A genome-wide map of human genetic interactions inferred from radiation hybrid genotypes

Abstract

Using radiation hybrid genotyping data, 99% of all possible gene pairs across the mammalian genome were tested for interactions based on co-retention frequencies higher (attraction) or lower (repulsion) than chance. Gene interaction networks constructed from six independent data sets overlapped strongly. Combining the data sets resulted in a network of more than seven million interactions, almost all attractive. This network overlapped with protein-protein interaction networks on multiple measures and also confirmed the relationship between essentiality and centrality. In contrast to other biological networks, the radiation hybrid network did not show a scale-free distribution of connectivity but was Gaussian-like, suggesting a closer approach to saturation. The radiation hybrid (RH) network constitutes a platform for understanding the systems biology of the mammalian cell.

Figure 1.

Interaction type and workflow. (A) Attractive interaction. Extra copies of gene A and gene B in the same clone promote survival. (B) Repulsive interaction. Extra copies of A and B in the same clone hinder survival effects. (C) Workflow. Tasks, red squares; externally generated data sets, blue circles; and internally generated data sets, green circles.

Figure 2.

Exclusion and inclusion in G3 data set of candidate interactions. (A) Excluded candidate interaction one marker wide. (Upper panel) Marker 11787 located on chromosome 11 is coretained with a single marker on chromosome 17, marker 15564 (red arrow). (Lower panel) Marker 15564 is coretained with markers on chromosome 11 between 74 Mb and 80 Mb, including marker 11787 (blue arrow). (B) Plot of −log₁₀P for excluded candidate shown in A. Ten markers on each side of markers 11787 and 15564 are displayed. (C) Included interaction. (Upper panel) Marker 3086 on chromosome 2 is co-retained with markers on chromosome 11 between 124 Mb and 128 Mb, including peak marker 12114 (red arrow). (Lower panel) Marker 12114 on chromosome 11 is co-retained with markers on chromosome 2 between 238 Mb and 243 Mb, including peak marker 3086 (blue arrow). (D) Plot of −log₁₀P for interaction shown in (C). Ten markers on each side of markers 3086 and 12114 are displayed.

Figure 3.

Fully combined RH network. (A) Co-retention between marker at 130,440,601 bp (blue arrow) on chromosome 2 and markers on chromosome 6 (left). Co-retention between marker at 57,433,004 bp (red arrow) on chromosome 6 and markers on chromosome 2 (right). (B) Gene–gene interactions at FDR <10⁻⁸. (C) Number of edges per gene (degree) for fully combined network at FDR <5%. Horizontal lines show hotspots (red, FDR <40%; green, FDR <1%) assuming a Poisson distribution (Brem and Kruglyak 2005; Park et al. 2008).

Figure 4.

RH network interactions and overlap with Human Protein Reference Database (HPRD). (A) Number of interactions for combined panels. (B) Combined panel overlap with HPRD. (C) Adjusted −log₁₀P for combined panel overlap with HPRD. (D) Uncertainty and combined panel overlap with HPRD at FDR <5%. (E) Uncertainty and adjusted −log₁₀P for combined panel overlap with HPRD at FDR <5%. Data set abbreviations: M, mouse; R, rat; and D, dog.

Figure 5.

Network topology. (A) Subnetwork of gene COX1 (PTGS1) and all genes up to two edges away at FDR <10⁻⁶. (B) Subnetwork of gene MTOR (FRAP1) and all genes up to three edges away at FDR <10⁻⁸. (C) Degree distribution of fully combined RH network at FDR <5%. Number of degrees, k, and point probability of node with k degrees, P(k), plotted on log scales. (D) Degree distribution of HPRD network. (E) Degree distribution of fully combined RH network at FDR <10⁻⁸.