DOCSLIB.ORG

Inbred Strain Variant Database (Isvdb): a Repository for Probabilistically Informed Sequence Differences Among the Collaborative Cross Strains and Their Founders

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Inbred Strain Variant Database (Isvdb): a Repository for Probabilistically Informed Sequence Differences Among the Collaborative Cross Strains and Their Founders View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Carolina Digital Repository MULTIPARENTAL POPULATIONS Inbred Strain Variant Database (ISVdb): A Repository for Probabilistically Informed Sequence Differences Among the Collaborative Cross Strains and Their Founders Daniel Oreper,*,†,1 Yanwei Cai,*,†,1 Lisa M. Tarantino,†,§ Fernando Pardo-Manuel de Villena,†,‡ and William Valdar†,‡,2 *Curriculum in Bioinformatics and Computational Biology, †Department of Genetics, ‡Lineberger Comprehensive Cancer § Center, and Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy University of North Carolina, Chapel Hill, North Carolina 27599-7264 ORCID IDs: 0000-0003-4569-5160 (D.O.); 0000-0002-3950-3794 (Y.C.); 0000-0001-9984-2600 (L.M.T.); 0000-0002-5738-5795 (F.P.-M.d.V.); 0000-0002-2419-0430 (W.V.) ABSTRACT The Collaborative Cross (CC) is a panel of recently established multiparental recombinant KEYWORDS inbred mouse strains. For the CC, as for any multiparental population (MPP), effective experimental design Collaborative and analysis benefit from detailed knowledge of the genetic differences between strains. Such differences Cross can be directly determined by sequencing, but until now whole-genome sequencing was not publicly inbred strain available for individual CC strains. An alternative and complementary approach is to infer genetic online GUI differences by combining two pieces of information: probabilistic estimates of the CC haplotype mosaic variant from a custom genotyping array, and probabilistic variant calls from sequencing of the CC founders. The imputation computation for this inference, especially when performed genome-wide, can be intricate and time- haplotype consuming, requiring the researcher to generate nontrivial and potentially error-prone scripts. To provide multiparental standardized, easy-to-access CC sequence information, we have developed the Inbred Strain Variant populations Database (ISVdb). The ISVdb provides, for all the exonic variants from the Sanger Institute mouse MPP sequencing dataset, direct sequence information for CC founders and, critically, the imputed sequence information for CC strains. Notably, the ISVdb also: (1) provides predicted variant consequence metadata; (2) allows rapid simulation of F1 populations; and (3) preserves imputation uncertainty, which will allow imputed data to be refined in the future as additional sequencing and genotyping data are collected.TheISVdbinformationishousedinanSQL database and is easily accessible through a custom online interface (http://isvdb.unc.edu), reducing the analytic burden on any researcher using the CC. The Collaborative Cross (CC) is a large panel of recombinant inbred mouse Copyright © 2017 Oreper et al. doi: https://doi.org/10.1534/g3.117.041491 strains derived from a genetically diverse set of eight inbred founder strains: Manuscript received January 5, 2017; accepted for publication March 20, 2017. A/J (AJ), C57BL/6J (B6), 129S1Sv/ImJ (129), NOD/ShiLtJ (NOD), NZO/ This is an open-access article distributed under the terms of the Creative HlLtJ (NZO), CAST/EiJ (CAST), PWK/PhJ (PWK), and WSB/EiJ (WSB). Commons Attribution 4.0 International License (http://creativecommons.org/ These eight founder strains were first outcrossed for three generations to licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. produce mice with contributions from all eight founder strains. These Supplemental material is available online at http://www.g3journal.org/lookup/ outcrosses were initiated, with differentfounderorderings,inover1000in- suppl/doi:10.1534/g3.117.041491/-/DC1. dependent breedingfunnels(Shorteret al. 2017). Mice within each