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JAK2V617F is the most frequent driver mutation in myeloproliferative neoplasms (MPNs) and is associated with vascular complications. However, the impact of hematopoietic JAK2V617F on the aortic aneurysms (AAs) remains unknown. Our cross-sectional study indicated that 9 (23%) out of 39 MPN patients with JAK2V617F exhibited the presence of AAs. Next, to clarify whether the hematopoietic JAK2V617F contributes to the AAs, we applied a bone marrow transplantation (BMT) with the donor cells from Jak2V617F transgenic (JAK2V617F) mice or control wild-type (WT) mice into lethally irradiated apolipoprotein E-deficient mice. Five weeks after BMT, the JAK2V617F-BMT mice and WT-BMT mice were subjected to continuous angiotensin II infusion to induce AA formation. Four weeks after angiotensin II infusion, the abdominal aorta diameter in JAK2V617F-BMT mice was significantly enlarged compared to that in the WT-BMT mice. Additionally, the abdominal AA-free survival rate was significantly lower in the JAK2V617F-BMT mice. Hematopoietic JAK2V617F accelerated aortic elastic lamina degradation as well as activation of matrix metalloproteinase (MMP)-2 and MMP-9 in the abdominal aorta. The numbers of infiltrated macrophages were significantly upregulated in the abdominal aorta of the JAK2V617F-BMT mice accompanied by STAT3 phosphorylation. The accumulation of BM-derived hematopoietic cells carrying JAK2V617F in the abdominal aorta was confirmed by use of reporter GFP-transgene. BM-derived macrophages carrying JAK2V617F showed increases in mRNA expression levels of Mmp2, Mmp9, and Mmp13. Ruxolitinib decreased the abdominal aorta diameter and the incidence of abdominal AA in the JAK2V617F-BMT mice. Our findings provide a novel feature of vascular complications of AAs in MPNs with JAK2V617F.

Background: Exposure to certain carcinogens together with host genetic predisposition likely has an influence on cervical carcinogenesis. Objective: Our aim was to evaluate synergistic effects of glutathione S-transferase (GST) polymorphisms and risk behaviors (i.e., smoking and contraceptive use) on squamous cell cervical cancer (SCCA) development in northeastern Thailand. Methods: Subjects were 198 (SCCA) patients and 198 age-matched healthy controls. Multiplex PCR and PCR-RFLP were used to determine GSTT1 and GSTA1 gene polymorphism, respectively. Results: Interaction between the four polymorphic loci of GSTs (GSTM1, GSTT1, GSTP1 and GSTA1) and increased risk for cervical cancer was not observed. The three genotypes of GSTM1 consistently showed significant risks of smoking with a lower OR for the Null individuals (1.741) at around one -fourth of wild type homozygous individuals (8.000). The effects of GST polymorphisms on cervical cancer risk under the use of hormonal contraceptives apparently did not occur. Conclusions: The predisposition of smoking risk is related to the GST genotype. It is suggested that knowing one’s own genotype data will contribute to the prevention of SCCA by controlling risk habits.

Background: CYP1A1 is an enzyme in phase I of the cytochrome P450 (CYP) superfamily, and plays a key role in detoxification of carcinogens. Host genetic predisposition in the CYP1A1 may be associated with an increased susceptibility to cervical cancer.The study aimed to evaluate four common polymorphisms of the CYP1A1 and cervical cancer susceptibility among Northeast Thai women. Methods: A case-control study was conducted involving 204 patients with squamous cell cervical cancer (SCCA) and 204 age-matched healthy controls. DNA was extracted from peripheral blood leucocytes. CYP1A1 m1, m3, and m4 genotypes were detected using PCR-RFLP, whereas the CYP1A1 m2 genotype was investigated using real-time PCR. Haplotype analysis was performed using PHASE algorithm version 2.1.1. Results: CYP1A1 m3 was monomorphic. Association between the common CYP1A1 polymorphisms, m1 and m2, and cervical cancer risk was not observed (p>0.05), nor was any association found between the m1–m2–m4 haplotype and cervical cancer risk (p>0.05). Interestingly, the CA genotype of CYP1A1 m4 was observed in 30.88% of the cervical cancer patients but was absent in healthy controls. Conclusion: Our results demonstrated a possible involvement of the CYP1A1 m4 polymorphism but no other common polymorphisms (viz., m1, m2, and m3) in the risk for cervical cancer.This finding may be useful when screening for risk of cervical cancer among Northeast Thai women.

Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by pulmonary arterial remodeling. Clonal somatic mutations including JAK2V617F, the most frequent driver mutation among myeloproliferative neoplasms, have recently been identified in healthy individuals without hematological disorders. Here, we reveal that clonal hematopoiesis with JAK2V617F exacerbates PH and pulmonary arterial remodeling in mice. JAK2V617F-expressing neutrophils specifically accumulate in pulmonary arterial regions, accompanied by increases in neutrophil-derived elastase activity and chemokines in chronic hypoxia-exposed JAK2V617F transgenic (JAK2V617F) mice, as well as recipient mice transplanted with JAK2V617F bone marrow cells. JAK2V617F progressively upregulates Acvrl1 (encoding ALK1) during the differentiation from bone marrow stem/progenitor cells peripherally into mature neutrophils of pulmonary arterial regions. JAK2V617F-mediated STAT3 phosphorylation upregulates ALK1-Smad1/5/8 signaling. ALK1/2 inhibition completely prevents the development of PH in JAK2V617F mice. Finally, our prospective clinical study identified JAK2V617F-positive clonal hematopoiesis is more common in PH patients than in healthy subjects. These findings indicate that clonal hematopoiesis with JAK2V617F causally leads to PH development associated with ALK1 upregulation., Pulmonary hypertension is characterized by increased pulmonary arterial pressure, driven in part by inflammatory infiltrates. Here, the authors show that in mice, transgenic expression of mutant JAK2 leads to clonal hematopoiesis and lung accumulation of elastase- and cytokine-expressing neutrophils, and that the phenotype can be reversed by ALK1 inhibition.

