Y-chromosomal factor is involved in neonatal lethality in (♀ DDD × ♂DH-Dh/+) F1-Dh/+ male mice

The dominant hemimelia(Dh) mutation causes various developmental abnormalities in mice. Most -Dh/+ males, crosses between DDD females and DH-Dh/+ males, have lethal abnormalities during the neonatal period. This is a consequence of synergism among three independent gene loci; that is, theDh allele on chromosome (Chr) 1, the DDD allele on an X Chr-linked locus, and a Y Chr-linked locus in some strains. With regard to the Y Chr derived fromMus musculus musculus (M. m. musculus), the Y Chrs of C57BL/6J and BALB/cA caused lethality, but the Y Chr of C3H/HeJ did not, suggesting that not allM. m. musculus Y Chrs are the same. In the present study, whether Y Chrs derived fromM. m. domesticus andM. m. castaneus could cause lethality was investigated. Among seven inbred strains, including AKR/J, DDD, RF/J, SJL/J, SWR/J, TIRANO/Ei, and CAST/Ei, Y Chrs of AKR/ J, DDD, SJL/J, SWR/J, and TIRANO/Ei caused lethality, but Y Chrs of RF/J and CAST/Ei did not. It was unlikely that the mitochondrial genome of the DDD strain contributed to the lethality. The X Chr-linked locus could not compensate for the role of the Y Chr-linked locus. These results suggest that not allM. m. domesticus Y Chrs are the same.     

Geographic origin of the Y Chromosomes in “old” inbred strains of mice

Six distinct Y Chromosomes (Chr) were identified among 39 standard inbred strains of mice with five probes that identified Y Chr-specific restriction fragments on Southern blots. Three Y Chr types, distributed among 31 strains, were of Asian Mus musculus origin. The remaining three Y Chr types, distributed among eight strains, were of M. domesticus origin. The Asian source of the M. musculus Y Chr was confirmed by determining the DNA sequence of 221 bp from an open reading frame within the Sry (sex determining region Y) gene (Gubbay et al., Nature 346 245–250, 1990) in three inbred strains (C57BL/6J, AKR/J, and SWR/J) and comparing the sequence to the homologous sequences derived from wild caught European and Asian M. musculus males. These data indicate that a minimum of six male mice contributed to the formation of the old inbred strains.     

The musculus-type Y Chromosome of the laboratory mouse is of Asian origin

Mus musculus domesticus, M.m. bactrianus, M. m. musculus, M.m. castaneus, and M.m. molossinus wild mice were investigated for polymorphisms of the Y Chromosome (Chr) genes Zinc finger-Y (Zfy) and Sex-determining region-Y (Sry). Zfy divided the Y Chrs of these mice into domesticus- (domesticus) and musculus-types (musculus, castaneus, molossinus). M.m. bactrianus specimens had both Y Chrs, possibly owing to the introgression of a musculus-type Y into this population. Sry identified a subpopulation of musculus-type Y chromosomes. This subpopulation, designated the molossinus-type, was found in M.m. molossinus, a M. musculus subspecies specimen from northern China (Changchun), and laboratory mice. The cumulative data suggest that M.m. musculus of northern China and Korea are subpopulation distinct from M.m. musculus of Europe and central China and that this subpopulation invaded Japan, giving rise to M.m. molossinus. Furthermore, the data suggest that the musculus-type Y of the laboratory mouse originated from this subpopulation, corroborating early historical record reporting that Chinese and Japanese mice that were imported into Europe for the pet trade contributed to the genome of the laboratory mouse.     

Norwegian house mice (Mus musculus musculus/domesticus): distributions, routes of colonization and patterns of hybridization

We investigated the distributions and routes of colonization of two commensal subspecies of house mouse in Norway: Mus musculus domesticus and M. m. musculus. Five nuclear markers (Abpa, D11 cenB2, Btk, SMCY and Zfy2) and a morphological feature (tail length) were used to differentiate the two subspecies and assess their distributions, and mitochondrial (mt) D‐loop sequences helped to elucidate their colonization history. M. m. domesticus is the more widespread of the two subspecies, occupying the western and southern coast of Norway, while M. m. musculus is found along Norway’s southeastern coast and east from there to Sweden. Two sections of the hybrid zone between the two subspecies were localized in Norway. However, hybrid forms also occur well away from that hybrid zone, the most prevalent of which are mice with a M. m. musculus‐type Y chromosome and an otherwise M. m. domesticus genome. MtDNA D‐loop sequences of the mice revealed a complex phylogeography within M. m. domesticus, reflecting passive human transport to Norway, probably during the Viking period. M. m. musculus may have colonized earlier. If so, that leaves open the possibility that M. m. domesticus replaced M. m. musculus from much of Norway, with the widely distributed hybrids a relict of this process. Overall, the effects of hybridization are evident in house mice throughout Norway.     

