Muons penetrate much further than X-rays, they do essentially zero damage, and they are provided for free by the cosmos.
Image credit: Science Source/Digital Globe.
Article Figures & SI
Figures
- Fig. 1.
Number of unique gene-phenotype associations, identification of phenologs, and the example of a worm model of breast cancer. (A) The rate of associating genes to organism-level phenotypes in model organisms greatly exceeds that in humans (data from refs. 8–11, 14). Thus, appropriate mapping of model organism phenotypes to human diseases could significantly accelerate discovery of human disease gene associations. Orthologous phenotypes (phenologs) offer one such approach. (B) Phenologs can be identified based on significantly overlapping sets of orthologous genes (gene A is orthologous to A', B to B', etc.), such that each gene in a given set (green box or cyan box) gives rise to the same phenotype in that organism. The phenotypes may differ in appearance between organisms because of differing organismal contexts. As gene-phenotype associations are often incompletely mapped, genes currently linked to only one of the orthologous phenotypes become candidate genes for the other phenotype; that is, the gene A' is a new candidate for phenotype 2. (C) An example of a phenolog mapping high incidence of male C. elegans progeny to human breast/ovarian cancers (details in text).
- Fig. 2.
Systematic identification of phenologs. (A) For a pair of organisms, sets of genes known to be associated with mutational phenotypes are assembled, considering only orthologous genes between the two organisms. Pairs of mutational phenotypes—one phenotype from each organism, each associated with a set of genes—are then compared to determine the extent of overlap of the associated gene sets, calculating the significance of overlap by the hypergeo-metric probability. Comparison of the distribution of observed probabilities with those derived from the same analysis following permutation of gene-phenotype associations reveals that many more orthologous phenotypes are observed than expected by random chance, as shown in B for the case of the human-yeast comparison (also Fig. S1), and summarized for each organism pair in C.
- Fig. 3.
Example of a nonobvious disease model revealed by phenologs: a yeast model of angiogenesis. (A) The sets of 8 genes (considering only mouse/yeast orthologs) associated with mouse angiogenesis defects and 67 genes associated with yeast hypersensitivity to the hypercholesterolemia drug lovastatin significantly overlap, suggesting that the yeast gene set may predict angiogenesis genes. This prediction was verified in Xenopus embryos for eight genes (three from literature support and five based upon vascular expression patterns) (Fig. S3) and studied in detail for the case of the transcription factor sox13. (B) sox13 is expressed in developing Xenopus vasculature, as measured by in situ hybridization (also Fig. S4). (C) Morpholino (MO) knockdown of sox13 induces defects in vasculature, measured using in situ hybridization versus the vasculature markers erg (defects observed in 31 of 49 animals tested) or agtrl1 (12 of 19 animals tested) (Fig S5). Such defects are rare in untreated control animals and five base pair mismatch morpholino (MM) knockdowns (0 of 22 control animals tested with agtrl1, 2 of 46 tested with erg; 5 of 28 MM animals tested with erg). (D) Hemorrhaging (white arrows) is apparent in stage 45 Xenopus embryos because of dysfunctional vasculature following sox13 morpholino knockdown (12 of 50 animals tested; two also showed unusually small hearts with defective morphology; Right: magnification of yellow boxed region in Middle), but is rare in control animals (1 of 45 tested untreated animals, 1 of 22 sox13-MM knockdown animals tested). All phenotypes in Figs. 3 and 4 are significantly different from controls by χ2 tests (P < 0.001). (E) In an in vitro human umbilical vein endothelial cell model of angiogenesis, knockdown of human SOX13 by siRNA disrupts tube formation (an in vitro model for capillary formation) to an extent comparable to knockdown of a known effector of angiogenesis (HOXA9) and significantly more than untreated cells or cells transfected with an off-target (scrambled) negative control siRNA. (Scale bar, 100 μm.)
- Fig. 4.
Phenologs reveal plant models of human disease, including a model of Waardenburg syndrome (WS) neural crest defects. (A) Many orthologous phenotypes are observed between Arabidopsis and worms, yeast, mouse, and humans, with hundreds more than expected by chance. Many mammalian/plant phenologs relate to vertebrate developmental defects, including models for WS and other birth defects. (B) Considering only human/Arabidopsis orthologs, the three known WS genes significantly overlap the five genes associated with negative gravitropism defects in Arabidopsis. The plant gene set suggests unique candidate WS genes. (C) In situ hybridization versus candidate sec23ip in developing Xenopus embyros confirms neural crest cell expression. (D) Unilateral morpholino knockdown of sec23ip induces (E) defects in neural crest cell migration on the side with the knockdown (E'') but not the control side (E'), measured using in situ hybridization versus two independent markers of neural crest cells, snai2-a (defects observed in 23 of 35 animals tested) and twist (8 of 14 animals tested) (Fig S7). Such defects are rare in untreated control animals and off-target morpholino (OM) knockdowns (0 of 21 control animals tested with snai2-a; 1 of 14 OM animals tested with snai2-a; 0 of 14 OM animals tested with twist).
Tables
- Table 1.
Examples from the >6,200 significant phenologs detected among human diseases and mouse, yeast, worm, and Arabidopsis mutant phenotypes
Phenotype1 Phenotype2 n1 n2 k P value PPV Hs Cataracts Mm Cataracts 19 47 11 6 × 10−24 1.00 Hs X-linked conductive deafness Mm Circling 47 50 12 2 × 10−20 1.00 Hs Bardet-Biedl syndrome Mm Absent sperm flagella 11 5 4 8 × 10−13 1.00 Mm Lymphoma Sc CANR mutator high 14 11 6 1 × 10−11 1.00 Hs Zellweger syndrome Sc Reduced number of peroxisomes 8 6 4 1 × 10−9 1.00 Hs Susceptible to autism Mm Abnormal social investigation 5 16 3 1 × 10−8 1.00 Mm Abnormal heart development At Defective response to red light 25 9 4 3 × 10−7 1.00 Hs Refsum disease At Defective protein import into peroxisomal matrix 4 5 2 1 × 10−5 1.00 Mm Absent posterior semicircular canal At Shade avoidance defect 2 4 2 1 × 10−6 0.99 Mm Spleen hypoplasia Sc Uge (enlarged cells) 5 16 3 3 × 10−6 0.99 Mm Gastrointestinal hemorrhage Ce Abnormal body wall muscle cell polarization 6 3 2 4 × 10−6 0.98 Hs Mental retardation At Cotyledon development defects 13 5 2 1 × 10−4 0.98 Hs Congenital disorder of glycosylation Sc CID 604586 sensitive 10 25 3 2 × 10−4 0.98 Hs Hemolytic anemia Sc Hydroxyurea sensitive 11 23 3 2 × 10−4 0.98 Hs Amyotrophic lateral sclerosis Sc Increased resistance to wortmannin 2 34 2 2 × 10−4 0.97 n1 indicates the number of orthologs in organism 1 with phenotype1, n2 the number in organism 2 with phenotype2, and k the number in both sets. The significance of each phenolog is assessed by the hypergeometric probability (P value), the positive predictive value (PPV) when considering multiple testing (1 – FDR), and the reciprocal best-hit criterion (bold text). At, Arabidopsis; Ce, worm; Hs, human; Mm, mouse; Sc, yeast.
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Systematic discovery of nonobvious human disease models through orthologous phenotypes
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