Genetic contributions of nonautoimmune SWR mice toward lupus nephritis.

(SWR x New Zealand Black (NZB))F(1) (or SNF(1)) mice succumb to lupus nephritis. Although several NZB lupus susceptibility loci have been identified in other crosses, the potential genetic contributions of SWR to lupus remain unknown. To ascertain this, a panel of 86 NZB x F(1) backcross mice was immunophenotyped and genome scanned. Linkage analysis revealed four dominant SWR susceptibility loci (H2, Swrl-1, Swrl-2, and Swrl-3) and a recessive NZB locus, Nba1. Early mortality was most strongly linked to the H2 locus on chromosome (Chr) 17 (log likelihood of the odds (LOD) = 4.59 - 5.38). Susceptibility to glomerulonephritis was linked to H2 (Chr 17, LOD = 2.37 - 2.70), Swrl-2 (Chr 14, 36 cM, LOD = 2.48 - 2.71), and Nba1 (Chr 4, 75 cM, LOD = 2.15 - 2.23). IgG antinuclear autoantibody development was linked to H2 (Chr 17, LOD = 4.92 - 5.48), Swrl-1 (Chr 1, 86 cM, colocalizing with Sle1 and Nba2, LOD = 2.89 - 2.91), and Swrl-3 (Chr 18, 14 cM, LOD = 2.07 - 2.13). For each phenotype, epistatic interaction of two to three susceptibility loci was required to attain the high penetrance levels seen in the SNF(1) strain. Although the SWR contributions H2, Swrl-1, and Swrl-2 map to loci previously mapped in other strains, often linked to very similar phenotypes, Swrl-3 appears to be a novel locus. In conclusion, lupus in the SNF(1) strain is truly polygenic, with at least four dominant contributions from the SWR strain. The immunological functions and molecular identities of these loci await elucidation.     

Polygenetic susceptibility and resistance to 4-nitroquinoline 1-oxide-induced tongue carcinomas in the rat

Oral administration of 4-nitroquinoline 1-oxide (4NQO) to rats induced a high incidence of tongue carcinomas (TCs). The inbred Dark-Agouti (DA) strain of rats showed much higher susceptibility to 4NQO-induced TCs than the Wistar-Furth (WF) strain. Our previous study on crosses between the two strains postulated a semidominant susceptibility gene in DA and a semidominant resistance gene in WF rats. This hypothesis was confirmed by the genetic analysis of the back-crosses to either parent with PCR-based microsatellite assay. Using the number of TCS with >5 mm diameter as a quantitative parameter, we mapped a quantitative trait locus Stc1 (Susceptibility to TC) favouring TC development near the locus D19Mit9 on Chr. 19 with a peak LOD score of 6.08. Two other regions in Chr. 3 and Chr. 14 showed weak linkage for susceptibility, but were not statistically significant. On the other hand, another quantitative trait locus Rtc1 (Resistance to TC) providing resistance to TCs was mapped on Chr. 1 between the loci of D1Mit1 and D1Mit3 with a peak LOD score of 3.30. Quantitative parameters such as the number of tumours in the tongue or upper alimentary tract, the frequency of larger tumours and their maximum size were closely correlated and principally determined by Stc1 and Rtc1. Therefore the susceptibility to 4NQO-induced TCs in crosses between DA and WF is explained by the combinations of genotypes at these two loci. Possible candidate genes for Stc1 and Rtc1 are discussed.     

Mapping genes that control hormone-induced ovulation rate in mice.

