Natural resistance to infection with Legionella pneumophila: chromosomal localization of the Lgn1 susceptibility gene

Legionella pneumophila is a strict intracellular pathogen that replicates in the professional phagocytes of the human and guinea pig host. Although murine macrophages from most inbred strains are non-permissive to intracellular replication of L. pneumophila, inflammatory macrophages from the mouse strain A/J are completely permissive to intracellular replication of this bacterium. This genetic difference is controlled by the expression of a single autosomal gene designated Lgn1, with non-permissiveness behaving as completely dominant over permissiveness. We have used a total of 25 AXB/BXA recombinant inbred mouse strains and 182 (A/JxC57BL/6J)xA/J segregating backcross progeny (A/J, permissive; C57BL/6J, non-permissive) to map the Lgn1 gene. Animals were individually type for tolerance to intracellular replication by in vitro infection of their inflammatory macrophages with L. pneumophila. All animals segregated into two non-overlapping groups. Examination of the strain distribution pattern of the AXB/BXA strains for Lgn1 initially identified linkage to Chromosome (Chr) 13 markers. Genotyping of the 25 AXB/BXA strains and the 182 backcross progeny for 11 Chr 13 markers established that Lgn1 mapped to Chr 13, with the gene order and intergene distance D13Mit231-(5.5±1.5)-D13Mit193-(2.2±0.9)-D13Mit194-(1.1±0.6)-D13Mit128-(2.6±1.0)-Lgn1-(2.2±0.9)-D13Mit70-(3.9±1.3)-D13Mit73-(7.2±1.7)-D13Mit53-(0.7±0.5)-D13Mit32-(0.7±0.5)-D13Mit77-(0.7±0.5)-D13Mit78. This portion of Chr 13 is homologous to the distal portion of human Chr 5, 5q11–5q13, suggesting a possible location of a human LGN1 homolog. Understanding the molecular basis of the high permissiveness of A/J macrophage to L. pneumophila may shed light on the survival strategy of this bacterium in highly permissive human phagocytes. This may be achieved by positional cloning of Lgn1, and the identification of the Lgn1 subchromosomal region reported here is a first step towards that goal.     

Fine genetic mapping of the proximal part of mouse Chromosome 2 excludes Pax-8 as a candidate gene for Danforth's short tail (Sd)

Danforth's short tail (Sd) is a semidominant mutation of the mouse with effects on the skeleton and the urogenital system. In view of its phenotype and its position in the proximal part of Chromosome (Chr) 2, three genes qualified as possible candidates: Pax-8, a paired box-containing gene; Midkine (Mdk), a retinoic acid-responsive gene; and a new locus (Etl-4) identified by enhancer trapping with a lacZ reporter gene which showed expression in the notochord, the mesonephric mesenchyme, and the apical ectodermal ridge. Three different backcrosses involving all three genes in different combinations were set up and analyzed. From our results we conclude that Sd, Etl-4, Pax-8, and Mdk are independent loci, with Etl-4 being the closest genetic marker (1.1±1.4 cM) to the Danforth's short tail (Sd) gene.     

Re-localization of Actsk-1 to mouse Chromosome 8, a new region of homology with human Chromosome 1

We present here the genetic mapping of the -skeletal actin locus (Actsk-1) on mouse Chromosome (Chr) 8, on the basis of the PCR analysis of a microsatellite in an interspecific backcross. Linkage and genetic distances were established for four loci by analysis of 192 (or 222) meiotic events and indicated the following gene order: (centromere)-Es-1-11.7 cM-Tat-8.3 cM-Actsk-1-0.5 cM-Aprt. Mapping of ACTSK to human Chr 1 and of TAT and APRT to human Chr 16 demonstrates the existence of a new short region of homology between mouse Chr 8 and human Chr 1. Intermingling on this scale between human and mouse chromosomal homologies that occurred during evolution creates disorders in comparative linkage studies.     

