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In the breeding of domestic animals, selection of economically desired traits has been the most important consideration for the improvement of animals, but excluding negative factors in animal production, such as causative genes for hereditary diseases, is also required for the genetic improvement of domestic animals. The incidence of various hereditary diseases has been reported in Japanese beef cattle and these diseases have caused serious problems in the breeding and raising of healthy beef cattle. This article reviews the identification of causative genes for the following three hereditary diseases in Japanese beef cattle: (i) Chediak–Higashi syndrome; (ii) renal tubular dysplasia; and (iii) bovine chondrodysplastic dwarfism. Chediak–Higashi syndrome is a hereditary bleeding disorder reported in Japanese black cattle. To identify the cause of this disease, we cloned and sequenced the bovine LYST gene, which has been found to be involved in Chediak–Higashi syndrome in humans, and found that an amino acid substitution of histidine to arginine at amino acid residue 2015 is the causative mutation in the cattle disease. Renal tubular dysplasia is a hereditary disease of Japanese black cattle showing renal failure and growth retardation. We mapped the locus for this disease to the 4 cM region of bovine chromosome 1 by linkage analysis and found a large deletion in this region. The deleted region contained the PCLN1 gene encoding a tight-junction protein of renal epithelial cells, and we concluded that deletion of the PCLN1 gene is responsible for the disease. Bovine chondrodysplastic dwarfism is a hereditary disease of Japanese brown cattle, displayed by short limbs and joint abnormalities. We mapped the locus for the disease to a region of bovine chromosome 6 by linkage analysis. By constructing YAC and BAC contigs covering this region and sequence analysis, we identified a novel gene ( LIMBIN), which plays an essential role in bone formation in this region, and found two mutations responsible for the disease. The identification of these mutations provided the basis for DNA-based diagnostic systems for these three diseases, and after development of the diagnosis systems, the incidences of these hereditary diseases have dramatically decreased. [ABSTRACT FROM AUTHOR]

The achondroplastic mouse is a spontaneous mutant characterized by disproportionate dwarfism with short limbs and tail due to disturbed chondrogenesis during endochondral ossification. These abnormal phenotypes are controlled by an autosomal recessive gene (cn). In this study, linkage analysis using 115 affected mice of F2 progeny mapped the cn locus on an ∼0.8-cM region of chromosome 4, and natriuretic peptide receptor 2 (Npr2) gene was identified as the most potent candidate for the cn mutant in this region. This gene encodes a receptor for C-type natriuretic peptide (CNP) that positively regulates longitudinal bone growth by producing cGMP in response to CNP binding to the extracellular domain. Sequence analyses of the Npr2 gene in cn/cn mice revealed a T to G transversion leading to the amino acid substitution of highly conserved Leu with Arg in the guanylyl cyclase domain. In cultured chondrocytes of cn/cn mice, stimulus with CNP did not significantly increase intracellular cGMP concentration, whereas it increased in +/+ mice. Transfection of the mutant Npr2 gene into COS-7 cells also showed similar results, indicating that the missense mutation of the Npr2 gene in cn/cn mice resulted in disruption of the guanylyl cyclase activity of the receptor. We therefore concluded that the dwarf phenotype of cn/cn mouse is caused by a loss-offunction mutation of the Npr2 gene, and cn/cn mouse will be a useful model to further study the molecular mechanism regulating endochondral ossification by CNP/natriuretic peptide receptor B signal. [ABSTRACT FROM AUTHOR]

Context: Conception rate, which is an important parameter to evaluate female fertility, has been gradually decreasing in Japanese Black cattle during the past decades. Meiosis is an essential biological process in gamete formation and meiotic failure could be a cause of infertility or reduced fertility in mammals. Of note, single nucleotide polymorphisms (SNPs) in the MLH3 gene involved in meiotic recombination were reported to affect the genome-wide recombination rate of meiosis in cattle. Aims: The present study was conducted to investigate the association of SNPs in the MLH3 gene with conception rate in Japanese Black cattle. Methods: On the basis of the reproductive data of 2045 Japanese Black cattle born from 1990 to 2009, we selected two groups of the reproductive females with high conception rate (n = 103) and low conception rate (n = 109). Then, we genotyped the SNPs in MLH3 gene in both reproductive groups by sequencing and polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). The significant association of SNPs with conception rate in Japanese Black cattle was estimated by Fisher's exact test, by using R commander. Key results: We found the presence of five SNPs of MLH3 gene in Japanese Black cattle, including non-synonymous variants of MLH3 N408S that has been reported to be involved in meiotic recombination rate and MLH3 S591G newly identified in the present study. Comparison of genotype distributions and allele frequencies of the MLH3 N408S between high and low conception-rate groups indicated a significant difference between these groups, suggesting that this SNP is associated with conception rate. However, there is no significant difference between MLH3 S591G with conception rate in Japanese Black cattle. Conclusions: We found a significant association between a non-synonymous variant of MLH3 N408S and conception rate, suggesting that this SNP can be a potential marker for selecting the Japanese Black cattle for improving fertility. We also identified a novel non-synonymous variant of MLH3 S591G in Japanese Black cattle. Implications: These findings will be informative for future marker-assisted selection to improve the fertility of Japanese Black cattle. This is the first report of a genetic variant implicated in meiotic recombination being linked to female fertility in cattle. Conception rate, which is an important parameter to evaluate female fertility, has been gradually decreasing in Japanese Black cattle during the past decades. In this study, we found a non-synonymous variant of the MLH3 gene that has been reported to be involved in meiotic recombination rate is also significantly associated with conception rate. This novel variant is suggested to use as a potential marker for selecting the Japanese Black cattle for improving fertility. This article belongs to the Collection Sustainable Animal Agriculture for Developing Countries 2023. [ABSTRACT FROM AUTHOR]