Background Homo sapiens have experienced admixture many times in the last few thousand years. To examine how admixture affects local adaptation, we investigated genomes of modern Polynesians, who are shaped through admixture between Austronesian-speaking people from Southeast Asia (Asian-related ancestors) and indigenous people in Near Oceania (Papuan-related ancestors). Methods In this study local ancestry was estimated across the genome in Polynesians (23 Tongan subjects) to find the candidate regions of admixture-enabled selection contributed by Papuan-related ancestors. Results The mean proportion of Papuan-related ancestry across the Polynesian genome was estimated as 24.6% (SD = 8.63%), and two genomic regions, the extended major histocompatibility complex (xMHC) region on chromosome 6 and the ATP-binding cassette transporter sub-family C member 11 (ABCC11) gene on chromosome 16, showed proportions of Papuan-related ancestry more than 5 SD greater than the mean (> 67.8%). The coalescent simulation under the assumption of selective neutrality suggested that such signals of Papuan-related ancestry enrichment were caused by positive selection after admixture (false discovery rate = 0.045). The ABCC11 harbors a nonsynonymous SNP, rs17822931, which affects apocrine secretory cell function. The approximate Bayesian computation indicated that, in Polynesian ancestors, a strong positive selection (s = 0.0217) acted on the ancestral allele of rs17822931 derived from Papuan-related ancestors. Conclusions Our results suggest that admixture with Papuan-related ancestors contributed to the rapid local adaptation of Polynesian ancestors. Considering frequent admixture events in human evolution history, the acceleration of local adaptation through admixture should be a common event in humans.

Hereditary ATTR amyloid cardiomyopathy is defined as the intramyocardial deposition of amyloid fibrils derived from the mutation of transthyretin (TTR). A 51-year-old man was referred to our hospital for congestive heart failure. He and his family had no past history of heart diseases. Echocardiography showed remarkable left ventricular hypertrophy and reduced ejection fraction. Endomyocardial biopsy specimens presented positive staining of Congo-Red and transthyretin. A genetic test showed heterozygous V122I TTR gene mutation, which is very rare in Japan. We diagnosed him as with sporadic ATTR amyloidosis with mutation, and tafamidis was administered to stabilize TTR tetramer. Since the phenotype of ATTR amyloidosis varies depending on its penetration rate, it is crucial to always keep in mind the possibility of hereditary ATTR amyloidosis even in the case of amyloidosis with no clear family history.

Heart failure causes increased venous pressure, leading to liver dysfunction. The fibrosis-4 index is a simple index for liver fibrosis and has been reported to be useful for predicting prognosis in heart failure; however, its impact on patients with pulmonary hypertension due to left heart disease (PH-LHD) has not yet been fully elucidated.We enrolled consecutive 230 hospitalized patients who had been diagnosed as having PH-LHD. The fibrosis-4 index was calculated as follows: [aspartate transaminase (U/L) × age]/[alanine transaminase 1/2 (U/L) × platelet count (109/L) ]. We followed patients for all-cause mortality during the follow-up period (mean 1112 ± 822 days).The patients were divided into tertiles based on their fibrosis-4 index: the first tertile 0.335 to 1.381; the second tertile 1.391 to 2.311; and the third tertile 2.323 to 14.339. Compared with the first tertile, the third tertile had lower estimated glomerular filtration rates and hemoglobin levels. All-cause mortality was significantly higher in the third than in the first tertile. In a Cox proportional hazard model, the fibrosis-4 index was a predictor of all-cause mortality in PH-LHD patients (HR 1.212, 95% CI 1.099-1.337, P < 0.001).The fibrosis-4 index is associated with kidney function, anemia, and high mortality in PH-LHD patients.

DNA suffers various types of damage even in a normal condition, although they are rapidly repaired by mechanisms called DNA repair. Most progeroid syndromes are caused by genetic defects in specific molecules involved in the DNA repair. DNA damage activates a broad range of signaling pathway that leads to repair, cell cycle arrest, apoptosis and so on, which is called DNA damage response. Recent studies revealed that persistent DNA damage response triggers induction of cell senescence and senescence-associated secretory phenotype (SASP). Here, we review recent advances in the understanding of the molecular mechanisms by which SASP components are regulated, and discuss the possible roles of DNA damage and the DNA damage response, and SASP in the pathogenesis of cardiovascular disease.

Group housing of socially-deprived individuals facilitates welfare and socialisation of primates. Here, we studied behavioural and hormonal changes in the course of group formation among nine male chimpanzees, Pan troglodytes. Aggression, reassurance, and grooming were observed in various dyads during group formation. The pattern of fluctuations in salivary cortisol level changed through the process of group formation, with particularly high cortisol levels immediately after group interactions relative to other sampling timings during group formation. Salivary testosterone levels were unaffected by the process of group formation or sampling time. These results suggested that a combination of behavioural observation and hormonal analyses is a powerful approach to assess the impact of group formation.

Objectives Semenogelin 1 and 2 (SEMG1 and SEMG2) are known as semen coagulating proteins in primates with a repetitive structure of 60-amino acids. The number of repeats varies among species and is hypothesized to be related to the level of primate sperm competition. Gibbons until recently were thought to be monogamous primates, but it is now known that gibbon social structure is flexible. Thus, hypotheses of the relationship between the SEMGs evolution and mating systems were tested. Materials and methods The sequences of the exon 2 of the SEMG1 and SEMG2 were obtained from 50 captive gibbons comprising six species belonging to three genera (Hylobates, Symphalangus, and Nomascus). Then we quantified the levels of polymorphism and estimated rates of protein evolution by calculating d N /d S ratio. Results Several mutations that create a premature stop codon in the SEMG1 and a reduction in the repeats of the SEMG2 in the genus Hylobates were observed and may alter the coding properties for these proteins. We also found different level of nucleotide diversity in each gene and between genera. Strikingly, in Nomascus leucogenys we discovered a high d N /d S ratio in the SEMG1 and SEMG2. The Nomascus SEMG2 also showed significantly lower nucleotide diversity than the other two genera. Discussion These results are consistent with the presence of a strong positive selection in the Nomascus lineage even if the exact selective forces acting on these genes are not yet conclusively known. We were not able to demonstrate, among gibbons, unambiguous relationships between the SEMGs evolution and mating systems.

The objective of this study was to develop mathematical equations for describing the change in marbling in Japanese Black steers using longitudinal measurements. Serial ultrasound measurements were taken at 14, 16, 20, and 26 months of age and analyzed using an image analysis software. The longitudinal marbling measurements from the ultrasound images and carcasses were fitted into a nonlinear logistic curve. Data used for the analysis consisted of 749 steers that converged in nonlinear curve fitting and showed reasonable estimated parameters of the logistic curves. The average predicted mature beef marbling score (BMS) and maturation rate were 6.26 and 0.353, respectively, and the average maturity levels at 24 months of age were 83.9%. The heritability estimates for the predicted maturity traits were moderate, indicating that these traits may have potential for genetic improvement. There was a negative relationship between the expected progeny differences between carcass BMS and maturity traits, suggesting that genetic improvement by carcass BMS may lead to the selection of bulls with late maturity for marbling. The results indicate that ultrasound and model building for marbling can be useful tools to correctly select candidate bulls with high marbling in the early fattening period.