funnel 1These authors contributed equally to this work. 2 were subsequently inbred for multiple generations until two or more an- Corresponding author: Department of Genetics, University of North Carolina at fi Chapel Hill, 120 Mason Farm Rd., Suite 5113, Genetic Medicine Bldg., Chapel Hill, imals were identi ed by MegaMUGA genotyping as collectively having NC 27599-7264. E-mail: [email protected] over 90% of the genome fixed (i.e., homozygous and consistent for a Volume 7 | June 2017 | 1623 founder haplotype). These animals, hereafter termed the most recent com- mon ancestors (MRCAs), were then chosen to become the obligate ances- tors of all subsequent generations and bred to produce a distinct CC strain. ThesetofMRCAsfromallstrainscomposestheCC’s obligate ancestors; that is, the set of individuals that together circumscribes the initial genetic material that can be passed on to subsequent CC mice. As a result of this breeding scheme, the inbred CC strain genomes are random and independent mosaics of the eight founder haplotypes Collaborative Cross Consortium (2012); (Srivastava et al. 2017) (Figure 1; more details at http://csbio.unc.edu/CCstatus). This combination of independent genomes and high genetic di- versity, along with the reproducibility of inbred strains, has made the CC a unique resource in mammalian genetics, and early studies on the CC have begun to exploit these features (Aylor et al. 2011; Ferris et al. 2013; Phillippi et al. 2014; Rasmussen et al. 2014; Mosedale et al. 2017; Green et al. 2017; Gralinski et al. 2017). To make optimal use of the CC strains, it is desirable to have an accurate catalog of the genetic differences between them—specifically, the positions and other characteristics of all known CC strain genetic variants—and to be able to predict which variants will be polymorphic in future hypothetical crosses of CC strains and of CC strains with other laboratory strains. Such information could be determined directly by sequencing, but CC sequencing, soon to be released for a single male per strain (Srivastava et al. 2017), is not yet easily accessible. Furthermore, sequencing from a single animal will not resolve uncertainty arising from residual het- erozygosity, since two animals from the same strain could easily differ Figure 1 Breeding process for two Collaborative Cross (CC) strains. Both funnels begin by outcrossing the same eight founders, but the at residually heterozygous loci. More generally, whole-genome se- initial outcrossing order differs, resulting in completely independent quencing in most organisms is expensive and inconvenient. populations per funnel. Animals are outcrossed for three generations, A commonly used alternative is haplotype-based variant imputation, then inbred until genotyping reveals at least two animals with .90% whereby comparatively sparse and cheap genotyping data are combined consistent homozygosity by haploytpe. These homozygous animals with more complete information about allelic state in (even extremely [a.k.a., the most recent common ancestors (MRCAs)] are chosen to distant) relatives to infer allelic state at ungenotyped positions in the target become the obligate ancestors for the CC strains; all subsequent gen- sample. This typically involves inferring shared haplotype blocks and, by erations of a CC strain descend from a subset of the MRCAs. In (A), assuming that individuals sharing a haplotype block also share the arrows show CC1 MRCA regions of inconsistent homozygosity (L1) and corresponding allelic state, using this to impute genotype (Li et al. 2009; residual heterozygosity (L2 and L3). After further inbreeding, only L2 Marchini and Howie 2010). A broad array of such imputation methods continues to segregate. In (B), the CC2 MRCA set includes three an- imals rather than two. After further inbreeding, only L1 continues to have been developed for use in humans (e.g., Hawley and Kidd 1995; segregate, but a de novo mutation has become fixed at L2. Scheet and Stephens 2006; Marchini et al. 2007; Browning and Browning 2009; Howie