The complex geographic and temporal origins of chicken domestication have attracted wide interest in molecular phylogeny and phylogeographic studies as they continue to be debated up to this day. In particular, the population dynamics and lineage-specific divergence time estimates of chickens in Southeast Asia (SEA) and the Pacific region are not well studied. Here, we analyzed 519 complete mitochondrial DNA control region sequences and identified 133 haplotypes with 70 variable sites. We documented 82.7% geographically unique haplotypes distributed across major haplogroups except for haplogroup C, suggesting high polymorphism among studied individuals. Mainland SEA (MSEA) chickens have higher overall genetic diversity than island SEA (ISEA) chickens. Phylogenetic trees and median-joining network revealed evidence of a new divergent matrilineage (i.e., haplogroup V) as a sister-clade of haplogroup C. The maximum clade credibility tree estimated the earlier coalescence age of ancestral D-lineage (i.e., sub-haplogroup D2) of continental chickens (3.7 kya; 95% HPD 1985–4835 years) while island populations diverged later at 2.1 kya (95% HPD 1467–2815 years). This evidence of earlier coalescence age of haplogroup D ancestral matriline exemplified dispersal patterns to the ISEA, and thereafter the island clade diversified as a distinct group. [ABSTRACT FROM AUTHOR]

The dwg and dwg Bayer are allelic mutations of the mouse that are characterized by dwarfism, cataracts, and coat color change in homozygotes. The Ggt1 gene encodes γ-glutamyltransferase 1 (GGT1), an extracellular membrane-bound enzyme that is critical for glutathione homeostasis. Both the dwg locus and Ggt1 gene are localized on mouse chromosome 10, and the phenotypes of GGT1-deficient mice with targeted disruption of the Ggt1 gene show remarkable similarities with those of dwg/ dwg and dwg Bayer/ dwg Bayer mice. This evidence led us to hypothesize that the Ggt1 gene is responsible for dwg and dwg Bayer mutations. In this study we characterized dwg mutations by investigating their association with the Ggt1 gene. Histological analysis revealed reduced numbers of proliferative and hypertrophic chondrocytes in the growth plate of dwg/ dwg mice, which are characteristic abnormalities observed in GGT1-deficient mice. To identify the causative mutations of dwg mutations, we analyzed the Ggt1 gene in dwg/ dwg and dwg Bayer/ dwg Bayer mice. In dwg/ dwg mice, 13 nucleotides on exon 7 of the Ggt1 gene were deleted, resulting in the generation of aberrant transcripts due to disrupted pre-mRNA splicing. Furthermore, dwg Bayer/ dwg Bayer mice had a 46.7-kb deletion containing complete coding sequences of Ggt1 and AI646023 genes and the first exon of the Ggt5 gene, which is closely related to the Ggt1 gene as a member of the GGT gene family. These results indicate that both dwg and dwg Bayer have defective mutations of the Ggt1 gene. Thus, we concluded that mutations in the Ggt1 gene are responsible for the phenotypes of dwg/ dwg and dwg Bayer/ dwg Bayer mice. [ABSTRACT FROM AUTHOR]

Objective: The biological importance for the signaling of C-type natriuretic peptide (CNP) and natriuretic peptide receptor B (NPR-B) has been recognized. However, the details remain unclear and are debatable. The Npr2 is a gene of NPR-B, and we previously reported a unique phenotype of a spontaneous mutant mouse lacking Npr2 (Npr2slw/slw), such as severe ileus-like disorder with bloodless blood vessels. In this study, we analyzed the bloodless mesenteric vascular morphology of Npr2slw/slw by histological observation to clarify the effects of the CNP/NPR-B signal deficiency. Results: Blood vessels in the mesentery were clearly dilated in the preweaning Npr2slw/slw mice. Additionally, in the Npr2slw/slw mice, the lacteals were partially dilation or randomly direction mucosal epithelial cells in villi, and mesenteric adipocytes were undeveloped. These findings provide important information for understanding the role of CNP/NPR-B signals on intestine with mesentery. [ABSTRACT FROM AUTHOR]

Several studies have reported the gene polymorphisms associated with high‐altitude adaptation in goats. The FGF5 gene is a regulator in the hair‐growth and a SNP c.‐253G>A located within 5′UTR has been reported to cause long‐haired phenotype. The EPAS1 gene is a transcription factor for various genes that have hypoxia‐adaptive functions and a nonsynonymous SNP (Q579L) located in exon 5 has been reported to be associated with the mean corpuscular hemoglobin concentration. Nepal has large difference in altitudes in the north–south direction and four indigenous goat breeds are bred depending on the altitude. We used a total of 130 animals in Nepal, Chyangra (n = 37), Sinhal (n = 24), Khari (n = 33), and Terai (n = 36), and genotyped these two gene polymorphisms to compare the gene frequencies among the breeds and investigate the associations between breeding altitudes and allele frequencies. The genotyping results revealed that the mutant allele frequency in both polymorphisms tended to increase, as the breeding altitude of each population increased. In addition, correlation coefficients showed a relatively strong positive correlation between the breeding altitude and the mutant allele frequencies (r = 0.87 in FGF5 and r = 0.68 in EPAS1). These results suggested that both polymorphisms would significantly contribute to the high‐altitude adaptation in Nepalese goat breeds. [ABSTRACT FROM AUTHOR]