Background: Several studies have recently reported that transthyretin (ATTR) amyloidosis is present in patients with aortic stenosis (AS). We aimed to 1) examine the prevalence of ATTR amyloidosis in AS patients undergoing transcatheter aortic valve implantation (TAVI), 2) compare clinical characteristics between AS patients with and without ATTR, and 3) identify predictors of ATTR amyloidosis in AS patients. Methods and Results: We prospectively analyzed consecutive 32 patients with severe AS who underwent screening tests for ATTR in prior to TAVI. To detect ATTR, we performed cardiac technetium-99m pyrophosphate ( 99m Tc-PYP) scintigraphy in 24 patients and biopsies of fat tissue from the puncture site in 24 patients. Of 32 AS patients who were screened for ATTR, 6 (18.8%) patients were diagnosed as ATTR by cardiac 99m Tc-PYP scintigraphy (n=2) and fat biopsy (n=5). Compared with non-ATTR patients, ATTR patients presented higher levels of B-type natriuretic peptide (BNP, 242.3 vs. 1101.4 ng/ml, P=0.004), lower left ventricular ejection fraction (LVEF, 62.3 vs. 45.5%, P=0.002) and lower mean pressure gradient of AS (50.2 vs. 32.0 mmHg, P=0.016). In contrast, age, sex, STS score, clinical frailty scale, prevalence of chronic kidney disease and atrial fibrillation, and levels of hemoglobin, albumin, estimated glomerular filtration rate and troponin I were comparable between the two groups. Other echocardiographic parameters including interventricular septal wall thickness, posterior wall thickness and aortic valve area did not differ between the two groups. To detect ATTR among AS patients, receiver operating characteristic (ROC) analysis demonstrated that area under the curve of BNP, LVEF, and mean pressure gradient was 0.814, 0.766 and 0.846, respectively. Although TAVI was successfully completed in all patients, and there was no procedural complication in both groups, one of ATTR patients re-hospitalized due to decompensated heart failure 3 weeks after TAVI. Conclusion: In AS patients undergoing TAVI, especially in cases of low-flow low-gradient pattern and high BNP levels, screening of ATTR should be considered. In this population, cardiac 99m Tc-PYP scintigraphy and fat biopsy are useful to detect latent ATTR non-invasively.

Backgrounds: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vasoconstriction and organic stenosis due to abnormal proliferation of pulmonary vascular cells. Endothelin (ET)-1 induces pulmonary vasoconstriction hyperplasia and plays a pivotal role in the pathogenesis of PAH. The germline mutations of activin receptor-like kinase (ACVRL)-1, a serine/threonine kinase and receptor for TGF-β, have been reported in idiopathic and hereditary PAH. However, the relationship between ET-1 and ACVRL-1 in the pathogenesis of PAH is largely unknown. Thus, we investigated the molecular mechanism of ACVRL-1 expression induced by ET-1 in human pulmonary arterial endothelial cells (hPAECs). Methods: ACVRL-1 expression levels were measured using Western blotting and quantitative real-time polymerase chain reaction. The promoter activity of ACVRL-1 was evaluated using dual luciferase assay. hPAECs were pretreated with pertussis toxin (PTX), cell-permeable C3 toxin (C3T) and Y27632 to inhibit Gi, RhoA and Rho kinase, respectively. GTP-RhoA, an active form of RhoA, was assessed using pull-down assay. Results: ET-1 increased mRNA and protein expression of ACVRL-1 in hPAECs (1.8±0.2 folds, P Conclusion: These data indicate that ET-1 increases ACVRL-1 expression both at transcriptional and post-transcriptional mechanisms via the Gi/RhoA/Rho kinase/Sp-1 axis in human PAECs.

Background: It has been known that East Asian people, including Japanese, has a high bleeding risk (HBR) than Western. Therefore, risk stratification is important to detect HBR patients among patients who underwent percutaneous coronary intervention (PCI). The aim of the present study was to investigate the association between serum albumin level and bleeding events in patients who underwent PCI. Methods and Results: Consecutive 1027 patients who underwent PCI and had been discharged from our institution were enrolled. We divided the patients into three groups based on serum albumin levels at discharge: the first tertile (≤3.7 g/dL, n=358), second tertile (3.8-4.1 g/dL, n=308) and third tertile (≥4.2 g/dL, n=361). Clinical characteristics of three groups were as follows: mean age (the first, second and third tertile; 72.9, 69.3 and 63.4 years, P2 , P Conclusion: In patients who underwent PCI, low serum albumin level is independently associated with long-term bleeding events.

Gibbons in the genus Hylobates, which live in Southeast Asia, show great diversity, comprising seven to nine species. Natural hybridisation has been observed in the species contact zones, although the roles played by hybridisation and introgression in the evolution of these species remain unclear. To uncover the divergence history and the contributions of hybridisation and introgression to the evolution of Hylobates, random amplicon sequencing-direct (GRAS-Di) analysis was employed to genotype 47 gibbons, representing eight species from three genera. After quality filtering, over 300,000 autosomal single-nucleotide variant (SNV) sites were identified. The SNV-based autosomal phylogeny, together with the mitochondrial phylogeny, supported a divergence pattern beginning approximately 4.3 million years ago. First, the mainland species, H. pileatus and H. lar, consecutively diverged from the Sundaic island species. Second, H. moloch, in Java (and likely H. klossii, in the Mentawai Islands) diverged from the other species. Third, H. muelleri, in Borneo, and H. agilis/H. albibarbis, in Sumatra and southwestern Borneo, diverged. Lastly, H. agilis and H. albibarbis diverged from each other. The Patterson’s D-statistics indicated significant introgression between H. lar and H. pileatus, between H. lar and H. agilis, and between H. albibarbis and H. muelleri, and weak introgression was identified between H. moloch and H. albibarbis, and between H. moloch and H. muelleri abbotti, suggesting incomplete reproductive barriers among Hylobates species and that hybridisation and introgression occur whenever the distribution ranges contact. Some candidates for introgressed genomic regions were detected, and the functions of these would be revealed by further genome-wide studies.

