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PubMed2006

Mouse phenome research: implications of genetic background.

Now that sequencing of the mouse genome has been completed, the function of each gene remains to be elucidated through phenotypic analysis. The "genetic background" (in which each gene functions) is defined as the genotype of all other related genes that may interact with the gene of interest, and therefore potentially influences the specific phenotype. To understand the nature and importance of genetic background on phenotypic expression of specific genes, it is necessary to know the origin and evolutionary history of the laboratory mouse genome. Molecular analysis has indicated that the fancy mice of Japan and Europe contributed significantly to the origin of today's laboratory mice. The genetic background of present-day laboratory mice varies by mouse strain, but is mainly derived from the European domesticus subspecies group and to a lesser degree from Asian mice, probably Japanese fancy mice, which belong to the musculus subspecies group. Inbred laboratory mouse strains are genetically uniform due to extensive inbreeding, and they have greatly contributed to the genetic analysis of many Mendelian traits. Meanwhile, for a variety of practical reasons, many transgenic and targeted mutant mice have been created in mice of mixed genetic backgrounds to elucidate the function of the genes, although efforts have been made to create inbred transgenic mice and targeted mutant mice with coisogenic embryonic stem cell lines. Inbred mouse strains have provided uniform genetic background for accurate evaluation of specific genes phenotypes, thus eliminating the phenotypic variations caused by mixed genetic backgrounds. However, the process of inbreeding and selection of various inbred strain characteristics has resulted in inadvertent selection of other undesirable genetic characteristics and mutations that may influence the genotype and preclude effective phenotypic analysis. Because many of the common inbred mouse stains have been established from relatively small gene pools, common inbred strains have limitations in their genetic polymorphisms and phenotypic variations. Wild-derived mouse strains can complement deficiencies of common inbred mouse strains, providing novel allelic variants and phenotypes. Although wild-derived strains are not as tame as the common laboratory strains, their genetic characteristics are attractive for the future study of gene function.

Animals↗

PubMed2003

Genetic background influences cataractogenesis, but not lens growth deficiency, in Cx50-knockout mice.

PURPOSE: Deletion of connexin (Cx)50 produces microphthalmia with nuclear cataracts. To determine whether these two traits are influenced by genetic background and are dependent on each other, mice carrying the Cx50 deletion in two different strains were generated, and the growth defect and severity of cataracts were analyzed. METHODS: Cx50-knockout mice were generated in the 129S6 strain, and back-crossed into the C57BL/6J genetic background. To analyze the influence of genetic background on the observed phenotype, postnatal lens growth, lens clarity, lens histology and crystallin solubility were determined and compared between the two strains of Cx50-knockout mice. RESULTS: The growth deficiency persisted, regardless of genetic background, but genetic modifiers that differentially altered the solubility of crystallin proteins influenced the severity of cataracts. Expression levels of Cx46 were similar in all animals, regardless of genetic background, indicating that the differences were not due to a compensatory upregulation of Cx46. CONCLUSIONS: Taken together, these data indicate that the two components of the Cx50 phenotype are independent of each other and that cataractogenesis is under the influence of an unidentified genetic modifier.

Animals↗

PubMed2004

Influence of genetic background and gender on hypertension and renal failure in COX-2-deficient mice.