Genetic analysis of X-linked hybrid sterility in the house mouse

Hybrid sterility is a common postzygotic reproductive isolation mechanism that appears in the early stages of speciation of various organisms. Mus musculus musculus and Mus musculus domesticus represent two recently separated mouse subspecies particularly suitable for genetic studies of hybrid sterility. Here we show that the introgression of Chr X of M. m. musculus origin (PWD/Ph inbred strain, henceforth PWD) into the genetic background of the C57BL/6J (henceforth B6) inbred strain (predominantly of M. m. domesticus origin) causes male sterility. The X-linked hybrid sterility is associated with reduced testes weight, lower sperm count, and morphological abnormalities of sperm heads. The analysis of recombinant Chr Xs in sterile and fertile males as well as quantitative trait locus (QTL) analysis of several fertility parameters revealed an oligogenic nature of the X-linked hybrid sterility. The Hstx1 locus responsible for male sterility was mapped near DXMit119 in the central part of Chr X. To ensure full sterility, the PWD allele of Hstx1 has to be supported with the PWD allelic form of loci in at least one proximal and/or one distal region of Chr X. Mapping and cloning of Hstx1 and other genes responsible for sterility of B6–X^PWDY^B6 males could help to elucidate the special role of Chr X in hybrid sterility and consequently in speciation.     

Evolution of a long-range repeat family in Chromosome 1 of the genus Mus

Copy numbers and variation of a clustered long-range repeat family on Chromosome (Chr) 1 have been studied in different species of the genus Mus. The repeat sequence was present in all, as inferred from cross-hybridization with probes derived from the Mus musculus repeat family. Copy numbers determined by dot blot hybridization were very low, from three to six per haploid genome in M. caroli, M. cervicolor, and M. cookii. These species form one branch of the phylogenetic tree in the genus Mus. In the other group of phylogenetically related species—M. spicilegus, M. spretus, M. musculus and M. macedonicus—copy numbers ranged from 6 to 1810 per haploid genome. The repeat cluster is cytogenetically visible as a fine C-band in M. macedonicus and as a C-band positive homogeneously staining region (HSR) in several populations of M. m. domesticus and M. m. musculus. When cytogenetically visible, the clusters contained from 179 to 1810 repeats. Intragenomic restriction fragment length polymorphisms (RFLPs), which reflect sequence variation among different copies of the long-range repeat family, increased with higher copy numbers. The high similarity of the RFLP pattern among genomes with C-band positive regions in Chr 1 of M. m. musculus, M. m. domesticus, and M. macedonicus points to a close evolutionary relationship of their Chr 1 repeat families.     

DISSECTING THE GENETIC ARCHITECTURE OF F1 HYBRID STERILITY IN HOUSE MICE

Hybrid sterility as a postzygotic reproductive isolation mechanism has been studied for over 80 years, yet the first identifications of hybrid sterility genes in Drosophila and mouse are quite recent. To study the genetic architecture of F₁ hybrid sterility between young subspecies of house mouse Mus m. domesticus and M. m. musculus, we conducted QTL analysis of a backcross between inbred strains representing these two subspecies and probed the role of individual chromosomes in hybrid sterility using the intersubspecific chromosome substitution strains. We provide direct evidence that the asymmetry in male infertility between reciprocal crosses is conferred by the middle region of M. m. musculus Chr X, thus excluding other potential candidates such as Y, imprinted genes, and mitochondrial DNA. QTL analysis identified strong hybrid sterility loci on Chr 17 and Chr X and predicted a set of interchangeable autosomal loci, a subset of which is sufficient to activate the Dobzhansky–Muller incompatibility of the strong loci. Overall, our results indicate the oligogenic nature of F₁ hybrid sterility, which should be amenable to reconstruction by proper combination of chromosome substitution strains. Such a prefabricated model system should help to uncover the gene networks and molecular mechanisms underlying hybrid sterility.     

