A new conceptual framework for investigating complex genetic disease

• Main Author: Shobbir eHussain
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2015-11-01
• Series: Frontiers in Genetics
• Subjects: GWAS; complex traits; genome wide association studies; rare variants; Somatic Mosaicism; nanopore sequencing
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fgene.2015.00327/full

Some common diseases are known to have an inherited component, however their population- and familial-incidence patterns do not conform to any known monogenic Mendelian pattern of inheritance and instead they are currently much better explained if an underlying polygenic architecture is posited. Studies that have attempted to identify the causative genetic factors have been designed on this polygenic framework, but so far the yield has been largely unsatisfactory. Based on accumulating recent observations concerning the roles of somatic mosaicism in disease, in this article a second framework which posits a single gene-two hit model which can be modulated by a mutator/anti-mutator genetic background is suggested. I discuss whether such a model can be considered a viable alternative based on current knowledge, its advantages over the current polygenic framework, and describe practical routes via which the new framework can be investigated.