Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing

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Science  11 Mar 2010:
DOI: 10.1126/science.1186802


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 single nucleotide 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 unique value of complete genome sequencing in families.