A molecular characterization of the charismatic Faroe house mouse

Faroe house mice are a ‘classic’ system of rapid and dramatic morphological divergence highlighted by J. S. Huxley during the development of the Modern Synthesis. In the present study, we characterize these charismatic mice using modern molecular techniques, examining specimens from all Faroe islands occupied by mice. The aims were to classify the mice within the modern house mouse taxonomy (i.e. as either Mus musculus domesticus or Mus musculus musculus) using four molecular markers and a morphological feature, and to examine the genetic diversity and possible routes of colonization using mitochondrial (mt) control region DNA sequences and microsatellite data (15 loci). Mice on the most remote islands were characterized as M. m. domesticus and exhibited exceptionally low genetic diversity, whereas those on better connected islands were more genetically diverse and had both M. m. musculus and M. m. domesticus genetic elements, including one population which was morphologically M. m. musculus‐like. The mtDNA data indicate that the majority of the mice had their origins in south‐western Norway (or possibly southern Denmark/northern Germany), and probably arrived with the Vikings, earlier than suggested by Huxley. The M. m. musculus genetic component appears to derive from recent mouse immigration from Denmark. © 2011 The Linnean Society of London, Biological Journal of the Linnean Society, 2011, 102 , 471–482.     

Phylogenetic relationships among laboratory and wild-origin Mus musculus strains on the basis of genomic DNA RFLPs

Genetic distance measures between the laboratory mouse strains C57BL/6J and RF/J and the wild-origin Mus musculus mouse strains CAST/Ei, MOLF/Ei, POSCH I, and CZECH II were estimated by allelic patterns revealed by RFLP analysis. These results suggest phylogenetic relationships indicating that the mouse strains related to the subspecies M.m. domesticus (RF/J, POSCH I and C57BL/6J) are more closely related to the CAST/Ei strain (derived from M.m. castaneus) than to the strains CZECH II (M.m. musculus) and MOLF/Ei (M.m. molossinus). Furthermore, the hybrid strain C57BL/6J is more closely related to POSCH I (M.m. poschiavinus) than to RF/J as calculated by the method distance measures of Cavalli-Sforza and Edwards (Evolution 21,550, 1967), Nei's minimum (Am. Natural. 106,283, 1972) and unbiased minimum (Genetics 89,583, 1978), Edwards (Biometrics 27,873, 1971; Genetic Distance, p. 41, 1974) and Rogers modified (1986).     

Structure and Distribution of Endogenous Nonecotropic Murine Leukemia Viruses in Wild Mice

Virtually all of our present understanding of endogenous murine leukemia viruses (MLVs) is based on studies with inbred mice. To develop a better understanding of the interaction between endogenous retroviruses and their hosts, we have carried out a systematic investigation of endogenous nonecotropic MLVs in wild mice. Species studied included four major subspecies of Mus musculus (M. m. castaneus, M. m. musculus, M. m. molossinus, and M. m. domesticus) as well as four common inbred laboratory strains (AKR/J, HRS/J, C3H/HeJ, and C57BL/6J). We determined the detailed distribution of nonecotropic proviruses in the mice by using both env- and long terminal repeat (LTR)-derived oligonucleotide probes specific for the three different groups of endogenous MLVs. The analysis indicated that proviruses that react with all of the specific probes are present in most wild mouse DNAs tested, in numbers varying from 1 or 2 to more than 50. Although in common inbred laboratory strains the linkage of group-specific sequences in env and the LTR of the proviruses is strict, proviruses which combine env and the LTR sequences from different groups were commonly observed in the wild-mouse subspecies. The “recombinant” nonecotropic proviruses in the mouse genomes were amplified by PCR, and their genetic and recombinant natures were determined. These proviruses showed extended genetic variation and provide a valuable probe for study of the evolutionary relationship between MLVs and the murine hosts.     