Mapping of the mouse ornithine decarboxylase-related sequence family

A family of DNA sequences homologous to the mRNA encoding ornithine decarboxylase (ODC) and comprising 12 members in the mouse genome has been analyzed genetically. The inheritance of variant DNA restriction fragments detected by ODC cDNA probes on Southern blots of DNA from inbred strain mice was determined in six sets of recombinant inbred (RI) mouse strains. The distributions of these variations among the RI strains were then compared with the RI strain distribution patterns (SDPs) of previously mapped loci. This allowed the identification of nine independent ODC-related loci, of which eight could be localized to specific regions of the mouse genome: Odc-rs1 near Lamb2 on Chromosome (Chr) 1; Odc-rs2 near Psp on Chr 2; Odc-rs5, a complex locus comprising at least 5–7 copies of the ODC sequence, associated with Igk on Chr 6; Odc-rs6 between Abpa and Tam-1 on proximal Chr 7; Odc-rs7 near Hbb on distal Chr 7; Odc-rs12 near Agt and Emv-2 on distal Chr 8; Odc-rs8 associated with the Igh complex on Chr 12; and Odc-rs9 near Otf-3f on Chr 14. The ODC-related sequence family thus comprises a set of genomically dispersed marker loci, and alleles for several of these loci can be analyzed simultaneously in DNA from mice or cell lines. DNA from mice of 70 inbred strains has been characterized for alleles at all nine Odc-rs loci.     

Localization of the murine cholecystokinin A and B receptor genes

We have determined the chromosomal locations of the two cholecystokinin (CCK) receptor genes in the mouse. Genetic localization utilized an interspecific backcross panel formed from the cross (C57BL/6J x Mus spretus) F₁ x Mus spretus. Genomic DNAs from 94 individuals in the backcross were analyzed by Southern hybridization with rat CCK_A and CCK_B receptor cDNA probes. Unique map positions were determined by haplotype analysis with 650 previously mapped loci in the mouse backcross. The CCK_A receptor gene (Cckar) mapped to mouse Chromosome (Chr) 5, in tight linkage with the DNA marker D5Bir8. The CCK_B receptor gene (Cckbr) mapped to mouse Chr 7, tightly linked to the -hemoglobin locus (Hbb). This localization places Cckbr in the same region as the mouse obesity mutation tubby (tub), which also maps near Hbb (2.4±1.4 cM). Since CCK can function as a satiety factor when administered to rodents, localization of Cckbr near the tub mutation identifies this receptor as a possible candidate gene for this obesity mutation.     

Mapping of the structural gene for S-adenosyl homocysteine hydrolase to mouse Chromosome 2, and related sequences to Chromosomes 8 and X

Comparative mapping studies in human and mouse have shown that, to date, human Chromosome (Chr) 20 is completely syntenic with distal mouse Chr 2. The structural locus for S-adenosyl-l-homocysteine hydrolase (EC 3.3.1.1) in human, AHCY, maps to 20 qterq13.1, and we report here that the homologous locus in the mouse, Ahcy, maps to distal mouse Chr 2 with gene order Pcna-Ahcy-Ada. Analysis of 123 progeny of an interspecific backcross between a laboratory stock, AN, and Mus spretus using a rat cDNA probe revealed the presence of at least two other Ahcy-related sequences segregating independently in the mouse genome. One, Ahcy-rs1, was mapped to Chr 8 in the BXH recombinant inbred strains, and the other, Ahcy-rs2, shows a pattern of inheritance consistent with X-linkage.     

Synteny conservation of the Huntington's disease gene and surrounding loci on mouse Chromosome 5

The mouse homologs of the Huntington's disease (HD) gene and 17 other human Chromosome (Chr) 4 loci (including six previously unmapped) were localized by use of an interspecific cross. All loci mapped in a continuous linkage group on mouse Chr 5, distal to En2 and Il6, whose human counterparts are located on Chr y. The relative order of the loci on human Chr 4 and mouse Chr 5 was maintained, except for a break between D5H4S115E and Idua/rd, with relocation of the latter to the opposite end of the map. The mouse HD homolog (Hdh) mapped within a cluster of seven genes that were completely linked in our data set. In human these loci span a1.8 Mb stretch of human 4p 16.3 that has been entirely cloned. To date, there is no phenotypic correspondence between human and mouse mutations mapping to this region of synteny conservation.     

A molecular genetic linkage map of mouse chromosome 2

Interspecific backcross mice were used to create a molecular genetic linkage map of chromosome 2. Genomic DNAs from N2 progeny were subjected to Southern blot analysis using molecular probes that identified the Abl, Acra, Ass, C5, Cas-1, Fshb, Gcg, Hox-5.1, Jgf-1, Kras-3, Ltk, Pax-1, Prn-p, and Spna-2 loci; these loci were added to the 11 loci previously mapped to the distal region of chromosome 2 in the same interspecific backcross to generate a composite multilocus linkage map. Several loci mapped near, and may be the same as, known mutations. Comparisons between the mouse and the human genomes indicate that mouse chromosome 2 contains regions homologous to at least six human chromosomes. Mouse models for human diseases are discussed.     

