Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Feb;8(2):e1002463.
doi: 10.1371/journal.pgen.1002463. Epub 2012 Feb 9.

Systematic detection of epistatic interactions based on allele pair frequencies

Marit Ackermann  1 , Andreas Beyer
Affiliations

Systematic detection of epistatic interactions based on allele pair frequencies

Marit Ackermann et al. PLoS Genet. 2012 Feb.

Abstract

Epistatic genetic interactions are key for understanding the genetic contribution to complex traits. Epistasis is always defined with respect to some trait such as growth rate or fitness. Whereas most existing epistasis screens explicitly test for a trait, it is also possible to implicitly test for fitness traits by searching for the over- or under-representation of allele pairs in a given population. Such analysis of imbalanced allele pair frequencies of distant loci has not been exploited yet on a genome-wide scale, mostly due to statistical difficulties such as the multiple testing problem. We propose a new approach called Imbalanced Allele Pair frequencies (ImAP) for inferring epistatic interactions that is exclusively based on DNA sequence information. Our approach is based on genome-wide SNP data sampled from a population with known family structure. We make use of genotype information of parent-child trios and inspect 3×3 contingency tables for detecting pairs of alleles from different genomic positions that are over- or under-represented in the population. We also developed a simulation setup which mimics the pedigree structure by simultaneously assuming independence of the markers. When applied to mouse SNP data, our method detected 168 imbalanced allele pairs, which is substantially more than in simulations assuming no interactions. We could validate a significant number of the interactions with external data, and we found that interacting loci are enriched for genes involved in developmental processes.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Schematic overview of the test procedure.
Panel A shows the calculation of the test statistic, panel B depicts the calculation of the p-values. Family information is used for both parts.
Figure 2
Figure 2. Genome-wide map of allele incompatibilities.
The heatmap shows the negative formula image p-values of each LD block combination on different chromosomes. Light red spots show putatively interacting loci. Inset shows an enlargement of chromosome formula image versus chromosome formula image.
Figure 3
Figure 3. Number of interactions per autosome pair.
Results are based on the formula image significant LD block pairs involving formula image loci. The barplot on the right shows the average number of interactions per LD block for each chromosome. Chromosomes formula image, formula image, and formula image show the highest participation in interactions while the fewest interactions per LD block are on chromosome formula image.
Figure 4
Figure 4. ImAP p-value distribution.
Distribution of the p-values of the original data (black) and five simulations under the null hypothesis of no allelic incompatibilities (grey). The y-axis is concentrated on the interesting area of high density. The inset shows a zoom on the small p-values in formula image scale.
Figure 5
Figure 5. Correlated interaction profiles.
(A) Schematic showing relationship between epistatic interactions and molecular pathways. The genes x and y share three allele incompatibilities with genes from a parallel pathway. In the schematic interaction matrix on the right these shared interactions lead to correlated interaction profiles (rows are correlated; dashed line). (B) Example of two loci on chromosomes formula image and formula image sharing a common interacting locus on chromosome formula image. The position of the loci on the chromosomes is indicated by red bars. The putatively causal genes are written below the loci. Arrows indicate interactions with ImAP p-values formula image, the dashed line indicates a high congruence score (formula image).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Cordell HJ. Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans. Human molecular genetics. 2002;11:2463. - PubMed
    1. Kelley R, Ideker T. Systematic interpretation of genetic interactions using protein networks. Nature Biotechnology. 2005;23:561–566. - PMC - PubMed
    1. Beyer A, Bandyopadhyay S, Ideker T. Integrating physical and genetic maps: from genomes to interaction networks. Nature Reviews Genetics. 2007;8:699–710. - PMC - PubMed
    1. Hoh J, Ott J. Mathematical multi-locus approaches to localizing complex human trait genes. Nature Reviews Genetics. 2003;4:701–709. - PubMed
    1. Marchini J, Donnelly P, Cardon LR. Genome-wide strategies for detecting multiple loci that inuence complex diseases. Nature Genetics. 2005;37:413–417. - PubMed

Publication types