et al. 2009; Li et al. 2010) and livestock (e.g.,VanRadenet al. 2011; Hickey et al. 2012; Sargolzaei et al. 2014); from a known and relatively limited number of founders that can be (more) these typically either start by inferring haplotypes from the genotype affordably deeply sequenced and genotyped. This in turn reduces variant data or by approximating the pool of extant haplotypes via a large imputation uncertainty. For MPP RI strains in particular, once an animal’s reference panel, and then use those haplotypes as a means to impute variants are imputed, the need for even sparse genotyping is largely obvi- variant genotypes, which are assumed to be the primary interest. ated in its inbred descendants; they are effectively genotyped as well. In MPPs of model organisms, where the founder haplotypes are Haplotypes can, and have been, similarly imputed for the entire CC pop- usually known, it is more common for primary interest to focus on ulation based on the CC MRCAs. In particular, a hidden Markov model reconstructing the haplotype mosaic itself, e.g., for the purpose of linkage (HMM)-basedmethod(Fuet al. 2012) has previously been applied to disequilibrium mapping (Mott et al. 2000; Liu et al. 2010; King et al. 2012; MegaMUGA genotyping of the CC MRCA animals coupled with Fu et al. 2012; Gatti et al. 2014; Verbyla et al. 2014; Zheng et al. 2015). In MegaMUGA genotyping from founder animals, (Welsh et al. 2012; such cases, haplotype-based imputation of specific variants may proceed Morgan et al. 2015; Srivastava et al. 2017) to impute a probabilistic as a second, refinement step to inform fine-mapping and candidate estimate of each CC strain’s haplotype mosaic. Sequencing
Load more

Recommended publications
  • Genetic Analysis of Complex Traits in the Emerging Collaborative Cross
    Downloaded from genome.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Research Genetic analysis of complex traits in the emerging Collaborative Cross David L. Aylor,1 William Valdar,1,13 Wendy Foulds-Mathes,1,13 Ryan J. Buus,1,13 Ricardo A. Verdugo,2,13 Ralph S. Baric,3,4 Martin T. Ferris,1 Jeff A. Frelinger,4 Mark Heise,1 Matt B. Frieman,4 Lisa E. Gralinski,4 Timothy A. Bell,1 John D. Didion,1 Kunjie Hua,1 Derrick L. Nehrenberg,1 Christine L. Powell,1 Jill Steigerwalt,5 Yuying Xie,1 Samir N.P. Kelada,6 Francis S. Collins,6 Ivana V. Yang,7 David A. Schwartz,7 Lisa A. Branstetter,8 Elissa J. Chesler,2 Darla R. Miller,1 Jason Spence,1 Eric Yi Liu,9 Leonard McMillan,9 Abhishek Sarkar,9 Jeremy Wang,9 Wei Wang,9 Qi Zhang,9 Karl W. Broman,10 Ron Korstanje,2 Caroline Durrant,11 Richard Mott,11 Fuad A. Iraqi,12 Daniel Pomp,1,14 David Threadgill,5,14 Fernando Pardo-Manuel de Villena,1,14 and Gary A. Churchill2,14 1Department of Genetics, University of North Carolina–Chapel Hill, Chapel Hill, North Carolina 27599, USA; 2The Jackson Laboratory, Bar Harbor, Maine 04609, USA; 3Department of Epidemiology, University of North Carolina–Chapel Hill, Chapel Hill, North Carolina 27599, USA; 4Department of Microbiology and Immunology, University of North Carolina–Chapel Hill, Chapel Hill, North Carolina 27599, USA; 5Department of Genetics, North Carolina State University, Raleigh, North Carolina 27695, USA; 6Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
    [Show full text]
  • Early Testing As a Means of Evaluating F1 Heterosis Between Inbred Lines of Drosophila Melanogaster Sing-Yuan Loh Iowa State College
    Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1949 Early testing as a means of evaluating F1 heterosis between inbred lines of Drosophila melanogaster Sing-yuan Loh Iowa State College Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Genetics Commons Recommended Citation Loh, Sing-yuan, "Early testing as a means of evaluating F1 heterosis between inbred lines of Drosophila melanogaster " (1949). Retrospective Theses and Dissertations. 13635. https://lib.dr.iastate.edu/rtd/13635 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. in the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overiaps.