Although organisms belonging to different species and subspecies sometimes produce fertile offspring, a hallmark of the speciation process is reproductive isolation, characterized by hybrid sterility (HS) due to failure in gametogenesis. In mammals, HS is usually exhibited by males, the heterogametic sex. The phenotypic manifestations of HS are complex. The most frequently observed are abnormalities in both autosomal and sex chromosome interactions that are linked to meiotic prophase arrest or postmeiotic spermiogenesis aberrations and lead to defective or absent gametes. The aim of this study was to determine the HS phenotypes in intersubspecific F1 mice produced by matings between Mus musculus molossinus -derived strains and diverse Mus musculus domesticus -inbred laboratory mouse strains. Most of these crosses produced fertile F1 offspring. However, when female BALB/cJ (domesticus) mice were mated to male JF1/MsJ (molossinus) mice, the (BALB dom xJF1 mol )F1 males were sterile, whereas the (JF1 mol xBALB dom )F1 males produced by the reciprocal crossings were fertile; thus the sterility phenotype was asymmetric. The sterile (BALB dom xJF1 mol ) F1 males exhibited a high rate of meiotic metaphase arrest with misaligned chromosomes, probably related to a high frequency of XY dissociation. Intriguingly, in the sterile (BALB dom xJF1 mol )F1 males we observed aberrant allele-specific expression of several meiotic genes, that play critical roles in important meiotic events including chromosome pairing. Together, these observations of an asymmetrical HS phenotype in intersubspecific F1 males, probably owing to meiotic defects in the meiotic behavior of the XY chromosomes pair and possibly also transcriptional misregulation of meiotic genes, provide new models and directions for understanding speciation mechanisms in mammals. [ABSTRACT FROM AUTHOR]

Background: Mucopolysaccharidosis (MPS) VI is a rare, autosomal recessive congenital metabolic disorder caused by deficient activity of the lysosomal metabolic enzyme, N‐acetylgalactosamine 4‐sulfatase. Enzyme replacement therapy (ERT) is the current treatment for MPS VI, although it involves limited compliance to the therapy and high cost. The aim of this study was to develop a new method of treatment by conducting an orthotopic liver transplantation (LTx) using an animal model of human MPS VI, and to evaluate and examine its effectiveness for treating MPS VI. Methods: LTx was carried out from normal unaffected to affected MPS VI rats (MPR), which were then killed after LTx, and tissues from the heart, spleen, and knee joint, as well as serum, collected for biological and morphologic evaluation. Results: Liver‐transplanted (LTx) MPR had the same level of N‐acetylgalactosamine 4‐sulfatase activity in the liver and lungs as normal unaffected MPR, and the urinary secretion of mucopolysaccharides/glycosaminoglycan (GAG) in LTx MPR was significantly decreased. Furthermore, on histopathology, the spleens of LTx MPR showed elimination of vacuole cells. In the knee joints, growth plates became thinner, and on radiography the facial and cranial bones of LTx MPR were morphologically normal. Conclusions: LTx from normal to affected MPR was effective for symptoms of MPS and accumulation of GAG, suggesting that LTx could be a promising alternative approach for MPS VI. [ABSTRACT FROM AUTHOR]

Vietnamese Yellow cattle are native cattle well adapted to local tropical environment. The aim of this study was to investigate genetic characteristics of the Yellow cattle using molecular markers. We investigated the nucleotide sequences of mitochondrial DNA and SRY gene on Y chromosome, and genotyped SREBP‐1,SCD1,EDG1,NCAPG,DGAT1,MC1R, and HSP70 genes in the Yellow cattle population. The sequence analysis of the mitochondrial DNA showed that most of the cattle possesses zebu (Bos indicus) type I1 haplotype, suggesting relatively low genetic diversity in maternal lineage. The sequence analysis of the SRY gene indicates that while most of the males possess zebu type haplotype, taurine (Bos taurus) type haplotype was also observed, suggesting gene‐flow from taurine cattle. The results of the genotyping of the functional genes showed that the NCAPG,SCD,MC1R, and HsSP70 genes are polymorphic in the population, whereas the SREBP‐1,EDG1, and DGAT1 genes are monomorphic. Particularly, the presence of the desirable and undesirable alleles of the NCAPG and HSP70 genes, respectively, will be important for the selection of animals by potential performances in meat productivity and fertility. The present findings will be informative for future conservation and breeding of the Vietnamese Yellow cattle. [ABSTRACT FROM AUTHOR]

Myanmar native horses are small horses used mainly for drafting carts or carriages in rural areas and packing loads in mountainy areas. In the present study, we investigated genotype distributions and allele frequencies of the LCORL/ NCAPG, MSTN and DMRT3 genes, which are associated with body composition and locomotion traits of horses, in seven local populations of Myanmar native horses. The genotyping result of LCORL/ NCAPG showed that allele frequencies of C allele associated with higher withers height ranged from 0.08 to 0.27, and 0.13 in average. For MSTN, allele frequencies of C allele associated with higher proportion of Type 2B muscular fiber ranged from 0.05 to 0.23, and 0.09 in average. For DMRT3, allele frequencies of A allele associated with ambling gait ranged from 0 to 0.04, and 0.01 in average. The presences of the minor alleles of these genes at low frequencies suggest a possibility that these horse populations have not been under strong selection pressure for particular locomotion traits and body composition. Our findings of the presence of these minor alleles in Southeast Asian native horses are also informative for considering the origins of these minor alleles associated with body composition and locomotion traits in horse populations. [ABSTRACT FROM AUTHOR]