The present study was undertaken to determine whether the severity of renal failure or hypertension in homozygous cyclooxygenase (COX)-2-deficient (COX-2-/-) mice affected by genetic background or gender. COX-2 deletion was introduced into three congenic genetic backgrounds, 129/Sv (129/COX-2-/-), C57/BL6 (C57/COX-2-/-), and BALB/c (BALB/COX-2-/-), by backcrossing the original mixed-background knockout mice with the respective inbred strains for 9 or 10 generations. Evaluation of the severity of hypertension and renal failure was performed in knockout and wild-type mice at the age of 2.5-3.5 mo. Blood pressure measured by tail-cuff plethysmography was significantly elevated in the male 129/COX-2-/- mice (165.8 +/- 9.2 vs. 116 +/- 5.1 mmHg, P < 0.05), and to a much lesser extent in the female 129/COX-2-/- mice (127.4 +/- 3.3 vs. 102.4 +/- 3.3), whereas it was unchanged in the C57- or BALB/COX-2-/- mice regardless of gender. Urinary excretion of albumin, determined by EIA, was remarkably increased in the 129/COX-2-/- (16.4 +/- 4.1 vs. 0.16 +/- 0.043 mg albumin/mg creatinine, P < 0.001), and to a lesser extent in the male C57/COX-2-/- mice (0.595 +/- 0.416 vs. 0.068 +/- 0.019). Albumin excretion was not elevated in the male BALB/COX-2-/- or in female COX-2-/- mice on any of the three genetic backgrounds. Histological analysis showed abundant protein casts, dilated tubules, and infiltration of inflammatory cells in the male 129/COX-2-/- mice, but not in COX-2-/- mice in other strains or gender. However, the presence of small glomeruli in the nephrogenic zone was observed in all strains of COX-2 knockout mice, regardless of genetic background and gender. Therefore, we conclude that the severity of hypertension and renal failure in COX-2-deficient mice is influenced by genetic background and gender, whereas the incomplete maturation of outer cortical nephrons appears to be independent of genetic background effects.

Animals↗

PubMed2004

Phenotypic expression of the targeted null-mutation in the dopamine transporter gene varies as a function of the genetic background.

The dopamine transporter (DAT) plays a critical role in calibrating the duration and intensity of dopamine (DA) neurotransmission. Mice in which the DAT gene has been genetically deleted exhibit constitutively high levels of extrasynaptic DA and spontaneous hyperactivity. Numerous studies have characterized the adaptive molecular, physiological, and behavioural consequences of abnormal DA neurotransmission in these mice. In order to determine the genetic background contribution to these phenotypes, the DAT mutation was transferred on C57BL/6JOrl (B6) or DBA/2JOrl (D2) inbred backgrounds for more than ten generations of back-crossing to derive three B6-, D2-, and B6xD2(F(1))-DAT strains. We observed that the genetic background dramatically affects phenotypes previously reported on DAT knockout (KO) mice. Depending on the genetic background, it was possible to restore survival, growth rate and ability to lactate. Interactions with the genetic background were found to modulate both quantitative and qualitative patterns of novelty-driven spontaneous hyperactivity. The paradoxical calming effect of cocaine was observed for all DAT-KO mice. However, the genetic background influenced individual threshold responses to both locomotor and rewarding effects of cocaine. These findings reveal the extent of phenotypic variation associated with the DAT mutation. They also provide concrete arguments against the assumption that the normal function of a gene can be inferred directly from its mutant phenotype.

Analysis of Variance↗

PubMed2003

Model of robust induction of glomerulosclerosis in mice: importance of genetic background.

