Genetic linkage analysis of X-ray hypersensitivity in the LEC mutant rat

The LEC rat has been reported to exhibit X-ray hypersensitivity and deficiency in DNA double-strand break (DSB) repair. The present study was performed to map the locus responsible for this phenotype, the xhs (X-ray hypersensitivity), as the first step in identifying the responsible gene. Analysis of the progeny of (BN × LEC)F₁× LEC backcrosses indicated that the X-ray hypersensitive phenotype was controlled by multiple genetic loci in contrast to the results reported previously. Quantitative trait loci (QTL) linkage analysis revealed two responsible loci located on Chromosomes (Chr) 4 and 1. QTL on Chr 4 exhibited very strong linkage to the X-ray hypersensitive phenotype, while QTL on Chr 1 showed weak linkage. The Rad52 locus, mutation of which results in hypersensitivity to ionizing radiation and impairment of DNA DSB repair in yeast, was reported to be located on the synteneic regions of mouse Chr 6 and human Chr 12. However, mapping of the rat Rad52 locus indicated that it was located 23 cM distal to the QTL on Chr 4. Furthermore, none of the radio-sensitivity-related loci mapped previously in the rat chromosome were identical to the QTL on Chrs 4 and 1 in the LEC rat. Thus, it seems that X-ray hypersensitivity in the LEC rat is caused by mutation(s) in as-yet-undefined genes. Received: 14 February 2000 / Accepted: 17 May 2000     

Quantitative trait loci analysis of heat stress resistance of spermatocytes in the MRL/MpJ mouse

The MRL/MpJ mouse has previously been reported to possess an interesting phenotype in which spermatocytes are resistant to the abdominal temperature heat shock. In this study genetic analysis for it was performed. The phenotypes of F₂ progenies produced by mating MRL/MpJ and control strain C57BL/6 mice were not segregated into two types as parental phenotypes, suggesting that the phenotype is controlled by multiple genetic loci. Thus, quantitative trait loci (QTL) analysis was performed using 98 microsatellite markers. The weight ratio of the cryptorchid testis to the intact testis (testis weight ratio) and the Sertoli cell index were used for quantitative traits. QTL analysis revealed two significant QTLs located on Chrs 1 and 11 for testis weight ratio and one significant QTL located in the same region of Chr 1 for the Sertoli cell index. A microsatellite marker locus located in the peak of the QTL on Chr 1 did not recombine with the exonuclease 1 (Exo1) gene locus in 140 F₂ progenies. Mutation of the Exo1 gene was previously reported to be responsible for metaphase-specific apoptosis (MSA) of spermatocytes in the MRL/MpJ mouse. These results raise the possibility that mutation of the Exo1 gene is responsible for both MSA and heat stress resistance of spermatocytes in the MRL/MpJ mouse.     

Mapping the dominant wound healing and soft tissue regeneration QTL in MRL × CAST

We have used a mouse ear punch model and the QTL (quantitative trait loci) mapping technique to identify genes that are responsible for soft tissue regeneration. In the early studies, we have identified several QTL and have shown that the inheritance of ear healing was additive in one cross (MRL × SJL), and recessive in another cross (DBA × 129). Because CAST mice are genetically distinct and have a different genetic background, CAST would facilitate the identification of common and novel QTL when crossed with common inbred lines. We made a cross between super healer MRL and poor healer CAST and collected ear punch phenotype and marker genotype data from F₂. Ear punch healing exhibited a dominant mode of inheritance in this cross. There were three main QTL on Chromosomes 4, 9, and 17, and two suggestive QTL on Chromosomes 1 (new) and 7. Taken together, these QTL accounted for about 29% of total F₂ variance of MRL × CAST. Compared with another study using the same cross, we found a totally different set of QTL. Two QTL interactions were identified by a full QTL model: Chromosomes 4 × 17 and 9 × 17; the latter reached to a statistical level at p < 0.05. These interactions explained about 4% of the F₂ phenotypic variance. We conclude that soft tissue regeneration is controlled by multiple genes and locus vs. locus interactions. This work was supported by Assistance Award No. DAMD17-99-1-9571. The U.S. Army Medical Research Acquisition Activity, Fort Detrick, MD, is the awarding and administering acquisition office. The information contained in this publication does not necessarily reflect the position or policy of the U.S. Government and no official endorsement should be inferred.     

