What genes are good candidates for alternative animal modeling?
I set out to determine which important disease genes are good candidates for creating animal models in C. elegans. The first step was to turn to a database that has a comprehensive listing of human genes and their disease association. The DisGeNet database has nearly every human gene annotated for its level of disease association (17,549 genes as of June 2019). They provide a curated list that has 8400 genes with Gene-Disease Association (GDA) score of 0.1 or higher. For the top 1000 genes the GDA scores are 0.69 or higher, which indicates they scored high for having a significant disease association. These top 1000 were selected for examination of their ortholog status in C. elegans using the Diopt database. 749 othologies were detected, of which 411 had clear reciprocal nature (back-blast gives starting gene for the ortholog as best hit). The top 100 of these genes for high homology and detectable loss-of-function consequence were selected.
Tabulation of disease-associated genes with properties favorable for C. elegans humanization
The top 100 are tabulated in gene-alphabetical format below. These 100 genes have 8360 variants as known to be as problematic (Path, Likely Path, or VUS).
Use a search tool to quickly find out if your favorite gene occurs below.
(Note: gene knock out for 58% of these genes results in lethality.)
| Human gene | Disease association | Nematode gene (LOF) | Problem variants |
| ABCB1 | Colchicine resistance; Inflammatory bowel disease | pgp-9 (development) | 3 |
| ABCB6 | Dyschromatosis universalis hereditaria; Microphthalmia; Pseudohyperkalemia | hmt-1 (development) | 11 |
| ABCC1 | Peripheral Neuropathy | mrp-1 (development) | 38 |
| ACTG1 | Baraitser-Winter syndrome 2; Deafness, autosomal dominant 20/26 | act-4 (lethal) | 57 |
| ADA | Adenosine deaminase deficiency; Severe combined immunodeficiency | C06G3.5 (development) | 81 |
| ADAM10 | Reticulate acropigmentation of Kitamura; Alzheimer disease | sup-17 (lethal) | 5 |
| AGO2 | Alcoholic Intoxication, Chronic | alg-1 (lethal) | 1 |
| AHR | Retinitis pigmentosa; Malignant neoplasm | ahr-1 (development) | 2 |
| ALDH2 | Alcoholic Intoxication, Chronic | alh-1 (lethal) | 3 |
| APEX1 | Malignant neoplasm | exo-3 (development) | 2 |
| ATG5 | Spinocerebellar ataxia | atg-5 (morphology) | 2 |
| BMS1 | Aplasia cutis congenita | Y61A9LA.10 (lethal) | 1 |
| CALR | schizoaffective disorder | crt-1 (lethal) | 1 |
| CAT | type 2 diabetes mellitus | ctl-1 (development) | 2 |
| CDC42 | Takenouchi-Kosaki syndrome | cdc-42 (lethal) | 10 |
| CHEK1 | Malignant neoplasm | chk-1 (lethal) | 3 |
| CIB2 | Deafness, autosomal recessive; Usher syndrome | calm-1 (morphology) | 11 |
| CTSB | Keratolytic winter erythema | F57F5.1 (lethal) | 0 |
| CTSD | Ceroid lipofuscinosis, neuronal, 10 | asp-4 (morphology) | 103 |
| DECR1 | Schizophrenia | F53C11.3 (morphology) | 1 |
| EIF4E | Autism | ife-3 (lethal) | 0 |
| ENO1 | Enolase deficiency | enol-1 (lethal) | 0 |
| EPHX1 | Hypercholanemia; Malignant neoplasm; | W01A11.1 (development) | 3 |