    [Show full text]
  • No Comparable Place in Animal Breeding. Yet the Advantages of This
    DIALLEL ANALYSIS OF LITTER SIZE AND BODY WEIGHT IN RATS J. L. JINKS A.R.C. Unit of Biometrical Genetics, Department of Genetics, University of Birmingham and P. L. BROADHURST Institute of Psychiatry, Maudsley Hospital, University of London Received7.ii.63 1.INTRODUCTION THEdiallel cross method of assessing potential breeding material, which has been used for some forty years in plant breeding, has found no comparable place in animal breeding. Yet the advantages of this breeding programme apply equally to both plant and animal material especially now that much of animal breeding is directed towards the development of inbred strains and the testing of strains for their usefulness in increasing productivity by intercrossing. The following analysis of litter size and body weight in a diallel set of crosses among six inbred strains of rats show the value that this approach can have in practice. 2. MATERIAL Theorigin of the six inbred strains of rats (Raltus norvegicus, Rerkenhout) used and details of their maintenance and husbandry have been given by Broadhurst (1960). Some behavioural characteristics of these strains and of the 36 F1's produced from them by diallel crossing have already been described and analysed (Broadhurst, 5959, 1960). As part of the investigations the size of litters and their weights at birth were recorded and at 21 days of age (weaning) the pups were sexed and the total weight of the two sexes recorded separately. At 50 days and again a few days after ioo days of age each individual was weighed. It is with the analyses of these litter size and body weight data that we shall be concerned here.
    [Show full text]
  • Genealogies of Mouse Inbred Strains
    © 2000 Nature America Inc. • http://genetics.nature.com commentary Genealogies of mouse inbred strains Jon A. Beck1,2, Sarah Lloyd1,2, Majid Hafezparast1,2, Moyha Lennon-Pierce3, Janan T. Eppig3, Michael F.W. Festing4 & Elizabeth M.C. Fisher2 The mouse is a prime organism of choice for modelling human disease. Over 450 inbred strains of mice have been described, providing a wealth of different genotypes and phenotypes for genetic and other studies. As new strains are generated and others become extinct, it is useful to review periodically what strains are available and how they are related to each other, particularly in the light of available DNA polymorphism data from microsatellite and other markers. We describe the origins and relationships of inbred mouse strains, 90 years after the generation of the first inbred strain. Given the large collection of inbred strains available, and that published information on these strains is incomplete, we propose that all genealogical and genetic data on inbred strains be submitted to a common electronic database to ensure this valuable information resource is preserved and used efficiently. .com Humans have been interested in the inheritance of traits in mice non-agouti, a) was started by Little in 1909. Other inbred strains for at least 3,000 years. The oldest Chinese lexicon written in were generated over the next decade, including C57BL, C3H, 1100 BC has a word for spotted mice1,2. Interest gradually spread CBA and BALB/c (ref. 9). enetics.nature to the West, via the Imperial courts of Japan, and reports on the inheritance of mouse coat colour were published in Europe in the Phenotypic characteristics of inbred strains eighteenth century2.
    [Show full text]
  • Generation of Highly Homogeneous Strains of Zebrafish Through Full
    INVESTIGATION Generation of Highly Homogeneous Strains of Zebrafish Through Full Sib-Pair Mating Minori Shinya1 and Noriyoshi Sakai1 Genetic Strains Research Center, National Institute of Genetics, and The Graduate University for Advanced Studies (SOKENDAI), Mishima, Shizuoka 411-8540, Japan ABSTRACT Genetically homogeneous populations, such as inbred strains, are powerful experimental tools KEYWORDS that are ideally suited for studying immunology, cancer, and genetics of complex traits. The zebrafish, Danio Danio rerio rerio, has been underutilized in these research areas because homogeneous strains of experimental fish sib-pair mating have not been available in tractable condition. Here, we attempted to inbreed two zebrafish wild-type inbreeding strains, Tübingen and India, through full sib-pair mating. Although the inbred Tübingen strain failed to depression thrive and was lost after 13 generations, an inbred India strain (IM) has been maintained successfully. The IM loss of strain has endured 16 generations of inbreeding and has maintained a healthy condition. Two additional heterogeneity strains, IM12m and IM14m, were established as closed colonies from the branches of the IM strain. Geno- type analyses using genetic markers revealed a dramatic decrease in polymorphisms (62% dropped to 5%) in both IM (generation 14) and the two closed colonies. This indicates a high level of homogeneity in these strains. Furthermore, scale transplantations between individuals within each strain were successful. These data suggest that extremely homogeneous zebrafish strains have been established, thereby creating a valu- able resource for practical application. Genetically uniform strains of animals are valuable tools in biomedical evolutionarily and biomedically important traits (Frankel 1995; research. Multiple laboratories can use these strains without concern Kimura et al.