BACKGROUND: Increasing evidence suggests that genetic background plays an important role in the development of progressive glomerulosclerosis. The remnant kidney model (RKM) of progressive renal disease has been used extensively in rats. However, C57BL/6 mice are resistant to glomerulosclerosis with RKM induced by either pole amputation or renal artery ligation. A pole resection protocol, applied in 129/Sv mice, induced only mild glomerulosclerosis. We present here a highly reproducible, modified RKM approach to successfully establish a glomerulosclerosis model in mice. METHODS: Male C57BL/6 (N = 17), 129/Sv (N = 20) and Swiss-Webster (N = 3) mice underwent RKM as follows: the lower branch of the left renal artery was ligated to produce about one third infarct; the upper pole of the left kidney (about one third kidney size) was removed by cautery and the right kidney was nephrectomized to induce a total 5/6 nephrectomy (Nx). In some C57BL/6 mice, 7/8 nephrectomy was induced by removing additional renal mass from the upper pole of the left kidney by cautery. Systolic blood pressure (BP) was measured in conscious mice using a tail-cuff blood pressure monitor and animals were sacrificed at 9, 12, 18, and 24 weeks after nephrectomy. Kidneys were harvested for morphologic analysis. RESULTS: BP in C57BL/6 mice increased slightly after 5/6 nephrectomy over time without significant difference compared to baseline blood pressure except at 8 weeks (blood pressure at week 0, 98 +/- 1 mm Hg; week 4, 105 +/- 2 mm Hg; week 8, 113 +/- 4 mm Hg; and week 12, 110 +/- 3 mm Hg). Blood presssure remained normal in C57BL/6 mice at 18 weeks after 7/8 nephrectomy (103 +/- 2 mm Hg). Blood pressure in 129/Sv mice increased significantly after 5/6 nephrectomy from 4 to 12 weeks (week 0, 112 +/- 3 mm Hg; week 4, 161 +/- 9 mm Hg; week 8, 166 +/- 5 mm Hg; and week 12, 176 +/- 5 mm Hg; P < 0.01 weeks 4, 8, and 12 vs. week 0 blood pressure). Urine protein excretion in C57BL/6 mice increased only at 4 weeks after 5/6 nephrectomy, and was back to normal at 8 and 12 weeks (week 0, 13.2 +/- 1.4 mg/24 hours; week 4, 20.5 +/- 1.8 mg/24 hours; week 8, 18.8 +/- 1.6 mg/24 hours; and week 12, 17.2 +/- 1.2 mg/24 hours, P < 0.05 week 4 vs. week 0). 129/Sv mice developed significant proteinuria 12 weeks after 5/6 nephrectomy compared to their baseline and to levels achieved in C57BL/6 mice (week 0, 17.2 +/- 1 mg/24 hours; week 4, 14.9 +/- 1.8 mg/24 hours; week 8, 23.8 +/- 6.7 mg/24 hours; and week 12, 36.3 +/- 6.6 mg/24 hours, P < 0.01 week 12 vs. week 0; P < 0.01 129/Sv vs. C57BL/6 at week 12). Mortality varied in response to nephrectomy injury in the different strains. Ten percent of C57BL/6 and 43% of 129/Sv died within 12 weeks after 5/6 nephrectomy. Although 50% of C57BL/6 mice died by 12 weeks after 7/8 nephrectomy, there was only mild glomerulosclerosis (<5%) in C57BL/6 mice even at 24 weeks after 5/6 nephrectomy or 18 weeks after 7/8 nephrectomy. In contrast, glomerulosclerosis was marked in both 129/Sv mice and Swiss-Webster mice as early as 9 weeks after 5/6 nephrectomy: 42% of glomeruli showed sclerosis in 129/Sv mice [average sclerosis index (SI), 0 to 4+ scale, 1.08] vs. 24% in Swiss-Webster mice (average SI, 0.57). Tubulointerstitial fibrosis developed in parallel with glomerulosclerosis in both 129/Sv and Swiss-Webster mice. CONCLUSION: We conclude that genetic background is one of the important factors determining the susceptibility to the development of glomerulosclerosis in mice. We speculate that the superior effects of renal artery ligation plus cautery to produce glomerulosclerosis may result from higher blood pressure responses due to local ischemia activating the renin-angiotensin system.

Animals↗

PubMed1993

Genetic background alters the spectrum of tumors that develop in p53-deficient mice.

Using gene targeting in embryonic stem cells, we have generated mice with one or two null p53 germ line alleles. Mice with both p53 alleles inactivated are developmentally normal but highly susceptible to the early development of spontaneous tumors. Initial studies were performed in mice with a mixed inbred genetic background (75% C57BL/6 and 25% 129/Sv) (Donehower et al., Nature (London) 356, 215-221, 1992). To study the effect of genetic background on tumorigenesis in p53-deficient mice, we have put the p53 null allele into a pure 129/Sv background and monitored tumor development. 129/Sv mice with two p53 null alleles developed tumors sooner than the mixed genetic background p53-deficient animals. The most frequently observed tumor in p53 null mice of both genetic backgrounds was a malignant lymphoma. Because the 129/Sv strain has a low incidence of lymphoma, the frequent occurrence of lymphomas in all p53 null mice suggests that this particular tumor type may be a direct result of p53 loss and not a result of a particular genetic background. In addition to malignant lymphomas, the 129/Sv p53-deficient mice showed an increased incidence of aggressive teratocarcinomas (8 of 18 tumor-bearing males), a tumor type rare in virtually all inbred mice except for 129 strains. Thus, it appears that loss of p53 may accelerate a prior tumor predisposition and that genetic background can play a role in mediating both the rate and spectrum of tumor development in these mice.