The present study mapped quantitative trait loci (QTL) that control 6-fold genetic differences in hormone-induced ovulation rate (HIOR) between C57BL/6J (B6) (HIOR = 54) and A/J strain mice (HIOR = 9). (The gene name is Ovulation Rate Induced [ORI] QTL and the gene symbol is Oriq.) QTL linkage analysis was conducted on 167 (B6xA)xA backcross mice at 165 loci. Suggestive B6 ORI QTL that control the number of eggs in cumulus mapped, as follows, near: Cyp19 and D9Mit4 on chromosome (Chr) 9 (Oriq1); D2Mit433 on Chr2 (Oriq2); D6Mit316 on Chr6 (Oriq3); DXMit22 on ChrX (Oriq4) and were associated with a 2.7, 2.7, 2.6, and 4.2 egg increases in HIOR, respectively. Oriq3 was significant (LOD = 3.45) based on composite interval mapping. QTL linkage analysis of the number of eggs matured by endogenous gonadotropins and ovulated by eCG mapped a significant Oriq5 to Chr 10 and suggestive Oriq to Chr 6, 7, and X. These data provide the first molecular genetic markers for reproductive QTL that control major differences in ovarian responsiveness to gonadotropins. These and closely linked syntenic molecular markers will enable a more accurate prediction of ovarian responsiveness to gonadotropins and provide selection criteria for improving reproductive performance in diverse mammalian species.     

Low resolution mapping around the flavivirus resistance locus (Flv) on mouse Chromosome 5

Although the phenomenon of innate resistance to flaviviruses in mice was recognized many years ago, it was only recently that the genetic locus (Flv) controlling this resistance was mapped to mouse Chromosome (Chr) 5. Here we report the fine mapping of the Flv locus, using 12 microsatellite markers which have recently been developed for mouse Chr 5. The new markers were genotyped in 325 backcross mice of both (C3H/HeJxC3H/ RV)F₁xC3H/HeJ and (BALB/cxC3H/RV)F₁xBALB/c backgrounds, relative to Flv. The composite genetic map that has been constructed identifies three novel microsatellite loci, D5Mit68, D5Mit159, and D5Mit242, tightly linked to the Flv locus. One of those loci, D5Mit159, showed no recombinations with Flv in any of the backcross mice analyzed, indicating tight linkage (<0.3 cM). The other two, D5Mit68 and D5Mit242, exhibited two and one recombinations with Flv (0.6 and 0.3 cM) respectively, defining the proximal and distal boundaries of a 0.9-cM segment around this locus. The proximal flanking marker, D5Mit68, maps to a segment on mouse Chr 5 homologous to human Chr 4. This, together with the previous data produced by our group, locates Flv to a region on mouse Chr 5 carrying segments that are conserved on either human Chr 4, 12, or 7, but present knowledge does not allow precise identification of the syntenic element.     

Identification of quantitative trait loci that regulate obesity and serum lipid levels in MRL/MpJ x SJL/J inbred mice

The total body fat mass and serum concentration of total cholesterol, HDL cholesterol, and triglyceride (TG) differ between standard diet-fed female inbred mouse strains MRL/MpJ (MRL) and SJL/J (SJL) by 38-120% (P < 0.01). To investigate genetic regulation of obesity and serum lipid levels, we performed a genome-wide linkage analysis in 621 MRLx SJL F2 female mice. Fat mass was affected by two significant loci, D11Mit36 [43.7 cM, logarithm of the odds ratio (LOD) 11.2] and D16Mit51 (50.3 cM, LOD 3.9), and one suggestive locus at D7Mit44 (50 cM, LOD 2.4). TG levels were affected by two novel loci at D1Mit43 (76 cM, LOD 3.8) and D12Mit201 (26 cM, LOD 4.1), and two suggestive loci on chromosomes 5 and 17. HDL and cholesterol concentrations were influenced by significant loci on chromosomes 1, 3, 5, 7, and 17 that were in the regions identified earlier for other strains of mice, except for a suggestive locus on chromosome 14 that was specific to the MRL x SJL cross. In summary, linkage analysis in MRL x SJL F2 mice disclosed novel loci affecting TG, HDL, and fat mass, a measure of obesity. Knowledge of the genes in these quantitative trait loci will enhance our understanding of obesity and lipid metabolism.     

