Identification of human haploinsufficient genes and their genomic proximity to segmental duplications

被引:100
作者
Dang, Vinh T. [1 ,2 ]
Kassahn, Karin S. [1 ,2 ]
Marcos, Andres Esteban [1 ,2 ]
Ragan, Mark A. [1 ,2 ]
机构
[1] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia
[2] ARC Ctr Excellence Bioinformat, Brisbane, Qld, Australia
基金
澳大利亚研究理事会;
关键词
haploinsufficient genes; segmental duplications; copy number variation; low-copy repeats; non-allelic homologous recombination; human genome;
D O I
10.1038/ejhg.2008.111
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. European Journal of Human Genetics (2008) 16, 1350-1357; doi:10.1038/ejhg.2008.111; published online 4 June 2008
引用
收藏
页码:1350 / 1357
页数:8
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