Structural variants can be more informative for disease diagnostics, prognostics and translation than current SNP mapping and exon sequencing

Abstract

Introduction: In this article we discuss several human neurological diseases and their relationship to specific highly polymorphic small structural variants (SVs). Unlike genome-wide association analysis (GWAS), this methodology is not a genome screen to define new possibly associated genes, requiring statistical corrections for a million association tests. SVs provide local mapping information at a specific locus. Used with phylogenetic analysis, the specific association of length variants can be mapped and recognized.

Areas covered: This experimental strategy provides identification of DNA variants, particularly variable length Simple Sequence Repeats (SSRs or STRs or microsatellites) that provide specific local association data at the SV locus. Phylogenetic analysis that includes the specific appearance of different length SV variations can differentiate specific phenotypic risks in a population such as age of onset related to variable length polymorphisms and risk of phenotypic variations associated with several adjacent structural variations (SVs). We focus on data for three recent examples associated with Alzheimer’s disease, Levy Bodies, and Parkinson’s disease.

Expert opinion: SVs are understudied, but have led directly to mechanism of pathogenesis studies involving the regulation of gene expression. The identification of specific length polymorphisms associated with clinical disease has led to translational advances and new drug discovery.

KEYWORDS:

• Alzheimer’s disease
• amyotrophic lateral sclerosis
• Lewy Bodies
• mitochondrial metabolism
• structural variants

Declaration of interest

AD Roses is owner of Zinfandel Pharmaceuticals. All authors are either employees of or consultants to Zinfandel. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The work was supported by the state targets higher education institutions in 2014 and the planning period of 2015 and 2016 in terms of R&D [project codes: 3.720.2014/K].