title: 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 single-nucleotide polymorphisms. We also directly estimated a human intergeneration mutation rate of approximately 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.
authors.affiliation: Institute for Systems Biology, Seattle, WA 98103, USA.
authors.forename: Jared C
authors.initials: JC
authors.lastname: Roach
authors.forename: Gustavo
authors.initials: G
authors.lastname: Glusman
authors.forename: Arian F A
authors.initials: AF
authors.lastname: Smit
authors.forename: Chad D
authors.initials: CD
authors.lastname: Huff
authors.forename: Robert
authors.initials: R
authors.lastname: Hubley
authors.forename: Paul T
authors.initials: PT
authors.lastname: Shannon
authors.forename: Lee
authors.initials: L
authors.lastname: Rowen
authors.forename: Krishna P
authors.initials: KP
authors.lastname: Pant
authors.forename: Nathan
authors.initials: N
authors.lastname: Goodman
authors.forename: Michael
authors.initials: M
authors.lastname: Bamshad
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Radoje
authors.initials: R
authors.lastname: Drmanac
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Jorde
authors.forename: Leroy
authors.initials: L
authors.lastname: Hood
authors.forename: David J
authors.initials: DJ
authors.lastname: Galas
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000465:Algorithms; D000483:Alleles; D056444:Axonemal Dyneins / Q000235:genetics; D002925:Ciliary Motility Disorders / Q000235:genetics*; D003434:Crossing Over, Genetic; D000090722:Dihydroorotate Dehydrogenase; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D056726:Genetic Association Studies; D015894:Genome, Human; D006801:Humans; D040582:Inheritance Patterns; D017880:Limb Deformities, Congenital / Q000235:genetics; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000235:genetics; D009154:Mutation; D009679:Nuclear Family; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D013577:Syndrome
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D044925:Oxidoreductases Acting on CH-CH Group Donors; D056444:Axonemal Dyneins; C497507:DNAH5 protein, human