Genetic effects at pleiotropic loci are context-dependent with consequences for the maintenance of genetic variation in populations

H A Lawson, J E Cady, C Partridge, Jason B Wolf, C F Semenkovich, J M Cheverud

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Context-dependent genetic effects, including genotype-by-environment and genotype-by-sex interactions, are a potential mechanism by which genetic variation of complex traits is maintained in populations. Pleiotropic genetic effects are also thought to play an important role in evolution, reflecting functional and developmental relationships among traits. We examine context-dependent genetic effects at pleiotropic loci associated with normal variation in multiple metabolic syndrome (MetS) components (obesity, dyslipidemia, and diabetes-related traits). MetS prevalence is increasing in Western societies and, while environmental in origin, presents substantial variation in individual response. We identify 23 pleiotropic MetS quantitative trait loci (QTL) in an F(16) advanced intercross between the LG/J and SM/J inbred mouse strains (Wustl: LG, SM-G16; n = 1002). Half of each family was fed a high-fat diet and half fed a low-fat diet; and additive, dominance, and parent-of-origin imprinting genotypic effects were examined in animals partitioned into sex, diet, and sex-by-diet cohorts. We examine the context-dependency of the underlying additive, dominance, and imprinting genetic effects of the traits associated with these pleiotropic QTL. Further, we examine sequence polymorphisms (SNPs) between LG/J and SM/J as well as differential expression of positional candidate genes in these regions. We show that genetic associations are different in different sex, diet, and sex-by-diet settings. We also show that over-or underdominance and ecological crossover interactions for single phenotypes may not be common, however multidimensional synthetic phenotypes at loci with pleiotropic effects can produce situations that favor the maintenance of genetic variation in populations. Our findings have important implications for evolution and the notion of personalized medicine.
Original languageEnglish
Article numbere1002256
JournalPlos Genetics
Volume7
Issue number9
DOIs
Publication statusPublished - Sep 2011

Fingerprint

genetic variation
Maintenance
diet
metabolic syndrome
loci
gender
Diet
genomic imprinting
Population
Quantitative Trait Loci
imprinting
dominance (genetics)
quantitative trait loci
fat
Genotype
phenotype
Genomic Imprinting
genotype
Phenotype
Precision Medicine

Cite this

Genetic effects at pleiotropic loci are context-dependent with consequences for the maintenance of genetic variation in populations. / Lawson, H A; Cady, J E; Partridge, C; Wolf, Jason B; Semenkovich, C F; Cheverud, J M.

In: Plos Genetics, Vol. 7, No. 9, e1002256, 09.2011.

Research output: Contribution to journalArticle

@article{ed915c96c71c4dfe82fe8dd5921881c0,
title = "Genetic effects at pleiotropic loci are context-dependent with consequences for the maintenance of genetic variation in populations",
abstract = "Context-dependent genetic effects, including genotype-by-environment and genotype-by-sex interactions, are a potential mechanism by which genetic variation of complex traits is maintained in populations. Pleiotropic genetic effects are also thought to play an important role in evolution, reflecting functional and developmental relationships among traits. We examine context-dependent genetic effects at pleiotropic loci associated with normal variation in multiple metabolic syndrome (MetS) components (obesity, dyslipidemia, and diabetes-related traits). MetS prevalence is increasing in Western societies and, while environmental in origin, presents substantial variation in individual response. We identify 23 pleiotropic MetS quantitative trait loci (QTL) in an F(16) advanced intercross between the LG/J and SM/J inbred mouse strains (Wustl: LG, SM-G16; n = 1002). Half of each family was fed a high-fat diet and half fed a low-fat diet; and additive, dominance, and parent-of-origin imprinting genotypic effects were examined in animals partitioned into sex, diet, and sex-by-diet cohorts. We examine the context-dependency of the underlying additive, dominance, and imprinting genetic effects of the traits associated with these pleiotropic QTL. Further, we examine sequence polymorphisms (SNPs) between LG/J and SM/J as well as differential expression of positional candidate genes in these regions. We show that genetic associations are different in different sex, diet, and sex-by-diet settings. We also show that over-or underdominance and ecological crossover interactions for single phenotypes may not be common, however multidimensional synthetic phenotypes at loci with pleiotropic effects can produce situations that favor the maintenance of genetic variation in populations. Our findings have important implications for evolution and the notion of personalized medicine.",
author = "Lawson, {H A} and Cady, {J E} and C Partridge and Wolf, {Jason B} and Semenkovich, {C F} and Cheverud, {J M}",
year = "2011",
month = "9",
doi = "10.1371/journal.pgen.1002256",
language = "English",
volume = "7",
journal = "Plos Genetics",
issn = "1553-7390",
publisher = "Public Library of Science (PLOS)",
number = "9",

