Identification of human haploinsufficient genes and their genomic proximity to segmental duplications
TLDR
A rigorous text-searching and database-mining strategy is applied to extract, as comprehensively as possible, an annotated list of currently known human haploinsufficient genes, including their functions and associated diseases, and a custom-made Java visualization tool is described, HaploGeneMapper, to aid in visualizing the proximity of human haplosufficient genes to SDs and to enable identification of haplo Insufficient genes that are vulnerable to NAHR-mediated deletion.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.read more
Citations
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Journal ArticleDOI
Characterising and Predicting Haploinsufficiency in the Human Genome
TL;DR: It is demonstrated that genes with a high predicted probability of exhibiting haploinsufficiency are enriched among genes implicated in human dominant diseases and among genes causing abnormal phenotypes in heterozygous knockout mice.
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Phenotypic impact of genomic structural variation: insights from and for human disease
TL;DR: This Review describes how structural variants can affect molecular and cellular processes, leading to complex organismal phenotypes, including human disease, and presents advances in delineating disease-causing elements that are affected by structural variants.
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CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency
Navneet Matharu,Rattanasopha S,Rattanasopha S,Serena Tamura,Lenka Maliskova,Yi Wang,Adelaide Bernard,Aaron Hardin,Walter L. Eckalbar,Christian Vaisse,Nadav Ahituv +10 more
TL;DR: By delivering this system into the mouse hypothalamus using adeno-associated virus, they rescued the obesity phenotype caused by haploinsufficiency of either of two genes known to promote obesity when mutated in mice and humans, highlighting the translational potential of the CRISPR activation system to treat haplo Insufficient disease.
Journal ArticleDOI
microRNA target prediction programs predict many false positives.
Natalia Pinzón,Blaise Li,Laura Martinez,Anna Sergeeva,Jessy Presumey,Jessy Presumey,Florence Apparailly,Florence Apparailly,Hervé Seitz +8 more
TL;DR: The data suggest that the role of microRNAs in normal and pathological conditions has been overestimated due to the frequent overlooking of false positive rates, and that human haplo-insufficient genes tend to bear the most highly conserved microRNA binding sites.
Journal ArticleDOI
The generation of chromosomal deletions to provide extensive coverage and subdivision of the Drosophila melanogaster genome
R. Kimberley Cook,Stacey J Christensen,Jennifer A. Deal,Rachel A Coburn,Megan E. Deal,Jill Gresens,Thomas C. Kaufman,Kevin R. Cook +7 more
TL;DR: Drosophila melanogaster now has the most extensive genomic deletion coverage and breakpoint subdivision as well as the most comprehensive inventory of haploinsufficient genes of any multicellular organism.
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