Quantitative trait loci for urinary albumin in crosses between C57BL/6J and A/J inbred mice in the presence and absence of Apoe

We investigated the effect of apolipoprotein E (Apoe) on albuminuria in the males of two independent F2 intercrosses between C57BL/6J and A/J mice, using wild-type inbred strains in the first cross and B6-Apoe(-/-) animals in the second cross. In the first cross, we identified three quantitative trait loci (QTL): chromosome (Chr) 2 [LOD 3.5, peak at 70 cM, confidence interval (C.I.) 28-88 cM]; Chr 9 (LOD 2.0, peak 5 cM, C.I. 5-25 cM); and Chr 19 (LOD 1.9, peak 49 cM, C.I. 23-54 cM). The Chr 2 and Chr 19 QTL were concordant with previously found QTL for renal damage in rat and human. The Chr 9 QTL was concordant with a locus found in rat. The second cross, testing only Apoe(-/-) progeny, did not identify any of these loci, but detected two other loci on Chr 4 (LOD 3.2, peak 54 cM, C.I. 29-73 cM) and Chr 6 (LOD 2.6, peak 33 cM, C.I. 11-61 cM), one of which was concordant with a QTL found in rat. The dependence of QTL detection on the presence of Apoe and the concordance of these QTL with rat and human kidney disease QTL suggest that Apoe plays a role in renal damage.     

High-resolution genetic map and YAC contig around the mouse neurological locus reeler

Mutations at the recessive reeler locus (rl) on mouse Chromosome (Chr) 5 result in abnormal development of multiple central nervous system components, including the cerebral and cerebellar cortices. These abnormalities are characterized by highly disorganized laminar structures thought to have arisen from a post-migration failure of neuronal organization events that are probably mediated through cell-cell interactions. As a result of a mutagenesis scheme designed to generate visible recessive mutations induced by the drug chlorambucil, we had previously recovered a new allele of the reeler locus (rl ^Alb ) that is likely to involve a deletion based on the known mechanisms of chlorambucil action. We have constructed a high-resolution genetic map from two intercrosses segregating this allele. Our first cross, in which the mutation was outcrossed to the 101 strain prior to intercrossing, consisted of 196 meioses and resulted in the positioning of four loci proximal to rl, with D5Mit1 being the closest (2.6±1.1 cM). The second cross consisted of intercrossing rl heterozygotes derived from an outcross to the C57BL/6 strain. A total of 318 mice (636 meioses) gave rise to a panel of 41 recombinants, which were used to map a total of 14 loci within a 6.4-cM interval bounded by D5Mit1 and the En-2 gene. A yeast artificial chromosome contig consisting of clones containing two of these loci, D5Mit72 (located 0.31 cM distal to rl), and D5Mit61 (no recombinants with rl), has been assembled and is being used to locate the rl gene.     

Fine mapping of the circling (cir) gene on the distal portion of mouse chromosome 9

Circling mice manifest profound deafness, head-tossing, and bi-directional circling behavior, which they inherit in autosomal recessive manner. Histologic examination of the inner ear reveals abnormalities of the region around the organ of Corti, spiral ganglion neurons, and outer hair cells. A genetic linkage map was constructed for an intraspecific backcross between cir and C57BL/6J mice. The cir gene was mapped to a region between D9Mit116/D9Mit15 and D9Mit38 on mouse chromosome (Chr) 9. Estimated distances between cir and D9Mit116, and between cir and D9Mit38 were 0.70 +/- 0.40 and 0.23 +/- 0.23 cM, respectively. Order of the markers was defined as follows: centromere - D9Mit182 - D9Mit51/D9Mit79/D9Mit310 - D9Mit212/D184 - D9Mit116/D9Mit15 - cir - D9Mit38 - D9Mit20 - D9Mit243 - D9Mit16 - D9Mit55/D9Mit125 - D9Mit281. On the basis of genetic mapping, we constructed a yeast artificial chromosome (YAC) contig across the cir region. The cir gene is located between the lactotransferrin (ltf) and microtubule-associated protein (map4) genes. The distal portion of mouse Chr 9 encompassing the cir region is homologous with human chromosome 3p21, which contains the Deafness, form B: Autosomal Recessive Deafness (DFNB6) locus. Therefore, the circling mouse is a potential animal model for DFNB6 deafness in humans.     