Ellis-van Creveld (EvC) syndrome is a skeletal dysplasia, characterized by short limbs, postaxial polydactyly, and dental abnormalities. EvC syndrome is also categorized as a ciliopathy because of ciliary localization of proteins encoded by the two causative genes, EVC and EVC2 (aka LIMBIN). While recent studies demonstrated important roles for EVC/EVC2 in Hedgehog signaling, there is still little known about the pathophysiological mechanisms underlying the skeletal dysplasia features of EvC patients, and in particular why limb development is affected, but not other aspects of organogenesis that also require Hedgehog signaling. In this report, we comprehensively analyze limb skeletogenesis in Evc2 mutant mice and in cell and tissue cultures derived from these mice. Both in vivo and in vitro data demonstrate elevated Fibroblast Growth Factor (FGF) signaling in Evc2 mutant growth plates, in addition to compromised but not abrogated Hedgehog-PTHrP feedback loop. Elevation of FGF signaling, mainly due to increased Fgf18 expression upon inactivation of Evc2 in the perichondrium, critically contributes to the pathogenesis of limb dwarfism. The limb dwarfism phenotype is partially rescued by inactivation of one allele of Fgf18 in the Evc2 mutant mice. Taken together, our data uncover a novel pathogenic mechanism to understand limb dwarfism in patients with Ellis-van Creveld syndrome. [ABSTRACT FROM AUTHOR]

Objective Our objectives were to determine the expression of EVC2 in craniofacial tissues and investigate the effect of Evc2 deficiency on craniofacial bones using Evc2 knockout (KO) mouse model. Design Evc2 KO mice were generated by introducing a premature stop codon followed by the Internal Ribosomal Entry Site fused to β-galactosidase (LacZ). Samples from wild-type (WT), heterozygous (Het) and homozygous Evc2 KO mice were prepared. LacZ staining and immunohistochemistry (IHC) with anti-β-galactosidase, anti-EVC2 and anti-SOX9 antibodies were performed. The craniofacial bones were stained with alcian blue and alizarin red. Results The LacZ activity in KO was mainly observed in the anterior parts of viscerocranium. The Evc2 -expressing cells were identified in many cartilageous regions by IHC with anti-β-galactosidase antibody in KO and Het embryos. The endogenous EVC2 protein was observed in these areas in WT embryos. Double labeling with anti-SOX9 antibody showed that these cells were mainly chondrocytes. At adult stages, the expression of EVC2 was found in chondrocytes of nasal bones and spheno-occipital synchondrosis, and osteocytes and endothelial-like cells of the premaxilla and mandible. The skeletal double staining demonstrated that craniofacial bones, where the expression of EVC2 was observed, in KO had the morphological defects as compared to WT. Conclusion To our knowledge, our study was the first to identify the types of Evc2 -expressing cells in craniofacial tissues. Consistent with the expression pattern, abnormal craniofacial bone morphology was found in the Evc2 KO mice, suggesting that EVC2 may be important during craniofacial growth and development. [ABSTRACT FROM AUTHOR]

Marker-assisted selection (MAS) is expected to accelerate the genetic improvement of Japanese Black cattle. However, verification of the effects of the genes for MAS in different subpopulations is required prior to the application of MAS. In this study, we investigated the allelic frequencies and genotypic effects for carcass traits of six genes, which can be used in MAS, in eight local subpopulations. These genes are SCD, FASN and SREBP1, which are associated with the fatty acid composition of meat, and NCAPG, MC1R and F11, which are associated with carcass weight, coat color and blood coagulation abnormality, respectively. The frequencies of desirable alleles of SCD and FASN were relatively high and that of NCAPG was relatively low, and NCAPG was significantly associated with several carcass traits, including carcass weight. The proportions of genotypic variance explained by NCAPG to phenotypic variance were 4.83 for carcass weight. We thus confirmed that NCAPG is a useful marker for selection of carcass traits in these subpopulations. In addition, we found that the desirable alleles of six genes showed no negative effects on carcass traits. Therefore, selection using these genes to improve target traits should not have negative impacts on carcass traits. [ABSTRACT FROM AUTHOR]

Rev7 is a subunit of Polζ, one of the translesion DNA synthesis (TLS) polymerases involved in DNA damage repair. We recently found that Rev7 is also essential for germ cell development in mouse. In the present study, we found the development of ovarian tumors in Rev7 mutant mouse, suggesting the involvement of TLS deficiency in the etiology of ovarian tumor. The Rev7 mutant mice showed complete lack of oocytes and follicles in the ovary. The lack of follicles causes a significant increase of gonadotropin level and an increase in the proliferation of ovarian cells. As a result, the weight of the ovaries of Rev7 mutant mice increased with age and they developed tubulostromal adenomas. However, the remarkable overgrowth of ovaries occurred after gonadotropin level decreases at older ages, suggesting gonadotropin-independent progression of the ovarian tumors. In addition, the Rev7 mutant fibroblasts and ovarian cells showed significant accumulation of DNA damage. These findings suggest that not only increased gonadotropin levels but also lack of DNA damage repair function could be responsible for the development of ovarian tumors in the Rev7 mutant mouse. [ABSTRACT FROM AUTHOR]

Brain natriuretic peptide (BNP) contributes to heart formation during embryogenesis. After birth, despite a high number of studies aimed at understanding by which mechanism(s) BNP reduces myocardial ischemic injury in animal models, the actual role of this peptide in the heart remains elusive. In this study, we asked whether BNP treatment could modulate the proliferation of endogenous cardiac progenitor cells (CPCs) and/or their differentiation into cardiomyocytes. CPCs expressed the NPR-A and NPR-B receptors in neonatal and adult hearts, suggesting their ability to respond to BNP stimulation. BNP injection into neonatal and adult unmanipulated mice increased the number of newly formed cardiomyocytes (neonatal: +23 %, p = 0.009 and adult: +68 %, p = 0.0005) and the number of proliferating CPCs (neonatal: +142 %, p = 0.002 and adult: +134 %, p = 0.04). In vitro, BNP stimulated CPC proliferation via NPR-A and CPC differentiation into cardiomyocytes via NPR-B. Finally, as BNP might be used as a therapeutic agent, we injected BNP into mice undergoing myocardial infarction. In pathological conditions, BNP treatment was cardioprotective by increasing heart contractility and reducing cardiac remodelling. At the cellular level, BNP stimulates CPC proliferation in the non-infarcted area of the infarcted hearts. In the infarcted area, BNP modulates the fate of the endogenous CPCs but also of the infiltrating CD45 cells. These results support for the first time a key role for BNP in controlling the progenitor cell proliferation and differentiation after birth. The administration of BNP might, therefore, be a useful component of therapeutic approaches aimed at inducing heart regeneration. [ABSTRACT FROM AUTHOR]

