Jonathan E. Dickerson; Ana Zhu; David L. Robertson; Kathryn E. Hentges

“ From our study we can now present a composite profile of human disease gene types. We have found that DL and DV genes differ from each other in many of the characteristics we have analyzed. Overall, DL genes are more likely to be involved in more protein-protein interactions, encode nuclear proteins, be associated with diseases such as cancer and those affecting multiple systems, and have an autosomal dominant mode of inheritance. ”

“ Gene alleles with reduced function, called hypomorphic alleles, therefore can generate different phenotypes from those of null alleles. Although null or severe loss-of-function mutations in essential genes may indeed contribute to spontaneous miscarriages, hypomorphic mutations in the same genes can contribute to less severe abnormalities that are recognized as human disease. Therefore, the human orthologs of genes required for embryonic development in the mouse can cause disease in mutated forms through a variety of mechanisms. ”

“ This classification, however, over-estimates the size of the non-essential gene group, due to the inclusion of genes with no reported knockout data. As currently only approximately 9% of mouse genes have been knocked out (Dataset S1) , it is very likely that disease genes with no known mouse knockout phenotype would include both lethal and viable genes. Therefore, to include genes with no knockout data in the viable gene group confounds the analysis, and could lead to erroneous conclusions about the relative importance of lethal and viable genes in human disease. ”

“ While severe mutant alleles that eliminate protein function represent the null state and confer lethality, hypomorphic alleles simply reduce protein function below an optimal level, resulting in a phenotype recognized as disease. In this manner, lethal genes can have mutations that only reduce protein function and therefore present as disease in the human population, allowing for inheritance of these more mild alleles in genetic diseases. ”

“ We obtained the human–mouse orthology and mouse viable/lethal phenotype data from Mouse Genome Informatics (http://www.informatics.jax.org) [26] , to give 2,360 human genes with information about lethality status of the mouse knockout of their ortholog in the whole genome, without consideration of whether the gene is annotated as a human disease gene. ”

“ However, ubiquitous expression is not a comprehensive indicator of essentiality, and genes with housekeeping functions may not necessarily have lethal knockout phenotypes. Our work, thus, demonstrates that when essentiality, as inferred by mouse knockout phenotypes, is considered explicitly, disease genes themselves display differing characteristics based on their essentiality status. ”

“ It has been demonstrated that nuclear proteins have higher numbers of interaction partners in PPI networks [32] , which may explain the basis for the difference in connectivity between DL and DV genes.
Prior studies have suggested that essential genes contribute to human disease by causing spontaneous miscarriages and birth defects [5] , [7] , [8] , [9] , [36] . ”

“ The degree distributions (Table 2) verify the DU network is more similar to the DL network in connectivity (Wilcoxon–Mann–Whitney and Kolmogorov–Smirnov tests, both p<0.05) , than to the DV network. The outlying data points in the prior analysis of viable disease gene PPI networks [5] presumably reflect the inclusion of essential genes that have no mouse knockout (that we classify as DU) in their viable gene dataset (Table 2) .
Disease proteins segregate to different cellular compartments based on essentiality
Interactions between proteins can only occur when those proteins are co-localized. ”

“ Banerjee-Basu, S & Ouspenskaia, MV, “Loss-of-function mutations in growth differentiation factor-1 (GDF1) are associated with congenital heart defects in humans.”, Am J Hum Genet 81: 987–994, pmid:17924340 ↑ Ragge, NK ”