Mapping genetic loci that regulate lipid levels in a NZB/B1NJxRF/J intercross and a combined intercross involving NZB/B1NJ, RF/J, MRL/MpJ, and SJL/J mouse strains

The NZB/B1NJ (NZB) mouse strain exhibits high cholesterol and HDL levels in blood compared with several other strains of mice. To study the genetic regulation of blood lipid levels, we performed a genome-wide linkage analysis in 542 chow-fed F2 female mice from an NZBxRF/J (RF) intercross and in a combined data set that included NZBxRF and MRL/MpJxSJL/J intercrosses. In the NZBxRF F2 mice, the cholesterol and HDL concentrations were influenced by quantitative trait loci (QTL) on chromosome (Chr) 5 [logarithm of odds (LOD) 17-19; D5Mit10] that was in the region identified earlier in crosses involving NZB mice, but two QTLs on Chr 12 (LOD 4.7; D12Mit182) and Chr 19 (LOD 5.7; D19Mit1) were specific to the NZBxRF intercross. Triglyceride levels were affected by two novel QTLs at D12Mit182 (LOD 8.7) and D15Mit13 (LOD 3.5). The combined-cross linkage analysis (1,054 mice, 231 markers) 1) identified four shared QTLs (Chrs 5, 7, 14, and 17) that were not detected in one of the parental crosses and 2) improved the resolution of two shared QTLs. In summary, we report additional loci regulating lipid levels in NZB mice that had not been identified earlier in crosses involving the NZB strain of mice. The identification of shared loci from multiple crosses increases confidence toward finding the QTL gene.     

Two novel quantitative trait loci on mouse chromosomes 6 and 4 independently and synergistically regulate plasma apoB levels

An elevated plasma apolipoprotein B (apoB) level is a strong predictor of atherosclerosis and coronary heart disease. Epidemiologic and family linkage studies have suggested a genetic basis for the wide variations of plasma apoB levels in the general population. Using a human apoB transgenic (HuBTg) mouse model, we have previously shown that hepatic apoB-100 secretion is a major determinant of the high and low plasma human apoB levels in HuBTg mice of the C57BL/6 (B6) and 129/Sv (129) strains, respectively. In the present article, we present the identification of two novel quantitative trait loci (QTL) as major regulators of plasma human apoB levels in the F(2) and N(2) (backcrossed) offspring (n = 572) derived from crosses between the B6 and 129 mouse strains. These loci were designated ApoB regulator genes (Abrg), because the gene products are likely to be involved in the regulation of plasma apoB levels either directly or indirectly. The first locus, designated Abrg1, was mapped to chromosome 6 in 8-week-old male and female mice with a combined logarithm of odds ratio (LOD) score of 14 at the D6Mit55 marker ( approximately 45.9 cM). Abrg1 contributed approximately 35% of the genetic variance. The second locus, designated Abrg2, was mapped to chromosome 4 with an LOD score of 8.6 in 8-week-old male mice but an LOD score of only 2.0 in 8-week-old female mice at the D4Mit27 marker ( approximately 35 cM). Abrg2 contributed approximately 26% of the genetic variance. Epistasis between Abrg1 and Abrg2 was detected and accounted for approximately 12% of the genetic variance. The combination of these two QTL has major effects (>70%) on the regulation of plasma human apoB levels in the tested population. In summary, we have identified two novel loci that have a major role in the regulation of plasma apoB levels and are likely to regulate the secretory pathway of apoB. The human orthologs for the Abrg loci are strong candidates for human disorders characterized by altered plasma apoB levels, such as FCHL and familial hypobetalipoproteinemia.     

Cloning and genomic localization of the murine LPS-induced CXC chemokine (LIX) gene,Scyb5

LPS-induced CXC chemokine (LIX) is a murine chemokine similar to two human chemokines, ENA-78 (CXCL5) and GCP-2 (CXCL6). To clarify the relationship of LIX to human ENA-78 and GCP-2, we cloned and mapped the LIX gene. The organization of the LIX gene ( Scyb5) is similar to those of the human ENA-78 ( SCYB5) and GCP-2 ( SCYB6) genes. The intron-exon boundaries of the three genes are exactly conserved, and the introns have similar sizes. The first 100 bp of the 5' flanking regions are highly similar, with conserved NF-kappaB and GATA sites in identical positions in all three genes. Further 5', the Lix flanking region sequence diverges from those of ENA-78 and GCP-2, which remain highly similar for 350 bp preceding the start sites. Using a (C57BL/6 J x Mus spretus) F1 x C57BL/6J backcross panel, Lix was mapped to a locus near D5Ucla5 at 49.0 cM on Chromosome (Chr) 5. Mapping with the T31 radiation hybrid panel placed Lix between D5Mit360 and D5Mit6. Physical maps of the CXC chemokine clusters on murine Chr 5 and human Chr 21 were constructed using the Celera mouse genome database and the public human genome database. The sequence and mapping data suggest that the human ENA78-PBP-PF4 and GCP2- psi PBP-PF4V1 loci arose from an evolutionarily recent duplication of an ancestral locus related to the murine Lix-Pbp-Pf4 locus.     

