Analysis of genetic inheritance in a family quartet by whole-genome sequencing

Abstract

We analyzed the whole-genome sequences of a family of four, consisting of two siblings and their parents. Family-based sequencing allowed us to delineate recombination sites precisely, identify 70% of the sequencing errors (resulting in >99.999% accuracy), and identify very rare singlenucleotide polymorphisms. We also directly estimated a human intergeneration mutation rate of ∼1.1 x 10∼8 per position per haploid genome. Both offspring in this family have two recessive disorders: Miller syndrome, for which the gene was concurrently identified, and primary ciliary dyskinesia, for which causative genes have been previously identified. Family-based genome analysis enabled us to narrow the candidate genes for both of these Mendelian disorders to only four. Our results demonstrate the value of complete genome sequencing in families. Copyright by the American Association for the Advancement of Science; all rights reserved.