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The Proximal End of Mouse Chromosome 17: New Molecular Markers Identify a Deletion Associatedwith Quaking"'"""

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The Proximal End of Mouse Chromosome 17: New Molecular Markers Identify a Deletion Associatedwith Quaking Copyright 0 1992 by the Genetics Societyof America The Proximal End of Mouse Chromosome 17: New Molecular Markers Identify a Deletion AssociatedWith quaking"'""" Thomas Ebersole, Okkyung Rho and KarenArtzt Department of Zoology, The University of Texas, Austin, Texas 78712-1064 Manuscript received November 4, 1991 Accepted for publication January10, 1992 ABSTRACT Five randomly identified cosmids have been mapped proximal to the Leh66D locus on mouse chromosome 17. Two of these cosmids, AulO and Aull9, map near the neurological mutationquaking. Au119 is deleted in qk-blt/qk~ab'cDNA, whereas AulO is not. Au76 maps to a gene-rich region near the Tme locus. The Au76 locus encodes a member of a low copy gene family expressed in embryos, the adult central nervous system and testis. A second member of this family has been mapped to chromosome 15 near c-sis (PDGF-B). At the centromeric end of chromosome 17, Au116 maps near the Tu1 locus, and along with Au217rs identifies a region of unusually high recombinational activity between t-haplotypes and wild-type chromosomes. Au217I and II map to the large inverted repeats found at the proximal end of the wild-type chromosome. In addition, the Au2171 and/or II loci encode testis transcripts not expressed from t-haplotypes. HE attention given the proximal third of mouse and classical recombination analysis, many markers T chromosome 17 derives, in large part, from the have been mapped into the proximal end. The distri- analysis of t-haplotypes, a variant form found in wild bution of markers is, however, quite variable. The populations of mice. t-Haplotypes exhibit a set of well highest densities occur in the -3-Mbp interval be- defined characteristics: (1) recombinationsuppression tween Lehll9I and T (>3 markers/Mbp), and in the with wild-type chromosomes over a region of an esti- -1-Mbp Plg to Leh66D interval (>6 markers/Mbp). mated 40-Mbp, aconsequence of the existence of By comparison, the regions between T and Plg, and several large inversions (HAMMER,SCHIMENTI and proximal to Lehl191 arerelatively poorly marked (see SILVER1989; HERRMANN et al. 1986; SHIN et al. Figure 1). The combined physical distance involved 1983); (2) transmission ratiodistortion favoring t- in these underrepresented regions can only be esti- haplotype-bearing sperm in t/+ heterozygous males; mated, but a conservative minimum distance would (3) sterility of f/tY males; and (4) usually the presence be -1 0 Mbp, which would convert to less than one of one or more recessive lethal mutations (BENNETT marker per 1O6 bp. 1975). In order to enhance the genetic and physical maps The region encompassed by the inversions is called of the proximal end of chromosome 17 we report the the t-complex. The area within the two most proximal mapping of unique or low copy sequences from five inversions, In(l7)l and In(17)2, are referred toas the cosmids centromeric to theLeh66D locus in wild-type "proximal end." This region is delimited in wild-type chromosomes. These cosmids are part of a larger set chromosomes by the markers Tu1 and Leh66D. The mapping to the t-complex. They were identified by proximal end of t-haplotypes has been compared with screeninga Chinese hamster-mouse cell hybrid ge- its wild-type counterpart in terms of chromosome nomic library with mouse-specific repetitive element structure and apart from the inversions, anotable probes, followed by mapping of mouse-derived cos- structural difference involves an element of at least mids to the t-complex using t-haplotype us. wild-type 650 kbp existing in one copy in t-haplotypes which is restrictionfragment length polymorphism (RFLP) duplicated and inverted inwild-type chromosomes. analysis (EBERSOLE,LAI and ARTZT 1992). The data These elements are thought to serve as regions of presented here introduces new markers into under- matched chromatin which can yield rare recombina- represented regions of chromosome 17 proximal to tion events between t-haplotypes and wild-type chro- Leh66D. Furthermore, these new markers have al- mosomes (HERRMANN,BARLOW and LEHRACH 1987). lowed us to confirm previously described chromosome The resulting partial t-haplotypes have been valuable structure, identify aregion of unusual recombina- mapping tools for the region. tional activity between t-haplotypes and wild-type With the use of partial t-haplotypes, deletions oc- chromosomes, and show that theoriginal spontaneous curring in wild-type chromosomes or t-haplotypes, qk mutation (SIDMAN,DICKIE and APPEL 1964) is Generics 151: 183-190 (May, 1992) 184 T. Ebersole, 