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Kb Candidate Region on Chicken Chromosome 12

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Kb Candidate Region on Chicken Chromosome 12 GENETICS AND GENOMICS Narrowing the wingless-2 mutation to a 227 kb candidate region on chicken chromosome 12 A. E. Webb,∗,2,6 I. A. Youngworth,∗,6 M. Kaya,†,3 C. L. Gitter,∗,4 E. A. O’Hare,∗,5 B. May,∗ H. H. Cheng,† and M. E. Delany∗,1 ∗Department of Animal Science, University of California, Davis 95616; and †USDA-ARS, Avian Disease and Oncology Laboratory, East Lansing, MI 48823 ABSTRACT Wingless-2 (wg-2) is an autosomal re- element. Specifically, the wg-2 mutation was initially cessive mutation in chicken that results in an embry- mapped to a 7 Mb region of chromosome 12 using an onic lethal condition. Affected individuals exhibit a Illumina 3 K SNP array. Subsequent SNP genotyping multisystem syndrome characterized by absent wings, and exon sequencing combined with analysis from im- truncated legs, and craniofacial, kidney, and feather proved genome assemblies narrowed the region of in- malformations. Previously, work focused on phenotype terest to a maximum size of 227 kb. Within this re- description, establishing the autosomal recessive pat- gion, 3 validated and 3 predicted candidate genes are tern of Mendelian inheritance and placing the muta- found, and these are described. The wg-2 mutation is tion on an inbred genetic background to create the a valuable resource to contribute to an improved un- congenic line UCD Wingless-2.331. The research de- derstanding of the developmental pathways involved in scribed in this paper employed the complementary tools chicken and avian limb development as well as serving of breeding, genetics, and genomics to map the chromo- as a model for human development, as the resulting somal location of the mutation and successively nar- syndrome shares features with human congenital disor- row the size of the region for analysis of the causative ders. Key words: SNP genotyping, limb development, candidate gene, mutation 2018 Poultry Science 97:1872–1880 http://dx.doi.org/10.3382/ps/pey073 INTRODUCTION acterized by the complete absence of forelimbs, severely truncated or absent hindlimbs, craniofacial defects The wingless-2 (wg-2) mutation was originally iden- (maxillary region clefting), malformed kidneys, and ab- tified at the University of Connecticut in a flock normal plumage (Zwilling, 1956;Somes,1990;Pisenti of chickens synthesized from Rhode Island Red, et al., 1999). The mutation is inherited in an autosomal White Leghorn, Dorking breeds, and Red Jungle Fowl recessive pattern and is an embryonic lethal (Somes, (Zwilling, 1956). The wg-2 mutant phenotype is char- 1990;Pisenti,1995). Reciprocal tissue transplantations between mesoderm and ectoderm suggest that the wg-2 C The Author 2018. Published by Oxford University Press mutation affects ectoderm (Carrington and Fallon, on behalf of Poultry Science Association. This is an Open Ac- 1984; Hamburger and Hamilton, 1992). Wg-2 was the cess article distributed under the terms of the Creative Com- second wingless mutation characterized in the chicken; mons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/4.0/), which permits non-commercial re-use, dis- the first, now extinct, exhibited a similar phenotype tribution, and reproduction in any medium, provided the original and additionally was described as having incomplete or work is properly cited. For commercial re-use, please contact jour- absent lungs, air sacs, and kidneys (Waters and By- [email protected]. waters, 1943). An improved understanding of the wg-2 Received October 4, 2017. Accepted February 27, 2018. developmental mutation will lead to new knowledge of 1Corresponding author: [email protected] important developmental pathways in poultry affect- 2Current address: Center for Computational Genetics and Ge- ing limb, craniofacial (e.g., beak), kidney, and feather nomics, Temple University, Philadelphia, PA, 19122 3Current address: Eskisehir Osmangazi University, Department of development. Further, the wg-2 developmental muta- Agricultural Biotechnology, 26160 Eskisehir, Turkey tion is an important model system for the investigation 4Current address: International Crane Foundation, Baraboo, WI, of genes and pathways involved in human syndromes 53913 with craniofacial (cleft palate), limb (tetra-amelia, pho- 5Current address: Department of Biological Sciences, Towson Uni- versity, Towson, MD 21252 comelia) and organ (kidney) malformations. 6Joint first-authors. 