Investigation of the genetic architecture of a bone carcass weight QTL on BTA6

A previous analysis of an F₂/Backcross Charolais × Holstein cross population identified the presence of a highly significant QTL on chromosome 6 (BTA6) affecting the proportion of bone in the carcass. Two closely linked QTL affected birth weight (BW) and body length at birth (BBL). In this report, the marker density around the QTL on BTA6 was increased, adding four additional microsatellite markers across the chromosome and 46 SNPs within the target QTL confidence interval. Of the SNPs, 26 were in positional candidate genes and the remaining 20 provided an even distribution of markers in the target QTL region. As a bone‐related trait, the sum of the bone weight for all the left fore‐ and hindquarter joints of the carcass was analysed. We also studied the BW and BBL. Analyses of the data substantially reduced the QTL confidence interval. No strong evidence was found that the QTL for the three traits studied are different, and we conclude that the results are consistent with a single pleiotropic QTL influencing the three traits, with the largest effects on the proportion of bone in the carcass. The analyses also suggest that none of the SNPs tested is the sole causative variant of the QTL effects. Specifically, the SNP in the NCAPG gene previously reported as a causal mutation for foetal growth and carcass traits in other cattle populations was excluded as the causal mutation for the QTL reported here. Polymorphisms located in other previously identified candidate genes including SPP1, ABCG2, IBSP, MEPE and PPARGC1A were also excluded. The results suggest that SNP51_BTA‐119876 is the polymorphism in strongest linkage disequilibrium with the causal mutation(s). Further research is required to identify the causal variant(s) associated with this bone‐related QTL.     

RNA‐seq analysis reveals new candidate genes for drip loss in a Pietrain × Duroc × Landrace × Yorkshire population

Drip loss, one of the most important meat quality traits, is characterized by low heritability. To date, the genetic factors affecting the drip loss trait have not been clearly elucidated. The objective of this study was to identify critical candidate genes affecting drip loss. First, we generated a Pietrain × Duroc × Landrace × Yorkshire commercial pig population and obtained phenotypic values for the drip loss trait. Furthermore, we constructed two RNA libraries from pooled samples of longissimus dorsi muscles with the highest (H group) and lowest (L group) drip loss and identified the differentially expressed genes (DEGs) between these extreme phenotypes using RNA‐seq technology. In total, 25 883 genes were detected in the H and L group libraries, and none was specifically expressed in only one library. Comparative analysis of gene expression levels found that 150 genes were differentially expressed, of which 127 were upregulated and 23 were downregulated in the H group relative to the L group. In addition, 68 drip loss quantitative trait loci (QTL) overlapping with 63 DEGs were identified, and these QTL were distributed mainly on chromosomes 1, 2, 5 and 6. Interestingly, the triadin (TRDN) gene, which is involved in muscle contraction and fat deposition, and the myostatin (MSTN) gene, which has a role in muscle growth, were localized to more than two drip loss QTL, suggesting that both are critical candidate genes responsible for drip loss.     