Ancestral bias in the <Emphasis Type="Italic">Hras1</Emphasis> gene and distal Chromosome 7 among inbred mice

Inbred strains of mice vary in their frequency of liver tumors initiated by a mutation in the Hras1 (H-ras) proto-oncogene. We sequenced 4.5 kb of the Hras1 gene on distal Chr 7 in a diverse set of 12 commonly used laboratory inbred strains of mice and detected no sequence variation to account for strain-specific differences in Hras1 mutation prevalence. Furthermore, the Hras1 sequence is essentially monoallelic for an ancestral gene derived from the M. m. domesticus species. To determine if the monoallelism and associated low rate of polymorphism are unique to Hras1 or representative of the general chromosomal locale, we extended the sequence analysis to 12 genes in the final 8 Mb of distal Chr 7. A region of at least 2.5 Mb that encompasses several genes, including Hras1 and the H19/Igf2 loci, demonstrates virtually no sequence variation. The 12 inbred strains share one dominant haplotype derived from the M. m. domesticus allele. Chromosomal regions flanking the monoallelic segment exhibit a significantly higher rate of variation and multiple haplotypes, a majority of which are attributed to M. m. domesticus or M. m. musculus ancestry. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Nucleotide sequence data reported here are available in NCBI dbSNP build 127 under accession numbers listed in Supplementary Table 2.     

Polymorphism in hybrid male sterility in wild-derived Mus musculus musculus strains on proximal chromosome 17

The hybrid sterility-1 (Hst1) locus at Chr 17 causes male sterility in crosses between the house mouse subspecies Mus musculus domesticus (Mmd) and M. m. musculus (Mmm). This locus has been defined by its polymorphic variants in two laboratory strains (Mmd genome) when mated to PWD/Ph mice (Mmm genome): C57BL/10 (carrying the sterile allele) and C3H (fertile allele). The occurrence of sterile and/or fertile (wild Mmm × C57BL)F₁ males is evidence that polymorphism for this trait also exists in natural populations of Mmm; however, the nature of this polymorphism remains unclear. Therefore, we derived two wild-origin Mmm strains, STUS and STUF, that produce sterile and fertile males, respectively, in crosses with C57BL mice. To determine the genetic basis underlying male fertility, the (STUS × STUF)F₁ females were mated to C57BL/10 J males. About one-third of resulting hybrid males (33.8%) had a significantly smaller epididymis and testes than parental animals and lacked spermatozoa due to meiotic arrest. A further one-fifth of males (20.3%) also had anomalous reproductive traits but produced some spermatozoa. The remaining fertile males (45.9%) displayed no deviation from values found in parental individuals. QTL analysis of the progeny revealed strong associations of male fitness components with the proximal end of Chr 17, and a significant effect of the central section of Chr X on testes mass. The data suggest that genetic incompatibilities associated with male sterility have evolved independently at the proximal end of Chr 17 and are polymorphic within both Mmd and Mmm genomes.     

Differences in the organization and chromosomal allocation of satellite DNA between the European long tailed house miceMus domesticus andMus musculus

We compared the organization of satellite DNA (stDNA) and its chromosomal allocation inMus domesticus and inMus musculus. The two stDNAs show similar restriction fragment profiles after digestion (probed withM. domesticus stDNA) with some endonucleases of which restriction sequences are present in the 230–240 bp repetitive unit of theM. domesticus stDNA. In contrast, EcoRI digestion reveals thatM. musculus stDNA lacks most of the GAATTC restriction sites, particularly at the level of the half-monomer. The chromosome distribution of stDNA (revealed by anM. domesticus stDNA probe) shows different patterns in theM. domesticus andM. musculus karyotypes, with about 60% ofM. domesticus stDNA retained in theM. musculus genome. It is particularly noteworthy that the pericentromeric regions ofM. musculus chromosomes 1 and X are totally devoid ofM. domesticus stDNA sequences. In both groups, the differences in energy transfer between the stDNA-bound fluorochromes Hoechst 33258 and propidium iodide suggest that AT-rich repeated sequences have a much more clustered array in theM. domesticus stDNA, as if they are organized in tandem repeats longer than those ofM. musculus. Considering the data as a whole, it seems likely that the evolutionary paths of the two stDNAs diverged after the generation of the ancestral 230–240 bp stDNA repetitive unit through the amplification, in theM. domesticus genome, of a family repeat which included the EcoRI GAATTC restriction sequence.     