1872 CHICKEN WINGLESS-2 MAPS TO CHROMOSOME 12 1873 In the late 1980s at the University of California Davis Table 1. TaqManR primer-probe sequences for the SNP390 (UCD), a congenic inbred line was established by in- (rs14034687) genotyping assay used to predict UCD Wg-2.331 trogression of wg-2 in order to advance mapping and genotypes: +/+, +/wg-2, wg-2/wg-2. gene analysis research at a time wherein genomic tools SNP coordinate1 Chr 12: 5,061,391 were barely envisioned, much less the advent of the Amplicon coordinates1 Chr 12: 5,061,327 - 5,061,449 chicken sequencing project to advance poultry and ver- Forward primer 5 CTCTTTTGTTAGAGCTGTGCTATG- tebrate biology. The Wingless-2.331 (Wg-2.331)con- G3 genic inbred line was derived by first crossing known wg- Reverse primer 5 CAGGACTGTTGCTTTTGTTCTT- TATAGTTTT 3 2 carriers (+/wg-2) into the UCD 331.003 congenic line VIC probe (+/+) 5 CATGAACACAAAGCC 3 (Abplanalp et al., 1992; Pisenti et al., 1999). The +/wg- FAM prob e (wg-2/wg-2)5 CATGAACATAAAGCC 3 2 carrier progeny were confirmed by test-mating and 1Coordinates based on Dec 2015 Gallus gallus-5.0/galGal5 chicken as- then used to backcross to the parent line UCD 331.003. sembly for GGA 12. The backcross method using confirmed carrier (+/wg- 2) progeny was repeated for at least 7 generations, with by the UC Davis Institutional Animal Care and Use 2 additional backcrosses after the line was closed to Committee (Protocol #18816). improve fertility and viability, as per available breed- ing records and personal communications. This labor- intensive multi-year strategy placed the wg-2 locus in a Illumina 3,072 (3 K) SNP Array Analysis uniform genetic background (99+% inbred) such that Samples were collected from 9 adult Wg-2.331 birds only the introgressed region containing the mutation confirmed as carriers (+/wg-2) by test-mating and 11 along with other normal polymorphisms differs between phenotype-confirmed mutant embryos (wg-2/wg-2)at normal (+/+ or +/wg-2)andmutant(wg-2/wg-2)in- 10 d of embryogenesis (10E). DNA was isolated and pu- dividuals. The line was closed (inter se matings only) rified from blood stored in heparin (adults) or sodium and perpetuated using +/wg-2 parentsasbreedersaf- citrate (embryos). All DNA samples were isolated us- ter being verified by test crosses. Over more than 60 yr ing QIAampR Blood Mini Kit (Qiagen, Valencia, CA) of breeding, Mendelian ratios fit an autosomal recessive and sent to Illumina, Inc. (San Diego, CA) for analy- pattern of inheritance for the wg-2 mutation. sis. Samples were tested for 3,072 SNP evenly spaced Here, we describe genetic and genomic analyses of throughout the chicken genome (Gitter, 2006;Muir the congenic inbred line Wg-2.331 that have signifi- et al., 2008a; Muir et al., 2008b). SNP linked to wg-2 cantly advanced our knowledge of the genomic region should be homozygous in all wg-2 mutants, heterozy- incorporating the wg-2 mutation—work that took place gous in wg-2 carriers, and homozygous for the alterna- over a decade and spanned 4 chicken genome builds. tive allele in UCD 331.003. The work is presented in galGal5 coordinates for the sake of clarity, with references to the state of the build at the time when necessary. At the outset, the chromo- Genotyping Wg-2.331 Birds Using a Linked somal location and subregion of the wg-2 mutation was SNP mapped by using a custom Illumina 3 K SNP chicken array (Muir et al., 2008a) wherein a tightly linked SNP The 3 K SNP analysis found one SNP (rs14034687 was identified, which had the advantage of being pre- aka SNP-16–390-35,608-S-1 and referred to as dictive of carrier status. Subsequently, new SNP were “SNP390”) in complete linkage disequilibrium (LD) identified and used for fine-mapping, which, combined with the mutant phenotype and, thus, had high value with exon-based sequencing of candidate genes within in screening for wg-2 status. An Applied Biosystems the region, significantly narrowed the causative region. Custom TaqManR SNP Genotyping Assay was de- veloped for this purpose (Table 1). Real-time PCR was performed on DNA samples (10 ng/μl) isolated MATERIALS AND METHODS from Wg-2.331 individuals to determine genotypes for SNP390 using TaqManR Universal PCR Master Mix Genetic Lines (Applied Biosystems, Carlsbad, CA) under standard ◦ All birds are derived from the UCD Wg-2.331 de- conditions. After 15 min at 95 Ctoactivatethe polymerase, samples underwent 45 cycles of 95◦Cfor velopmental mutant congenic inbred chicken line. The ◦ birds initially carrying the wg-2 mutation were bred into 15 s, 60 C for 1 min, and a plate read. Genotypes the UCD 331.003 line, which is congenic with UCD 003 were confirmed by comparison to previously genotyped [a highly inbred line (F > .99)] except at the major his- (SNP390) or phenotype-confirmed samples represent- tocompatibility complex (Abplanalp et al., 1992)and ing the 3 forms of the SNP (normal +/+, +/wg-2; a small number of other SNP loci (Robb et al., 2011). mutant wg-2/wg-2) with test-mating to affirm carrier Samples throughout this paper are designated as wild status (+/wg-2). Samples were collected for DNA type +/+ (normal phenotype), carrier +/wg-2 (nor- preparation and genotype determination at one of mal phenotype), or mutant wg-2/wg-2 (abnormal phe- 3 time points, depending on the experiment: adults notype). The birds used in this research were cared for (blood), one d post-hatch chicks (pin feather), or by trained staff and according to a protocol approved embryos (blood).
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