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

By J. Roach, G. Glusman, Arian F. A. Smit, C. Huff, Robert M. Hubley, Paul T. Shannon, L. Rowen, K. Pant, N. Goodman, Michael Bamshad and 5 more. Science, 2010

666 citations recorded by the source corpus.

Runs in the Family The power to detect mutations involved in disease by genome sequencing is enhanced when combined with the ability to discover specific mutations that may have arisen between offspring and parents. Roach et al. (p. 636, published online 10 March) present the sequence of a family with two offspring affected with two genetic disorders: Miller syndrome and primary ciliary dyskinesia. Sequence analysis of the children and their parents not only showed that the intergenerational mutation rate was lower than anticipated but also revealed recombination sites and the occurrence of rare polymorphisms. Genomic sequencing of an entire family reveals the rate of spontaneous mutations in humans and identifies disease genes. 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 × 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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6bfec4568e6f90d5cc5b0133887571dcda35bc2e

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Citations in the corpus

Detection and quantification of rare mutations with massively parallel sequencing (2011, background): “Counting de novo mutations in humans, not present in their parents, has similarly led to new insights into the rate at which our species can evolve (2, 3).”
Genome Medicine: past, present and future (2011, background): “For example, sequencing and analysis of the genomes of two siblings and their parents made possible the direct measurement of the inter-generational mutation rate and identified genes potentially associated with two Mendelian disorders [2]; the gene causing one of these disorders was precisely ident”
Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data (2015, methodology): “Drug response predictions fromWGS data When run onWGS data from a single proband, STMP provides, for the first time, pharmacogenomic haplotype assignment and annotation of clinically associated pharmacogenomics alleles, including those that are defined on a single variant or haplotype bases.”
Low concordance of multiple variant-calling pipelines: practical implications for exome and genome sequencing (2013, methodology): “Previous calculations have estimated the average expected number of de novo non-synonymous coding mutations per individual exome to be approximately 1 to 2 [27-30].”
Genome-Wide Detection of Single Nucleotide and Copy Number Variations of a Single Human Cell (2012, neutral): “The mutation rate of this cancer cell line is about 10 fold higher than the mutation rate estimated based on germ line studies (29-31).”