TY - JOUR
T1 - How well do you know your mutation? Complex effects of genetic background on expressivity, complementation, and ordering of allelic effects
AU - Chandler, Christopher H.
AU - Chari, Sudarshan
AU - Kowalski, Alycia
AU - Choi, Lin
AU - Tack, David
AU - DeNieu, Michael
AU - Pitchers, William
AU - Sonnenschein, Anne
AU - Marvin, Leslie
AU - Hummel, Kristen
AU - Marier, Christian
AU - Victory, Andrew
AU - Porter, Cody
AU - Mammel, Anna
AU - Holms, Julie
AU - Sivaratnam, Gayatri
AU - Dworkin, Ian
N1 - Funding Information:
This work was funded by NSF award MCB-0922344, a NSERC Discovery grant and NSERC Discovery Accelerator Award to ID, and by NSF award DEB-1453298 to CHC, in addition to funds provided by Michigan State University, McMaster University, and SUNY Oswego. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to acknowledge all of the fly labs who provided alleles for this study, without which this work would have never been possible. Thanks to Lindy Johnson and Heather McGovern for help with fly work. We would also like to thank Dr. Trudy Mackay, Dr. Gregory Copenhaver and three anonymous reviewers for valuable feedback that has improved this manuscript.
Publisher Copyright:
© 2017 Chandler et al.
PY - 2017/11
Y1 - 2017/11
N2 - For a given gene, different mutations influence organismal phenotypes to varying degrees. However, the expressivity of these variants not only depends on the DNA lesion associated with the mutation, but also on factors including the genetic background and rearing environment. The degree to which these factors influence related alleles, genes, or pathways similarly, and whether similar developmental mechanisms underlie variation in the expressivity of a single allele across conditions and among alleles is poorly understood. Besides their fundamental biological significance, these questions have important implications for the interpretation of functional genetic analyses, for example, if these factors alter the ordering of allelic series or patterns of complementation. We examined the impact of genetic background and rearing environment for a series of mutations spanning the range of phenotypic effects for both the scalloped and vestigial genes, which influence wing development in Drosophila melanogaster. Genetic background and rearing environment influenced the phenotypic outcome of mutations, including intra-genic interactions, particularly for mutations of moderate expressivity. We examined whether cellular correlates (such as cell proliferation during development) of these phenotypic effects matched the observed phenotypic outcome. While cell proliferation decreased with mutations of increasingly severe effects, surprisingly it did not co-vary strongly with the degree of background dependence. We discuss these findings and propose a phenomenological model to aid in understanding the biology of genes, and how this influences our interpretation of allelic effects in genetic analysis.
AB - For a given gene, different mutations influence organismal phenotypes to varying degrees. However, the expressivity of these variants not only depends on the DNA lesion associated with the mutation, but also on factors including the genetic background and rearing environment. The degree to which these factors influence related alleles, genes, or pathways similarly, and whether similar developmental mechanisms underlie variation in the expressivity of a single allele across conditions and among alleles is poorly understood. Besides their fundamental biological significance, these questions have important implications for the interpretation of functional genetic analyses, for example, if these factors alter the ordering of allelic series or patterns of complementation. We examined the impact of genetic background and rearing environment for a series of mutations spanning the range of phenotypic effects for both the scalloped and vestigial genes, which influence wing development in Drosophila melanogaster. Genetic background and rearing environment influenced the phenotypic outcome of mutations, including intra-genic interactions, particularly for mutations of moderate expressivity. We examined whether cellular correlates (such as cell proliferation during development) of these phenotypic effects matched the observed phenotypic outcome. While cell proliferation decreased with mutations of increasingly severe effects, surprisingly it did not co-vary strongly with the degree of background dependence. We discuss these findings and propose a phenomenological model to aid in understanding the biology of genes, and how this influences our interpretation of allelic effects in genetic analysis.
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U2 - 10.1371/journal.pgen.1007075
DO - 10.1371/journal.pgen.1007075
M3 - Article
C2 - 29166655
AN - SCOPUS:85036629201
SN - 1553-7390
VL - 13
JO - PLoS genetics
JF - PLoS genetics
IS - 11
M1 - e1007075
ER -