characterising and predicting haploinsufficiency in the human genome描述和预测haploinsufficiency在人类基因组中.pdfVIP

Characterising and Predicting Haploinsufficiency in the Human Genome 1 2,3 2 1 Ni Huang , Insuk Lee , Edward M. Marcotte , Matthew E. Hurles * 1 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom, 2 Center for Systems and Synthetic Biology, Department of Chemistry and Biochemistry, Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas, United States of America, 3 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea 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 h