Mutation discovery in mice by whole exome sequencing

Fairfield, Heather; Gilbert, Griffith J; Barter, Mary; Corrigan, Rebecca R.; Curtain, Michelle; Ding, Yueming; D’Ascenzo, Mark; Gerhardt, Daniel J.; He, Chao; Huang, Wenhui; Richmond, Todd; Rowe, Lucy B.; Probst, Frank J.; Bergstrom, David E.; Murray, Stephen A.; Bult, Carol J.; Richardson, Joel E.; Kile, Benjamin T.; Gut, Ivo; Hager, Jörg; Sigurðsson, Snaevar; Mauceli, Evan; Palma, Federica Di; Lindblad‐Toh, Kerstin; Cunningham, Michael L.; Cox, Timothy C.; Justice, Monica J.; Spector, Mona S.; Lowe, Scott W.; Albert, Thomas; Donahue, Leah Rae; Jeddeloh, Jeffrey A.; Shendure, Jay

doi:10.1186/gb-2011-12-9-r86

Cited by 108 publications

(121 citation statements)

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“…informatics.jax.org/reference/J:157222). These mice, in which a Notch3 splice-donor site in intron 31 is abrogated (Fairfield et al, 2011), may thus be of interest for studying Notch3 gain-of-function developmental disorders.…”

Section: Notch3 In Development: a Cornucopia Of Congenital Disordersmentioning

confidence: 99%

The developmental biology of genetic Notch disorders

2017

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Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome. Furthermore, structure-abrogating mutations in NOTCH3 result in CADASIL. Here, we discuss these human congenital disorders in the context of known roles for Notch signaling during development. Drawing on recent analyses by the exome aggregation consortium (EXAC) and on recent studies of Notch signaling in model organisms, we further highlight additional Notch receptors or ligands that are likely to be involved in human genetic diseases.

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Section: Notch3 In Development: a Cornucopia Of Congenital Disordersmentioning

confidence: 99%

The developmental biology of genetic Notch disorders

2017

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“…To confirm the expected evolutionary relationships among the mouse strains used in this study, we estimated a phylogeny using published whole genome data for WSB/EiJ and SPRET/EiJ (Keane et al 2011) and new whole exome data from all other strains. Whole exomes were enriched for Illumina sequencing using an in-solution NimbleGen SeqCap EZ Mouse (Roche) exome design targeting 54.3 Mb of exonic regions in the mouse genome (Fairfield et al 2011). This in-solution platform performs well when used across different species of Mus with minimal biases in capture efficiency and sensitivity (B.…”

