The human gene connectome as a map of short cuts for morbid allele discovery

Yuval Itan, Shen Ying Zhang, Guillaume Vogt, Avinash Abhyankar, Melina Herman, Patrick Nitschke, Dror Fried, Lluis Quintana-Murci, Laurent Abel, Jean Laurent Casanova

نتاج البحث: نشر في مجلةمقالةمراجعة النظراء


High-throughput genomic data reveal thousands of gene variants per patient, and it is often difficult to determine which of these variants underlies disease in a given individual. However, at the population level, there may be some degree of phenotypic homogeneity, with alterations of specific physiological pathways underlying the pathogenesis of a particular disease. We describe here the human gene connectome (HGC) as a unique approach for human Mendelian genetic research, facilitating the interpretation of abundant genetic data from patients with the same disease, and guiding subsequent experimental investigations. We first defined the set of the shortest plausible biological distances, routes, and degrees of separation between all pairs of human genes by applying a shortest distance algorithm to the full human gene network. We then designed a hypothesis-driven application of the HGC, in which we generated a Toll-like receptor 3-specific connectome useful for the genetic dissection of inborn errors of Toll-like receptor 3 immunity. In addition, we developed a functional genomic alignment approach from the HGC. In functional genomic alignment, the genes are clustered according to biological distance (rather than the traditional molecular evolutionary genetic distance), as estimated from the HGC. Finally, we compared the HGC with three state-of-the-art methods: String, FunCoup, and HumanNet. We demonstrated that the existing methods are more suitable for polygenic studies, whereas HGC approaches are more suitable for monogenic studies. The HGC and functional genomic alignment data and computer programs are freely available to noncommercial users from http://lab. rockefeller. edu/casanova/HGC and should facilitate the genome-wide selection of disease-causing candidate alleles for experimental validation.

اللغة الأصليةالإنجليزيّة
الصفحات (من إلى)5558-5563
عدد الصفحات6
دوريةProceedings of the National Academy of Sciences of the United States of America
مستوى الصوت110
رقم الإصدار14
المعرِّفات الرقمية للأشياء
حالة النشرنُشِر - 2 أبريل 2013
منشور خارجيًانعم


أدرس بدقة موضوعات البحث “The human gene connectome as a map of short cuts for morbid allele discovery'. فهما يشكلان معًا بصمة فريدة.

قم بذكر هذا