Genetic map of seven polymorphic markers comprising a single linkage group on rat Chromosome 5

Seven polymorphic markers comprising a single linkage group were assigned to rat Chromosome (Chr) 5 by linkage analysis of the progeny of an F₂ intercross of Fischer (F344/N) and Lewis (LEW/N) inbred rats. Three genes, -L-fucosidase 1 (FUCA1), mitochondrial superoxide dismutase (SOD2), and glucose transporter (GLUT1), were mapped by restriction fragment length polymorphism (RFLP) analysis. Two genes, glucose transporter (GTG3) and elastase II (ELAII), one pseudogene for tubulin (TUBAPS), and one sequence related to the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene (PFKFBP1-related sequence) were mapped by simple sequence repeat (SSR) polymorphism analysis. The loci are in the following order: SOD2, GTG3/GLUT1, FUCA1, ELAII/PFKFBP1-related sequence, and TUBAPS. This linkage group covered 68.3 cM of rat Chr 5. The SSR markers were highly polymorphic in 13 inbred rat strains (SHR/N, WKY/N, MNR/N, MR/N, LOU/MN, BN/SsN, BUF/N, WBB1/N, WBB2/N, ACI/N, LER/N, F344/N, and LEW/N). These markers, located on rat Chr 5, will be useful in genetic studies of inbred rats.     

A single linkage group comprising 11 polymorphic DNA markers on rat Chromosome 3

Eleven polymorphic DNA markers were mapped to rat Chromosome (Chr) 3 by linkage analysis of F₂ progeny of F344/N and LEW/N rat strains. The markers, including seven genes and four anonymous loci, formed a single linkage group covering approximately 112 cM with the following order: Ptgs1 (prostaglandin G/H synthase I)-D3Arb178-Scn2a (sodium channel, type II, -polypeptide)-D3Arb1-Cat (catalase)-Bdnf (brain-derived neurotrophic factor)-D3Arb219-D3Arb2-Sus2 (seminal vesicle secretion II protein)-Sdc4 (ryudocan/syndecan4)-Stnl (statin-like protein). Eight of these markers were analyzed for polymorphisms in 14 additional inbred rat strains. Three to five alleles were detected for each marker, suggesting that they are highly polymorphic and useful for genetic mapping studies with inbred rat strains. Chromosomal syntenic conservation among rats, mice and humans is also discussed.     

Mapping of multiple mouse loci related to the farnesyl pyrophosphate synthetase gene

The prenyltransferases are a class of enzymes involved in the synthesis of sterol and nonsterol isoprene compounds. We report here the chromosomal mapping of nine loci in the mouse that hybridize to the cDNA for the enzyme farnesyl pyrophosphate synthetase (FPS), a prenyltransferase that catalyzes the synthesis of an intermediate common to both the sterol and nonsterol branches of the isoprene biosynthetic pathway. Mapping was performed with genomic DNA from a mouse-hamster somatic cell hybrid panel, and by linkage analysis with recombinant inbred strains and the progeny of an interspecific backcross. The mapped loci have been designated farnesyl pyrophosphate synthetase-like-1 (Fpsl-1) on mouse Chromosome (Chr) 3; Fpsl-2 on Chr 4; Fpsl-3, Fpsl-4, and Fpsl-5, dispersed on Chr 10; Fpsl-6 on Chr 12; Fpsl-7 on Chr 13; Fpsl-8 on Chr 17; and Fpsl-9 on Chr X. It is presently unclear which of these loci encode active prenyltransferases and which may correspond to pseudogenes. The strongly hybridizing loci provide convenient genetic markers for seven mouse chromosomes.     

