The epigenomic profile of RBFOX2, a haploinsufficient gene recently identified as a risk gene of congenital heart disease. Each small box represents 100 bp region around transcription start sites (TSSs) and the shade of the color reflect the strength of the histone mark signal in tissues under normal conditions. RBFOX2 has large expansion of active histone marks (H3K4me3 and H3K9ac), especially in heart and epithelial tissues (purple and gray rows), and tissue-specific suppression mark (H3K27me3) in blood samples.(Credit: Shen lab)
The genetics of developmental disorders, such as congenital heart disease and autism, are highly complex. There are roughly 500 to 1,000 risk genes that can lead to each of these diseases, and to date, only about a few dozen have been identified. Scientists have ramped up efforts to develop computational approaches to address challenges in accurately identifying genetic risk factors in ongoing genetic studies, and the availability of such tools would greatly assist researchers in gaining a deeper understanding of the root causes of these diseases.
Focusing on haploinsufficiency, a key biological mechanism of genetic risk in developmental disorders, Yufeng Shen , PhD, and his lab have developed a novel computational method that enables researchers to find new risk genes in these diseases. Their key idea is that the expression of haploinsufficient genes must be precisely regulated during normal development, and such regulation can be manifested in distinct patterns of genomic regulatory elements. Using data from the NIH Roadmap Epigenomics Project, they showed there is a strong correlation of certain histone marks and known haploinsufficient genes. Then based on supervised machine learning algorithms, they developed a new method, which they call Episcore , to predict haploinsufficiency from epigenomic data representing a broad range of tissue and cell types. Finally, they demonstrate the utility of Episcore in identification of novel risk variants in studies of congenital heart disease and intellectual disability.