Allelic variation, aneuploidy, and nongenetic mechanisms suppress a monogenic trait in yeast.
Clinically relevant features of monogenic diseases, including severity of symptoms and age of onset, can vary widely in response to environmental differences as well as to the presence of genetic modifiers affecting the trait's penetrance and expressivity. While a better understanding of modifier loci could lead to treatments for Mendelian diseases, the rarity of individuals harboring both a disease-causing allele and a modifying genotype hinders their study in human populations. We examined the genetic architecture of monogenic trait modifiers using a well-characterized yeast model of the human Mendelian disease classic galactosemia. Yeast strains with loss-of-function mutations in the yeast ortholog (GAL7) of the human disease gene (GALT) fail to grow in the presence of even small amounts of galactose due to accumulation of the same toxic intermediates that poison human cells. To isolate and individually genotype large numbers of the very rare (∼0.1%) galactose-tolerant recombinant progeny from a cross between two gal7Δ parents, we developed a new method, called "FACS-QTL." FACS-QTL improves upon the currently used approaches of bulk segregant analysis and extreme QTL mapping by requiring less genome engineering and strain manipulation as well as maintaining individual genotype information. Our results identified multiple distinct solutions by which the monogenic trait could be suppressed, including genetic and nongenetic mechanisms as well as frequent aneuploidy. Taken together, our results imply that the modifiers of monogenic traits are likely to be genetically complex and heterogeneous.
Pacific Northwest Diabetes Research Institute, Seattle, Washington 98122.
Amy
A
Sirr
Pacific Northwest Diabetes Research Institute, Seattle, Washington 98122.
Gareth A
GA
Cromie
Pacific Northwest Diabetes Research Institute, Seattle, Washington 98122.
Eric W
EW
Jeffery
Pacific Northwest Diabetes Research Institute, Seattle, Washington 98122.
Teresa L
TL
Gilbert
Pacific Northwest Diabetes Research Institute, Seattle, Washington 98122.
Catherine L
CL
Ludlow
Pacific Northwest Diabetes Research Institute, Seattle, Washington 98122.
Adrian C
AC
Scott
Pacific Northwest Diabetes Research Institute, Seattle, Washington 98122 aimee.dudley@gmail.com.
Aimée M
AM
Dudley
D000483:Alleles; D000782:Aneuploidy; D002874:Chromosome Mapping / Q000379:methods; D005690:Galactose / Q000378:metabolism; D037161:Galectins / Q000172:deficiency / Q000235:genetics; D060045:Genes, Modifier; D014644:Genetic Variation; D040641:Quantitative Trait Loci; D012441:Saccharomyces cerevisiae / Q000235:genetics*
D037161:Galectins; D005690:Galactose
QTL mapping; galactose; galactosemia, aneuploidy; genetic modifier