Origin and radiation of the house mouse: mitochondrial DNA phylogeny

On the basis of patterns of allele frequency variation in nuclear genes (Din et al., in press) it has been proposed that the house mouse M. musculus originated in the northern Indian subcontinent, from where it radiated in several directions to form the well-described peripheral subspecies (M. m. domesticus, M. m. musculus and M. m. castaneus). Here we use a mitochondrial DNA (mtDNA) phylogeny to test this hypothesis and to analyse the historical and demographic events that have accompanied this differentiation. This marker also provides a powerful means to check for genetic continuity between the central and peripheral populations. We studied restriction site polymorphism of samples from India and the Middle East as well as samples from the rest of Eurasia and northern Africa. M. m. domesticus and M. m. musculus are both monophyletic for mtDNA and belong to the subspecies-specific mtDNA lineages that have been described previously. Average nucleotide diversity is low in M. m. musculus (0.2–5%). It is not only higher in M. m. domesticus (0.7–0.9%) but the distribution of pairwise divergence is wider, and the rate of evolution in this branch appears to be higher than in M. m. musculus. The nucleotide diversity found in M. m. castaneus (0.4%) is due to the existence of two rather divergent linages with little intralineage variation. These two lineages are part of a diversified bush of the phylogenetic tree that also comprises several previously undescribed branches and includes all samples from the northern Indian subcontinent and Iran. The degree of diversity found in each of the samples from this region is high (1.2–2.4%) although they come from small geographic areas. This agrees well with the idea that the origin of the radiation was in the northern Indian subcontinent. However, as neither haplotypes on the M. m. domesticus nor on the M. m. musculus branches were found in this region, there appear to be important phylogeographic discontinuities between this central region and these peripherial subspecies. On the basis of the present result and the nuclear data (Din et al., in press), we propose that M. musculus originated in the north of the indian subcontinent. Our calibration of the evolutionary rate of mtDNA in mice suggests that the mouse settlement in this region could be as old as 900 000 years. Possibly from there, a first radiation could have reach the Middle East and the Caspian Sea, where the M. m. domesticus and M. m. musculus lineages, respectively, would have started to differentiate a few hundred thousand years ago, and from where they could have colonised the peripheral part of their ranges only recently.M. m. castaneus appears from its mtDNA to be recent offshoot of the northern Indian population. This multiple and gradual radiation ultimately led to recent peripheral secondary contacts, such as the well-known European hybrid zone.     

Genetic analysis of neonatal death with growth retardation in F1 male Dh/+ mice

Nearly all F₁ male mice with Dh/+ genotype between DDD female and DH–Dh/+ male die within a few days after birth; however, this is not observed in the reciprocal cross. The F₁ Dh/+ males usually exhibit growth retardation prior to death. To identify the putative genetic locus or loci in DDD genome that cause the abnormalities in the presence of the Dh, a linkage analysis was carried out in backcross progeny of a cross of (DDD female × DH–+/+ male) F₁ female × DH–Dh/+ male. Appearance of growth retardation was examined from the day of birth, and both growth-retarded and normally weaned Dh/+ males were genotyped for microsatellite marker loci spanning autosomes and the X Chromosome (Chr). Significant evidence for linkage was identified on the distal edge of the X Chr, near the microsatellite marker of DXMit135. Furthermore, among mice from DDD female × reciprocal F₁ Dh/+ male produced between DH–Dh/+ and progenitor strains (C57BL/6J, C3H/HeJ and BALB/cA), only the progeny from ♀DDD ×♂(♀DH–Dh/+×♂C3H/HeJ) F₁ Dh/+ male did not show any lethality and/or growth retardation. Thus, the lethality in F₁ Dh/+ males accompanied by growth retardation is caused by the interactions between the Dh gene, X Chr, and Y Chr. Based on the CAG repeat sequence length polymorphism among Mus musculus musculus Sry gene, C3H/HeJ was different from C57BL/6J, BALB/cA, and DH. These data suggest that there are at least two functional types of Y Chr in Mus musculus musculus. Received: 22 January 1999 / Accepted: 5 April 1999     

In situ analysis of centromeric satellite DNA segregating inMus species crosses

In situ hybridization of biotin-labeled mouse major satellite DNA clone pMR196 was applied toMus domesticus andMus spretus chromosomes (Chr). The same karyotypes were counterstained with distamycin A-DAPI to identify AT-rich heterochromatin. Chromosomes from the laboratory mouse, C57BL/6Ros (BL/6;M. domesticus) were uniformly labeled at the centromere except for the Y, while chromosomes from the divergentMus speciesM. spretus showed little or no hybridization. Differences betweenMus species in copy number of the major satellite DNA sequence were used to identify chromosomes ofM. domesticus andM. spretus in their F₁ hybrids and to discriminatedomesticus andspretus centromeres in backross progeny. The distribution pattern of heterochromatic regions demonstrated by distamycin A-DAPI counterstaining was comparable with that of in situ hybridization with pMR196, suggesting that A-T rich heterochromatin inM. domesticus is mainly constructed by the pMR196-related sequence. The in situ technique was used to examine segregation ofdomesticus centromeres in backcross progeny obtained by mating F₁ hybrid females withM. domesticus orM. spretus males. The segregation of centromeres did not deviate from the expected among the backcross progeny from C57BL/6Ros males, whereas chromosomes withM. domesticus centromeres were prone to appear in the progeny from backcross matings byM. spretus males.     