}

TY - JOUR

T1 - Genetic effects at pleiotropic loci are context-dependent with consequences for the maintenance of genetic variation in populations

AU - Lawson, H A

AU - Cady, J E

AU - Partridge, C

AU - Wolf, Jason B

AU - Semenkovich, C F

AU - Cheverud, J M

PY - 2011/9

Y1 - 2011/9

N2 - Context-dependent genetic effects, including genotype-by-environment and genotype-by-sex interactions, are a potential mechanism by which genetic variation of complex traits is maintained in populations. Pleiotropic genetic effects are also thought to play an important role in evolution, reflecting functional and developmental relationships among traits. We examine context-dependent genetic effects at pleiotropic loci associated with normal variation in multiple metabolic syndrome (MetS) components (obesity, dyslipidemia, and diabetes-related traits). MetS prevalence is increasing in Western societies and, while environmental in origin, presents substantial variation in individual response. We identify 23 pleiotropic MetS quantitative trait loci (QTL) in an F(16) advanced intercross between the LG/J and SM/J inbred mouse strains (Wustl: LG, SM-G16; n = 1002). Half of each family was fed a high-fat diet and half fed a low-fat diet; and additive, dominance, and parent-of-origin imprinting genotypic effects were examined in animals partitioned into sex, diet, and sex-by-diet cohorts. We examine the context-dependency of the underlying additive, dominance, and imprinting genetic effects of the traits associated with these pleiotropic QTL. Further, we examine sequence polymorphisms (SNPs) between LG/J and SM/J as well as differential expression of positional candidate genes in these regions. We show that genetic associations are different in different sex, diet, and sex-by-diet settings. We also show that over-or underdominance and ecological crossover interactions for single phenotypes may not be common, however multidimensional synthetic phenotypes at loci with pleiotropic effects can produce situations that favor the maintenance of genetic variation in populations. Our findings have important implications for evolution and the notion of personalized medicine.

AB - Context-dependent genetic effects, including genotype-by-environment and genotype-by-sex interactions, are a potential mechanism by which genetic variation of complex traits is maintained in populations. Pleiotropic genetic effects are also thought to play an important role in evolution, reflecting functional and developmental relationships among traits. We examine context-dependent genetic effects at pleiotropic loci associated with normal variation in multiple metabolic syndrome (MetS) components (obesity, dyslipidemia, and diabetes-related traits). MetS prevalence is increasing in Western societies and, while environmental in origin, presents substantial variation in individual response. We identify 23 pleiotropic MetS quantitative trait loci (QTL) in an F(16) advanced intercross between the LG/J and SM/J inbred mouse strains (Wustl: LG, SM-G16; n = 1002). Half of each family was fed a high-fat diet and half fed a low-fat diet; and additive, dominance, and parent-of-origin imprinting genotypic effects were examined in animals partitioned into sex, diet, and sex-by-diet cohorts. We examine the context-dependency of the underlying additive, dominance, and imprinting genetic effects of the traits associated with these pleiotropic QTL. Further, we examine sequence polymorphisms (SNPs) between LG/J and SM/J as well as differential expression of positional candidate genes in these regions. We show that genetic associations are different in different sex, diet, and sex-by-diet settings. We also show that over-or underdominance and ecological crossover interactions for single phenotypes may not be common, however multidimensional synthetic phenotypes at loci with pleiotropic effects can produce situations that favor the maintenance of genetic variation in populations. Our findings have important implications for evolution and the notion of personalized medicine.

UR - http://www.scopus.com/inward/record.url?scp=80053440989&partnerID=8YFLogxK

UR - http://dx.doi.org/10.1371/journal.pgen.1002256

U2 - 10.1371/journal.pgen.1002256

DO - 10.1371/journal.pgen.1002256

M3 - Article

VL - 7

JO - Plos Genetics

JF - Plos Genetics

SN - 1553-7390

IS - 9

M1 - e1002256

ER -