    [Show full text]
  • Genomes of the Mouse Collaborative Cross
    | MULTIPARENTAL POPULATIONS Genomes of the Mouse Collaborative Cross Anuj Srivastava,*,1 Andrew P. Morgan,†,‡,§,1 Maya L. Najarian,**,1 Vishal Kumar Sarsani,* J. Sebastian Sigmon,** John R. Shorter,†,‡ Anwica Kashfeen,** Rachel C. McMullan,†,‡,†† Lucy H. Williams,† Paola Giusti-Rodríguez,† Martin T. Ferris,†,‡ Patrick Sullivan,† Pablo Hock,†,‡ Darla R. Miller,†,‡ Timothy A. Bell,†,‡ Leonard McMillan,** Gary A. Churchill,*,2 and Fernando Pardo-Manuel de Villena†,‡,2 *The Jackson Laboratory, Bar Harbor, Maine 04609, and †Department of Genetics, ‡Lineberger Comprehensive Cancer Center, §Curriculum of Bioinformatics and Computational Biology, **Department of Computer Science, and ††Curriculum of Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina 27599 ORCID IDs: 0000-0003-1942-4543 (A.P.M.); 0000-0003-4732-5526 (J.R.S.); 0000-0003-1241-6268 (M.T.F.); 0000-0002-0781-7254 (D.R.M.); 0000-0002-5738-5795 (F.P.-M.d.V.) ABSTRACT The Collaborative Cross (CC) is a multiparent panel of recombinant inbred (RI) mouse strains derived from eight founder laboratory strains. RI panels are popular because of their long-term genetic stability, which enhances reproducibility and integration of data collected across time and conditions. Characterization of their genomes can be a community effort, reducing the burden on individual users. Here we present the genomes of the CC strains using two complementary approaches as a resource to improve power and interpretation of genetic experiments. Our study also provides a cautionary tale regarding the limitations imposed by such basic biological processes as mutation and selection. A distinct advantage of inbred panels is that genotyping only needs to be performed on the panel, not on each individual mouse.
    [Show full text]
  • Genomic Landscape of Rat Strain and Substrain Variation Hermsen Et Al
    Genomic landscape of rat strain and substrain variation Hermsen et al. Hermsen et al. BMC Genomics (2015) 16:357 DOI 10.1186/s12864-015-1594-1 Hermsen et al. BMC Genomics (2015) 16:357 DOI 10.1186/s12864-015-1594-1 RESEARCH ARTICLE Open Access Genomic landscape of rat strain and substrain variation Roel Hermsen1, Joep de Ligt1, Wim Spee1, Francis Blokzijl1, Sebastian Schäfer2, Eleonora Adami2, Sander Boymans1, Stephen Flink3, Ruben van Boxtel1, Robin H van der Weide1, Tim Aitman4, Norbert Hübner2, Marieke Simonis1, Boris Tabakoff3, Victor Guryev5 and Edwin Cuppen1* Abstract Background: Since the completion of the rat reference genome in 2003, whole-genome sequencing data from more than 40 rat strains have become available. These data represent the broad range of strains that are used in rat research including commonly used substrains. Currently, this wealth of information cannot be used to its full extent, because the variety of different variant calling algorithms employed by different groups impairs comparison between strains. In addition, all rat whole genome sequencing studies to date used an outdated reference genome for analysis (RGSC3.4 released in 2004). Results: Here we present a comprehensive, multi-sample and uniformly called set of genetic variants in 40 rat strains, including 19 substrains. We reanalyzed all primary data using a recent version of the rat reference assembly (RGSC5.0 released in 2012) and identified over 12 million genomic variants (SNVs, indels and structural variants) among the 40 strains. 28,318 SNVs are specific to individual substrains, which may be explained by introgression from other unsequenced strains and ongoing evolution by genetic drift.