Piwi-interacting RNAs (piRNAs) are gonad-specific small RNAs that provide defense against transposable genetic elements called transposons. Our knowledge of piRNA biogenesis is sketchy, partly due to an incomplete inventory of the factors involved. Here, we identify Tudor domain-containing 12 (TDRD12; also known as ECAT8) as a unique piRNA biogenesis factor in mice. TDRD12 is detected in complexes containing Piwi protein MILI (PIWIL2), its associated primary piRNAs, and TDRD1, all of which are already implicated in secondary piRNA biogenesis. Male mice carrying either a nonsense point mutation (reproductive mutant 23 or repro23 mice) or a targeted deletion in the Tdrd12 locus are infertile and derepress retrotransposons. We find that TDRD12 is dispensable for primary piRNA biogenesis but essential for production of secondary piRNAs that enter Piwi protein MIWI2 (PIWIL4). Cell-culture studies with the insect ortholog of TDRD12 suggest a role for the multidomain protein in mediating complex formation with other participants during secondary piRNA biogenesis. [ABSTRACT FROM AUTHOR]

Japanese Black cattle are at risk for genetic homogeneity due to intensive use of a few sires. Therefore, assessment of the actual genetic diversity of this breed is important for future breeding plans. In the present study, we investigated the genetic diversity within and among eight subpopulations of Japanese Black cattle using 52 microsatellite markers. The parameters for genetic diversity of Japanese Black cattle were comparable to those of other cattle breeds, suggesting that the relatively high genetic diversity of the breed. However, upon comparison among the eight subpopulations, the Hyogo subpopulation showed markedly low genetic diversity. The results of the pairwise FST values, phylogenetic network and structure analysis indicated that the Hyogo population has remarkably high level of genetic differentiation from other populations, while Yamagata, Niigata, Hiroshima and Kagawa populations have low levels of genetic differentiation. Furthermore, multidimensional scaling plots indicated that individuals in some subpopulations were separated from individuals in the other subpopulations. We conclude that while the overall genetic diversity of Japanese Black cattle is still maintained at a relatively high level, that of a particular subpopulation is significantly reduced, and therefore the effective population size of the breed needs to be controlled by correct mating strategies. [ABSTRACT FROM AUTHOR]

Estimates of genetic parameters were obtained for body measurement traits of 648 animals at 4 months of age, of 545 at 8 months and carcass traits of 14 972 animals with the use of an animal model by the restricted maximum likelihood procedure. The estimated heritabilities for carcass traits were high (0.41 to 0.54). At 4 months the estimated direct heritabilities for body measurement traits were moderate to high (0.28 to 0.64), except for chest width (0.19); at 8 months they were also moderate to high (0.23 to 0.49), except for chest depth and chest width (0.18 and 0.06, respectively). Maternal heritabilities for all body measurement traits were low at both ages. The results indicate that because of their moderate direct genetic correlations with body measurement traits, carcass weight, rib thickness and subcutaneous fat thickness can be improved; however, rib eye area and beef marbling standard show little such possibility considering their correlation with body measurement traits. [ABSTRACT FROM AUTHOR]

Long bone abnormality ( lbab/lbab) is a strain of dwarf mice. Recent studies revealed that the phenotype is caused by a spontaneous mutation in the Nppc gene, which encodes mouse C-type natriuretic peptide (CNP). In this study, we analyzed the chondrodysplastic skeletal phenotype of lbab/lbab mice. At birth, lbab/lbab mice are only slightly shorter than their wild-type littermates. Nevertheless, lbab/lbab mice do not undergo a growth spurt, and their final body and bone lengths are only ~60% of those of wild-type mice. Histological analysis revealed that the growth plate in lbab/lbab mice, especially the hypertrophic chondrocyte layer, was significantly thinner than in wild-type mice. Overexpression of CNP in the cartilage of lbab/lbab mice restored their thinned growth plate, followed by the complete rescue of their impaired endochondral bone growth. Furthermore, the bone volume in lbab/lbab mouse was severely decreased and was recovered by CNP overexpression. On the other hand, the thickness of the growth plate of lbab/+ mice was not different from that of wild-type mice; accordingly, impaired endochondral bone growth was not observed in lbab/+ mice. In organ culture experiments, tibial explants from fetal lbab/lbab mice were significantly shorter than those from lbab/+ mice and elongated by addition of 10 M CNP to the same extent as lbab/+ tibiae treated with the same dose of CNP. These results demonstrate that lbab/lbab is a novel mouse model of chondrodysplasia caused by insufficient CNP action on endochondral ossification. [ABSTRACT FROM AUTHOR]

