Functional modules, mutational load and human genetic disease

• Published in: Trends in genetics Vol. 26; no. 4; pp. 168 - 176
• Main Authors: Zaghloul, Norann A, Katsanis, Nicholas
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.04.2010; Cambridge, UK: Elsevier Trends Journals; Elsevier
• Subjects: Animals; Biological and medical sciences; Disease - genetics; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human; Genome-Wide Association Study; Humans; Medical Education; Molecular and cellular biology; Mutation; Human; Genetics; Mutation; Genetic disease
• ISSN: 0168-9525
• DOI: 10.1016/j.tig.2010.01.006

The ability to generate a massive amount of sequencing and genotyping data is transforming the study of human genetic disorders. Driven by such innovation, it is likely that whole exome and whole-genome resequencing will replace regionally focused approaches for gene discovery and clinical testing in the next few years. However, this opportunity brings a significant interpretative challenge to assigning function and phenotypic variance to common and rare alleles. Understanding the effect of individual mutations in the context of the remaining genomic variation represents a major challenge to our interpretation of disease. Here, we discuss the challenges of assigning mutation functionality and, drawing from the examples of ciliopathies as well as cohesinopathies and channelopathies, discuss possibilities for the functional modularization of the human genome. Functional modularization in addition to the development of physiologically relevant assays to test allele functionality will accelerate our understanding of disease architecture and enable the use of genome-wide sequence data for disease diagnosis and phenotypic prediction in individuals.