In the Cercopithecini ancestor two chromosomes, homologous to human chromosomes 20 and 21, fused to form the Cercopithecini specific 20/21 association. In some individuals from the genus Cercopithecus, this association was shown to be polymorphic for the position of the centromere, suggesting centromere repositioning events. We set out to test this hypothesis by defining the evolutionary history of the 20/21 association in four Cercopithecini species from three different genera. The marker order of the various 20/21 associations was established using molecular cytogenetic techniques, including an array of more than 100 BACs. We discovered that five different forms of the 20/21 association were present in the four studied Cercopithecini species. Remarkably, in the two Cercopithecus species, we found individuals in which one homolog conserved the ancestral condition, but the other homolog was highly rearranged. The phylogenetic analysis showed that the heterozygosity in these two species originated about 8 million years ago and was maintained for this entire arc of time, surviving multiple speciation events. Our report is a remarkable extension of Dobzhansky's pioneering observation in Drosophila concerning the maintenance of chromosomal heterozygosity due to selective advantage. Dobzhansky's hypothesis recently received strong support in a series of detailed reports on the fruit fly genome. Our findings are first extension to primates, indeed to Old World monkeys phylogenetically close to humans of an analogous situation. Our results have important implications for hypotheses on how chromosome rearrangements, selection, and speciation are related.

A common single nucleotide polymorphism (SNP) located in intron 4 of the EFEMP1 gene, rs3791675, has been reported to be associated with human height in European and Asian populations. The objective of this study is to examine the possible association of rs3791675-G with taller height in Oceanian populations. The rs3791675 SNP was genotyped for 636 adult subjects living in Tonga (Tonga population) and Solomon Islands (Munda, Kusaghe, and Rawaki populations). The allele frequency of rs3791675-G ranged from 0.29 to 0.66. A multiple regression analysis adjusted for age and sex was performed to test the association of rs3791675 with height in each population. The results revealed that a single copy of the rs3791675-G allele significantly increased height by 1.2 cm in Tonga population (P-value = 0.031), while no significant association was detected in Munda, Kusaghe, and Rawaki populations. Since the partial regression coefficients of rs3791675-G estimated in regression models were positive in all the populations, the lack of association in the Solomon Islanders may have come from small effect size of rs3791675-G in them as well as small sample size. To confirm the present finding, replication studies in other Oceanian populations are required.

Pulmonary arterial hypertension is a fatal disease caused by pulmonary arterial vasoconstriction and organic stenosis due to the proliferation of pulmonary smooth muscle cells and endothelial cells. Endothelial dysfunction, including impaired nitric oxide (NO) bioavailability, plays a crucial role in the pathogenesis of pulmonary hypertension, and endothelial nitric oxide synthase (eNOS) is an important modulator of pulmonary vasodilatation. Although senescence marker protein (SMP) 30 is known as an anti-aging protein, the role of SMP30 in pulmonary vessels is still unclear. In this study, we examined the role of SMP30 in pulmonary vasculature using SMP30-deficient mice.We used female SMP30-deficient mice and wild-type littermate (WT) mice at the age of 12 to 18 weeks. The WT and SMP30-deficient mice were exposed to normoxia or hypoxia (10% oxygen for 4 weeks). In normoxia, the right ventricular systolic pressure (RVSP) was not different between the WT and SMP30-deficient mice, but in hypoxia, the RVSP was significantly higher in the SMP30-deficient mice compared to the WT mice (P < 0.05). The hypoxia-induced increases in right ventricular hypertrophy and medial smooth muscle area of the pulmonary artery were comparable between the WT and the SMP30-deficient mice. Western blotting showed that eNOS phosphorylation in lung tissue was reduced in the SMP30-deficient mice compared to the WT mice in normoxia. However, in hypoxic conditions, eNOS phosphorylation was reduced in both the WT and SMP30-deficient mice with no differences in Akt phosphorylation.Our study demonstrated that SMP30 is involved in the development of hypoxia-induced pulmonary hypertension by impairment of eNOS activity.

Deficiency of X-ray repair cross-complementing protein 3 (XRCC3), a DNA-damage repair molecule, and the 241Met variant of XRCC3 have been reported to increase endoreduplication, which induces polyploidy. The aims of this study were to determine the impact of the XRCC3 polymorphism on the incidence of hypertension-induced left ventricular hypertrophy (LVH) and to investigate the mechanisms underlying any potential relationship. Patients undergoing chronic hemodialysis (n = 77) were genotyped to assess for the XRCC3 Thr241Met polymorphism. The XRCC3 241Thr/Met genotype was more frequent in the LVH (+) group than in the LVH (-) group (42.3 vs. 13.7%, χ2 = 7.85, p = 0.0051). To investigate possible mechanisms underlying these observations, human XRCC3 cDNA of 241Thr or that of 241Met was introduced into cultured CHO cells. The surface area of CHO cells expressing XRCC3 241Met was larger than that expressing 241Thr. Spontaneous DNA double-strand breaks accumulated to a greater degree in NIH3T3 cells expressing 241Met (3T3-241Met) than in those expressing 241Thr (3T3-241Thr). DNA damage caused by radiation induced cell senescence more frequently in 3T3-241Met. The levels of basal and TNF-α-stimulated MCP-1 mRNA and protein secretion were higher in 3T3-241Met. Finally, FACS analysis revealed that the cell percentage in G2/M phase including polyploidy was significantly higher in 3T3-241Met than in 3T3-241Thr. Furthermore, the basal level of MCP-1 mRNA positively correlated with the cell percentage in G2/M phase and polyploidy. These data suggest that the XRCC3 241Met increases the risk of LVH via accumulation of DNA damage, thereby altering cell cycle progression and inducing cell senescence and a proinflammatory phenotype.

The genetic structure of the people of mainland Japan and Okinawa has been gradually unveiled in recent years. However, previous anthropological studies dealing with people in the Amami islands, located between mainland Japan and Okinawa, were less informative because of the lack of genetic data. In this study, we collected DNAs from 104 subjects in two of the Amami islands, Amami-Oshima island and Kikai island. We analyzed the D-loop region of mtDNA, four Y-STRs, and four autosomal nonsynonymous SNPs to clarify the Amami islanders’ genetic structure compared with peoples in Okinawa, mainland Japan, and other regions of East Asia. We found that the Amami islanders showed a genetically intermediate position between mainland Japan and Okinawa in mtDNA and Y-STR. However, the frequencies of several autosomal SNPs in the Amami islanders indicated a significant difference from mainland Japanese, which may be because of the gene flow from Okinawa but not natural selection. Moreover, extremely high or low frequencies of several alleles implied a founder effect in Kikai islanders. Note that there is room for the interpretation of the results because of the small sample size and number of alleles in the present study. Geographically broad and detailed samplings and genome-wide analyses are awaited.

