Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing
Open accessAbstract
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.
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In genome research, an average sequence coverage depth of 30-fold has been accepted as sufficient for detecting single-nucleotide polymorphisms and nucleotide insertions or deletions.
“In genome research, an average depth of sequence coverage of 30-fold has been accepted as sufficient for single-nucleotide polymorphism (SNP) and nucleotide insertion or deletion (indel) detection (15–22).”
From Carrier testing for severe childhood recessive diseases by next-generation sequencing (2011) · cites this paper as [22]
The passage describing the family's sequencing (section labelled Abstract; page unavailable) reports an average coverage of 40× and identification of single-nucleotide variants. It does not establish that 30× coverage is accepted as sufficient for detecting SNPs and indels, or report indel detection. (LLM, conf=0.83)
Experimental — accuracy not yet measuredTarget capture and next-generation sequencing have shown efficacy and, recently, scalability for resequencing human genomes and exomes.
“Target capture and next-generation sequencing (NGS) have shown efficacy and, recently, scalability for resequencing human genomes and exomes, providing an alternative potential paradigm for comprehensive carrier testing (15–22).”
From Carrier testing for severe childhood recessive diseases by next-generation sequencing (2011) · cites this paper as [22]
The paper’s sequencing-method and family-analysis passages (section labeled Abstract; page unavailable) describe short-read sequencing of four complete human genomes and its effectiveness in narrowing candidate genes for two disorders. They do not demonstrate target capture, exome resequencing, or scalability beyond this family quartet. (LLM, conf=0.86)
Experimental — accuracy not yet measuredData on the sensitivity and specificity of genotyping disease mutations, especially polynucleotide indels, gross insertions and deletions, copy number variations, and complex rearrangements, are very limited.
“Data demonstrating the sensitivity and specificity of genotyping of disease mutations, particularly polynucleotide indels, gross insertions and deletions, copy number variations (CNVs), and complex rearrangements, are very limited (20–22).”
From Carrier testing for severe childhood recessive diseases by next-generation sequencing (2011) · cites this paper as [22]
The passages on sequencing errors and CNV-related assembly problems (section labelled Abstract; page unavailable) address technical difficulties, but do not say that sensitivity and specificity data for genotyping disease mutations are very limited. Searches for indels, large insertions and deletions, CNVs, and complex rearrangements found no passage making that broader claim. (LLM, conf=0.73)
Experimental — accuracy not yet measuredThe average depth of sequencing was greater than 50×, making variant calling reliable and accurate, with a presumed error rate on par with other studies using Complete Genomics sequence data.
“As the average depth of sequencing was >50 × in our study, variant calling was reliable and accurate, with a presumed error rate on par with other studies using the Complete Genomics sequence data.27”
From Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease (2015) · cites this paper as [27]
Obtaining phase from sequence data alone is not trivial.
“Thus, leveraging phase information in an association study of rare variants may be crucial, but obtaining phase from sequence data alone is not trivial.24, 91–93”
From Statistical analysis strategies for association studies involving rare variants (2010) · cites this paper as [24]
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References 23 · Cited by 1,084
Research works printed but not linked: 4
- [5]Kruglyak L Daly MJ Reeve-Daly MP Lander ES Am J Hum Genet 58 1347 Jun 1996 8651312 PMC1915045
- [11]Haile-Selassie Y Nature 412 178 Jul 12 2001 11449272
- [12]Haile-Selassie Y Asfaw B White TD Am J Phys Anthropol 123 1 Jan 2004 14669231
- [13]Haile-Selassie Y Suwa G White TD Science 303 1503 Mar 5 2004 15001775
- Authors
- Roach, J. C., Glusman, G., Smit, A. F. A., Huff, C. D., Hubley, R., Shannon, P. T., Rowen, L., Pant, K. P., Goodman, N., Bamshad, M., Shendure, J., Drmanac, R., Jorde, L. B., Hood, L., & Galas, D. J.
- Affiliations
- Institute for Systems Biology (US)
- University of Utah (US)
- Complete Genomics (United States) (US)
- University of Washington (US)
- Corresponding author
- Roach, Jared C.
- Glusman, Gustavo
- Smit, Arian F. A.
- Huff, Chad D.
- Hood, Leroy
- Galas, David J.
- ORCID
- Venue
- Science
- Published
- 2010-04-30
- Volume
- 328
- Issue
- 5978
- Pages
- 636-639
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3037280
- OpenAlex
- W2168142506
- Cited by
- 1,084
- References
- 23
- Citations by year
- 2026: 13 · 2025: 24 · 2024: 26 · 2023: 20 · 2022: 55 · 2021: 45 · 2020: 25 · 2019: 42 · 2018: 71 · 2017: 36 · 2016: 65 · 2015: 79 · 2014: 103 · 2013: 107 · 2012: 160
- FWCI
- 85.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL094976)
- National Human Genome Research Institute (R21HG004749, RC2HG005608, R01HG002939, RZ1HG004749)
- National Institute of General Medical Sciences (R01GM081083, GM 076547, P50GM076547)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD048895)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- recombination mapping, sequencing error correction, mutation rate estimation, Miller syndrome, primary ciliary dyskinesia, monogenic disorders, recessive disorders, candidate gene identification
- MeSH terms
- Abnormalities, Multiple, Dihydroorotate Dehydrogenase, Algorithms, Alleles, Ciliary Motility Disorders, Crossing Over, Genetic, Female, Genes, Dominant, Genes, Recessive, Humans, Male, Mandibulofacial Dysostosis, Mutation, Nuclear Family, Pedigree, Syndrome, Genome, Human, Sequence Analysis, DNA, Limb Deformities, Congenital, Polymorphism, Single Nucleotide, Inheritance Patterns, Oxidoreductases Acting on CH-CH Group Donors, Axonemal Dyneins, Genetic Association Studies
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