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Cytological Identification of the Chromosome Carrying the Ixth Linkage Group (Including H-2) in the House Mouse (Mus Musculus X Mus Poschiavinus)

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Cytological Identification of the Chromosome Carrying the Ixth Linkage Group (Including H-2) in the House Mouse (Mus Musculus X Mus Poschiavinus) Proc. Nat. A cad. Sci. USA Vol. 68, No. 7, pp. 1.594-1597, July 1971 Cytological Identification of the Chromosome Carrying the IXth Linkage Group (Including H-2) in the House Mouse (Mus musculus X Mus poschiavinus) JAN KLEIN Department of Oral Biolog- and Department of Human Genetics, The University of Michigan, Ann Arbor, Michigan 48104 Communicated by James V. Neel, May 5, 1,971 ABSTRACT Musposchiavinus X M. musculus hybrids, the method is demonstrated by identification of the chromo- which had seven metacentric chromosomes derived from some carrying the IXth linkage group. the poschiavinus complement, were repeatedly back- crossed to M. musculus and selected for the chromosome MATERIAL AND METHODS carrying the H-2 complex. A line called TI/Klj was estab- lished which had one metacentric chromosome. It was Plan of experiment shown by linkage tests and by cytogenetic studies that one arm of this metacentric chromosome corresponds to The experiment was based on two assumption.s: first, that 14 the M. musculus acrocentric chromosome carrying link- pairs of acrocentric chromosomes of M. musculus are homolo- age group IX, in which the H-2 complex is found. The gous to the arms of the metacentric chromosomes of M. distance from the H-2 locus to the centromere was tenta- poschiavinus; second, that the IXth linkage group of M. tively estimated as 14 map units. musculus is carried by one arm of one of the seven metacentrics Among all mammals, the house mouse, Mus musculus L., is of M1. poschiavinus rather than by one of the six poschiavinus genetically one of the best-defined species. Several hundred acrocentrics. The concept of the experiment was to replace, by genes are known in the mouse, 19 out of 20 linkage groups have repeated backerossing of M. poschiavinus to M. musculus, all been identified, and some of the linkage groups have been poschiavinus chromosomes with musculus chromosomes except tagged with as many as 20 different markers. In contrast to the the one metacentric assumed to carry a segment homologous relatively advanced state of the formal genetics, the cyto- to the histocompatibility-2 (H-2) complex of the IXth linkage genetics of the mouse is in a rudimentary stage. Cytogenetic group of the house mouse. The retention of the chromosome investigation is handicapped by difficulties in identification of carrying H-2 was accomplished by selection. Since no products individual mouse chromosomes. The 20 pairs of somatic corresponding to known H-2 antigens of the house mouse were chromosomes at metaphase show a continuous gradation in detected in the tobacco mouse, the selection was carried out length from the smallest to the largest; all 40 chromosomes indirectly (Fig. 1). In the original M. poschiavinus X M. have effectively terminal centromeres, and all show very little musculus hybrids which were made available to us by Drs. S. morphologic differentiation. These factors make the mouse Ohno and L. A. Herzenberg, the musculus genome was sup- chromosomes very difficult to classify. plied by strain BALB/c (H-2d/H-2d). Thus, the hybrids were The discovery by Gropp and coworkers of Robertsonian H-2?/H-2d. They were backcrossed in my laboratory to strain variation in the so-called tobacco mouse, M. poschiavinus B10. BR (H-2k/H-2k), the first backcross generation was sero- FATIO (1), could represent a major breakthrough in the logically typed with anti-H-2d and anti-H-2k antisera, and mouse cytogenetics. It provides an opportunity to approach animals of the H-2?/H-2k type were distinguished from those the problem of individualization of mouse chromosomes from of the H-2d/H-2k type. The former were used for further mat- a different angle. The tobacco-mouse is an endemic species in one high-altitude Swiss valley, the Val Poschiavo/Grison. Its H-2? /H-2? x H-2d/H-2d karyotype is characterized by the presence of seven pairs of metacentric chromosomes and six pairs of acrocentrics (2n = H-2/ H-2 x H-k/H-2 26; this is equivalent to the 40 arms of Mus musculus chromo- Test with anti-H-2d , select ( H 2dH-2k H, H somes). Each of the seven metacentric chromosomes is thought negative animals discard to have evolved from two acrocentrics by centric fusion. The x H-2d/H2d species interbreeds with M. musculus and the hybrids are H-2?