ABSTRACT This study was conducted to evaluate the importance of maternal effect on body measurement traits at an early stage of growth, and to estimate the genetic relationships between direct and maternal effects and among body measurement traits at 0 month (0-mo) and 4 months (4-mo) of age in a population of Japanese Black calves. Body measurements and body weight of 889 Japanese Black calves were estimated with the use of an animal model by the Residual Maximum Likelihood procedure. Direct heritabilities were low to moderate, ranging between 0.17 ± 0.09 and 0.48 ± 0.13 at 0-mo, and slightly lower, ranging between 0.15 ± 0.07 and 0.33 ± 0.13 at 4-mo. Estimated maternal heritabilities were low to moderate, ranging between 0.08 ± 0.07 and 0.33 ± 0.07 at 0-mo and 0.13 ± 0.06 to 0.33 ± 0.06 at 4-mo. The direct genetic correlations between 0-mo and 4-mo were moderate to highly positive, ranging from 0.53 ± 0.23 to 0.96 ± 0.09. The estimated direct genetic correlation of chest width with other width traits was low and positive at both ages, whereas with hip width it was high and positive (0.80 ± 0.09) at 0-mo, suggesting that simultaneous improvement of body width of the front and back parts is possible. Maternal genetic effects were relatively independent of direct genetic effects for body measurement traits and can be considered in genetic evaluation. [ABSTRACT FROM AUTHOR]

A case of lysosomal storage disease has been reported in a calf of Japanese Black cattle. Lysosomal storage diseases are hereditary diseases caused by deficiency of lysosomal hydrolases. The clinical and pathological features and accumulated substrates of the affected animal indicated a possibility of sialidosis or galactosialidosis caused by deficiency of neuraminidase (NEU1) or protective protein for β-galactosidase (PPGB). In the present study, we investigated nucleotide sequences of the genes encoding these two proteins to evaluate whether mutation of these genes is involved in this disease. We determined cattle genomic sequences of these two genes by using bovine EST sequences and the nucleotide sequences of all exons of these genes were compared between affected and normal animals. The results showed several nucleotide substitutions, but none of them was a functional mutation or specific to the affected animal. Furthermore, genotyping of the microsatellite markers in the vicinity of these two genes revealed no homozygosity of the chromosomal regions including these genes in the affected animal. These findings indicated that neither NEU1 nor PPGB gene is responsible for the lysosomal storage disease of Japanese Black cattle and therefore the disease is neither sialidosis nor galactosialidosis. [ABSTRACT FROM AUTHOR]

Abstract: Multiple ocular defects (MOD) in cattle is an autosomal recessive hereditary disorder characterized by dysplasia of the lens, retinal detachment, persistence of the hyaloid artery, and microphthalmia. The locus responsible for MOD has been mapped to the proximal region of bovine chromosome 18. In the present study, we refined the localization of the MOD locus to a 1.0-Mb interval by haplotype analysis using a pedigree of affected animals. Comparison of nucleotide sequence of genes in this region revealed a one-nucleotide insertion in the WFDC1 gene, which resulted in a frame shift mutation and premature termination codon at the middle of the protein. WFDC1 is a small secretory protein containing a WAP-type four disulfide core domain. Specific expression of Wfdc1 was observed in the lens, retina, and optic nerves of embryonic and adult mouse eyes by immunohistochemical staining and in situ hybridization. The present finding demonstrated the essential role of WFDC1 in mammalian eye development. [Copyright &y& Elsevier]

Abstract: Long bone abnormality (lbab/lbab) is a spontaneous mutant mouse characterized by dwarfism with shorter long bones. A missense mutation was reported in the Nppc gene, which encodes C-type natriuretic peptide (CNP), but it has not been confirmed whether this mutation is responsible for the dwarf phenotype. To verify that the mutation causes the dwarfism of lbab/lbab mice, we first investigated the effect of CNP in lbab/lbab mice. By transgenic rescue with chondrocyte-specific expression of CNP, the dwarf phenotype in lbab/lbab mice was completely compensated. Next, we revealed that CNP derived from the lbab allele retained only slight activity to induce cGMP production through its receptor. Histological analysis showed that both proliferative and hypertrophic zones of chondrocytes in the growth plate of lbab/lbab mice were markedly reduced. Our results demonstrate that lbab/lbab mice have a hypomorphic mutation in the Nppc gene that is responsible for dwarfism caused by impaired endochondral ossification. [Copyright &y& Elsevier]

Mucopolysaccharidosis VI (MPS VI) is caused by deficient activity of arylsulfatase B (ARSB), resulting in intralysosomal storage of dermatan sulfate (DS) and multisystem disease without central nervous system involvement. After gene transfer, muscle or liver can theoretically be converted into factories for systemic ARSB secretion, leading to uptake by non-transduced cells. We have injected newborn MPS VI rats and cats with adeno-associated viral (AAV) vectors expressing ARSB under the control of liver-specific, muscle-specific, or universally active promoters. After systemic or intramuscular (IM) administration of AAV, therapeutic levels of circulating ARSB are achieved, resulting in skeletal improvements and significant decrease in glycosaminoglycan (GAG) storage, inflammation and apoptosis (despite a neutralizing immune response to ARSB in MPS VI rats). In addition, we have observed wide-spread dissemination of vector after IM AAV administration. This results in secretion of therapeutic levels of ARSB when the universally active cytomegalovirus (CMV) but not the muscle-specific muscle creatine kinase (MCK) promoter is used, suggesting that transduction of extramuscular sites rather than enzyme secretion from muscle occurs after muscle ARSB gene transfer. We conclude that AAV-mediated expression of ARSB from liver represents a feasible therapeutic strategy for MPS VI, potentially avoiding multiple infusions of costly recombinant enzyme associated with enzyme replacement therapy.Molecular Therapy (2007) 16 1, 30–37. doi:10.1038/sj.mt.6300325 [ABSTRACT FROM AUTHOR]