High mobility group box 1 (HMGB1), a ubiquitous DNA-binding protein, promotes angiogenesis and tissue repair, resulting in restored cardiac function after myocardial infarction (MI). Although dipeptidyl peptidase 4 (DPP4) degrades certain peptides, it remains unclear as to whether HMGB1 is a substrate of DPP4 and whether DPP4 inhibition prevents the cleavage of HMGB1.In transgenic mice with cardiac-specific overexpression of HMGB1 (TG) and wild-type mice (WT), a diabetic state was induced by streptozotocin, and MI was created by ligation of the left anterior descending coronary artery. To inhibit DPP4 activity, a DPP4 inhibitor anagliptin was used. The plasma levels of HMGB1, infarct size, echocardiographic data, angiogenesis, and vascular endothelial growth factor (VEGF) expression in the peri-infarct area were compared among non-diabetic MI WT/TG, diabetic MI WT/TG, and anagliptin-treated diabetic MI WT/TG mice.DPP4 activity was increased in the diabetic state and blocked by anagliptin administration. The HMGB1 plasma levels were reduced in the diabetic TG compared with the non-diabetic TG mice, but DPP4 inhibition with anagliptin increased HMGB1 plasma levels in the diabetic TG mice. The infarct area was significantly larger in the diabetic TG than in the non-diabetic TG mice, and it was reduced by DPP4 inhibition. Cardiac function, angiogenesis, and VEGF expression were impaired in the diabetic TG mice, but they were ameliorated by the DPP4 inhibition to levels similar to those found in the non-diabetic TG mice.The DPP4 inhibitor ameliorated cardiac function by inhibiting the inactivation of HMGB1 in diabetic mice after MI.

The exact cause of steatosis, one of defects in Japanese beef carcasses, has not been elucidated to date, because it is very difficult to diagnose cyclopedically with certain reproducibility due to the bias in the outbreak. Therefore, the objective of this study was to assess the influence of polymorphisms in retinol dehydrogenase 16 (RDH16), myoferlin (MYOF) and vascular endothelial growth factor receptors 1 and 2 (VEGFR1, VEGFR2) on carcass-graded Musculus trapezius steatosis. For logistic regression analysis, 646 carcasses shipped from 29 farms in Miyazaki, Japan, were used. The GG genotype in RDH16 showed significant odds ratios against AA and AG. In VEGFR1, CT had a significant odds ratio against CC. After evaluating for interaction, highly significant odds ratios were observed in the combinations that included the GG risk genotype in RDH16. It is noteworthy that there was no steatosis in the combination GG (RDH16) and CC (VEGFR1). It may be concluded that there is a possibility that steatosis can be suppressed by the CC genotype in VEGFR1. The current study revealed the influence of genetic polymorphisms on M. trapezius steatosis that had not been reported until now, and may help elucidate the cause of steatosis.

Cytogenetics has historically played a key role in research on squirrel monkey (genus Saimiri) evolutionary biology. Squirrel monkeys have a diploid number of 2n = 44, but vary in fundamental number (FN). Apparently, differences in FN have phylogenetic implications and are correlated with geographic regions. A number of hypothetical mechanisms were proposed to explain difference in FN: translocations, heterochromatin, or, most commonly, pericentric inversions. Recently, an additional mechanism, centromere repositioning, was discovered, which can alter chromosome morphology and FN. Here, we used chromosome banding, chromosome painting, and BAC-FISH to test these hypotheses. We demonstrate that centromere repositioning on chromosomes 5 and 15 is the mechanism that accounts for differences in FN. Current phylogenomic trees of platyrrhines provide a temporal framework for evolutionary new centromeres (ENC) in Saimiri. The X-chromosome ENC could be up to 15 million years (my) old that on chromosome 5 as recent as 0.3 my. The chromosome 15 ENC is intermediate, as young as 2.24 my. All ENC have abundant satellite DNAs indicating that the maturation process was fairly rapid. Callithrix jacchus was used as an outgroup for the BAC-FISH data analysis. Comparison with scaffolds from the S. boliviensis genome revealed an error in the last marmoset genome release. Future research including at the sequence level will provide better understanding of chromosome evolution in Saimiri and other platyrrhines. Probably other cases of differences in chromosome morphology and FN, both within and between taxa, will be shown to be due to centromere repositioning and not pericentric inversions.

Polymorphisms in genes involved in lipid metabolism have been reported to be associated with fatty acid composition of adipose tissue. However, the relationship of these polymorphisms with premortem ultrasonic traits is unknown. The objective of this study, therefore, was to assess the association between polymorphisms in fatty acid synthase, stearoyl-coenzyme A desaturase (SCD), sterol regulatory element-binding protein 1 (SREBP1), diacylglycerol acyltransferase 1, and nuclear receptor subfamily 1, group H, number 3 genes with ultrasonic and carcass traits in Japanese Black steers (n = 300) under progeny testing at the Livestock Improvement Association of Miyazaki. To have a comprehensive analysis of the association between the aforementioned genetic polymorphisms and ultrasonic traits, longitudinal measurements of ultrasonic traits were taken. Furthermore, the association of these genetic polymorphisms and carcass traits was evaluated. The polymorphisms in the SCD gene and SREBP1 were associated (P

Objective Autophagy is a bulk degradation system for intracellular proteins which contributes to skeletal muscle homeostasis, according to previous studies in humans and rodents. However, there is a lack of information on the physiological role of autophagy in the skeletal muscle of meat animals. This study was planned as a pilot study to investigate changes in expression of two major autophagy-related genes, microtubule-associated protein 1 light chain 3β (MAP1LC3B) and autophagy related 7 (ATG7) in fattening beef cattle, and to compare them with skeletal muscle growth. Methods Six castrated Japanese Black cattle (initial body weight: 503±20 kg) were enrolled in this study and fattened for 7 months. Three skeletal muscles, M. longissimus, M. gluteus medius, and M. semimembranosus, were collected by needle biopsy three times during the observation period, and mRNA levels of MAP1LC3B and ATG7 were determined by quantitative reverse-transcription polymerase chain reaction. The expression levels of genes associated with the ubiquitin-proteasome system, another proteolytic mechanism, were also analyzed for comparison with autophagy-related genes. In addition, ultrasonic scanning was repeatedly performed to measure M. longissimus area as an index of muscle growth. Results Our results showed that both MAP1LC3B and ATG7 expression increased over the observation period in all three skeletal muscles. Interestingly, the increase in expression of these two genes in M. longissimus was highly correlated with ultrasonic M. longissimus area and body weight. On the other hand, the expression of genes associated with the ubiquitin-proteasome system was unchanged during the same period. Conclusion These findings suggest that autophagy plays an important role in the growth of skeletal muscle of fattening beef cattle and imply that autophagic activity affects meat productivity.

