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Characterising and predicting haploinsufficiency in the human genome.

ABSTRACT: Haploinsufficiency, wherein a single functional copy of a gene is insufficient to maintain normal function, is a major cause of dominant disease. Human disease studies have identified several hundred haploinsufficient (HI) genes. We have compiled a map of 1,079 haplosufficient (HS) genes by systematic identification of genes unambiguously and repeatedly compromised by copy number variation among 8,458 apparently healthy individuals and contrasted the genomic, evolutionary, functional, and network properties between these HS genes and known HI genes. We found that HI genes are typically longer and have more conserved coding sequences and promoters than HS genes. HI genes exhibit higher levels of expression during early development and greater tissue specificity. Moreover, within a probabilistic human functional interaction network HI genes have more interaction partners and greater network proximity to other known HI genes. We built a predictive model on the basis of these differences and annotated 12,443 genes with their predicted probability of being haploinsufficient. We validated these predictions of haploinsufficiency by demonstrating 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. We have transformed these gene-based haploinsufficiency predictions into haploinsufficiency scores for genic deletions, which we demonstrate to better discriminate between pathogenic and benign deletions than consideration of the deletion size or numbers of genes deleted. These robust predictions of haploinsufficiency support clinical interpretation of novel loss-of-function variants and prioritization of variants and genes for follow-up studies.

SUBMITTER: Huang N

PROVIDER: S-EPMC2954820 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Characterising and predicting haploinsufficiency in the human genome.

Huang Ni N Lee Insuk I Marcotte Edward M EM Hurles Matthew E ME

PLoS genetics 20101014 10

Haploinsufficiency, wherein a single functional copy of a gene is insufficient to maintain normal function, is a major cause of dominant disease. Human disease studies have identified several hundred haploinsufficient (HI) genes. We have compiled a map of 1,079 haplosufficient (HS) genes by systematic identification of genes unambiguously and repeatedly compromised by copy number variation among 8,458 apparently healthy individuals and contrasted the genomic, evolutionary, functional, and networ ...[more]

PMID: 20976243

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Project description:ObjectiveWe aim to characterise persistent high utilisers (PHUs) of healthcare services, and correspondingly, transient high utilisers (THUs) and non-high utilisers (non-HUs) for comparison, to facilitate stratifying HUs for targeted intervention. Subsequently we apply machine learning algorithms to predict which HUs will persist as PHUs, to inform future trials testing the effectiveness of interventions in reducing healthcare utilisation in PHUs.Design and settingThis is a retrospective cohort study using administrative data from an Academic Medical Centre (AMC) in Singapore.ParticipantsPatients who had at least one inpatient admission to the AMC between 2005 and 2013 were included in this study. HUs incurred Singapore Dollar 8150 or more within a year. PHUs were defined as HUs for three consecutive years, while THUs were HUs for 1 or 2 years. Non-HUs did not incur high healthcare costs at any point during the study period.Outcome measuresPHU status at the end of the third year was the outcome of interest. Socio-demographic profiles, clinical complexity and utilisation metrics of each group were reported. Area under curve (AUC) was used to identify the best model to predict persistence.ResultsPHUs were older and had higher comorbidity and mortality. Over the three observed years, PHUs' expenditure generally increased, while THUs and non-HUs' spending and inpatient utilisation decreased. The predictive model exhibited good performance during both internal (AUC: 83.2%, 95% CI: 82.2% to 84.2%) and external validation (AUC: 79.8%, 95% CI: 78.8% to 80.8%).ConclusionsThe HU population could be stratified into PHUs and THUs, with distinctly different utilisation trajectories. We developed a model that could predict at the end of 1 year, whether a patient in our population will continue to be a HU in the next 2 years. This knowledge would allow healthcare providers to target PHUs in our health system with interventions in a cost-effective manner.

Project description:Nerve regeneration is a key biological process in those recovering from neural trauma. From animal models it is known that the regenerative capacity of the peripheral nervous system (PNS) relies heavily on the remarkable ability of Schwann cells to undergo a phenotypic shift from a myelinating phenotype to one that is supportive of neural regeneration. In rodents, a great deal is known about the molecules that control this process, such as the transcription factors c-Jun and early growth response protein 2 (EGR2/KROX20), or mark the cells and cellular changes involved, including SOX10 and P75 neurotrophin receptor (p75NTR). However, ethical and practical challenges associated with studying human nerve injury have meant that little is known about human nerve regeneration.The present study addresses this issue, analysing 34 denervated and five healthy nerve samples from 27 patients retrieved during reconstructive nerve procedures. Using immunohistochemistry and Real-Time quantitative Polymerase Chain Reaction (RT-qPCR), the expression of SOX10, c-Jun, p75NTR and EGR2 was assessed in denervated samples and compared to healthy nerve. Nonparametric smoothing linear regression was implemented to better visualise trends in the expression of these markers across denervated samples.It was found, first, that two major genes associated with repair Schwann cells in rodents, c-Jun and p75NTR, are also up-regulated in acutely injured human nerves, while the myelin associated transcription factor EGR2 is down-regulated, observations that encourage the view that rodent models are relevant for learning about human nerve injury. Second, as in rodents, the expression of c-Jun and p75NTR declines during long-term denervation. In rodents, diminishing c-Jun and p75NTR levels mark the general deterioration of repair cells during chronic denervation, a process thought to be a major obstacle to effective nerve repair. The down-regulation of c-Jun and p75NTR reported here provides the first molecular evidence that also in humans, repair cells deteriorate during chronic denervation.

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Characterising and predicting haploinsufficiency in the human genome.

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Characterising and predicting haploinsufficiency in the human genome.

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