Systematic Detection of Epistatic Interactions Based on Allele Pair Frequencies

In search of genetic markers of myocardial infarction (MI) risk, which have prognostic significance for Russians, we performed a replication study of MI association with genetic variants of PCSK9 (rs562556), APOE (epsilon polymorphism, rs7412 and rs429358), LPL (rs320), MTHFR (rs1801133), eNOS (rs2070744), and the 9p21 region (rs1333049) in 405 patients with MI and 198 controls. Significant MI association was observed with variants of the lipid metabolism genes (PCSK9, APOE and LPL), and of eNOS. The SNPs in the MTHFR gene and the 9p21 region were not significantly associated with MI one by one but were included in several different MI-associated allelic combinations identified by multilocus analysis. Since we have not revealed nonlinear epistatic interactions between the components of the identified combinations, we postulate that the cumulative effect of genes that form a combination arises from the summation of their small independent contributions. The prognostic significance of the additive composite model built from the PCSK9, APOE, LPL, and eNOS genes as genetic markers was assessed using ROC analysis. After we included these markers in the previously published composite model of individual genetic risk of MI, the prognostic efficacy in our sample reached AUC = 0.676. However, the results obtained in this study certainly need to be replicated in an independent sample of Russians.

Download Full-text

Faculty Opinions recommendation of The environment affects epistatic interactions to alter the topology of an empirical fitness landscape.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718013855.793477508 ◽

2013 ◽

Author(s):

Santiago F Elena

Keyword(s):

Fitness Landscape ◽

Epistatic Interactions

Download Full-text

Mapping and Epistatic Interactions of QTLs for Pericarp Thickness in Sweet Corn

ACTA AGRONOMICA SINICA ◽

10.3724/sp.j.1006.2015.00359 ◽

2015 ◽

Vol 41 (3) ◽

pp. 359 ◽

Cited By ~ 1

Author(s):

Yong-Tao YU ◽

Gao-Ke LI ◽

Xi-Tao QI ◽

Chun-Yan LI ◽

Ji-Hua MAO ◽

...

Keyword(s):

Sweet Corn ◽

Epistatic Interactions ◽

Pericarp Thickness

Download Full-text

Heritability of the Effect of Corticosteroids on Intraocular Pressure

Acta geneticae medicae et gemellologiae ◽

10.1017/s1120962300025658 ◽

1970 ◽

Vol 19 (1-2) ◽

pp. 264-267 ◽

Cited By ~ 4

Author(s):

F.H. Reuling ◽

J.T. Schwartz

Keyword(s):

Intraocular Pressure ◽

Clinical Signs ◽

Topical Steroids ◽

Frequency Distributions ◽

Steroid Response ◽

Large Numbers ◽

Wide Range ◽

Allele Pair ◽

High Level ◽

Genetically Determined

In the late 1950's and early 1960's, it became evident that some glaucoma patients developed elevations of intraocular pressure, which were difficult to control, following prolonged use of systemic or ocular medications containing corticosteroids (Chandler, 1955, Alfano, 1963; Armaly, 1963). In addition, some patients without glaucoma, when treated with steroids for long periods of time, developed clinical signs of chronic simple glaucoma (McLean, 1950; François, 1954; Covell, 1958; Linner, 1959; Goldman, 1962). Fortunately, the elevation of intraocular pressure was reversible if the drug was discontinued.Over the past decade, extensive investigation of the “steroid response” has been undertaken. For this presentation, the steroid response may be considered as a gradual elevation of intraocular pressure, occurring over several weeks, in an eye being medicated with corticosteroid drops several times a day. The elevation in pressure is usually accompanied by a reduction in the facility of aqueous outflow. When relatively large numbers of subjects were tested with topical steroids, so that a wide range of responsiveness could be observed, a variation in individual sensitivity was demonstrated. Frequency distributions of intraocular pressure or change in pressure following steroids showed a skew toward the high side. On the basis of trimodal characteristics which they observed in such frequency distributions, Becker and Hahn (1964), Becker (1965) and Armaly (1965, 1966) considered the possible existence of several genetically determined subpopulations. These investigators distinguished three subpopulations on the basis of low, intermediate, and high levels of pressure response. It was hypothesized that these levels of response characterized three phenotypes, corresponding to the three possible genotypes of an allele pair, wherein one member of the pair determined a low level of response, and the other member determined a high level of response (Armaly, 1967).