Sarcoidosis is a systemic granulomatous disease including heart (cardiac sarcoidosis, CS). It has recently been reported that isolated CS, which presenting primarily cardiac symptoms without clinical evidence of sarcoid involvement in other organs. Diagnostic and prognostic biomarkers of CS, especially in isolated CS, have not yet been established.We studied plasma levels of angiotensin-converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R), B-type natriuretic peptide (BNP) and cardiac troponin I (cTnI) in consecutive 172 patients with diagnosed sarcoidosis. We compared these markers between non-cardiac sarcoidosis (non-CS, n = 123, 71.5%) and CS patients (n = 49, 28.5%), including non-isolated CS (n = 30, 17.4%) and isolated CS (n = 19, 11.1%). ROC analysis revealed that BNP identified CS with AUC of 0.85 (P < 0.01) in sarcoidosis patients. In addition, ACE and sIL-2R levels were significantly higher in non-isolated CS than in isolated CS (P < 0.05). Furthermore, in the Cox proportional hazard analysis, cTnI, but not ACE, IL2R or BNP, was a predictor of fatal arrhythmia in sarcoidosis patients (HR 2.418, P = 0.003).Higher ACE and sIL2-R are associated with systemic lesions, whereas BNP is a useful marker for detecting cardiac involvement in sarcoidosis patients. cTnI is a predictor of fatal arrhythmia in CS patients. A multiple biomarker approach supports comprehensive management of sarcoidosis.

A missense variant (rs373863828:G A; p.Arg457Gln) of the CREBRF gene is strongly associated with a higher body mass index (BMI; kg/mThe aim of this study is to examine the association of rs373863828:G A with levels of serum lipids in four Pacific populations.A total of 613 adult subjects were recruited from Tonga (Polynesians) and the Solomon Islands (Melanesians and Micronesians). Multiple regression analyses adjusted for age and sex were performed to examine the association of rs373863828 with levels of serum lipids in each population.A significant association of rs373863828:G A with lower level of HDL-cholesterol was detected in the Tonga population (β = -3.32 and p-value = 0.030). The expected change in HDL-cholesterol with respect to a single copy of the rs373863828-A allele was 3.32 mg/dL. However, the association between rs373863828-A and lower levels of HDL-cholesterol was not significant after further adjustment for BMI in the Tonga population (β = -2.32 and p-value = 0.13).The rs373863828-A allele may not directly affect the level of serum HDL-cholesterol independent of BMI. To confirm the present findings, association studies with large sample sizes and functional analyses are required.

Background The common deletion of the glutathione S-transferase Mu 1 (GSTM1) gene in humans has been shown to be involved in xenobiotic metabolism and associated with bladder cancer. However, the evolution of this deletion has not been investigated. Results In this study, we conducted comparative analyses of primate genomes. We demonstrated that the GSTM gene family has evolved through multiple structural variations, involving gene duplications, losses, large inversions and gene conversions. We further showed experimentally that the GSTM1 was polymorphically deleted in both humans and also in chimpanzees, through independent deletion events. To generalize our results, we searched for genic deletions that are polymorphic in both humans and chimpanzees. Consequently, we found only two such deletions among the thousands that we have searched, one of them being the GSTM1 deletion and the other surprisingly being another metabolizing gene, the UGT2B17. Conclusions Overall, our results support the emerging notion that metabolizing gene families, such as the GSTM, NAT, UGT and CYP, have been evolving rapidly through gene duplication and deletion events in primates, leading to complex structural variation within and among species with unknown evolutionary consequences. Electronic supplementary material The online version of this article (10.1186/s12864-018-4676-z) contains supplementary material, which is available to authorized users.

OBJECTIVES In group-living primates, it has been reported that the alpha male exhibits high concentrations of cortisol and testosterone in the context of mating competition. We investigated how the presence of females affected salivary cortisol and testosterone levels in males from a small captive group of chimpanzees (Pan troglodytes). Specifically, we assessed whether the presence of females resulted in a rapid increase in salivary cortisol and testosterone levels in the alpha male. MATERIALS AND METHODS We compared the social behavior and salivary hormone concentrations of four males before and after the presentation of receptive females. Three times a day, we collected saliva samples, a useful matrix for investigating short-term hormonal changes, and measured cortisol and testosterone concentration by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS The frequency of inter-male aggression increased in the presence of females, indicating intense competition among males. Salivary cortisol levels increased in all males in the presence of females; however, the increase was significantly more pronounced in the alpha male. We found a complex three-way interaction among the presence of females, sampling timings, and male dominance rank in the analysis of salivary testosterone. Contrary to our prediction, a post hoc analysis revealed that salivary testosterone levels decreased after female introduction and that the alpha male did not show a higher level of salivary testosterone. CONCLUSIONS Our study provides experimental evidence suggesting that the presence of females plays a significant role in the rank-related variation in the cortisol levels in male chimpanzees. Furthermore, our findings demonstrate the usefulness of salivary hormones for detecting short-term physiological changes in studies of socioendocrinology.

Sex/autosome translocations are rare events. The only known example in catarrhines is in the silvered-leaf monkey. Here the Y chromosome was reciprocally translocated with chromosome 1. The rearrangement produced an X1X2Y1Y2 sex chromosome system. At least three chromosomal variants of the intact chromosome 1 are known to exist. We characterized in high resolution the translocation products (Y1 and Y2) and the polymorphic forms of the intact chromosome 1 with a panel of more than 150 human BAC clones. We showed that the translocation products were extremely rearranged, in contrast to the high level of marker order conservation of the other silvered-leaf monkey chromosomes. Surprisingly, each translocation product appeared to form independent “chromosome lineages”; each having a myriad of distinct rearrangements. We reconstructed the evolutionary history of the translocation products by comparing the homologous chromosomes of two other colobine species: the African mantled guereza and the Indian langur. The results showed a massive reuse of breakpoints: only 12, out of the 40 breaks occurred in domains never reused in other rearrangements, while, strikingly, some domains were used up to four times. Such frequent breakpoint reuse if proved to be a general phenomenon has profound implications for mechanisms of chromosome evolution.

