The role of buffer genes in preventing genetic disease

Simon Crane
University of Oxford

European scientists working for the U.K. Sanger Wellcome Institute have demonstrated that a small set of key ‘hub’ genes might shape the susceptibility of animals to genetic disease [1].

The researchers used RNA interference (RNAi) to determine interactions between genes present in the nematode worm, Caenorhabditis elegans. RNAi is used in molecular biology to selectively disrupt the expression of a specific gene; introducing fragments of double-stranded RNA complementary in sequence to a target gene can silence expression of that particular gene.

After testing 65,000 pairs of genes for interactions, a set of six core genes, which interact with over 25% of all other genes investigated, was identified. Moreover, these linked ‘partner’ genes are involved in diverse biological processes, suggesting that the highly connected ‘hub’ genes exert their influence through an extensive network of interactions [1].

To determine the consequences of losing hub gene activity, RNAi was targeted sequentially at the six genes individually. Significantly, reducing the activity of a hub gene markedly increases the damaging effects of mutations in other genes in the worm; this suggests that if DNA mutates due to cell cycle replication errors, exposure to radiation or other external chemical agents, hub genes act like molecular shock absorbers to minimise the effect of damage and reduce the harmful consequences of mutation [1].

Discovering a guardian group of buffer genes which defend against the impact of mutation is remarkable. The complexity of human genetic disorders has been thought to often result from separate mutations in multiple and unrelated genes, all of which are required to mutate and synergise to give the final disease phenotype. The difficulty in tackling genetic syndromes often lies in not knowing which combinations of mutations can induce disease.

The ability of this paradigm to entirely articulate a complete model for genetic disease has, however, encountered reasonable and substantiated criticism in the past [2]. In view of this, the authors propose a developed model in which, although a series of mutations in several pathway-specific genes can cause illness, mutation in a hub gene will trigger effects in seemingly random pathways. Because hub genes are highly connected with so many genes, an inactivated hub gene may impact disparate and seemingly unrelated cellular processes.

Mapping interactions of human genes may reveal that hubs equivalent to those postulated in worms operate to modulate the effects of a large range of different mutations in humans as well. This advancement could potentially provide a new conceptual framework with which to understand and remedy genetic diseases.

[1] Fraser et al., “Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways”. Nature Genetics Vol. 38 (8), pp896-903 (2006)
http://www.nature.com/ng/journal/v38/n8/pdf/ng1844.pdf.

[2] Badano and Katsanis, “Beyond Mendel: An evolving view of human genetic disease transmission” Nature Reviews Genetics 3, pp779-789 (2002) http://www.nature.com/nrg/journal/v3/n10/full/nrg910_fs.html.

Image courtesy of cancergenome.nih.gov