-circuit models differing in the location of the positive feedback loop with respect to the gene can all reproduce the homozygous data. However, when the resulting fitted models are applied to the hemizygous donors, one model (the one with the positive feedback located at the level of gene transcription) is superior in describing the experimentally observed gene-expression profile. In that way, our work shows that zygosity can help us relate the structure and function of gene regulatory networks.
KW - Journal Article
U2 - 10.1016/j.bpj.2017.05.010
DO - 10.1016/j.bpj.2017.05.010
M3 - Journal article
C2 - 28700913
SN - 0006-3495
VL - 113
SP - 148
EP - 156
JO - Biophysical Journal
JF - Biophysical Journal
IS - 1
ER -