Forelimb-girdle muscular anomaly is a hereditary disorder of Japanese Black cattle characterized by tremors and astasia caused by hypoplasia of the forelimb-girdle muscles. The locus responsible for this disorder has been mapped on a middle region of bovine chromosome 26. In this study, we applied marker-assisted selection to identify the carriers of this disorder. Four microsatellite markers, DIK4440, BM4505, MOK2602 and IDVGA-59, linked to the disorder locus were genotyped in 37 unaffected offspring of a carrier sire. Transmission of the mutant or wild-type allele of the disorder locus of the sire to the 37 offspring was determined by examining the haplotypes of these markers. The results showed that nine and 18 of the 37 animals possessed the paternally transmitted mutant and wild-type alleles, respectively, and therefore, the nine animals with the mutant allele were identified as carriers. We concluded that the marker-assisted selection using these four markers can be applied for the identification of the carriers of forelimb-girdle muscular anomaly of Japanese Black cattle. [ABSTRACT FROM AUTHOR]

Short-limbed dwarfism (SLW) is a new mutant mouse characterized by a dwarf phenotype with markedly short body, limbs, and tail. In the present study, we investigated the skeletal phenotypes of the SLW mouse and determined the chromosomal localization to identify the gene responsible for the phenotypes (slw). Skeletal preparations stained with alcian blue and alizarin red revealed that longitudinal growth of the extremities of the affected (slw/slw) mice was significantly reduced in comparison with that of normal mice, whereas the positions and numbers of skeletal elements were normal. Histological examination of tibial growth plates of the affected mice showed that the numbers of proliferating and hypertrophic chondrocytes were obviously diminished. These phenotypes resembled to those of human chondrodysplasias caused by defective chondrocyte proliferation and differentiation. We mapped the slw locus on an 11.7-cM interval of the proximal region of mouse chromosome 4 by linkage analysis. Furthermore, allelism test using Npr2cn locus, a mutant allele of Npr2 gene encoding a natriuretic peptide receptor B, revealed that slw locus is an allele of the Npr2 gene. These results suggest that the dwarf phenotype of the SLW mouse is caused by the disturbed endochondral ossification, and a mutation in the Npr2 gene is expected to be responsible for the phenotypes of the SLW mouse. [ABSTRACT FROM AUTHOR]

The hairy ears ( Eh) mutation in the mouse originated from neutron irradiation experiments and is associated with chromosomal inversion on chromosome 15. Eh/+ mice have small pinna and extra hairs on the pinna but the phenotypic features of Eh/Eh mice are unclear. In this study we found that Eh/Eh mice died shortly after birth and had a cleft palate caused by impaired growth of palate shelves. Because genes located on the breakpoints of inversion are likely to be responsible for the defects associated with chromosomal inversions, we determined the breakpoints of the Eh inversion. We used a new genetic method that uses recombinant chromosomes resulting from crossing over between two overlapping inversions to determine the breakpoints. Koa is a mouse mutation associated with inversion of chromosome 15, which partially overlaps with the Eh inversion. We made Eh +/+ Koa double heterozygotes and obtained the recombinant chromosomes possessing deletion and duplication of the regions flanked by the breakpoints of both inversions, which were generated by crossing over within the overlapped region of these inversions. By defining the deleted regions we identified the breakpoints of the Eh inversion. We then examined the expression of genes in the vicinities of the breakpoints and found ectopic expression of the Hoxc5 gene and a transcript with unknown function in the developing palate of Eh/Eh mice, which is likely to be responsible for the cleft palate. [ABSTRACT FROM AUTHOR]

Mice carrying the piebald mutation exhibit white coat spotting due to the regional absence of neural crest-derived melanocytes. We reported previously that the piebald locus encodes the Ednrb gene and that piebald mice express low levels of structurally intact Ednrb mRNA and EDNRB protein (Hosoda, K., Hammer, R. E., Richardson, J. A., Baynash, A. G., Cheung, J. C., Giaid, A., and Yanagisawa, M. (1994) Cell 79, 1267–1276). Here, we report that both the life span of the Ednrb mRNA and the promoter activity of the Ednrb gene are indistinguishable between wild-type and piebald mice. Introns 2–6 of the Ednrb gene in piebald mice were correctly excised with an efficiency indistinguishable from those in wild-type mice in exon trapping experiments. We found that the piebald allele of the Ednrb gene has a 5.5-kb retroposon-like element in intron 1 possessing canonical sequences of a polyadenylation signal and a splice acceptor site. Abnormal hybrid transcripts carrying exon 1 of the Ednrb gene and a portion of the 5.5-kb element are expressed in piebald mice. The insertion of the 5.5-kb element into a heterologous intron in a mammalian expression vector markedly reduced the expression of the reporter gene. Premature termination and aberrant splicing of the Ednrb transcript caused by the retroposon-like element in intron 1 lead to a reduced level of the normal Ednrb transcript, which is responsible for the partial loss-of-function phenotype of piebald mice. [ABSTRACT FROM AUTHOR]

Hemophilia A is a severe congenital bleeding disorder characterized by subcutaneous hematoma and hemorrhage into muscles resulting from a deficiency of blood coagulation factor VIII. The authors have recently reported two cases of hemophilia A in Japanese Brown cattle and identified a nucleotide substitution in the factor VIII gene, resulting in an amino acid substitution of Leu to His, as a possible cause of the deficiency. In the present study, a simple and effective polymerase chain reaction (PCR)-based diagnostic method was developed to identify carriers of this disorder, using a mismatch primer in combination with restriction enzyme digestion. The PCR reaction amplified a 118 bp fragment, which was not digested by the BspT104I restriction enzyme in affected animals but was digested into two fragments in normal animals. Both digested and undigested fragments were observed in carrier animals. This method was applied to identify the carriers of hemophilia A in a population of Japanese Brown cattle. By screening 155 DNA samples from Japanese Brown cattle, except for the dam of the two probands, no carriers were identified. It was therefore concluded that the probands represent isolated cases of hemophilia A, and that the frequency of the mutant allele in the Japanese Brown cattle population is very low. [ABSTRACT FROM AUTHOR]