Section: Experimental Design and Choice Of Mouse Strainsmentioning

confidence: 99%

Contrasting Levels of Molecular Evolution on the Mouse X Chromosome

et al. 2016

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The mammalian X chromosome has unusual evolutionary dynamics compared to autosomes. Faster-X evolution of spermatogenic protein-coding genes is known to be most pronounced for genes expressed late in spermatogenesis, but it is unclear if these patterns extend to other forms of molecular divergence. We tested for faster-X evolution in mice spanning three different forms of molecular evolution-divergence in protein sequence, gene expression, and DNA methylation-across different developmental stages of spermatogenesis. We used FACS to isolate individual cell populations and then generated cell-specific transcriptome profiles across different stages of spermatogenesis in two subspecies of house mice (Mus musculus), thereby overcoming a fundamental limitation of previous studies on whole tissues. We found faster-X protein evolution at all stages of spermatogenesis and faster-late protein evolution for both X-linked and autosomal genes. In contrast, there was less expression divergence late in spermatogenesis (slower late) on the X chromosome and for autosomal genes expressed primarily in testis (testis-biased). We argue that slower-late expression divergence reflects strong regulatory constraints imposed during this critical stage of sperm development and that these constraints are particularly acute on the tightly regulated sex chromosomes. We also found slower-X DNA methylation divergence based on genome-wide bisulfite sequencing of sperm from two species of mice (M. musculus and M. spretus), although it is unclear whether slower-X DNA methylation reflects development constraints in sperm or other X-linked phenomena. Our study clarifies key differences in patterns of regulatory and protein evolution across spermatogenesis that are likely to have important consequences for mammalian sex chromosome evolution, male fertility, and speciation.KEYWORDS faster X evolution; gene expression; DNA methylation; fluorescence-activated cell sorting; postmeiotic sex chromosome repression (PSCR) T HE X chromosome plays a disproportionately large role in adaptation and speciation (Bachtrog et al. 2011;Ellegren 2011;Charlesworth 2013), but the underlying molecular and evolutionary drivers of these patterns remain unclear. On one hand, the X chromosome often shows strong signatures of evolutionary constraint. For example, the evolution of dosage compensation via epigenetic X-chromosome inactivation (XCI) in females (Lyon 1961(Lyon , 1962 imposes regulatory constraints that select for strong conservation of X-linked gene content in placental mammals (Ohno 1967;Kohn et al. 2004). On the other hand, these inherent constraints are punctuated by strong specialization in X-linked gene content (Emerson et al. 2004;Mueller et al. 2008Mueller et al. , 2013Potrzebowski et al. 2008;Zhang et al. 2010;Sin et al. 2012) and numerous examples of rapid X-linked evolution Singh 2003, 2006;Baines and Harr 2007;Kousathanas et al. 2014;Nam et al. 2015).The X chromosome is predicted to evolve faster than the autosomes if beneficial mutations...

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“…Caenorhabditis elegans, Drosophila, mouse and various fungi (Smith et al, 2008;Blumenstiel et al, 2009;Irvine et al, 2009;Schneeberger et al, 2009;Cuperus et al, 2010;Doitsidou et al, 2010;Zuryn et al, 2010;Austin et al, 2011;Fairfield et al, 2011;Uchida et al, 2011). However, these approaches are not universally applicable owing to differences in genome sizes, reference genome qualities and availability of inbred lines.…”

Section: Research Article Cloning By Sequencingmentioning

confidence: 99%

Rapid positional cloning of zebrafish mutations by linkage and homozygosity mapping using whole-genome sequencing

et al. 2012

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SUMMARYForward genetic screens in zebrafish have identified >9000 mutants, many of which are potential disease models. Most mutants remain molecularly uncharacterized because of the high cost, time and labor investment required for positional cloning. These costs limit the benefit of previous genetic screens and discourage future screens. Drastic improvements in DNA sequencing technology could dramatically improve the efficiency of positional cloning in zebrafish and other model organisms, but the best strategy for cloning by sequencing has yet to be established. Using four zebrafish inner ear mutants, we developed and compared two approaches for 'cloning by sequencing': one based on bulk segregant linkage (BSFseq) and one based on homozygosity mapping (HMFseq). Using BSFseq we discovered that mutations in lmx1b and jagged1b cause abnormal ear morphogenesis. With HMFseq we validated that the disruption of cdh23 abolishes the ear's sensory functions and identified a candidate lesion in lhfpl5a predicted to cause nonsyndromic deafness. The success of HMFseq shows that the high intrastrain polymorphism rate in zebrafish eliminates the need for time-consuming map crosses. Additionally, we analyzed diversity in zebrafish laboratory strains to find areas of elevated diversity and areas of fixed homozygosity, reinforcing recent findings that genome diversity is clustered. We present a database of >15 million sequence variants that provides much of this approach's power. In our four test cases, only a single candidate single nucleotide polymorphism (SNP) remained after subtracting all database SNPs from a mutant's critical region. The saturation of the common SNP database and our open source analysis pipeline MegaMapper will improve the pace at which the zebrafish community makes unique discoveries relevant to human health.

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Mutation discovery in mice by whole exome sequencing

Cited by 108 publications

References 20 publications

The developmental biology of genetic Notch disorders

The developmental biology of genetic Notch disorders

Contrasting Levels of Molecular Evolution on the Mouse X Chromosome

Rapid positional cloning of zebrafish mutations by linkage and homozygosity mapping using whole-genome sequencing

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