Investigation of a QTL region for loin eye area and fatness on pig Chromosome 1

Previously, quantitative trait loci (QTL) for tenth-rib backfat (TENTHRIB) and loin eye area (LEA) were identified on pig Chromosome 1 (SSC 1) near microsatellite S0008 from a three-generation Berkshire × Yorkshire cross (BY). This work attempted to refine these QTL positions and identify genes associated with these QTL. Genotypes of BY (n = 555) were determined by PCR-RFLP or PCR tests for 13 polymorphisms identified in BY F₀ individuals for candidate genes, BAC end sequences, and genomic clones. Using least-squares regression interval mapping, the LEA QTL was estimated at S0008; the TENTHRIB QTL position was shifted approximately 1 cM downstream from S0008. Of the genes/sequences mapped in the QTL region, CL349415 was significantly associated with TENTHRIB (p = 0.02) and solute carrier family 2, member 12 (SLC2A12) was significantly associated with LEA (p = 0.02). These results suggest that the gene(s) responsible for the LEA and TENTHRIB QTL effects are tightly linked to S0008 or that the high informativeness of S0008 relative to surrounding markers is influencing the QTL position estimates. In addition, janus kinase 2 (JAK2) was mapped to a suggestive LEA QTL region and showed association with LEA (p = 0.009), fatness, color, and pH traits in BY.     

Scraggly, a new hair loss mutation on mouse Chromosome 19

By use of chlorambucil, we have generated a mouse mutation called scraggly (sgl) that exhibits skin and hair defects. Homozygous mutant mice exhibit hair loss, skin defects, and abnormalities in sebaceous lipid composition. We have constructed a high-resolution genetic map of mouse Chromosome (Chr) 19 that links this mutation to the anonymous DNA marker D19Umi1. An additional cross, (BALB/c × CAST/Ei) F₁× BALB/c, was used to map markers around this mutation as well as to map the potential candidate genes, Fgf8 and Cyp17. Allelism tests between sgl and asebia (ab), another hair loss mutation on mouse Chr 19, showed that these genes were separate and distinct. Received: 8 December 1998 / Accepted: 10 May 1999     

Flt-2L, a locus in barley controlling flowering time, spike density, and plant height

Flowering time represents an important adaptive trait for temperate cereal crops and may also impact on frost damage in cereal reproductive tissues by enabling escape or by influencing accumulation of genuine tolerance. The Flowering time-2L (Flt-2L) quantitative trait locus (QTL) on the distal end of barley chromosome arm 2HL overlaps with QTL for rachis internode length and reproductive frost damage. Flt-2L was also found to be associated with plant height. By combining marker analysis with phenotyping in progeny families of selected Amagi Nijo × WI2585 F₆ recombinants, we were able to map quantitative flowering time, rachis internode length, and plant height effects on 2HL as discrete Mendelian traits. The three developmental characters showed codominant modes of expression and perfectly cosegregated with one another in a 1.3-cM marker interval, indicating control by the same gene or closely linked genes. Twelve genes were identified in the related intervals in the rice and Brachypodium distachyon genomes. The HvAP2 gene cosegregated with Flt-2L and represents a plausible candidate for Flt-2L, since it is highly similar to the wheat domestication gene Q which has similar developmental effects. These data will contribute to isolation of the Flt-2L gene(s) and help establish the basis of the frost damage QTL. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Identifying Quantitative Trait Loci Affecting Resistance to Congenital Hypothyroidism in 129+Ter/SvJcl Strain Mice