Interval Mapping of High Growth (Hg), a Major Locus That Increases Weight Gain in Mice

The high growth locus (hg) causes a major increase in weight gain and body size in mice. As a first step to map-based cloning of hg, we developed a genetic map of the hg-containing region using interval mapping of 403 F(2) from a C57BL/6J-hghg X CAST/EiJ cross. The maximum likelihood position of hg was at the chromosome 10 marker D10Mit41 (LOD = 24.8) in the F(2) females and 1.5 cM distal to D10Mit41 (LOD = 9.56) in the F(2) males with corresponding LOD 2 support intervals of 3.7 and 5.4 cM, respectively. The peak LOD scores were significantly higher than the estimated empirical threshold LOD values. The localization of hg by interval mapping was supported by a test cross of F(2) mice recombinant between the LOD 2 support interval and the flanking marker. The interval mapping and test-cross results indicate that hg is not allelic with candidate genes Igf1 or decorin (Dcn), a gene that was mapped close to hg in this study. The hg inheritance was recessive in females, although we could not reject recessive or additive inheritance in males. Possible causes for sex differences in peak LOD scores and for the distortion of transmission ratios observed in F(2) males are discussed. The genetic map of the hg region will facilitate further fine mapping and cloning of hg, and allow searches for a homologous quantitative trait locus affecting growth in humans and domestic animals.     

The ter primordial germ cell deficiency mutation maps near Grl-1 on mouse Chromosome 18

A single recessive gene, ter (teratoma), causes germ cell deficiency and a high incidence of congenital testicular teratomas in the 129/Sv-ter strain of the mouse. Linkage analyses between the ter gene and 36 marker genes of 19 chromosomes were performed with matings between the C57BL/6J-ter congenic strain and four inbred strains. Results showed that the ter gene was linked to D18Mit9, D18Mit14, and D18Mit17 on Chromosome (Chr) 18. Gene order estimated on the basis of recombination distance (in centimorgans) was [centromere-D18Mit14-5.1 (cM)-ter-0 (cM)-D18Mit17-23.8 (cM)-D18Mit9]. D18Mit17 is the microsatellite DNA of the Grl-1 (glucocorticoid receptor-1) locus. We conclude that the ter gene is closely linked to Grl-1 on Chr 18 and is a new mutation involving the developmental modification of primordial germ cells in mice.Deceased     

A chromosomal translocation causing multiple abnormalities including open eyelids at birth and glomerulonephritis

We have characterized the phenotype of a mouse with a t(2;13) reciprocal translocation induced by chlorambucil. It results in abnormal eyelid formation as well as a series of neurological, physiological, and immunological abnormalities. This mutant has been termed T(2;13)1Fla/+. T(2;13)1Fla/+ mice exhibit open eyelids at birth, a dilute coat color, hyperactivity, and occasional circling and stargazing activity. At 1-6 months, T(2;13)1Fla/+ mice show signs of immune complex-mediated glomerulonephritis and die prematurely. Additionally, double-stranded DNA autoantibodies have been found in sera of T(2;13)1Fla/+ mice. Cytogenetic analysis situated the translocation breakpoint at the proximal end of Chromosome (chr) 2 at band A2, and on Chr 13 at band A4. The mutant phenotype completely correlated with the presence of the translocation. Additional genetic studies have mapped the mutation and translocation breakpoint to Chr 13 between D13Mit16 and D13Mit64, and to Chr 2 proximal to D2Mit5. By fluorescent in situ hybridization (FISH), the position of this mutation/translocation on Chr 13 has been mapped to a region less than 1cM from D13Mit61.     