Influence of five pyrethroid insecticides on microbial populations and activities in soil

Laboratory tests were conducted to determine the effects of five pyrethroid insecticides—permethrin (FMC 33297) [3-phenoxybenzyl (±)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate]; FMC 45498 [(S)--cyano-3-phenoxybenzyl-(R)-cis-2-(2,2-dibromovinyl)-3,3-dimethylcyclopropanecarboxylate]; Shell WL 41706 [(±)--cyano-3-phenoxybenzyl 2,2,3,3-tetramethylcyclopropane-carboxylate]; Shell WL 43467 [(±)--cyano-3-phenoxy benzyl (±)-cis,trans-2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropanecarboxylate]; and Shell WL 43775 [(±)--cyano-3-phenoxybenzyl (±)-2-(4-chlorophenyl)-3-methylbutyrate]—at 0.5 and 5g/g on microbial populations and activities in a sandy loam. The insecticides had antimicrobial activity in early stages of incubation. The populations recovered after 2 to 4 weeks and stimulatory effects on populations were also observed in later stages. No inhibition of acetylene (C₂H₂) reduction was evident with any of the insecticides. However, WL 43467 at both concentrations and permethrin and WL 41706 at 5 g/g increased nitrification after 4 weeks. Soil microbial respiration, as indicated by oxygen consumption, increased with increasing concentration of insecticides, suggesting the possibility of microbial degradation of the insecticides. Dehydrogenase activity showed that none of the insecticides inhibited formazan (2,3,5-triphenyltetrazolium formazan) formation, whereas urease activity was stimulated in most cases. The studies indicated that some of the pyrethroid insecticides may exert transient effects on populations and activities of the microflora in a sandy loam, but these were short-lived and minor in nature.     

Genetic mapping near the myd locus on mouse Chromosome 8

Myodystrophy (myd), an autosomal recessive mutation of the mouse characterized by progressive weakness and dystrophic muscle histology, maps to the central portion of Chromosome (Chr) 8 (Lane et al. J. Hered 67, 135, 1976). This portion of Chr 8 contains the genes for a mitochondrial uncoupling protein (Ucp) and kallikrein (Kal3), which map to distal 4q in the human, providing evidence for a segment of homology. Characteristics of the myd phenotype coupled with this homology suggest that myd may be a mouse homolog of facioscapulohumeral muscular dystrophy (FSHD), which maps to human 4q35. We have confirmed and expanded the region of mouse 8-human 4 homology by generating a map of Chr 8 in an interspecific backcross of C57BL/6J and a partially inbred strain derived from M. spretus. The map is comprised of the genes for Ucp, coagulation factor XI (Cf11), and chloride channel 5 (Clc5), all of which have homologs on distal human 4q, 15 microsatellite loci, and the membrane cofactor protein pseudogene (Mcp-ps). To place myd in the genetic map, 75 affected progeny from an intersubspecific backcross of animals heterozygous for myd with Mus musculus castaneus were genotyped with Chr 8 microsatellite loci. The mutation maps between D8Mit30 and D8Mit75, an interval that is flanked by genes with human homologs at distal 4q. These results are consistent with the possibility that myd is the mouse homolog of FSHD.     

Genetic map of rat Chromosome 5 including the fatty (fa) locus

Thirteen loci, including the obesity gene fatty (fa), were incorporated into a linkage map of rat Chromosome (Chr) 5. These loci were mapped in obese (fa/fa) progeny of a cross between BN×13M-fa/+ F₁ animals. Obese rats were scored for BN and 13M alleles at four loci (Ifna, D1S85h, C8b, and Lck1) by restriction fragment length polymorphisms and at eight additional loci (Glut1, Sv4j2, R251, R735, R980, R252, R371, and R1138) by simple sequence length polymorphisms (SSLP). The resulting map spans 67.3 cM of Chr 5, presenting nine previously unmapped loci and one locus (Lck1) previously assigned to Chr 5 by use of somatic cell hybrid lines. Seven of the eight SSLP loci are newly identified; the SSLP linkage group alone spans 56.8 cM. The order of the loci is Sv4j2-R251-R735-R980-R1138-Ifna-fa-D1S85h-C8b-(Glut1-R252-R371)-Lck1. One locus, D1S85h, was found to lie only 0.4 cM from fa, close enough to serve as a reliable marker for the prediction of phenotype from genotype, and will be useful also for studies on the development of obesity in the fatty rat.     

A genetic linkage map of rat Chromosome 5 reveals extensive linkage conservation with mouse Chromosome 4

Linkages among three biochemical loci (Acol, Ahd2, and Mup1) and four microsatellite loci (A8, Glut1, Jun, and Pnd) were determined to construct a linkage map of rat Chromosome (Chr) 5. Consequently, an extensive linkage map on rat Chr 5 was constructed with the following gene order: A8-Aco1-Mup1-Jun-Glut1-Ahd2-Pnd. In this linkage map, the Jun and A8 loci are newly placed, and two previously reported linkage groups on rat Chr 5 are connected by the Jun locus. The linkage map indicates an extensive linkage conservation between the loci on rat Chr 5 and those on mouse Chr 4.     

