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

2010/03/10 by Jared C. Roach, Gustavo Glusman, Arian F. A. Smit +12 · 7 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Genomics and Rare Diseases #Genetics and Neurodevelopmental Disorders #RNA modifications and cancer #Genetics #Biology #Primary ciliary dyskinesia #Offspring #Whole genome sequencing #Genome #Sequence (biology) #Mutation #Inheritance (genetic algorithm) #DNA sequencing #Gene #Medicine #Pregnancy

paper · doi:10.1126/science.1186802

openalex publication_date 2010/03/10 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01

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.

Citations

• Initial sequence of the chimpanzee genome and comparison with the human genome
• Genomic Divergences between Humans and Other Hominoids and the Effective Population Size of the Common Ancestor of Humans and Chimpanzees
• Late Miocene Teeth from Middle Awash, Ethiopia, and Early Hominid Dental Evolution
• A new hominid from the Upper Miocene of Chad, Central Africa
• Estimate of the Mutation Rate per Nucleotide in Humans

Cited by

• Regional Differences in the Accumulation of SNPs on the Male-Specific Portion of the Human Y Chromosome Replicate Autosomal Patterns: Implications for Genetic Dating
• A glimpse into past, present, and future DNA sequencing
• Systems cancer medicine: towards realization of predictive, preventive, personalized and participatory (P4) medicine
• Ancestral Origins and Genetic History of Tibetan Highlanders
• Identification of Genetic Variation on the Horse Y Chromosome and the Tracing of Male Founder Lineages in Modern Breeds
• Resequencing Data Provide No Evidence for a Human Bottleneck in Africa during the Penultimate Glacial Period
• Leroy Hood [wikipedia]

Related

• Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole‐exome sequencing
• Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence
• Use of Linkage Analysis, Genome-Wide Association Studies, and Next-Generation Sequencing in the Identification of Disease-Causing Mutations
• The distribution of highly deleterious variants across human ancestry groups
• Human de novo mutation rates from a four-generation pedigree reference