Download Full-text

EpiPen: An R Package to Investigate Two-Locus Epistatic Models

Twin Research and Human Genetics ◽

10.1017/thg.2014.25 ◽

2014 ◽

Vol 17 (4) ◽

Cited By ~ 2

Author(s):

Raymond K. Walters ◽

Charles Laurin ◽

Gitta H. Lubke

Keyword(s):

Power Analysis ◽

R Package ◽

Simulation Studies ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Epistatic Interactions ◽

Model Interpretation ◽

Genome Wide ◽

Using Data ◽

Power Analyses

Epistasis is a growing area of research in genome-wide studies, but the differences between alternative definitions of epistasis remain a source of confusion for many researchers. One problem is that models for epistasis are presented in a number of formats, some of which have difficult-to-interpret parameters. In addition, the relation between the different models is rarely explained. Existing software for testing epistatic interactions between single-nucleotide polymorphisms (SNPs) does not provide the flexibility to compare the available model parameterizations. For that reason we have developed an R package for investigating epistatic and penetrance models, EpiPen, to aid users who wish to easily compare, interpret, and utilize models for two-locus epistatic interactions. EpiPen facilitates research on SNP-SNP interactions by allowing the R user to easily convert between common parametric forms for two-locus interactions, generate data for simulation studies, and perform power analyses for the selected model with a continuous or dichotomous phenotype. The usefulness of the package for model interpretation and power analysis is illustrated using data on rheumatoid arthritis.

Download Full-text

Genetic Screens for Factors Involved in the Notum Bristle Loss of Interspecific Hybrids Between Drosophila melanogaster and D. simulans

Genetics ◽

10.1093/genetics/156.1.269 ◽

2000 ◽

Vol 156 (1) ◽

pp. 269-282

Author(s):

Toshiyuki Takano-Shimizu

Keyword(s):

Drosophila Melanogaster ◽

Interspecific Cross ◽

Species Variation ◽

Genetic Screens ◽

Pure Species ◽

Epistatic Interactions ◽

X Chromosomes ◽

Powerful Means ◽

Different Populations ◽

Deficiency Screening

Abstract Interspecific cross is a powerful means to uncover hidden within- and between-species variation in populations. One example is a bristle loss phenotype of hybrids between Drosophila melanogaster and D. simulans, although both the pure species have exactly the same pattern of bristle formation on the notum. There exists a large amount of genetic variability in the simulans populations with respect to the number of missing bristles in hybrids, and the variation is largely attributable to simulans X chromosomes. Using nine molecular markers, I screened the simulans X chromosome for genetic factors that were responsible for the differences between a pair of simulans lines with high (H) and low (L) missing bristle numbers. Together with duplication-rescue experiments, a single major quantitative locus was mapped to a 13F–14F region. Importantly, this region accounted for most of the differences between H and L lines in three other independent pairs, suggesting segregation of H and L alleles at the single locus in different populations. Moreover, a deficiency screening uncovered several regions with factors that potentially cause the hybrid bristle loss due to epistatic interactions with the other factors.

Download Full-text

Hidden Effects of X Chromosome Introgressions on Spermatogenesis in Drosophila simulans × D. mauritiana Hybrids Unveiled by Interactions Among Minor Genetic Factors

Genetics ◽

10.1093/genetics/150.2.745 ◽

1998 ◽

Vol 150 (2) ◽

pp. 745-754 ◽

Cited By ~ 3

Author(s):

Xulio R Maside ◽

José P Barral ◽

Horacio F Naveira

Keyword(s):

Male Sterility ◽

X Chromosome ◽

Seminal Vesicles ◽

Genetic Dissection ◽

Research Strategies ◽

Hybrid Male ◽

Hybrid Male Sterility ◽

Epistatic Interactions ◽

Drosophila Mauritiana ◽

Chromosome Segments

Abstract One of the most frequent outcomes of interspecific hybridizations in Drosophila is hybrid male sterility. Genetic dissection of this reproductive barrier has revealed that the number of responsible factors is very high and that these factors are frequently engaged in complex epistatic interactions. Traditionally, research strategies have been based on contrasting introgressions of chromosome segments that produce male sterility with those that allow fertility. Few studies have investigated the phenotypes associated with the boundary between fertility and sterility. In this study, we cointrogressed three different X chromosome segments from Drosophila mauritiana into D. simulans. Hybrid males with these three segments are usually fertile, by conventional fertility assays. However, their spermatogenesis shows a significant slowdown, most manifest at lower temperatures. Each of the three introgressed segments retards the arrival of sperm to the seminal vesicles. Other small disturbances in spermatogenesis are evident, which altogether lead to an overall reduction in the amount of motile sperm in their seminal vesicles. These results suggest that a delay in the timing of spermatogenesis, which might be brought about by the cumulative action of many different factors of minor segment, may be the primary cause of hybrid male sterility.