Animals↗

PubMed1998

A resistant genetic background leading to incomplete penetrance of intestinal neoplasia and reduced loss of heterozygosity in ApcMin/+ mice.

Previous studies of Min/+ (multiple intestinal neoplasia) mice on a sensitive genetic background, C57BL/6 (B6), showed that adenomas have lost heterozygosity for the germ-line ApcMin mutation in the Apc (adenomatous polyposis coli) gene. We now report that on a strongly resistant genetic background, AKR/J (AKR), Min-induced adenoma multiplicity is reduced by about two orders of magnitude compared with that observed on the B6 background. Somatic treatment with a strong mutagen increases tumor number in AKR Min/+ mice in an age-dependent manner, similar to results previously reported for B6 Min/+ mice. Immunohistochemical analyses indicate that Apc expression is suppressed in all intestinal tumors from both untreated and treated AKR Min/+ mice. However, the mechanism of Apc inactivation in AKR Min/+ mice often differs from that observed for B6 Min/+ mice. Although loss of heterozygosity is observed in some tumors, a significant percentage of tumors showed neither loss of heterozygosity nor Apc truncation mutations. These results extend our understanding of the effects of genetic background on Min-induced tumorigenesis in several ways. First, the AKR strain carries modifiers of Min in addition to Mom1. This combination of AKR modifiers can almost completely suppress spontaneous intestinal tumorigenesis associated with the Min mutation. Second, even on such a highly resistant genetic background, tumor formation continues to involve an absence of Apc function. The means by which Apc function is inactivated is affected by genetic background. Possible scenarios are discussed.

Adenoma↗

PubMed1992

Craniometric measurements of craniofacial malformations in the X-linked hypophosphatemic (Hyp) mouse on two different genetic backgrounds: C57BL/6J and B6C3H.

This study reports data on craniometric measurements in the X-linked hypophosphatemic (Hyp) mouse on two different genetic backgrounds: C57BL/6J and B6C3H. Heads of normal females "+/+," normal males "+/Y," heterozygous mutant females "Hyp/+," and hemizygous mutant males "Hyp/Y" for each genetic background were examined. Data were collected via skull measurements. On a C57BL/6J background, the neurocranium of mutants "Hyp/+" and "Hyp/Y" was shorter and slightly higher than in normal counterparts. On a B6C3H background, mutant mice "Hyp/+" and "Hyp/Y" were shorter in neurocranial length than in normal counterparts. Viscerocranial height was larger in "Hyp/Y" than in normal counterparts. No differences in neurocranial and mandibular height were found. Mutant mice on a C57BL/6J background were compared to mutant mice on a B6C3H background. No differences in neurocranial length were found. Cranial length was shorter in "Hyp/Y" on C57BL/6J than in "Hyp/+" on B6C3H. Facial length parameters were shorter in "Hyp/Y" on C57BL/6J than in "Hyp/Y" and "Hyp/+" mutant mice on B6C3H. Mandibular length was shorter in "Hyp/Y" on C57BL/6J than in "Hyp/+" on C57BL/6J and both mutant mice ("Hyp/Y" and "Hyp/+") on a B6C3H background. The results of this study indicate that craniofacial growth is less affected in mutant mice on a B6C3H genetic background than in mutant mice on a C57BL/6J genetic background.

Animals↗

PubMed1975

Effect of the genetic background on recombination frequency in the cn-vg region of the second chromosome of natural populations of Drosophila melanogaster.

Newly established test stocks made it possible to follow the effect of three different defined genetic backgrounds (first and third chromosomes) on recombination frequency in the cn-vg region of the second chromosomes isolated from four natural populations of Drosophila melanogaster. One background was composed of the chromosomes with inversions obtained from the stock (see article) and another two backgrounds were of the standard type consisting one-half of the original chromosomes from the natural population and one-half of the chromosomes of the stocks Oregon R or Samarkand. Using the analysis of variance significant differences in RF values were found between and within populations and especially between the different backgrounds. Some simple and double interactions between the above factors played a role. The highest RF values were obtained on the background [corrected] with inversions. The effect of the different genetic backgrounds [corrected] by the action of the genetic modifiers of RF. The different genetic backgrounds affected the variations in RF values in individual populations and the different populations reacted differentially to the changed genetic background. The design of the experiment permitted an estimation of the causal compoenents of variance and heritability of RF from the sib analysis. The additive component of variance was present in only two of the populations under test; the respective estimates of heritability were very low.