0. Rho and K. Artzt associated witha deletion. Also included in this report been added to 7%,and hybridization was continued for 12- are the map positions of some members of two low 24 hr. A 100-200-n BPsam le of probe DNA was random copy gene families detected with these cosmids. One primed to at least 10 cpm/pg. Three to four million cpm/ ml were added to 200 pg/ml sonicated salmon sperm DNA, family, from a locus duplicated on wild-type chromo- denatured and added to the bag. For probes containing some 17 (loci: Dl 7Au217I and Dl 7Au217II), encodes repetitive sequences, 100-200 pg/ml sonicated cold mouse two testis transcripts not expressed in t-haplotypes. DNA were also added,the mixture was denatured and The other family, a member of which is found at the incubated for 1-2 hrat 42" in 8-10 ml hybridization Dl 7Au76 locus, encodes transcripts found in testicular solution, and then added to the bag. All blots were washed twice in 2 X SSC, 0.1 % SDS at 65",followed by a final wash germ cells, early embryos, and, in later embryos and in 0.1 X SSC, 0.1% SDS at 65". adults, in restricted parts of the central nervous sys- tem. RESULTS MATERIALS AND METHODS AuZO and Ad29 are two loci near qR: The probes P10 and P119 both detect polymorphisms between DNA and probe sources: Characterization of the break- points of the partial t-haplotpes t6 and P,and of the wild type and t-haplotypes with TaqI. P10 detects a deletion chromosomes Thp, gr,TzzH, TP" and TPb2are 5.0-kbp or 3.8-kbp wild-type band, depending on the found in Committee on the Mouse Chromosome 17 (199 1). strain. In t-haplotypes a 2.6-kbp band is present and The partial t-haplotypes r5=and t""'tf are described in also a faint doublet at about 1.2 kbp (Figure 2). The HOWARDet al. (1990). Additional references for some chro- wild-type bands are missing in PP and Ttorl,but not mosomes follow: Thp, JOHNSON (1974); p,SELBY (1973); also see BENNETTet al. (1975); BABIARZ(1 983); Tto", SARV- p or FZH(refer to Figure 1 for a depiction of these ETNICK et d. (1986); fd, VOJTISKOVA et al. (1976); pb2, chromosomes). Furthermore, the locus is duplicated WINKINGand SILVER(1984); t6, HERRMANN,BARLOW and in kub2, that is, Tto"/kub2 DNA hasboth wild-type and LEHRACH(1987). DNA was prepared from liver usingstand- t-type bands, whereas Ttorlcarries neither. An identi- ard methods or from spleen in 0.5% low-melting-point cal situation existswith P119: wild-typebands are agarose plugs. Wild type refers either to the C3H/DiSn or BTBRTF/Nev mouse strains. Identification of the five cos- deleted in pfi and Ttorl,but not 70' or TZ", and the mids is reported in a companion study (EBERSOLE, LAIand locus is duplicated in Pb2(data not shown). The ARTZT,1992). Probes for thenew loci described here were D17RP17 locus has been previously mapped to this derived from genomic fragments from cosmid clones or, in same region using the samechromosomes (HERR- the case of P217c, cDNA isolated using the cosmid clone MANN et al. 1986; MANN,SILVER and ELLIOTT1986). 217. The 1.4-kbp cDNA (DI5Au76rse) was detected in a testicular cell cDNA library using pooled BglII fragments The qk locus is known to be deleted in Ttorland pp, from the chromosome I7 cosmid 76. The cDNA, when but not p (BENNETTet al. 1975; ERICKSON, LEWIS hybridized back to cosmid 76, will cross-hybridize to it and and SLUSSER1978), and it has been mapped within detect a 1.7-kbp BamHI fragment (P76). All blots were 0.3 cMof D17RP17 (KING and DOVE 1991). We, washed under stringent conditions: 0.1 X SSC, 0.1% sodium therefore, expected AulO and Au119 to map near qk dodecyl sulfate (SDS), 65", 10-15 min final wash. Nomenclature: Because allthe probes derive from mouse and be useful in the cloning of the gene affected in chromosome 17, for simplicity, each locus will be referred this interesting neurological mutation. We tested to by an abbreviation of the formal name, hence Dl 7AuIO these two loci in quaking miceby hybridization of will be called AulO, etc. Loci on chromosomes other than precompeted whole cosmid to restriction enzyme di- I7 will be referred to with the full name. The original qk gests of qk"/qk" liver DNA. As shown in Figure 3, the mutation has been renamed qkvinbl' to distinguish it from the Aull9 cosmid detects several bands in control lanes recessive lethal ethylnitrosurea (ENU)-induced alleles (KING and DOVE1991). but not any in qk"/qk" DNA. This indicates that most The probes for each locus are named with a P followed if not all of the -40-kbp Au119 cosmid is deleted in by the locus name, P10 is a 4.2-kbp BamHI genomic frag- qk"/qk" mice. This result was verified using two other ment from locus AulO; P116, a 2.8-kbp Hind111 genomic enzymes and two other DNA preparations, one from fragment; P119, a 8.0-kbp EcoRI genomic fragment; P76, a spleen and the other from liver.
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