Computational Advances in Structural Biology

Abstract:

Autozygosity is ubiquitous in consanguineous populations.  All variants within autozygous intervals of the human genome are rendered homozygous.  This has traditionally been used to map disease-causing variants in the context of autosomal recessive diseases.  Insights from these variants have been crucial to the advancement of structural biology.  However, if these variants represent “positive controls”, the autozygome offers a very rich supply of “negative controls” i.e. variants that are rendered homozygous without causing disease.  Very little effort has been made to catalogue this homozygous variation.  Conversely, autozygosity can reveal novel aspects about a context-specific pathogenicity of some variants e.g. complex compound heterozygosity.  The uncovering of pathogenic variants by autozygosity instantly flags heterozygous parents and other relatives as candidates for the study of physiological changes that may represent attractive drug targets.  This goes beyond the traditional definition of loss of function variants to those whose loss of function is actually observed rather than predicted, which is especially salient to missense variations.