Tyrosylprotein sulfotransferase 2 (TPST2) is one of the enzymes responsible for tyrosine O-sulfation and catalyzes the sulfation of the specific tyrosine residue of thyroid stimulating hormone receptor (TSHR). Since this modification is indispensable for the activation of TSH signaling, a non-functional TPST2 mutation (Tpst2^grt) in DW/J-grt mice leads to congenital hypothyroidism (CH) characterized by severe thyroid hypoplasia and dwarfism related to TSH hyporesponsiveness. Previous studies indicated that the genetic background of the 129^+Ter/SvJcl (129) mouse strain ameliorates Tpst2^grt-induced CH. To identify loci responsible for CH resistance in 129 mice, we performed quantitative trait locus (QTL) analysis using backcross progenies from susceptible DW/J and resistant 129 mice. We used the first principal component calculated from body weights at 5, 8 and 10 weeks as an indicator of CH, and QTL analysis mapped a major QTL showing a highly significant linkage to the distal portion of chromosome (Chr) 2; between D2Mit62 and D2Mit304, particularly close to D2Mit255. In addition, two male-specific QTLs showing statistically suggestive linkage were also detected on Chrs 4 and 18, respectively. All QTL alleles derived from the 129 strain increased resistance to growth retardation. There was also a positive correlation between recovery from thyroid hypoplasia and the presence of the 129 allele at D2Mit255 in male progenies. These results suggested that the major QTL on Chr 2 is involved in thyroid development. Moreover, since DW/J congenic strain mice carrying both a Tpst2^grt mutation and 129 alleles in the major QTL show resistance to dwarfism and thyroid hypoplasia, we confirmed the presence of the resistant gene in this region, and that it is involved in thyroid development. Further genetical analysis should lead to identification of genes for CH tolerance and, from a better understanding of thyroid organogenesis and function, the subsequent development of new treatments for thyroid disorders.     

Identification of genetic determinants of IGF‐1 levels and longevity among mouse inbred strains

The IGF‐1 signaling pathway plays an important role in regulating longevity. To identify the genetic loci and genes that regulate plasma IGF‐1 levels, we intercrossed MRL/MpJ and SM/J, inbred mouse strains that differ in IGF‐1 levels. Quantitative trait loci (QTL) analysis of IGF‐1 levels of these F2 mice detected four QTL on chromosomes (Chrs) 9 (48 Mb), 10 (86 Mb), 15 (18 Mb), and 17 (85 Mb). Haplotype association mapping of IGF‐1 levels in 28 domesticated inbred strains identified three suggestive loci in females on Chrs 2 (13 Mb), 10 (88 Mb), and 17 (28 Mb) and in four males on Chrs 1 (159 Mb), 3 (52 and 58 Mb), and 16 (74 Mb). Except for the QTL on Chr 9 and 16, all loci co‐localized with IGF‐1 QTL previously identified in other mouse crosses. The most significant locus was the QTL on Chr 10, which contains the Igf1 gene and which had a LOD score of 31.8. Haplotype analysis among 28 domesticated inbred strains revealed a major QTL on Chr 10 overlapping with the QTL identified in the F2 mice. This locus showed three major haplotypes; strains with haplotype 1 had significantly lower plasma IGF‐1 and extended longevity (P < 0.05) than strains with haplotype 2 or 3. Bioinformatic analysis, combined with sequencing and expression studies, showed that Igf1 is the most likely QTL gene, but that other genes may also play a role in this strong QTL.     

Evaluation of the causality of the low‐density lipoprotein receptor gene (LDLR) for serum lipids in pigs

A significant quantitative trait locus (QTL) for low‐density lipoprotein cholesterol (LDL‐C) and total cholesterol (TC) was identified around the LDLR gene on chromosome 2 (SSC2) in a White Duroc × Erhualian F₂ resource population and Sutai pigs in our previous study. However, in previous reports, the causality of LDLR with serum lipids is controversial in pigs. To systematically assess the causality of LDLR with serum lipids, association analyses were successively performed in three populations: Sutai pigs, a White Duroc × Erhualian F₂ resource population and a Duroc × (Landrace × Large White) population. We first performed a haplotype‐based association study with 60K SNP genotyping data and evidenced the significant association with LDL‐C and TC around the LDLR gene region. We also found that there is more than one QTL for LDL‐C and TC on SSC2. Then, we evaluated the causalities of two missense mutations, c.1812C>T and c.1520A>G, with LDL‐C and TC. We revealed that the c.1812C>T SNP showed the strongest association with LDL‐C (P = 5.40 × 10^?11) and TC (P = 3.64 × 10^?8) and explained all the QTL effect in Sutai pigs. Haplotype analysis found that two missense SNPs locate within a 1.93‐Mb haplotype block. One major haplotype showed the strongest significant association with LDL‐C (P = 4.62 × 10^?18) and TC (P = 1.06 × 10^?9). However, the c.1812C>T SNP was not identified in the White Duroc × Erhualian intercross, and the association of c.1520A>G with both LDL‐C and TC did not achieve significance in this F₂ population, suggesting population heterogeneity. Both missense mutations were identified in the Duroc × (Landrace × Large White) population and showed significant associations with LDL‐C and TC. Our data give evidence that the LDLR gene should be a candidate causative gene for LDL‐C and TC in pigs, but heterogeneity exists in different populations.     