Titin is associated with myocardial stiffness and hypertrophy, and mutations in its gene have been identified in cardiac myopathies such as dilated cardiomyopathy (DC). It has recently been reported that in damaged muscle, the N-terminal fragment of titin (Titin-N) is cleaved by calpain-3, and urinary Titin-N (U-TN) could be a marker of sarcomere damage. We aimed to investigate the impact of U-TN on prognosis of DC. We measured urinary levels of Titin-N/creatinine ratio (U-TN/Cr; pmol/mg/dl) in 102 patients with DC, and followed up all the patients (mean 1,167 days). The patients were divided into 3 groups based on the U-TN/Cr: first (U-TN/Cr

Consideration of the shortened fattening period seems to be worthwhile for the realization of profitable beef production. In this study, change of fatty acid composition of the lumbar longissimus during the final stage of fattening was investigated in Japanese Black cattle. Each of 110 fattening animals was sampled three times: the initial two samples were taken by biopsy (25.7 months and 27.5 months on average) and the final one was from carcasses (29.9 months on average). Preliminary analysis indicated that removing muscle tissues from the constant body position of the living animals should be essential for sampling. Average monounsaturated fatty acids (MUFA) at three sampling points were 58.1%, 58.5% and 60.5%, and the differences of the third sampling with the first and second samplings were significant. Both in steers and heifers, MUFA also increased as the fattening stage proceeded, and MUFA of the heifers at all the sampling points were significantly higher than those of the steers. The increasing rate of MUFA rose from 0.21 percentage points (pp)/month at period 1 (from the first sampling to the second sampling) to 0.84 pp/month at period 2 (from the second sampling to the slaughter).

Macaca fascicularis aurea (Burmese long-tailed macaque) is 1 of the 10 subspecies of Macaca fascicularis. Despite having few morphological differences from other subspecies, a recent phylogeographic study showed that M. f. aurea is clearly distinct genetically from Macaca fascicularis fascicularis (common long-tailed macaque) and suggests that M. f. aurea experienced a disparate evolutionary pathway versus other subspecies. To construct a detailed evolutionary history of M. f. aurea and its relationships with other macaque species, we performed phylogenetic analyses and divergence time estimation of whole mitochondrial genomes (2 M. f. aurea, 8 M. f. fascicularis, and 16 animals of 12 macaque species) and 2871 bp of the Y chromosome (1 M. f. aurea, 2 M. f. fascicularis, and 5 animals of 5 macaque species) and haplotype network analysis of 758 bp of the Y chromosome (1 M. f. aurea, 2 M. f. fascicularis, and 21 animals of 19 macaque species). Whereas the Y chromosome of M. f. aurea clustered with those of the fascicularis species group in the phylogenetic and haplotype network analyses, its mtDNA clustered within the clade of the sinica species group. Based on this phylogenetic incongruence and the estimated divergence times, we propose that proto-M. f. aurea underwent hybridization with a population of the sinica species group between 2.5 and 0.95 MYA after divergence from the common ancestor of M. fascicularis. Hybridization and introgression might have been central in the evolution of M. f. aurea, similar to what occurred in the evolution of other macaque species and subspecies.

It has been suggested that a ‘thrifty’ genotype hypothesis can account for high prevalence of obesity in the island populations of Oceania. A recent genome-wide association study revealed that a missense variant, rs373863828-A (p.Arg457Gln), of the CREBRF gene (encoding CREB3 regulatory factor) was associated with an excessive increase in body mass index (BMI) in Samoans. In the present study, the association of rs373863828-A with an increase in BMI was examined in four Austronesian (AN)-speaking populations in Oceania. We found that rs373863828-A was frequently observed (frequency of 0.15) in Tongans (Polynesians), and was strongly associated with higher BMI (P=6.1 × 10−4). A single copy of the rs373863828-A allele increased BMI by 3.09 kg m−2 after adjustment of age and sex. No significant association was detected in the other three AN-speaking populations (Melanesians and Micronesians) living in Solomon Islands. This was probably due to the low allele frequency (0.02–0.06) of rs373863828-A as well as small sample size. The rs373863828-A allele was not found in both AN-speaking and non-AN-speaking Melanesians living in Papua New Guinea. Our results suggest that rs373863828-A of CREBRF, a promising thrifty variant, arose in recent ancestors of AN-speaking Polynesians.

OBJECTIVES It has long been recognized that in gibbons both sexes disperse from the natal group. However, the fate of dispersed individuals was rarely documented. Here we provide the first detailed information on sex differences in dispersal patterns by analyzing the spatial genetic structure of a well-known white-handed gibbon (Hylobates lar) population. MATERIALS AND METHODS Mitochondrial DNA (mtDNA) and Y-chromosomal haplotypes, and autosomal microsatellite genotypes were determined for individuals of the Mo Singto study site, Khao Yai National Park, Thailand. Mantel tests for the three genetic marker types were performed for 17 gibbon groups comprising 23 adult males and 18 adult females. RESULTS Significant positive Mantel correlations were observed for spatial distance and both autosomal microsatellite-based as well as Y-chromosomal haplotype-based genetic distance among adult males. Neighboring adult males tended to be genetically related and share Y-chromosomal haplotypes. Conversely, no significant Mantel correlations were observed either in autosomal microsatellites or mtDNA among adult females. DISCUSSION Our results confirm, at a genetic level, hypotheses from long-term demographic observations that white-handed gibbon males of the Mo Singto population primarily disperse into adjacent groups. Instead, females disperse more opportunistically either to adjacent or more distant groups. This sex-specific difference reflects an apparent greater tolerance between males than between females. The higher tolerance of adult males allows the formation of stable multimale groups and facilitates male dispersal into an adjacent group. Stable multifemale groups have never been documented for white-handed gibbons probably due to feeding competition between females.

Objective Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), likely prevent cardiovascular disease, however their mechanisms remain unclear. Recently, the role of DNA damage in atherogenesis has been receiving considerable attention. Here, we investigated the effects of EPA and DHA on DNA damage in vascular endothelial cells to clarify their antiatherogenic mechanisms. Methods and results We determined the effect of EPA and DHA on H2O2-induced DNA damage response in human aortic endothelial cells. Immunofluorescence staining showed that γ-H2AX foci formation, a prominent marker of DNA damage, was significantly reduced in the cells treated with EPA and DHA (by 47% and 48%, respectively). H2O2-induced activation of ATM, a major kinase orchestrating DNA damage response, was significantly reduced with EPA and DHA treatment (by 31% and 33%, respectively). These results indicated EPA and DHA attenuated DNA damage independently of the DNA damage response. Thus the effects of EPA and DHA on a source of DNA damage were examined. EPA and DHA significantly reduced intracellular reactive oxygen species under both basal condition and H2O2 stimulation. In addition, the mRNA levels of antioxidant molecules, such as heme oxygenase-1, thioredoxin reductase 1, ferritin light chain, ferritin heavy chain and manganese superoxide dismutase, were significantly increased with EPA and DHA. Silencing nuclear factor erythroid 2-related factor 2 (NRF2) remarkably abrogated the increases in mRNA levels of antioxidant molecules and the decrease in intracellular reactive oxygen species. Furthermore, EPA and DHA significantly reduced H2O2-induced senescence-associated β-galactosidase activity in the cells (by 31% and 22%, respectively), which was revoked by NRF2 silencing. Conclusions Our results suggested that EPA and DHA attenuate oxidative stress-induced DNA damage in vascular endothelial cells through upregulation of NRF2-mediated antioxidant response. Therefore omega-3 fatty acids likely help prevent cardiovascular disease, at least in part, by their genome protective properties.

