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A linkage disequilibrium-based statistical test for Genome-Wide Epistatic Selection Scans in structured populations

Abstract

The quest for signatures of selection using single nucleotide polymorphism (SNP) data has proven efficient to uncover genes involved in conserved and/or adaptive molecular functions, but none of the statistical methods were designed to identify interacting alleles as targets of selective processes. Here, we propose a statistical test aimed at detecting epistatic selection, based on a linkage disequilibrium (LD) measure accounting for population structure and heterogeneous relatedness between individuals. SNP-based (\(T_{r_v}\)) and window-based (\(T_{corPC1_v}\)) statistics fit a Student distribution, allowing to test the significance of correlation coefficients. As a proof of concept, we use SNP data from the Medicago truncatula symbiotic legume plant and uncover a previously unknown gene coadaptation between the MtSUNN (Super Numeric Nodule) receptor and the MtCLE02 (CLAVATA3-Like) signaling peptide. We also provide experimental evidence supporting a MtSUNN-dependent negative role of MtCLE02 in symbiotic root nodulation. Using human HGDP-CEPH SNP data, our new statistical test uncovers strong LD between SLC24A5 (skin pigmentation) and EDAR (hairs, teeth, sweat glands development) world-wide, which persists after correction for population structure and relatedness in Central South Asian populations. This result suggests that epistatic selection or coselection could have contributed to the phenotypic make-up in some human populations. Applying this approach to genome-wide SNP data will facilitate the identification of coadapted gene networks in model or non-model organisms.

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Fig. 1: Evolution of inter-locus epistatic selection detected with linkage disequilibrium on simulated data.
Fig. 2: Detection power of epistatic selection models for SNP-based and window-based LD measures.
Fig. 3: LD distribution between the bait gene MtSUNN and all genes of M. truncatula genome.
Fig. 4: Experimental validation of the CLE02 signaling peptide/SUNN receptor genetic relationship in M. truncatula symbiotic nodulation.
Fig. 5: LD distribution between the bait SNPs of SLC24A5 and EDAR genes and all other HGDP-CEPH SNPs in the whole human population samples (n = 952).
Fig. 6: Schematic human population structure inferred from the kinship matrix, the geographic distribution of alleles, and the LD between SLC24A5 and EDAR.

Data availability

The M. truncatula SNP dataset (hapmap format) used in this study can be retrieved at http://www.medicagohapmap.org/downloads/mt40. The Human SNP dataset from the HGDP-CEPH Human Genome Diversity Panel can be retrieved at ftp://ftp.cephb.fr/hgdp_supp1 (http://www.cephb.fr/hgdp/). R scripts to implement the statistical test based on Tr, \(T_{r_v}\), TcorPC1, or \(T_{corPC1_v}\), along with an example dataset, are available at https://github.com/leaboyrie/LD_corpc1.

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Acknowledgements

This work was supported by the “DeCoD” project funded by the French Agence Nationale de la Recherche (grant number ANR-16-CE20-0017-01). The PhD position of LB was funded by the “DeCoD” project. We thank the bioinformatics platform Toulouse Midi-Pyrenees (Genotoul). This work was performed in the LRSV (Toulouse, France), part of the “Laboratoire d’Excellence” (LABEX) entitled TULIP (grant number ANR-10-LABX-41). We thank Carole Laffont (IPS2, CNRS, Gif-sur-Yvette, France) for providing results about MtCLE13 expression. Work in the Florian Frugier laboratory has benefited from a French State grant (Saclay Plant Sciences, grant number ANR-17-EUR-0007, EUR SPS-GSR) and an ANR grant (“PSYCHE”, grant number ANR-16-CE20-0009-01). We thank Thomas Bataillon, two other anonymous reviewers, and Pierre-Marc Delaux for useful criticisms and comments to improve the manuscript.

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Boyrie, L., Moreau, C., Frugier, F. et al. A linkage disequilibrium-based statistical test for Genome-Wide Epistatic Selection Scans in structured populations. Heredity 126, 77–91 (2021). https://doi.org/10.1038/s41437-020-0349-1

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