Fine mapping of a seizure susceptibility locus on mouse Chromosome 1: nomination of Kcnj10 as a causative gene

Previous quantitative trait loci (QTL) mapping studies document that the distal region of mouse Chromosome (Chr) 1 contains a gene(s) that is in large part responsible for the difference in seizure susceptibility between C57BL/6 (B6) (relatively seizure-resistant) and DBA/2 (D2) (relatively seizure-sensitive) mice. We now confirm this seizure-related QTL (Szs1) using reciprocal, interval-specific congenic strains and map it to a 6.6-Mb segment between Pbx1 and D1Mit150. Haplotype conservation between strains within this segment suggests that Szs1 may be localized more precisely to a 4.1-Mb critical interval between Fcgr3 and D1Mit150. We compared the coding region sequences of candidate genes between B6 and D2 mice using RT-PCR, amplification from genomic DNA, and database searching and discovered 12 brain-expressed genes with SNPs that predict a protein amino acid variation. Of these, the most compelling seizure susceptibility candidate is Kcnj10. A survey of the Kcnj10 SNP among other inbred mouse strains revealed a significant effect on seizure sensitivity such that most strains possessing a haplotype containing the B6 variant of Kcnj10 have higher seizure thresholds than those strains possessing the D2 variant. The unique role of inward-rectifying potassium ion channels in membrane physiology coupled with previous strong association between ion channel gene mutations and seizure phenotypes puts even greater focus on Kcnj10 in the present model. In summary, we confirmed a seizure-related QTL of large effect on mouse Chr 1 and mapped it to a finely delimited region. The critical interval contains several candidate genes, one of which, Kcnj10, exhibits a potentially important polymorphism with regard to fundamental aspects of seizure susceptibility.     

Analysis of factors decreasing testis weight in MRL mice

MRL/MpJ (MRL) mouse testes have several unique characteristics, including the appearance of oocytes, the occurrence of metaphase-specific apoptosis of meiotic spermatocytes, and the presence of heat-shock-resistant spermatocytes. In the present study we used chromosomal mapping to determine the genomic background associated with small testis size in MRL mice. We prepared and analyzed C57BL/6-based congenic mice carrying MRL mouse loci. Quantitative trait loci (QTL) analysis revealed susceptibility loci for small testis size at 100 cM on chromosome (Chr) 1 and at around 80 cM on Chr 2. Analysis with B6.MRLc1 and B6.MRLc2 congenic mice and double-congenic mice confirmed the QTL data and showed that low testis weight in MRL mice was caused by germ cell apoptosis. Through histological examinations we found that B6.MRLc1 and B6.MRLc2 mice showed stage-specific apoptosis in their testes, the former at metaphase stage XII and the later at pachytene stage IV. Metaphase-specific apoptosis of spermatocytes occurs due to mutation of the exonuclease 1 (Exo1) gene located at 100 cM on Chr 1. Thus, the mutation of the Exo1 gene is also responsible for low testis weight caused by metaphase-specific apoptosis. In conclusion, testis weight is reduced in MRL mice due to apoptosis of germ cells caused by mutations in loci on Chrs 1 and 2.     

