1. ¹ARC Centre of Excellence in Bioinformatics, Brisbane, Queensland, Australia
2. ²Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia

Correspondence: Professor MA Ragan, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. Tel: +61 7 3346 2616; Fax: +61 7 3346 2101; E-mail: m.ragan@imb.uq.edu.au

³These authors contributed equally to this work.

Received 21 February 2008; Revised 6 May 2008; Accepted 9 May 2008; Published online 4 June 2008.

Abstract

Despite the significance of haploinsufficiency in human disease, no systematic study has been reported into the types of genes that are haploinsufficient in human, or into the mechanisms that commonly lead to their deletion and to the expression of the haploinsufficient phenotype. We have applied a rigorous text-searching and database-mining strategy to extract, as comprehensively as possible, from PubMed and OMIM an annotated list of currently known human haploinsufficient genes, including their functions and associated diseases. Gene-set enrichment analysis shows that genes-encoding transcription factors, and genes that function in development, the cell cycle, and nucleic acid metabolism are overrepresented among haploinsufficient genes in human. Many of the phenotypes associated with loss-of-function or deletion of one copy of a haploinsufficient gene describe mental retardation, developmental or metabolic disorders, or tumourigenesis. We also found that haploinsufficient genes are less likely than the complete set of human genes to be situated between pairs of segmental duplications (SDs) that are in close proximity to each other on the same chromosome. Given that SDs can initiate non-allelic homologous recombination (NAHR) and the deletion of adjacent genomic regions, this suggests that the location of haploinsufficient genes between SD pairs, from whence they may suffer intra-genomic rearrangement and loss, is selectively disadvantageous. We describe a custom-made Java visualization tool, HaploGeneMapper, to aid in visualizing the proximity of human haploinsufficient genes to SDs and to enable identification of haploinsufficient genes that are vulnerable to NAHR-mediated deletion.