    [Show full text]
  • Genomic and Phenotypic Characterization of a Wild Medaka Population: Towards the Establishment of an Isogenic Population Genetic Resource in Fish
    INVESTIGATION Genomic and Phenotypic Characterization of a Wild Medaka Population: Towards the Establishment of an Isogenic Population Genetic Resource in Fish Mikhail Spivakov,*,1,2 Thomas O. Auer,†,1,3 Ravindra Peravali,‡ Ian Dunham,* Dirk Dolle,*,† Asao Fujiyama,§ Atsushi Toyoda,§ Tomoyuki Aizu,§ Yohei Minakuchi,§ Felix Loosli,‡,4 Kiyoshi Naruse,**,4 Ewan Birney,*,4 and Joachim Wittbrodt†,4 *European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK, †Centre for Organismal Studies, Heidelberg University, Germany, ‡Karslruhe Institute of § Technology, Karlsruhe, Germany, Comparative Genomics Laboratory, Center for Information Biology, National Institute of Genetics, Mishima, Japan, and **National Institute for Basic Biology, Laboratory of Bioresources, Okazaki, Japan ABSTRACT Oryzias latipes (medaka) has been established as a vertebrate genetic model for more than KEYWORDS a century and recently has been rediscovered outside its native Japan. The power of new sequencing Medaka methods now makes it possible to reinvigorate medaka genetics, in particular by establishing a near- inbreeding isogenic panel derived from a single wild population. Here we characterize the genomes of wild medaka population catches obtained from a single Southern Japanese population in Kiyosu as a precursor for the establishment of genomics a near-isogenic panel of wild lines. The population is free of significant detrimental population structure and strain specific has advantageous linkage
    [Show full text]
  • Breeding Strategies for Maintaining Colonies of Laboratory Mice a Jackson Laboratory Resource Manual
    Breeding Strategies for Maintaining Colonies of Laboratory Mice A Jackson Laboratory Resource Manual This manual describes breeding strategies and techniques for maintaining colonies of laboratory mice. These techniques have been developed and used by The Jackson Laboratory for nearly 80 years. They are safe, reliable, economical, efficient, and ensure that the mouse strains produced are genetically well-defined. Cover Photos Front cover: JAX® Mice strain B6SJL-Tg(SOD1*G93A)1Gur/J (002726) with red plastic enrichment toy. This strain is a model of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease. (left), JAX® Mice strain C57BL/6J (000664), our most popular strain, with litter of nine-day old pups.(middle), A technician at The Jackson Laboratory—West working with mice in one of our production rooms. (right). ©2009 The Jackson Laboratory Table of Contents Introduction .....................................................................................................................................1 Fundamentals of Mouse Reproduction ........................................................................................2 Mouse Breeding Performance .......................................................................................................4 Breeding Performance Factors ...............................................................................................4 Optimizing Breeding Performance ........................................................................................5 Breeding Schemes ............................................................................................................................7
    [Show full text]
  • How to Refresh Your Mutant Or Transgenic Mouse Strains
    RESEARCH MODELS How to Refresh Your Mutant or Transgenic Mouse Strains Author: Maintaining experimental mouse colonies requires a great spread and become homozygous in all of the mice. If any of Peter Kelmenson, deal of coordination. It is necessary to constantly evaluate those mutations alter the phenotype of the strain, problems Technical Information Scientist, the breeding performance, adjust the colony size to match will arise that can impact research significantly. Smaller The Jackson Laboratory required production, genotype the mice, and then plan colonies of mice, like a small research colony, will be more and execute the experiments. With all this, it is easy to affected by genetic drift than large colonies (Figure 1). have concerns about genetic drift far down on the list of There are many examples of how genetic changes can lead priorities. However, for mutant or transgenic mouse strains to phenotypic changes for mutant and transgenic mouse on inbred backgrounds, dealing with potential genetic drift models. The way to mitigate the impact of genetic drift needs to be a priority. on mutant and transgenic mouse strains is to refresh the Why Do Mouse Models Need to Be Refreshed? genetic background of your strains every 5-10 generations Spontaneous mutations will continually arise in any colony by backcrossing to the inbred control strain. of mice and, through random chance, some of them will Figure 1 Figure 1. The risk of propagating a spontaneous mutation is higher in small colonies versus large colonies. A) The probability of using a mouse that carries any given mutation (light blue) for breeding is higher in a small colony than a large colony.