Leucoanthocyanidin dioxygenase gene (PpLDOX): a potential functional marker for cold storage browning in peach

Enzymatic browning of the peach fruit mesocarp is a major component of the postharvest physiological disorder commonly called chilling injury or internal breakdown (IB). Previously, we detected a major quantitative trait locus (QTL; qP-Brn5.1^m) affecting browning in peach using two related progeny populations (Pop-DG and Pop-G). In this report, a gene encoding the leucoanthocanidin dioxygenase (PpLDOX) enzyme was identified as the gene potentially responsible for this QTL. PpLDOX has a high similarity with the LDOX gene of the anthocyanin biosynthesis pathway of Arabidopsis thaliana. It was co-located with qP-Brn5.1^m via the bin mapping technique with the Prunus reference T×E map. A silent SNP within the PpLDOX coding sequence was used to locate the gene more precisely on the Pop-DG map and confirm its bin assignment. These results demonstrate both the utility of comparative mapping within Prunus using the T×E reference map and the power of the bin mapping approach for easily mapping genes in the Prunus genome. An SSR polymorphism was observed in the intron of PpLDOX gene sequence. The SSR co-segregated with the SNP and was used to assess association of PpLDOX with browning in 27 peach and nectarine cultivars. Cumulative evidence obtained indicates that PpLDOX partially explains genetic variation for cold storage browning susceptibility in peach and nectarine. This functional gene has potential use in marker-assisted breeding of new cultivars with lower IB susceptibility and for genotyping current cultivars for possible differential handling during storage to reduce symptom incidence.     

Characterization of <Emphasis Type="Italic">fs10.1</Emphasis>, a major QTL controlling fruit elongation in <Emphasis Type="Italic">Capsicum</Emphasis>

We previously identified fs10.1 as a major QTL controlling fruit shape (index of length to width) in an interspecific F₂ cross of Capsicum annuum (round fruit) × C. chinense (elongated fruit) in pepper. To more precisely map and characterize the QTL, we constructed near-isogenic lines for fs10.1 and mapped it in a BC₄F₂ population. In this population, fs10.1 segregated as a Mendelian locus and mapped 0.3 cM away from the closest molecular marker. We further verified the effect of fs10.1 in an F₂ population from an independent cross between elongated- and conical-fruited parents. To identify additional allelic variation at fruit shape loci, we screened an EMS-mutagenized population of the blocky-fruited cv. Maor and identified the mutant E-1654 with elongated fruit. This fruit shape mutation was mapped to the fs10.1 region and was determined to be allelic to the QTL. By measuring fruit shape of near-isogenic lines for fs10.1 during fruit development, we found that the shape of the fruit is determined primarily in the first 2 weeks after anthesis. Histological measurements of cell size and cell shape in pericarp sections of fruits of the isogenic lines throughout fruit development indicated that the shape of the fruit is determined primarily by cell shape and that the development of fruit shape is correlated with cell shape.     

Murine phosphatidylserine-specific phospholipase A1 (Ps-pla1) maps to Chromosome 16 but is distinct from the lpd (lipid defect) locus

We have previously generated a mouse transgenic line with an insertional mutation designated lpd that demonstrates a phenotype of hypertriglyceridemia and fatty liver. Since the recently identified phosphatidylserine-specific phospholipase A1 (PS-PLA1) demonstrates significant homology to triglyceride lipases, we reasoned that the mouse Ps-pla1 gene may be the disrupted gene within the lpd locus. Using a rat PS-PLA1 cDNA sequence to search the EST database, we identified a mouse EST homolog AA839424. Sequencing analysis of AA839424 revealed a putative Ps-pla1 protein of 456 amino acids with extensive overall structural conservation with human and rat PS-PLA1 and with triglyceride lipases. Conserved sequences in Ps-pla1 include a lipase consensus sequences G×S×G, a catalytic triad, and eight of the ten conserved cysteine residues that are required for tertiary structure. Mouse Ps-pla1 carries a phosphatidylserine-binding motif that is absent in all triglyceride lipases. Using a mouse whole-genome radiation hybrid (WG-RH) mapping panel (T31), we mapped mouse Ps-pla1 to Chromosome (Chr) 16 between genetic markers D16Mit194 and D16Mit38, which is 17.1 cM centromeric to the lpd locus. On the basis of chromosome location, we conclude that Ps-pla1 and lpd are distinct genes in lipid metabolism. Received: 31 May 2000 / Accepted: 5 October 2000     

