Functional modules, mutational load and human genetic disease

Norann A. Zaghloul, Elias Nicholas Katsanis*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

78 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)168-176
Number of pages9
JournalTrends in Genetics
Volume26
Issue number4
DOIs
StatePublished - Apr 2010

ASJC Scopus subject areas

  • Genetics

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