Joint Variant and <i>De Novo</i> Mutation Identification on Pedigrees from High-Throughput Sequencing Data

Cleary, John G.; Braithwaite, Ross; Gaastra, Kurt; Hilbush, Brian S.; Inglis, Stuart J.; Irvine, Sean A.; Jackson, Alan A.; Littin, Richard; Nohzadeh-Malakshah, Sahar; Rathod, Mehul; Ware, David; Trigg, Len; Vega, Francisco

doi:10.1089/cmb.2014.0029

Cited by 84 publications

(85 citation statements)

References 31 publications

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“…Of the possible allelic combinations of the mother and child at each site (Table S8) 4 combinations are informative if only the mother is phased while 8 are informative if both the mother and child are phased. We first obtained a gold standard phased set of calls for the NA12878 duo by using the CEPH 13 member pedigree and only considered sites for which the phase and genotype information are consistent across all members of the pedigree, who had been previously sequenced (59). This approach yielded a set of 53 crossovers with a mean interval length of 40.5kb.…”

Section: Sm S155 Obtaining Recombination Breakpoints Using Phased Pamentioning

confidence: 99%

Health and population effects of rare gene knockouts in adult humans with related parents

Narasimhan

Hunt

Mason

et al. 2015

Preprint

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Abstract:Complete gene knockouts are highly informative about gene function. We exome sequenced 3,222 British Pakistani heritage adults with high parental relatedness, discovering 1,111 rare variant homozygous likely loss of function (rhLOF) genotypes predicted to disrupt (knockout) 781 genes. Based on depletion of rhLOF genotypes, we estimate that 13.6% of knockouts are incompatible with adult life, finding on average 1.6 heterozygous recessive lethal LOF variants per adult. Linking to lifelong health records, we observed no association of rhLOF genotypes with prescription or doctor consultation rate, and no disease related phenotypes in 33 of 42 individuals with rhLOF genotypes in recessive Mendelian disease genes. Phased genome sequencing of a healthy PRDM9 knockout mother, her child and controls, showed meiotic recombination sites localised away from PRDM9 dependent hotspots, demonstrating PRDM9 redundancy in humans. Main Text:The study of gene function by correlating genotype with phenotype has provided profound biological insights for several decades. In particular, complete gene knockouts, typically caused by homozygous loss of function (LOF) genotypes, have been used to identify the function of many genes, predominantly through studies in model organisms and of severe Mendelian inherited diseases in humans. However, information on the consequences of knocking out most genes in humans is still missing. Naturally occurring complete gene knockouts, whilst exceptional in outbred populations, offer the opportunity to study directly the lifelong effects of systemic gene inactivation in a living human. They provide a key entry point into human biology that can then be tested in other systems, and can lead to direct validation of specific biological hypotheses. The first large survey of LOF variants in adult humans demonstrated ~100 predicted LOF genotypes per individual, describing around ~20 genes carrying homozygous predicted LOF alleles and hence likely completely inactivated(1). As expected almost all these homozygous genotypes were common (allele frequency) variants, and were concentrated in genes likely to have weak or neutral effects on fitness and health, for instance olfactory receptors. In contrast, rare predicted LOF genotypes in these outbred . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/031641 doi: bioRxiv preprint first posted online Nov. 14, 2015; samples were usually heterozygous and thus of uncertain overall impact on gene function. Several approaches have been described recently to identify naturally occurring human knockouts. A large exome sequencing aggregation study (ExAC), of predominantly outbred individuals, identified 1,775 genes with homozygous predicted LOF genotypes in 60,706 individuals(2). In population isolates, 1,171 genes with complete predicted LOF were identified in 104,220 Icelandic individuals(3), and modest enrichment for homozygou...

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Section: Sm S155 Obtaining Recombination Breakpoints Using Phased Pamentioning

confidence: 99%

Health and population effects of rare gene knockouts in adult humans with related parents

Narasimhan

Hunt

Mason

et al. 2015

Preprint

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“…Reads were aligned to the reference human genome (GRCh37) and pedigree-informed variant calling was performed with the Real Time Genomics (RTG) integrated analysis tool rtgFamily v.3.2. 22 All variants were annotated with SnpEff v.3.4 23 and filtered to include SNPs and indels predicted to result in altered mRNA splicing or protein sequence. Rare variants were identified on the basis of a MAF < 0.01 in both the NHLBI Exome Sequencing Project (ESP) Exome Variant Server and 1000 Genomes database (October 2013).…”

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confidence: 99%

Loss-of-Function Alanyl-tRNA Synthetase Mutations Cause an Autosomal-Recessive Early-Onset Epileptic Encephalopathy with Persistent Myelination Defect

Simons

Griffin

Helman

et al. 2015

The American Journal of Human Genetics

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Mutations in genes encoding aminoacyl-tRNA synthetases are known to cause leukodystrophies and genetic leukoencephalopathies-heritable disorders that result in white matter abnormalities in the central nervous system. Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI. Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families: the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS. The two identified mutations were found to result in a significant reduction in function. Mutations in AARS were previously associated with an autosomal-dominant inherited form of axonal neuropathy, Charcot-Marie-Tooth disease type 2N (CMT2N). The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations.

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“…However with current approaches the likelihood of detecting insertions and deletions of DNA (indels) is inversely proportional to the size of the indel (25). A number of integrated open source software tools exist as alternatives to GATK including FreeBayes and the RTG suite, each which may offer advantages over GATK in areas such as detection of indels, calling variants within familial pedigrees, and processing time (26,27). …”

Section: Current Methods In Genome Sequencingmentioning

confidence: 99%

A primer to clinical genome sequencing

Priest

2017

Current Opinion in Pediatrics

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Purpose of review Genome sequencing is now available as a clinical diagnostic test. There is a significant knowledge and translation gap for non-genetic specialists of the processes necessary to generate and interpret clinical genome sequencing. The purpose of this review is to provide a primer on contemporary clinical genome sequencing for non-genetic specialists describing the human genome project, current techniques and applications in genome sequencing, limitations of current technology, and techniques on the horizon. Recent Findings As currently implemented, genome sequencing compares short pieces of an individual’s genome to a reference sequence developed by the human genome project. Genome sequencing may be used for obtaining timely diagnostic information, cancer pharmacogenomics, or in clinical cases when previous genetic testing has not revealed a clear diagnosis. At present, the implementation of clinical genome sequencing is limited by the availability of clinicians qualified for interpretation, and current techniques in used clinical testing do not detect all types of genetic variation present in a single genome. Summary Clinicians considering a genetic diagnosis have wide array of testing choices which now includes genome sequencing. Though not a comprehensive test in its current form, genome sequencing offers more information than gene-panel or exome sequencing and has the potential to replace targeted single-gene or gene-panel testing in many clinical scenarios.

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Joint Variant and De Novo Mutation Identification on Pedigrees from High-Throughput Sequencing Data

Cited by 84 publications

References 31 publications

Health and population effects of rare gene knockouts in adult humans with related parents

Health and population effects of rare gene knockouts in adult humans with related parents

Loss-of-Function Alanyl-tRNA Synthetase Mutations Cause an Autosomal-Recessive Early-Onset Epileptic Encephalopathy with Persistent Myelination Defect

A primer to clinical genome sequencing

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