Three novel quantitative trait loci for skin thickness in swine identified by linkage and genome‐wide association studies

Skin is the largest organ in the pig body and plays a key role in protecting the body against pathogens and excessive water loss. Deciphering the genetic basis of swine skin thickness would enrich our knowledge about the skin. To identify the loci for porcine skin thickness, we first performed a genome scan with 194 microsatellite markers in a White Duroc × Erhualian F₂ intercross. We identified three genome‐wide significant QTL on pig chromosomes (SSC) 4, 7 and 15 using linkage analysis. The most significant QTL was found on SSC7 with a small confidence interval of ~5 cM, explaining 23.9 percent of phenotypic variance. Further, we conducted a genome‐wide association study (GWAS) using Illumina PorcineSNP60 Beadchips for the F₂ pedigree and a population of Chinese Sutai pigs. We confirmed significant QTL in the F₂ pedigree and replicated QTL on SSC15 in Chinese Sutai pigs. A meta‐analysis of GWASs on both populations detected a genomic region associated with skin thickness on SSC4. GWAS results were generally consistent with QTL mapping. Identical‐by‐descent analysis defined QTL on SSC7 in a 683‐kb region harboring an interesting candidate gene: HMGA1. On SSC15, the linkage disequilibrium analysis showed a haplotype block of 2.20 Mb that likely harbors the gene responsible for skin thickness. Our findings provide novel insights into the genetic basis of swine skin thickness, which would benefit further understanding of porcine skin function.     

A new mouse model for infantile neuroaxonal dystrophy,inad mouse, maps to mouse Chromosome 1

Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive hereditary neurodegenerative disease of humans. So far, no responsible gene has been cloned or mapped to any chromosome. For chromosome mapping and positional cloning of the responsible gene, establishment of an animal model would be useful. Here we describe a new mouse model for INAD, named inad mouse. In this mouse, the phenotype is inherited in an autosomal recessive manner, symptoms occur in the infantile period, and the mouse dies before sexual maturity. Axonal dystrophic change appearing as spheroid bodies in central and peripheral nervous system was observed. These features more closely resembled human INAD than did those of the gad mouse, the traditional mouse model for INAD. Linkage analysis linked the inad gene to mouse Chromosome 1, with the highest LOD score (=128.6) at the D1Mit45 marker, and haplotype study localized the inad gene to a 7.5-Mb region between D1Mit84 and D1Mit25. In this linkage area some 60 genes exist: Mutation of one of these 60 genes is likely responsible for the inad mouse phenotype. Our preliminary mutation analysis in 15 genes examining the nucleotide sequence of exons of these genes did not find any sequence difference between inad mouse and C57BL/6 mouse.     

Mitochondrial DNA haplogroup ‘R’ is associated with Noonan syndrome of South India

Mutations in PTPN11 gene was responsible for ～50% of the Noonan syndrome (NS), however, we did not find any mutation in PTPN11 in any of seven NS patients analysed. Whereas, the complete mtDNA sequencing revealed 146 mutations, of which five, including one heteroplasmic (A11144R; Thr → Ala) non-synonymous mutation, were novel and exclusively observed in NS patients. Interestingly all the seven probands and their maternal relatives were clustered under a major haplogroup R and its novel sub-haplogroups (R7b1b, R30a1, R30c, T2b7, U9a1) exclusive in NS, therefore we strongly suggest that these haplogroups may influence NS in South Indian populations.