Analysis of genetic inheritance in a family quartet by whole-genome sequencing.
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.
Roach
Jared C
JC
Institute for Systems Biology, Seattle, WA 98103, USA.
Glusman
Gustavo
G
Smit
Arian F A
AF
Huff
Chad D
CD
Hubley
Robert
R
Shannon
Paul T
PT
Rowen
Lee
L
Pant
Krishna P
KP
Goodman
Nathan
N
Bamshad
Michael
M
Shendure
Jay
J
Drmanac
Radoje
R
Jorde
Lynn B
LB
Hood
Leroy
L
Galas
David J
DJ
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
D000090722:Dihydroorotate Dehydrogenase; D044925:Oxidoreductases Acting on CH-CH Group Donors; D056444:Axonemal Dyneins; C497507:DNAH5 protein, human