Subcongenic analyses reveal complex interactions between distal chromosome 4 genes controlling diabetogenic B cells and CD4 T cells in nonobese diabetic mice

Autoimmune type 1 diabetes (T1D) in humans and NOD mice results from interactions between multiple susceptibility genes (termed Idd) located within and outside the MHC. Despite sharing ～88% of their genome with NOD mice, including the H2(g7) MHC haplotype and other important Idd genes, the closely related nonobese resistant (NOR) strain fails to develop T1D because of resistance alleles in residual genomic regions derived from C57BLKS mice mapping to chromosomes (Chr.) 1, 2, and 4. We previously produced a NOD background strain with a greatly decreased incidence of T1D as the result of a NOR-derived 44.31-Mb congenic region on distal Chr. 4 containing disease-resistance alleles that decrease the pathogenic activity of autoreactive B and CD4 T cells. In this study, a series of subcongenic strains for the NOR-derived Chr. 4 region was used to significantly refine genetic loci regulating diabetogenic B and CD4 T cell activity. Analyses of these subcongenic strains revealed the presence of at least two NOR-origin T1D resistance genes within this region. A 6.22-Mb region between rs13477999 and D4Mit32, not previously known to contain a locus affecting T1D susceptibility and now designated Idd25, was found to contain the main NOR gene(s) dampening diabetogenic B cell activity, with Ephb2 and/or Padi2 being strong candidates as the causal variants. Penetrance of this Idd25 effect was influenced by genes in surrounding regions controlling B cell responsiveness and anergy induction. Conversely, the gene(s) controlling pathogenic CD4 T cell activity was mapped to a more proximal 24.26-Mb region between the rs3674285 and D4Mit203 markers.     

Linkage analysis reveals two independent loci for ocular disorders in a local Japanese Black cattle population

A vision-impairing ocular disorder was observed in a local Japanese Black cattle population, and assumed to be an autosomal recessive disease based on the presence of a founder cow. A genome scan using seven affected half-sib pairs revealed a linkage to BTA5 (Z(max) = 7.0, LOD(max) = 2.0), designated the bovine ocular disorder 1 (bod1) locus. Of the seven animals, three were heterozygous at the bod1 locus. Analysis in these three animals revealed linkage to markers on BTA18, and this locus was designated bod2. Detailed haplotype inspection of 16 affected animals indicated linkage to BTA5 in 12 animals, BTA18 in three animals, and linkage to both BTA5 and BTA18 in one animal. The bod1 locus was mapped to a 25 cM interval between DIK5237 and DIK5210 on BTA5 (Z(max) = 17.0, LOD(max) = 11.8), and bod2 was mapped to a 7 cM interval between DIK5411 and INRA038 on BTA18 (Z(max) = 13.0, LOD(max) = 4.0). This study demonstrated that the independent involvement of loss of function mutations in two loci is likely responsible for this genetic heterogeneity.     

Interval mapping and congenic strains for a blood pressure QTL on rat Chromosome 13

The renin locus (Ren) on rat Chromosome (Chr) 13 had previously been shown to cosegregate with blood pressure in crosses involving Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats. In the present work, interval mapping of blood pressure on Chr 13 with a large F₂ (S × R), n = 233, population yielded a maximum LOD = 4.2 for linkage to blood pressure, but the quantitative trait locus (QTL) was only poorly localized to a large 35-centiMorgan (cM) segment of Chr 13. In the linkage analysis, the S-rat QTL allele (S) was associated with higher, and the R-rat QTL allele (R) with lower blood pressure, the difference between homozygotes being about 20 mm Hg. A congenic strain was made by introgressing the R-rat Ren allele into the recipient S strain. This congenic strain showed a 24 mm Hg reduction (P = 0.004) in blood pressure compared with S rats for rats fed 2% NaCl diet for 24 days; this difference was confirmed by two other independent tests. Two congenic substrains were derived from the first congenic strain with shorter R Chr 13 segments on the S background. Comparisons among these congenic strains showed that a blood pressure QTL was in the 24-cM chromosomal segment between Syt2 and D13M1Mit108. This segment does not include the renin locus, which is thus excluded from being the gene on rat Chr 13 responsible for genetic differences in blood pressure detected by linkage analysis. Received: 20 December 1996 / Accepted: 7 April 1997     

A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3.