/H-2k fertile (although the fertility is low). If it were possible to Test with anti-H-2k select ( H-2d/H-2k 1 2 incorporate the poschiavinus metacentrics one at a time into negative animals discard the musculus chromosome complement, identify them, and tag H-2?I H-2d x H-2k/ H-2k them with appropriate markers, this would greatly facilitate the distinction of individual mouse chromosomes and open etc. avenues for detailed In this cytogenetic investigation. prelimi- chromosome of M. nary communication, a method is described through which Hypothetical H-2 poschiavinus. such individualization can be achieved and the practicality of FIG. 1. Plan of experiment. 1594 Downloaded by guest on September 28, 2021 Proc. Nat. Acad. Sci. USA 68 (1971) Indentification of Alouse Chromosomes 1595 < t~~~~t j i / jta>t 7 4 hItA0F (it#Qtv IJI, v*_ FIG. 3. Somatic chromosome complement of T1/+ heterozy- gote with 1 metacentric and 38 acrocentric chromosomes. FIG. 2. Somatic chromosome complement of (M. poschiavinus X M. musculus) F, hybrid with 7 metacentric and 25 acrocentric direct hemagglutination test and in vitro absorption. Details chromosomes. on the production of antisera have been published elsewhere (5). ings; the latter were discarded. Karyotypes of the H-2?/H-2k RESULTS animals were determined, and mice with the lowest number of Breeding experiment metacentric chromosomes were backcrossed to strain B1O.D2 (H-2d/H-2d). The animals of the second backcross generation The experiment was started with six M. poschiavinus X M. were typed with the same two antisera, but this time mice of musculus (strain BALB/c) hybrids. The diploid chromosome the H-2?/H-2d type were selected for karyotyping and further complement of these hybrids contained 33 chromosomes, 7 of mating. This procedure was repeated until only one meta- them metacentric and 23 acrocentric (Fig. 2). The hybrids centric chromosome, presumably carrying the H-2 complex, were backcrossed to strain B1O.BR, and several lines were remained in the backcross animals. When this was achieved, a started from these crosses. Of these, only line 61 was eventu- line with this single metacentric was established and genetic ally retained; the other lines were discontinued. Among the and cytogenetic studies were carried out to prove that one arm animals in the first backeross generation of line 61 was a fe- of the metacentric chromosome indeed carried the IXth link- male which was serologically typed as H-2?/H-2k and whose age group of the house mouse. karyotype contained three metacentric chromosomes. This female was mated with a B10.D2 male, and from the second Cytological methods backcross generation a female of the type H-2?/IH-2d and The chromosome constitution of animals to be used for breed- having two metacentric chromosomes was selected and mated ing was ascertained by a biopsy method. In males, one testis with a B10.BR male. In the third backcross generation, female was removed under Nembutal anaesthesia at the age of 6 no. 1007 had only one metacentric chromosomes (Fig. 3) and weeks or more and meiotic chromosome preparations were was typed as H-2?/H-2k. Thus, after three generations of back- made by the air-drying method of Evans et al. (2). In females, crossing the number of metacentric chromosomes was reduced mitosis was stimulated by a subcutaneous injection of 0.2 ml of from 7 to 1. The metacentric chromosome retained was complete Freund's adjuvant, spleens were removed 4-6 days presumed to have one arm carrying the IXth linkage group of later, and mitotic chromosome preparations were made by an 1M1. musculus. On the assumption that this metacentric chromo- air-drying procedure based on the method of Ford and Hamer- some arose by translocation (centric fusion) involving two ton (3). The operated animals were mated for breeding pur- acrocentric chromosomes, it was given the symbol T(9;?) 1 pos poses 5 days after the operation. Chromosome preparations of Kij. By further mating of female no. 1007, a T1/+ hetero- animals not needed for breeding were made from bone marrow zygous line was established and used in subsequent genetic (3). All preparations were stained with Giemsa. and cytological studies. Serological methods Genetic studies The H-2 phenotypes of the segregants were determined by Evidence for homology between one arm of the TI chromo- direct hemagglutination test in PVP (4) using two mono- some and the acrocentric chromosome carrying the IXth specific antisera, anti-H-2.4 (testing for H-2d) and anti- linkage group was obtained by linkage tests between Ti and H-2.23 (testing for H-2k). Antigens which might have been the H-2 system (Table 1). The preliminary tests indicated determined by the poschiavinus homologue of the IXth linkage 10-17% recombination between the H-2 complex and Ti group were tested for with a battery of oligospecific antisera by (centromere). This result definitely located the H-2 system on Downloaded by guest on September 28, 2021 1596 Genetics: Klein Proc. Nat. A cad. Sci. USA 68 (1971) .... Y: M-:- 0 ~I-,,,'W I~~,'*I C Inv Noo i. w fl _t ~ A.~~ FIG. 5. First metaphase of Ti +/+ Ti38 hybrid with 1 pen- FIG. 4.
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