Congenital multiple ocular defects (MOD) in Japanese black cattle is a hereditary ocular disorder with an autosomal recessive manner of inheritance, showing developmental defects of the lens, retina, and iris, persistent embryonic eye vascularization, and microphthalmia. In the present study, we mapped the locus responsible for the disorder by linkage analysis using 240 microsatellite markers covering the entire bovine genome and an inbred pedigree obtained from commercial herds. The linkage analysis demonstrated a significant linkage between the disorder locus and markers on the proximal region of bovine Chromosome (BTA) 18 with the maximum LOD score of 5.1. Homozygosity mapping using the haplotype of the linked markers further refined the critical region. The results revealed the localization of the locus responsible for MOD in an approximately 6.6-cM region of BTA18. Comparison of published linkage and radiation hybrid (RH) maps of BTA18 with its evolutionary ortholog, human Chromosome (HSA) 16, revealed several potential candidate genes for the disorder including the MAF and FOXC2 genes. [ABSTRACT FROM AUTHOR]

Factor XI deficiency in Japanese black cattle is an hereditary mild bleeding disorder with an autosomal recessive mode of inheritance. To characterize the molecular lesion causing factor XI deficiency in cattle, we isolated an entire coding region of the bovine F11 gene, which comprises 15 exons and 14 introns, and determined its nucleotide sequences. Comparison of the nucleotide sequences of the F11 gene between affected and unaffected animals revealed an insertion of 15 nucleotides in exon 9 of the affected animals. The insertion results in a substitution of one amino acid with six amino acids in a highly conserved amino acid sequence in the fourth apple domain of factor XI protein. Genotyping of the F11 gene in 109 Japanese black cattle revealed that the insertion clearly corresponded to the factor XI activities of the animals. We therefore concluded that the insertion of 15 nucleotides in the F11 gene is the causative mutation for factor XI deficiency in Japanese black cattle. Genotyping of the F11gene by detecting the insertion will be an effective DNA-based diagnostic system to prevent incidence of the disease. [ABSTRACT FROM AUTHOR]

Meiosis is a critical stage of gametogenesis in which alignment and synapsis of chromosomal pairs occur, allowing for the recombination of maternal and paternal genomes. Here we show that FK506 binding protein (Fkbp6) localizes to meiotic chromosome cores and regions of homologous chromosome synapsis. Targeted inactivation of Fkbp6 in mice results in aspermic males and the absence of normal pachytene spermatocytes. Moreover, we identified the deletion of Fkbp6 exon 8 as the causative mutation in spontaneously male sterile as/as mutant rats. Loss of Fkbp6 results in abnormal pairing and misalignments between homologous chromosomes, nonhomologous partner switches, and autosynapsis of X chromosome cores in meiotic spermatocytes. Fertility and meiosis are normal in FkbpS mutant females. Thus, Fkbp6 is a component of the synaptonemal complex essential for sex-specific fertility and for the fidelity of homologous chromosome pairing in meiosis. [ABSTRACT FROM AUTHOR]

Intractable gastrointestinal (GI) diseases often develop during infancy. Our group previously reported that natriuretic peptide receptor B (NPR-B)-deficient Npr2slw/slw mice exhibit severe intestinal dysfunction, such as stenosis and distention, which resembles the dysfunction observed in Hirschsprung's disease-allied disorders. However, the root cause of intestinal dysfunction and the detailed of pathophysiological condition in the intestine are not yet clear. Here, we report that the intestine of preweaning Npr2slw/slw mice showed bloodless blood vessels, and nodes were found in the lymphatic vessel. Additionally, the lacteals, smooth muscle, blood vessel, and nerves were barely observed in the villi of preweaning Npr2slw/slw mice. Moreover, intramuscular interstitial cells of Cajal (ICC-IM) were clearly reduced. In contrast, villi and ICC-IM were developed normally in surviving adult Npr2slw/slw mice. However, adult Npr2slw/slw mice exhibited partially hypoplastic blood vessels and an atrophied enteric nervous. Furthermore, adult Npr2slw/slw mice showed markedly reduced white adipose tissue. These findings suggest that the cause of GI dysfunction in preweaning Npr2slw/slw mice is attributed to defective intestinal development with microcirculation disorder. Thus, it is suggested that NPR-B signaling is involved in intestinal development and control of microcirculation and fat metabolism. This report provides new insights into intractable GI diseases, obesity, and NPR-B signaling. [ABSTRACT FROM AUTHOR]

This study aims to estimate the mitochondrial genetic diversity and structure of Japanese Polled and Kuchinoshima feral cattle, which are maintained in small populations. We determined the mitochondrial DMA (mtDNA) displacement loop (D-loop) sequences for both cattle populations and analyzed these in conjunction with previously published data from Northeast Asian cattle populations. Our findings showed that Japanese native cattle have a predominant, Asian-specific mtDNA haplogroup T4 with high frequencies (0.43-0.81). This excluded Kuchinoshima cattle (32 animals), which had only one mtDNA haplotype belonging to the haplogroup T3. Japanese Polled showed relatively lower mtDNA diversity in the average sequence divergence (0.0020) than other Wagyu breeds (0.0036-0.0047). Japanese Polled have been maintained in a limited area of Yamaguchi, and the population size is now less than 200. Therefore, low mtDNA diversity in the Japanese Polled could be explained by the decreasing population size in the last three decades. We found low mtDNA diversity in both Japanese Polled and Kuchinoshima cattle. The genetic information obtained in this study will be useful for maintaining these populations and for understanding the origin of Japanese native cattle. [ABSTRACT FROM AUTHOR]