Linkage of Agt and Actsk-1 to distal mouse Chromosome 8 loci: a new conserved linkage

Angiotensinogen is an ₂ involved in the maintenance of blood pressure and electrolyte balance. We have refined the position of the mouse angiotensinogen locus (Agt) on Chromosome (Chr) 8 and have also confirmed the assignment of the human angiotensinogen locus (AGT) to Chr 1. The segregation of several restriction fragment length variants (RFLVs) was followed in two interspecific backcross sets and in four recombinant inbred (RI) mouse sets. Analysis of the segregation patterns closely linked Agt to Aprt and Emv-2, which places the angiotensionogen locus on the distal end of mouse Chr 8. Additionally, a literature search has revealed that the strain distribution pattern (SDP) for the mouse skeletal -actin locus 1 (Actsk-1, previously Actal, Acta, or Acts) is nearly identical to the SDP for Agt in two RI sets. On the basis of this information we were able to reassign Actsk-1 to mouse Chr 8. By screening a panel of human-mouse somatic cell hybrids, we confirmed that the human angiotensioogen locus lies on Chr 1. This information describes a new region of conserved linkage homology between mouse Chr 8 and human Chr 1. It also defines the end of a large region of conserved linkage homology between mouse Chr 8 and human Chr 16.     

Conformational aspects of the actions of some piperidine dicarboxylic acids at excitatory amino acid receptors in the mammalian and amphibian spinal cord

A series of piperidine dicarboxylates (PDA) have been tested for excitatory amino acid agonist and antagonist activity and for synaptic depressant properties in the spinal cords of frogs and immature rats in vitro and of cats in vivo. The substances tested comprised (±)-cis-2,3-PDA, (±)-cis-2,4-PDA, (±)-cis-2,5-PDA, (±)-cis-2,6-PDA, (±)-trans-2,3-PDA, (±)-trans-2,3-PDA and both (+) and (–) forms ofcis-2,3-PDA. Peak excitatory amino acid agonist activity was observed with (±)-trans-2,3- and (±)-trans-2,4-PDA. Excitatory amino acid antagonism and synaptic depressant activity was observed only withcis-dicarboxylates, this activity being greatest in the 2,3-analogue. The agonist actions of piperidine dicarboxylates were effectively depressed by the specific NMDA receptor antagonist, (–)-2-amino-5-phosphonovalerate and, where tested, also byd--aminoadipate and low concentrations of Mg²⁺. It was concluded that the major part of these agonist actions were mediated by NMDA receptors. The main structural feature of the NMDA agonist actions of these substances was considered to be their close relationship to N-alkyl-aspartic and glutamic acid molecules, with thetrans arrangement of the respective 2,3- and 2,4-situated carboxyl groups promoting most effective interaction with the active sites of the NMDA receptor. (±)-Cis-2,3-PDA depressed excitatory responses induced by NMDA, kainate, quisqualate, (±)-trans-2,3-PDA and (±)-trans-2,4-PDA, or evoked by dorsal root stimulation. Both monosynaptic and polysynaptic excitation were susceptible to the depressant action of this substance. The (–) isomer ofcis-2,3-PDA carried both excitatory amino acid agonist and antagonist activity and also the synaptic depressant properties observed with the racemic form of this substance. The (+) isomer showed little pharmacological activity. It is proposed that the structure-activity features of these heterocyclic amino acids indicate some of the conformational requirements for interaction with physiological excitatory amino acid receptors.This paper is dedicated to Dr. Derek Richter on his seventy-fifth birthday.     

A linkage map of mouse Chromosome 1 using an interspecific cross segregating for the gld autoimmunity mutation

An interspecific backross was used to define a high resolution linkage map of mouse Chromosome (Chr) 1 and to analyze the segregation of the generalized lymphoproliferative disease (gld) mutation. Mice homozygous for gld have multiple features of autoimmune disease. Analysis of up to 428 progeny from the backcross [(C3H/HeJ-gld x Mus spretus)F₁ x C3H/HeJ-gld] established a map that spans 77.6 cM and includes 56 markers distributed over 34 ordered genetic loci. The gld mutation was mapped to a less than 1 cM segment on distal mouse Chr 1 using 357 gld phenotype-positive backcross mice. A second backcross, between the laboratory strains C57BL/6J and SWR/J, was examined to compare recombination frequency between selected markers on mouse Chr 1. Significant differences in crossover frequency were demonstrated between the interspecific backcross and the inbred laboratory cross for the entire interval studied. Sex difference in meiotic crossover frequency was also significant in the laboratory mouse cross. Two linkage groups known to be conserved between segments of mouse Chr 1 and the long arm of human Chrs 1 and 2 where further defined and a new conserved linkage group was identified that includes markers of distal mouse Chr 1 and human Chr 1, bands q32 to q42.     