Animals↗

PubMed2003

Testing an 'aging gene' in long-lived drosophila strains: increased longevity depends on sex and genetic background.

Molecular advances of the past decade have led to the discovery of a myriad of 'aging genes' (methuselah, Indy, InR, Chico, superoxide dismutase) that extend Drosophila lifespan by up to 85%. Despite this life extension, these mutants are no longer lived than at least some recently wild-caught strains. Typically, long-lived mutants are identified in relatively short-lived genetic backgrounds, and their effects are rarely tested in genetic backgrounds other than the one in which they were isolated or derived. However, the mutant's high-longevity phenotype may be dependent on interactions with alleles that are common in short-lived laboratory strains. Here we set out to determine whether one particular mutant could extend lifespan in long-lived genetic backgrounds in the fruit fly, Drosophila melanogaster. We measured longevity and resistance to thermal stress in flies that were transgenically altered to overexpress human superoxide dismutase (SOD) in the motorneurones in each of 10 genotypes. Each genotype carried the genetic background from a different naturally long-lived wild-caught Drosophila strain. While SOD increased lifespan on average, the effect was genotype- and sex-specific. Our results indicate that naturally segregating genes interact epistatically with the aging gene superoxide dismutase to modify its ability to extend longevity. This study points to the need to identify mutants that increase longevity not only in the lab strain of origin but also in naturally long-lived genetic backgrounds.

Aging↗

PubMed1999

Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background.

Tuberous sclerosis (TSC) is an autosomal dominant genetic disorder in which benign hamartomas develop in multiple organs, caused by mutations in either TSC1 or TSC2. We developed a murine model of Tsc2 disease using a gene targeting approach. Tsc2-null embryos die at embryonic days 9.5-12.5 from hepatic hypoplasia. Tsc2 heterozygotes display 100% incidence of multiple bilateral renal cystadenomas, 50% incidence of liver hemangiomas, and 32% incidence of lung adenomas by 15 months of age. Progression to renal carcinoma, fatal bleeding from the liver hemangiomas, and extremity angiosarcomas all occur at a rate of less than 10%. The renal cystadenomas develop from intercalated cells of the cortical collecting duct and uniformly express gelsolin at high levels, enabling detection of early neoplastic lesions. The tumor expression pattern of the mice is influenced by genetic background, with fewer large renal cystadenomas in the outbred Black Swiss background and more angiosarcomas in 129/SvJae chimeric mice. The slow growth of the tumors in the heterozygote mice matches the limited growth potential of the great majority of TSC hamartomas, and the influence of genetic background on phenotype correlates with the marked variability in expression of TSC seen in patients.

Animals↗

PubMed2000

The influence of the genetic background on the interaction of retinoic acid with Lx mutation of the rat.

The teratogenic effect of RA was found to be significantly influenced both by genetic background and by the genotype of malformation mutation Lx. The presence of the Lx mutation and BN genetic background strongly increases the teratogenic effect of RA. On the contrary, the SHR genetic background was shown to protect foetuses from RA teratogenic affliction. Recombinant inbred strain BXH2 is endowed with a specific combination of BN and SHR genes, and following RA administration it exhibits the same embryolethal effect as the BN genetic background alone. Without the Lx mutation there was no effect of RA on hind limbs in SHR/SHR or SHR/BN progeny whilst there was a significantly higher occurence of oligodactyly in SHR/BN on forelimbs as compared to SHR/SHR (92.2% vs 11.5%). In +/Lx progeny, forelimbs were significantly more afflicted with oligodactyly in SHR/BN +/Lx in comparison with both SHR/SHR and SHR/BXH2 foetuses, which indicates that BN modifiers responsible for oligodactyly were not passed to the BXH2 strain. On the contrary, hind limbs of SHR/BXH2, +/Lx progeny exhibited the highest affliction (62% of polydactyly and/or oligodactyly). In homozygous Lx/Lx progeny, polydactyly prevailed in forelimbs of SHR/BXH2 following RA administration, whilst in BN/BN progeny oligodactyly was the most frequent affliction. On the hind limbs, the highest reduction of toe number after RA treatment was connected with BN modifiers. The polymorphism of normal morphogenetic factors was shown to be responsible not only for Lx. phenotypic manifestation, but also for the variability in the response to RA teratogenic action.