| ERCC1 | Cerebrooculofacioskeletal syndrome | ercc-1 (lethal) | 17 |
| ERCC2 | Cerebrooculofacioskeletal syndrome 2; Trichothiodystrophy 1, photosensitive; Xeroderma pigmentosum, group D | xpd-1 (lethal) | 72 |
| ERCC3 | Trichothiodystrophy 2, photosensitive; Xeroderma pigmentosum, group B | xpb-1 (lethal) | 33 |
| FASN | Obesity disease | fasn-1 (lethal) | 83 |
| FH | Fumarase deficiency; Leiomyomatosis and renal cell cancer | fum-1 (lethal) | 1830 |
| G6PD | Hemolytic anemia, G6PD deficient (favism); Resistance to malaria due to G6PD deficiency | gspd-1 (lethal) | 91 |
| GAD1 | Cerebral palsy, spastic quadriplegic, 1 | unc-25 (movement) | 35 |
| GAPDH | hepatocellular carcinoma | gpd-2 (lethal) | 0 |
| GCH1 | Dystonia, DOPA-responsive, with or without hyperphenylalaninemia; Hyperphenylalaninemia, BH4-deficient, B | cat-4 (movement) | 76 |
| GGT1 | Glutathioninuria; chronic hepatitis B | H14N18.4 (development) | 1 |
| GNA12 | ulcerative colitis | gpa-12 (lethal) | 2 |
| GPI | Hemolytic anemia, nonspherocytic, due to glucose phosphate isomerase deficiency | gpi-1 (development) | 11 |
| GPT | non-alcoholic fatty liver disease | C32F10.8 (lethal) | 46 |
| GSK3B | bipolar disorder | gsk-3 (lethal) | 0 |
| GSR | Hemolytic anemia due to glutathione reductase deficiency | gsr-1 (lethal) | 0 |
| HCCS | Microphthalmos | cchl-1 (lethal) | 8 |
| HDAC2 | chronic obstructive Airway Disease | hda-1 (lethal) | 1 |
| HPRT1 | HPRT-related gout; Lesch-Nyhan syndrome | hprt-1 (morphology) | 55 |
| HRAS | Bladder cancer, somatic; Congenital myopathy with excess of muscle spindles; Costello syndrome; Nevus sebaceous or woolly hair nevus, somatic; Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic; Spitz nevus or nevus spilus, somatic; Thyroid carcinoma, follicular, somatic | let-60 (lethal) | 81 |
| HSP90AA1 | Breast Cancer | hsp-90 (lethal) | 0 |
| HSPA4 | bipolar disorder | hsp-110 (lethal) | 0 |
| HSPA5 | hepatocellular carcinoma | hsp-3 (lethal) | 0 |
| HSPA9 | Anemia, sideroblastic, 4; Even-plus syndrome | hsp-6 (lethal) | 6 |
| HSPD1 | Leukodystrophy, hypomyelinating, 4; Spastic paraplegia 13, autosomal dominant | hsp-60 (lethal) | 35 |
| IDH1 | Glioma, susceptibility to, somatic | idh-1 (development) | 3 |
| ILK | cardiomyopathy | pat-4 (lethal) | 33 |
| ISYNA1 | Malignant neoplasm | inos-1 (development) | 0 |
| ITPR1 | Gillespie syndrome; Spinocerebellar ataxia | itr-1 (lethal) | 139 |
| MAP2K1 | Cardiofaciocutaneous syndrome 3 | mek-2 (lethal) | 93 |
| MAP2K7 | Malignant neoplasm | mek-1 (development) | 2 |
| MAPK1 | gastric carcinogenesis | mpk-1 (lethal) | 2 |
| MAPK14 | schizophrenia | pmk-1 (lethal) | 1 |
| MFN2 | Charcot-Marie-Tooth disease; Hereditary motor and sensory neuropathy | fzo-1 (development) | 202 |
| MRE11 | Ataxia-telangiectasia-like disorder | mre-11 (development) | 515 |
| MSH2 | Colorectal cancer; Mismatch repair cancer syndrome; Muir-Torre syndrome | msh-2 (development) | 1905 |
| MTHFR | Homocystinuria; Neural tube defects; Schizophrenia; Thromboembolism; Vascular disease | mthf-1 (development) | 212 |
| MTOR | Focal cortical dysplasia; Smith-Kingsmore syndrome | let-363 (lethal) | 65 |