The rat Ruby (<Emphasis Type="Italic">R</Emphasis>) locus is <Emphasis Type="Italic">Rab38</Emphasis>: identical mutations in Fawn-hooded and Tester-Moriyama rats derived from an ancestral Long Evans rat sub-strain

Hermansky-Pudlak syndrome (HPS) is a group of rare, recessive disorders in which oculocutaneous albinism, progressive pulmonary fibrosis, bleeding diathesis, and other abnormalities result from defective biogenesis of multiple cytoplasmic organelles. Seven different HPS genes are known in humans; in mouse, at least 16 loci are associated with HPS-like mutant phenotypes. In the rat, only two HPS models are known, Fawn-hooded (FH) and Tester Moriyama (TM), non-complementing strains in which HPS-like hypopigmentation and platelet storage pool deficiency result from a mutation of the Ruby (red eyed dilution; R) locus on Chromosome (Chr) 1. We have identified the R locus as the Rab38 gene, establishing that rat R is homologous to mouse chocolate (cht). Further, we show that FH and TM rats have identical Rab38 Met1Ile mutations, occurring on an identical Chr 1 marker allele haplotype, indicating that these two strains derive from a common ancestor. This ancestor appears to have been a sub-strain of the outbred Long Evans (LE) strain, and several modern LE sub-strains carry the Rab38 Met1Ile R mutation on the same Chr 1 marker haplotype. These findings have significant implications for the many past and ongoing studies that involve the FH and LE-derivative rat strains. Hermansky-Pudlak syndrome (HPS; MIM 203300) is a group of autosomal recessive diseases in which oculocutaneous albinism (OCA), progressive and fatal pulmonary fibrosis, and bleeding diathesis due to platelet storage pool deficiency result from defects in the biogenesis of specific cytoplasmic organelles and granules: melanosomes, lysosomes, and platelet dense granules (reviewed in Spritz 1999, 2000; Spritz et al. 2003). In humans, seven different HPS genes are known (Oh et al. 1996; DellAngelica et al. 1999; Anikster et al. 2001; Suzuki et al. 2002; Li et al. 2003; Zhang et al. 2003). In the mouse, at least 16 loci associated with HPS-like mutant phenotypes are known, seven of which are homologous to the human HPS loci (Swank et al. 1998; Bennett and Lamoreux 2003). The nucleotide sequence data reported in this paper have been submitted to GenBank and have been assigned the accession number AY425759. (Naoki Oiso) Present address: Department of Dermatology, Saiseikai Tondabayashi Hospital, Tondabayashi, Osaka 584-0082, Japan.     

3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL): cloning and characterization of a mouse liver HL cDNA and subchromosomal mapping of the human and mouse HL genes

3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL) is a homodimeric mitochondrial matrix enzyme that catalyzes the last step of ketogenesis. Using a human HL cDNA as a probe, we isolated a 1.4-kb mouse HL cDNA (HLM) from a mouse liver library and extended the sequence in the 5 direction, using RACE PCR to include the complete coding sequence. The nucleotide sequence of the mouse HL coding region is 85.7% identical to human HL, and 52.6% to Ps. mevalonii HL. Peptide identities of 87.4% and 54.3% respectively were observed. Southern analysis of 29 strains of laboratory mice and of Mus spretus revealed a total of about 25 kb of hybridizing fragments and three polymorphic fragments in both EcoRI and HindIII digestions. The mouse HL locus (Hmgcl) was localized on Chromosome (Chr) 4: Pmv-19-12.6±3.6 cM-Hmgcl-7.3±2.3 cM-Xmv-8-1.5±1.0 cM-Gpd1. The human HL locus (HMGCL) was mapped to distal Chr 1p by analysis of a human-hamster hybrid cell panel and by in situ hybridization.