    [Show full text]
  • Baseline Mrna Expression Differs Widely Between Common Laboratory Strains of Zebrafish
    Portland State University PDXScholar Biology Faculty Publications and Presentations Biology 2018 Baseline mRNA Expression Differs widely Between Common Laboratory Strains of Zebrafish Lindsay Holden Portland State University Kim H. Brown Portland State University, [email protected] Follow this and additional works at: https://pdxscholar.library.pdx.edu/bio_fac Part of the Biology Commons, and the Cell and Developmental Biology Commons Let us know how access to this document benefits ou.y Citation Details Holden, L. A., & Brown, K. H. (2018). Baseline mRNA expression differs widely between common laboratory strains of zebrafish. Scientific reports, 8(1), 4780. This Article is brought to you for free and open access. It has been accepted for inclusion in Biology Faculty Publications and Presentations by an authorized administrator of PDXScholar. Please contact us if we can make this document more accessible: [email protected]. www.nature.com/scientificreports OPEN Baseline mRNA expression difers widely between common laboratory strains of zebrafsh Received: 17 November 2017 Lindsay A. Holden & Kim H. Brown Accepted: 6 March 2018 Common strains of wildtype zebrafsh (Danio rerio) have unique genomic features including SNPs and Published: xx xx xxxx CNV, but strain information often goes unreported in the literature. As a result, the confounding efects of interstrain variation makes repetition of studies in zebrafsh challenging. Here we analyze hepatic mRNA expression patterns between three common zebrafsh strains (AB, Tuebingen (TU), and WIK) using Agilent 4 × 44 K gene expression microarrays to establish baseline mRNA expression across strains and between sexes. We observed wide variation in sex-specifc gene expression within AB and WIK strains (141 genes in AB and 67 genes in WIK), but no signifcant variation between sexes within TU.
    [Show full text]
  • Using the HPA Stress Axis As a Biological Readout for Backcrossing Strategies
    Neuropsychopharmacology (2017) 42, 1749–1751 © 2017 American College of Neuropsychopharmacology. All rights reserved 0893-133X/17 www.neuropsychopharmacology.org Commentary Strained in Planning Your Mouse Background? Using the HPA Stress Axis as a Biological Readout for Backcrossing Strategies Jennifer C Chan1, Amanda B Houghton1 and Tracy L Bale*,1 1 Department of Biomedical Sciences, School of Veterinary Medicine and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Neuropsychopharmacology (2017) 42, 1749–1751; doi:10.1038/npp.2017.66; published online 19 April 2017 The use of transgenic mouse lines over the last several decades antidepressant treatment compared to other inbred strains has been indispensible for modeling human conditions and (Lucki et al, 2001). In comparison, substrains of the 129 probing mechanisms underlying disease. Importantly, select- background display significant difficulty with hippocampal- ing the correct mouse background strain can be difficult and dependent learning tasks and fear extinction (Hefner et al, is, no doubt, critical to experimental outcomes, interpretation 2008; Camp et al, 2012), and another popular inbred strain, of results, and reproducibility. In the fields of stress and FVB/N, also has problems with learning tasks and prominent neuropsychiatric disease research, strain-dependent differ- visual impairments (Brown and Wong, 2007). Moreover, the ences in treatment sensitivity, neuroanatomical development, C57BL/6 mouse was the first rodent to have its genome stress and physiological responses, and performance on completely sequenced, again adding to its popularity amongst behavioral tests have directed laboratories toward using researchers and the disproportionately available literature and preferred mouse strains for reliable, robust results. resources for this strain (Waterston et al, 2002).
    [Show full text]