Hereditary spastic paraplegia is a genetically and phenotypically heterogeneous disorder. Both pure and complicated forms have been described, with autosomal dominant, autosomal recessive, and X-linked inheritance. Various loci (SPG1-SPG6) associated with this disorder have been mapped. Here, we report linkage analysis of a large consanguineous family affected with autosomal recessive spastic paraplegia with age at onset of 25-42 years. Linkage analysis of this family excluded all previously described spastic paraplegia loci. A genomewide linkage analysis showed evidence of linkage to chromosome 16q24.3, with markers D16S413 (maximum LOD score 3.37 at recombination fraction [theta] of .00) and D16S303 (maximum LOD score 3.74 at straight theta=.00). Multipoint analysis localized the disease gene in the most telomeric region, with a LOD score of 4.2. These data indicate the presence of a new locus linked to pure recessive spastic paraplegia, on chromosome 16q24.3, within a candidate region of 6 cM.     

A rat homolog of the mouse deafness mutant jerker (je)

An autosomal recessive deafness mutant was discovered in our colony of Zucker (ZUC) rats. These mutants behave like shaker-waltzer deafness mutants, and their inner ear pathology classifies them among neuroepithelial degeneration type of deafness mutants. To determine whether this rat deafness mutation (−) defines a unique locus or one that has been previously described, we mapped its chromosomal location. F₂ progeny of (Pbrc:ZUC × BN/Crl) A/a B/b H/h+/− F₁ rats were scored for coat color and behavioral phenotypes. Segregation analysis indicated that the deafness locus might be loosely linked with B on rat Chromosome (Chr) 5 (RNO5). Therefore, 40 −/− rats were scored for BN and ZUC alleles at four additional loci, D5Mit11, D5Mit13, Oprd1, and Gnb1, known to map to RNO5 or its homolog, mouse Chr 4 (MMU4). Linkage analysis established the gene order (cM distance) as D5Mit11–(19.3)–B–(17.9)–D5Mit13–(19.2)–Oprd1–(21.5) − (1.2) Gnb1, placing the deafness locus on distal RNO5. The position of the deafness locus on RNO5 is similar to that ofjerker (je) on MMU4; the phenotypes and patterns of inheritance of the deafness mutation and je are also similar. It seems likely that the mutation affects the rat homolog of je. The rat deafness locus should, therefore, be named jerker and assigned the gene symbol Je. Received: 13 June 1995 / Accepted: 4 January 1996     

Quantitative trait loci for baseline erythroid traits

A substantial genetic contribution underlies variation in baseline peripheral blood counts. We performed quantitative trait locus/loci (QTL) analyses to identify chromosome (Chr) regions harboring genes influencing the baseline erythroid parameters in F₂ intercrosses between NZW/LacJ, SM/J, and C57BLKS/J inbred mice. We identified multiple significant QTL for red blood cell (RBC) count, hemoglobin (Hgb) and hematocrit (Hct) levels, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean cell hemoglobin concentration (CHCM). We identified four RBC count QTL: Rbcq1 (Chr 1, peak LOD score at 62 cM,), Rbcq2 (Chr 4, 60 cM), Rbcq3 (Chr 11, 34 cM), and Rbcq4 (Chr 10, 60 cM). Three MCV QTL were identified: Mcvq1 (Chr 7, 30 cM), Mvcq2 (Chr 11, 6 cM), and Mcvq3 (Chr 10, 60 cM). Single significant loci for Hgb (Hgbq1, Chr 16, 32 cM), Hct (Hctq1, Chr 3, 42 cM), and MCH (Mchq1, Chr 10, 60 cM) were identified. The data support the existence of a common RBC/MCH/MCV locus on Chr 10. Two QTL for CHCM (Chcmq1, Chr 2, 48 cM; Chcmq2, Chr 9, 44 cM) and an interaction between Chcmq2 with a locus on Chr 19 were identified. These analyses emphasize the genetic complexity underlying the regulation of erythroid peripheral blood traits in normal populations and suggest that genes not previously recognized as significantly impacting normal erythropoiesis exist.