A strategy for identifying nuclear modifier genes by massively parallel whole-genome sequencing
(English)Manuscript (preprint) (Other academic)
Leber hereditary optic neuropathy (LHON) results from mutations in mtDNA, butadditional factors are required for disease expression. LHON is thus a model for theconcept of modifiers affecting expression of single gene diseases. No modifier factorhas yet been clearly identified. Here we describe a large, consanguineous familyaffected by LHON with offspring showing variable disease expression. This providesan opportunity to investigate the presence of nuclear modifiers in homozygousgenomic regions. We analyzed genomes from six members, parents and foursiblings. Each genome was sequenced to >23x coverage and approximately 3.8million single nucleotide variants and small indels per individual were called, where17,000‐20,000 were located in the exome. As a first step, we hypothesize that amodifier gene affecting penetrance of the LHON mutation, and another modifiergene predisposing to an aggravated phenotype, are located in the protein‐codingparts of the genome (the exome). As we gain experience in data analysis, this can befollowed by extended analyses of additional genomic regions. Our initial, simplehypothesis generated five lists of candidate modifier genes, conforming to fivedifferent models of inheritance. In total, 86 candidate genes were identified and 11of these genes contained 14 variants that were further validated by Sangersequencing. Additional Sanger validation in another two affected siblings reducedthe number of candidate genes to two potential disease‐causing variants.
LHON, whole-genome sequencing, DNA, SNVs
IdentifiersURN: urn:nbn:se:kth:diva-48041OAI: oai:DiVA.org:kth-48041DiVA: diva2:456666
QS 20112011-11-152011-11-152011-11-15Bibliographically approved