Abnormalities, Drug-Induced↗

PubMed2004

The impact of genetic background on neurodegeneration and behavior in seizured mice.

We used pilocarpine-induced seizures in mice to determine the impact of genetic background on the vulnerability of hippocampal neurons and associated changes of behavioral performance. The susceptibility of hippocampal neurons to seizure-induced cell death paralleled the severity of the seizures and depended on genetic background. Hippocampal neurons in C57BL/6 mice were most resistant to cell death, whereas they were highly vulnerable in FVB/N mice. The degree of neuronal degeneration in F1 hybrid mice obtained by crossing the two strains was at an intermediate level between the parent strains. Two weeks after the severe seizures, performance in a water-maze place navigation task showed a bimodal distribution. Seventeen of 19 (90%) F1 mice were completely unable to learn while the other two learned reasonably well. Of 28 C57BL/6 mice with similarly severe seizures, six were as strongly impaired as their F1 counterparts (22%). The remaining 22 performed normally, indicating a much lower probability of C57BL/6 mice to be affected. Treated mice showed a deficit of open-field exploration which was strongly correlated with the impairment in the place navigation task and was again more severe in F1 mice. Our results show that the vulnerability of hippocampal neurons to pilocarpine-induced seizures, as well as the associated behavioral changes, depended on genetic background. Furthermore, they confirm and extend our earlier finding that a relatively modest reduction of hippocampal cell death can be associated with dramatic changes of behavioral performance and emphasize the importance of tightly-controlled genetic backgrounds in biological studies.

Animals↗

PubMed2000

Quantitative trait loci for life span in Drosophila melanogaster: interactions with genetic background and larval density.

The genetic architecture of variation in adult life span was examined for a population of recombinant inbred lines, each of which had been crossed to both inbred parental strains from which the lines were derived, after emergence from both high and low larval density. QTL affecting life span were mapped within each sex and larval density treatment by linkage to highly polymorphic roo-transposable element markers, using a composite interval mapping method. We detected a total of six QTL affecting life span; the additive effects and degrees of dominance for all were highly sex- and larval environment-specific. There were significant epistatic interactions between five of the life span QTL, the effects of which also differed according to genetic background, sex, and larval density. Five additional QTL were identified that contributed to differences among lines in their sensitivity to variation in larval density. Further fine-scale mapping is necessary to determine whether candidate genes within the regions to which the QTL map are actually responsible for the observed variation in life span.

Analysis of Variance↗

PubMed2005

Natural variability of metabolites in maize grain: differences due to genetic background.

Understanding the impact of genetic diversity on crop biochemical composition is a prerequisite to the interpretation and potential relevance of biochemical differences experimentally observed between genotypes. This is particularly important in the context of comparative safety assessments for crops developed by new technologies such as genetic engineering. To interrogate the natural variability of biochemical composition, grain from seven maize hybrids grown at four geographically distinct sites in Europe was analyzed for levels of proximates (fat, protein, moisture, ash, and carbohydrates), fiber, amino acids, fatty acids, four vitamins, nine minerals, and secondary metabolites. Statistical evaluation of the compositional data at the p < 0.05 level compared each hybrid against every other hybrid (head-to-head) for all analytes at each site and then across all sites to understand the factors contributing to variability. Of the 4935 statistical comparisons made in this study, 40% (1986) were found to be significant. The magnitude of differences observed, as a percent, ranged between 0.84 and 149% when all individual sites and the combined sites were considered. The large number of statistically significant differences in the levels of these analytes between seven commercial hybrids emphasizes the importance of genetic background and environment as determinants of the biochemical composition of maize grain, reflects the inherent natural variability in those analytes across a representative sampling of maize hybrids, and provides a baseline of the natural range of these nutritional and antinutritional components in maize for comparative compositional assessments.

Algorithms↗

PubMed1996

Refinement of the background genetic map of Xq26-q27 and gene localisation for Börjeson-Forssman-Lehmann Syndrome.