Genetic differentiation of subspecies of the house mouse Mus musculus and their taxonomic relationships inferred from RAPD-PCR data

Genetic differentiation of six subspecies of the house mouse Mus musculus (Mus musculus musculus, M. m. domesticus, M. m. castaneus, M. m. gansuensis, M. m. wagneri, and M. m. ssp. (bactrianus?) was examined using RAPD-PCR analysis. In all, 373 loci of total length of about 530 kb were identified. Taxonspecific molecular markers were detected and the levels of genetic differences among the subspecies were estimated. Different degree of subspecific genetic differentiation was shown. The most similar subspecies pairs were M. m. castaneus-M. m. domesticus and M. m. musculus-M. m. gansuensis. In our phylogenetic reconstruction, M. m. wagneri proved to be most different from all the other subspecies. Genetic distances between it and other subspecies were two-to threefold higher than those between the “good”species of the subgenus Mus (e.g., between M. m. musculus and M. spicilegus, M. musculus and M. abbotti). The estimates of genetic similarity and the phylogenetic relationships between six house mouse subspecies inferred from RAPD partially conformed to the results based on cytogenetic and allozyme data. However, they were considerably different from phylogenetic reconstructions based on sequencing of the control mtDNA region, which reflects mutual inconsistency of different systems of inheritance.     

Polymorphic HSRs in chromosome 1 of the two semispecies Mus musculus musculus and M. m. domesticus have a common origin in an ancestral population

HSRs (homogeneously staining regions) are the cytological correlates of DNA amplification. In the house mouse, Mus musculus, many populations are polymorphic for the presence or absence of HSRs on chromosome 1. In the semispecies M. m. domesticus the amplified DNA is present within one HSR, whereas in M. m. musculus chromosomes 1 with two HSRs are found. Hybridization of HSR-specific probes to Southern blots of HSR-carrying genomic DNAs from different localities and semispecies revealed similar complex band patterns. the remaining variation is restricted to sequences with a low degree of amplification. Variation is higher between semispecies than within one semispecies. It is assumed that HSRs are derived from one original amplification event and that unequal recombination is the mechanism underlying the length variation of HSRs present today in both semispecies. Evidence from G-banding and in situ hybridization shows that the two HSRs of M. m. musculus originated from a single HSR by means of a paracentric inversion, where one break-point was located within the single HSR and the second outside the HSR. As a consequence of the paracentric inversion the two HSRs of M. m. musculus are permanently linked together. Since exchange of genes between the two semispecies is restricted to a narrow hybrid zone the amplification that gave rise to the HSR most probably occurred prior to the divergence into the semispecies M. m. domesticus and M. m. musculus about 1 million years ago.by D. Schweizer     

A High-Resolution Map in the Chromosomal Region Surrounding theLpsLocus

TheLpslocus on mouse chromosome 4 controls host responsiveness to lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria. The C3H/HeJ inbred mouse strain is characterized by a mutantLpsallele (Lps^d) that renders it hyporesponsive to LPS and naturally tolerant of its lethal effects. To identify theLpsgene by a positional cloning strategy, we have generated a high-resolution linkage map of the chromosomal region surrounding this locus. We have analyzed a total of 1604 backcross mice from a preexisting interspecific backcross panel of 259 (Mus spretus× C57BL/6J)F1 × C57BL/6J and two novel panels of 597 (DBA/2J × C3H/HeJ)F1 × C3H/HeJ and 748 (C57BL/6J × C3H/HeJ)F1 × C3H/HeJ segregating atLps.A total of 50 DNA markers have been mapped in a 11.8-cM span overlapping theLpslocus. This positions theLpslocus within a 1.1-cM interval, flanked proximally by a large cluster of markers, including three known genes (Cd30l, Hxb,andAmbp), and distally by two microsatellite markers (D4Mit7/D4Mit178). The localization of theLpslocus is several centimorgans proximal to that previously assigned.