Problems when inferring human gene-phenotype associations from model organism by sequence orthology

[liulizhi1996]

Model organisms, especially the laboratory mouse Mus musculus, provide useful knowledge about human diseases. I am studying human gene-HPO term annotations and want to utilize phenotype annotations of animal models to improve the prediction of HPO annotations of human genes.

However, I find a strange problem. Taking keratoconjunctivitis sicca as an example, the associated human genes and mouse genes are largely different:

• HP:0001097 There are 41 related human genes, such as AEBP1, B2M, BTNL2, etc. https://rgd.mcw.edu/rgdweb/ontology/annot.html?acc_id=HP:0001097&species=Human#annot

• MP:0013466 There are only 3 mouse genes associated with keratoconjunctivitis sicca, i.e. Chd7, Ctnnb1, and Nrtn. https://rgd.mcw.edu/rgdweb/ontology/annot.html?acc_id=MP:0013466&species=Mouse#annot

If I map these mouse genes to their orthologous human genes, the intersection of two gene sets is empty. Why are the genes related to the same phenotype so different between human and model organism? Is there something wrong here?

Moreover, I check the related human and mouse genes to DOID:12895 (keratoconjunctivitis sicca), they are

• Human: CCL20, CCR5, IL6, MUC4, MUC5AC, NRTN, TNF https://rgd.mcw.edu/rgdweb/ontology/annot.html?acc_id=DOID:12895&species=Human#annot

• Mouse: Ccl20, Ccr5, Il6, Muc4, Muc5ac, Nrtn, Tnf https://rgd.mcw.edu/rgdweb/ontology/annot.html?acc_id=DOID:12895&species=Mouse#annot

Some genes here are inferred from sequence orthology by RGD. But it is strange that the annotated genes here are quite different from those in HP/MP annotations. Why are the genes associated with the same phenotype so different? Is it feasible/reliable to infer gene-phenotype associations from sequence orthology like what RGD does here?

[matentzn]

Thank you @liulizhi1996 for making the ticket. We will discuss it in the context of mapping-commons/mh_mapping_initiative#9, so I will close it here.