A detailed map of genetic markers was constructed around the gene for the X-linked mental retardation syndrome of Börjeson-Forssman-Lehmann (BFLS). A multipoint linkage map of framework markers across Xq26-27, based on CEPH families, was integrated with the physical map, based on a YAC contig, to confirm marker order. The remaining genetic markers, which could not be ordered by linkage, were added to create the comprehensive genetic back-ground map, in the order determined by physical mapping, to determine genetic distances between adjacent markers. This background genetic map is applicable to the refinement of the regional localisation for any disease gene mapping to this region. The BFLS gene was localised using this background map in an extended version of the family described by Turner et al. [1989]. The regional localisation for BFLS extends between recombination events at DXS425 and DXS105, an interval of 24.6 cM on the background genetic map. The phenotypic findings commonly seen in the feet of affected males and obligate carrier females may represent a useful clinical indicator of carrier status in potential female carriers in the family. Recombination between DXS425 and DXS105 in a female with such characteristic feet suggests that the distal limit of the regional localisation for the BFLS gene might reasonably be reduced to DXS294 for the purpose of selecting candidate genes, reducing the interval for the BFLS gene to 15.5 cM. Positional candidate genes from the interval between DXS425 and DXS105 include the SOX3 gene, mapped between DXS51(52A) and DXS98(4D-8). SOX3 may have a role in regulating the development of the nervous system. The HMG-box region of this single exon gene was examined by PCR for a deletion and then sequenced. No deviation from normal was observed, excluding mutations in the conserved HMG-box region as the cause of BFLS in this family.

Chromosome Mapping↗

PubMed2001

The evolution of pandemic clones of methicillin-resistant Staphylococcus aureus: identification of two ancestral genetic backgrounds and the associated mec elements.

Previous surveillance studies carried out by our laboratories, primarily in Southern and Eastern Europe, Latin America, and the United States, have characterized 3,067 methicillin-resistant Staphylococcus aureus (MRSA) hospital isolates by a combination of molecular typing methods. Nearly 70% of these isolates could be classified into five clonal types showing extensive geographic spread. Representative isolates of these clonal types were now reexamined for their genetic relatedness by multilocus sequence typing (MLST) and by sequencing the polymorphic region of protein A (spaA typing), and also for the type of the Staphylococcal Chromosomal Cassette (SCCmec) resident in the bacteria. Three of the previously classified clonal types (Iberian, Brazilian, and Hungarian clones) shared a common or closely related genetic background A, which was the same as the background of the earliest European isolates of MRSA from England and Denmark. The Pediatric and New York/Japan clones belonged to a completely different genetic background B. The three recently described SCCmec types were specifically associated with different pandemic clones: types I and III with isolates of genetic background A and type II with isolates of genetic background B. A novel SCCmec related to type I, called SCCmec type IV, was identified in some MRSA strains belonging to genetic background A as well as B. Structural variations in SCCmec types I and III were also observed. The data allow tentative identification of an evolutionary pathway for the emergence of pandemic MRSA clones and also provide evidence for the multiple, yet restricted, numbers of acquisition of the mec element by S. aureus.

Bacterial Proteins↗

PubMed1997

Assessment of locomotor activity, acoustic and tactile startle, and prepulse inhibition of startle in inbred mouse strains and F1 hybrids: implications of genetic background for single gene and quantitative trait loci analyses.

As the use of transgenic and null mutation techniques in the development of animal models of disorders increases, the importance of selecting the appropriate genetic background also increases. The genetic background of the mouse strains used as models for various disorders is critical because of the potential for epistatic effects on the expression of transgenes and null mutations. Twelve strains of inbred mice and seven F1 hybrids were tested in multiple behavioural tasks including open-field locomotor activity, Y-maze activity, auditory and tactile startle and prepulse inhibition of startle response. Differences across genotypes were found for all variables measured. The range of variability among genotypes was dependent on the specific measure so careful consideration must be made in selecting a strain for testing a particular behaviour. Because of the polygenic nature of each of the behavioural phenotypes, the impact of a single gene manipulation may vary depending on the genetic background on which it is expressed. Moreover, quantitative trait loci methods could be applied to these behaviours.

Acoustic Stimulation↗