| MTR | Homocystinuria-megaloblastic anemia, cblG complementation type; Neural tube defects, folate-sensitive, susceptibility to | metr-1 (development) | 200 |
| NME1 | Neuroblastoma | ndk-1 (lethal) | 144 |
| NT5C2 | Spastic paraplegia | Y71H10B.1 (lethal) | 14 |
| ODC1 | Colonic adenoma recurrence | odc-1 (fecundity) | 5 |
| P4HB | Cole-Carpenter syndrome 1 | pdi-2 (lethal) | 2 |
| PC | Pyruvate carboxylase deficiency | pyc-1 (development) | 329 |
| PCNA | Ataxia-telangiectasia-like disorder 2 | pcn-1 (lethal) | 1 |
| PCYT1A | Spondylometaphyseal dysplasia | pcyt-1 (development) | 15 |
| PEPD | Prolidase deficiency | K12C11.1 (lethal) | 60 |
| PGK1 | Phosphoglycerate kinase 1 deficiency | pgk-1 (development) | 28 |
| PHGDH | Neu-Laxova syndrome; Phosphoglycerate dehydrogenase deficiency | C31C9.2 (development) | 42 |
| PLK1 | Neoplasms | plk-1 (lethal) | 0 |
| PNP | Immunodeficiency | K02D7.1 (movement) | 46 |
| PNPLA2 | Neutral lipid storage disease with myopathy | atgl-1 (lethal) | 66 |
| PPP3CA | Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development; Epileptic encephalopathy, infantile or early childhood, 1 | tax-6 (movement) | 8 |
| PSEN1 | Acne inversa; Alzheimer disease; Cardiomyopathy, dilated; Dementia, frontotempora; Pick disease | sel-12 (development) | 134 |
| PTDSS1 | Lenz-Majewski hyperostotic dwarfism | pssy-1 (morphology) | 6 |
| RAD51 | Fanconi anemia, complementation group R; Mirror movements 2; Breast cancer, susceptibility to | rad-51 (lethal) | 11 |
| RAP1A | Kabuki syndrome | rap-1 (lethal) | 0 |
| RPS19 | Diamond-Blackfan anemia 1 | rps-19 (lethal) | 37 |
| SDHB | Gastrointestinal stromal tumor; Paraganglioma and gastric stromal sarcoma; Paragangliomas 4; Pheochromocytoma | sdhb-1 (lethal) | 276 |
| SDHC | Gastrointestinal stromal tumor; Paragangliomas | mev-1 (lethal) | 134 |
| SDHD | Mitochondrial complex II deficiency; Paragangliomas; Pheochromocytoma | sdhd-1 (development) | 146 |
| SFRP1 | Narcolepsy | sfrp-1 (morphology) | 1 |
| SLC6A2 | Orthostatic intolerance | dat-1 (movement) | 50 |
| SMARCA1 | brain malformation | isw-1 (lethal) | 1 |
| SMARCA2 | Nicolaides-Baraitser syndrome | swsn-4 (lethal) | 90 |
| SMARCB1 | Coffin-Siris syndrome; Rhabdoid tumors; Schwannomatosis | snfc-5 (lethal) | 93 |
| SMC1A | Cornelia de Lange syndrom3 | him-1 (lethal) | 110 |
| SMC3 | Cornelia de Lange syndrome | smc-3 (lethal) | 75 |
| SOD1 | Amyotrophic lateral sclerosis 1 | sod-1 (development) | 43 |
| SOD2 | Cardiomyopathy, Dilated | sod-3 (development) | 2 |
| TAT | Tyrosinemia | tatn-1 (lethal) | 59 |
| TBP | Spinocerebellar ataxia; Parkinson disease | tbp-1 (lethal) | 3 |
| TIMM8A | Mohr-Tranebjaerg syndrome | ddp-1 (development) | 19 |
| TYMS | Colorectal Carcinoma | tyms-1 (lethal) | 2 |
| USO1 | Malignant neoplasm | uso-1 (morphology) | 0 |
| VCP | Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia; Charcot-Marie-Tooth disease, type 2Y; Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1 | cdc-48.2 (lethal) | 77 |
| WLS | Bone density | mig-14 (lethal) | 31 |
| XPR1 | Basal ganglia calcification | Y39A1A.22 (development) | 5 |