Download Full-text

Genome‐wide interaction study reveals epistatic interactions for beef lipid‐related traits in Nellore cattle

Animal Genetics ◽

10.1111/age.13124 ◽

2021 ◽

Author(s):

S. T. Amorim ◽

N. B. Stafuzza ◽

S. Kluska ◽

E. Peripolli ◽

A. S. C. Pereira ◽

...

Keyword(s):

Interaction Study ◽

Epistatic Interactions ◽

Genome Wide ◽

Nellore Cattle

Download Full-text

The Genetic Basis of the Interspecific Differences in Wing Size in Nasonia (Hymenoptera; Pteromalidae): Major Quantitative Trait Loci and Epistasis

Genetics ◽

10.1093/genetics/161.2.673 ◽

2002 ◽

Vol 161 (2) ◽

pp. 673-684

Author(s):

J Gadau ◽

R E Page ◽

J H Werren

Keyword(s):

Quantitative Trait Loci ◽

Qtl Analysis ◽

Quantitative Trait ◽

Wing Length ◽

Size Difference ◽

Phenotypic Variance ◽

Wing Size ◽

Epistatic Interactions ◽

Trait Loci ◽

Wing Width

Abstract There is a 2.5-fold difference in male wing size between two haplodiploid insect species, Nasonia vitripennis and N. giraulti. The haploidy of males facilitated a full genomic screen for quantitative trait loci (QTL) affecting wing size and the detection of epistatic interactions. A QTL analysis of the interspecific wing-size difference revealed QTL with major effects and epistatic interactions among loci affecting the trait. We analyzed 178 hybrid males and initially found two major QTL for wing length, one for wing width, three for a normalized wing-size variable, and five for wing seta density. One QTL for wing width explains 38.1% of the phenotypic variance, and the same QTL explains 22% of the phenotypic variance in normalized wing size. This corresponds to a region previously introgressed from N. giraulti into N. vitripennis that accounts for 44% of the normalized wing-size difference between the species. Significant epistatic interactions were also found that affect wing size and density of setae on the wing. Screening for pairwise epistatic interactions between loci on different linkage groups revealed four additional loci for wing length and four loci for normalized wing size that were not detected in the original QTL analysis. We propose that the evolution of smaller wings in N. vitripennis males is primarily the result of major mutations at few genomic regions and involves epistatic interactions among some loci.

Download Full-text

Effects of intra-gene fitness interactions on the benefit of sexual recombination

Biochemical Society Transactions ◽

10.1042/bst0340560 ◽

2006 ◽

Vol 34 (4) ◽

pp. 560-561 ◽

Cited By ~ 6

Author(s):

R.A. Watson ◽

D.M. Weinreich ◽

J. Wakeley

Keyword(s):

Nucleotide Sequence ◽

Point Mutation ◽

Sequence Space ◽

Fitness Effect ◽

Epistatic Interactions ◽

Genetic Sequence ◽

High Fitness ◽

Sexual Recombination ◽

Evolutionary Trajectories ◽

Asexual Populations

Whereas spontaneous point mutation operates on nucleotides individually, sexual recombination manipulates the set of nucleotides within an allele as an essentially particulate unit. In principle, these two different scales of variation enable selection to follow fitness gradients in two different spaces: in nucleotide sequence space and allele sequence space respectively. Epistasis for fitness at these two scales, between nucleotides and between genes, may be qualitatively different and may significantly influence the advantage of mutation-based and recombination-based evolutionary trajectories respectively. We examine scenarios where the genetic sequence within a gene strongly influences the fitness effect of a mutation in that gene, whereas epistatic interactions between sites in different genes are weak or absent. We find that, in cases where beneficial alleles of a gene differ from one another at several nucleotide sites, sexual populations can exhibit enormous benefit compared with asexual populations: not only discovering fit genotypes faster than asexual populations, but also discovering high-fitness genotypes that are effectively not evolvable in asexual populations.

Download Full-text