Human essential hypertension is partly caused by genetic factors. Angiotensinogen (AGT), G-protein β3-subunit (GNB3) and cytochrome P450 3A5 (CYP3A5) are candidate hypertension susceptibility genes and risk alleles at these loci have been thought to arise owing to human adaptation to climatic changes following the migration out-of-Africa. This study aimed to reveal the frequencies of hypertension-susceptibility genotypes in Pacific Island populations and associations of these single-nucleotide polymorphisms (SNPs) to hypertension. Genotyping was conducted for 804 individuals from Melanesian, Micronesian and Polynesian populations at SNPs in the genes encoding AGT (rs699, rs5049 and rs5051), GNB3 (rs5443) and CYP3A5*1/*3 (rs776746). Associations between these SNPs and hypertension were tested for 383 Melanesian Solomon Islanders. We found that the A/A genotype at rs5049 was a risk factor for hypertension (P=0.025) in the Melanesian Solomon Islanders; three SNPs for AGT were in linkage disequilibrium. The ancestral alleles of rs699, rs5051 and rs776746, and the derived allele of rs5443 were as frequent in the populations surveyed here as in other equatorial populations. Although other polymorphisms associated with hypertension and additional populations remain to be studied, these findings suggest that the Pacific Islanders' susceptibility to hypertension arose because of human migration and adaptation.

OBJECTIVE:Obesity is a growing health concern in the Oceanic populations. To investigate the genetic factors associated with adult obesity in the Oceanic populations, the association of single nucleotide polymorphisms (SNPs) of the beta-2 adrenergic receptor (ADRB2) gene with obesity was examined in 694 adults living in Tonga and Solomon Islands.\nRESULTS:A screening for variation in 16 Oceanic subjects detected 17 SNPs in the entire region of ADRB2, of which nine SNPs including two non-synonymous ones, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu), were further genotyped for all subjects. The rs34623097-A allele, at a SNP located upstream of ADRB2, showed the strongest association with risk for obesity in a logistic regression analysis adjusted for age, sex, and population (P=5.6 × 10^, odds ratio [OR]=2.5, 95% confidence interval [CI]=1.5–4.2). The 27Glu was also significantly associated with obesity in the single-point association analysis (P=0.013, OR=2.0, 95%CI=1.2–3.4); however, this association was no longer significant after adjustment for rs34623097 since these SNPs were in linkage disequilibrium with each other. A copy of the obesity-risk allele, rs34623097-A, led to a 1.6 kg/m^2 increase in body mass index (BMI; defined as weight in kilograms divided by height in meters squared) (P=0.0019). A luciferase reporter assay indicated that rs34623097-A reduced the transcriptional activity of the luciferase reporter gene by approximately 10% compared with rs34623097-G. An electrophoretic mobility shift assay demonstrated that rs34623097 modulated the binding affinity with nuclear factors. An evolutionary analysis implies that a G>A mutation at rs34623097 occurred in the Neandertal genome and then the rs34623097-A allele flowed into the ancestors of present-day humans.\nCONCLUSION:The present results suggest that rs34623097-A, which would lead to lower expression of ADRB2, contributes to the onset of obesity in the Oceanic populations., 論文

Inter-specific hybrid zones for Hylobates gibbons are known in Southeast Asia. Among these, one hybrid zone between Hylobates lar and H. pileatus is located in Khao Yai National Park, Thailand. To find molecular evidence for the natural hybridization of the gibbons in this region, we studied mitochondrial DNA (mtDNA) of 68 gibbons of the H. lar phenotype living adjacent to the hybrid zone. Nucleotide sequencing of a fragment of mtDNA spanning hyper variable segment I showed that nine gibbons had an mtDNA haplotype of H. pileatus, and that seven of these nine gibbons belonged to a single maternal lineage over three generations. It is thus confirmed that introgression between H. lar and H. pileatus exists and the initial hybridization took place ages ago.

T-cell immunoglobulin domain and mucin domain containing protein 1 (TIM1), also known as a cellular receptor for hepatitis A virus (HAVCR1) or a molecule induced by ischemic injury in the kidney (KIM1), is involved in the regulation of immune responses. We investigated a natural selection history of TIM1 by comparative sequencing analysis in 24 different primates. It was found that TIM1 had become a pseudogene in multiple lineages of the New World monkey. We also investigated T cell lines originated from four different New World monkey species and confirmed that TIM1 was not expressed at the mRNA level. On the other hand, there were ten amino acid sites in the Ig domain of TIM1 in the other primates, which were suggested to be under positive natural selection. In addition, mucin domain of TIM1 was highly polymorphic in the Old World monkeys, which might be under balanced selection. These data suggested that TIM1 underwent a lineage-specific evolutionary pathway in the primates.

It has been established that various species exhibit personality, defined as intra-individual consistency and inter-individual variation in behavioural phenotypes. For example, certain individuals may demonstrate consistently greater behavioural reactions and elevated stress responses. We conducted playback experiments and hormonal analyses on male chimpanzees (Pan troglodytes) in captivity to investigate the patterns and proximate mediators of individual variations in behavioural reactions. We found intra-individual consistency and inter-individual variation in behavioural reactions (intensive vigilance towards the direction of speakers) to vocalisations by unfamiliar chimpanzees. This behavioural reaction was positively correlated with changes in salivary cortisol concentration, suggesting that stress is a proximate factor mediating the variation in behavioural reactions. The males who were highly responsive to the conspecific vocalisation also exhibited high behavioural reactions towards the neutral broadcast stimulus (the jungle crow’s Corvus macrorhynchos ‘ka’ vocalisation). This observation is consistent with the notion that male chimpanzees vary in intrinsic behavioural tendency to different stimuli.

MLXIPL is a transcription factor integral to the regulation of glycolysis and lipogenesis in the liver. Common variants of the MLXIPL gene (MLXIPL) are known to influence plasma triglyceride levels in people of European descent. As MLXIPL has a key role in energy storage, genetic variations of the MLXIPL may be relevant to physiological adaptations to nutritional stresses that have occurred during the evolution of modern humans. In the present study, we assessed the phenotypic consequences of the Q241H variant of MLXIPL in populations of Asian and Oceanian origin and also surveyed the prevalence of Q241H variant in populations worldwide. Multiple linear regression models based on 2373 individuals of Asian origin showed that the H allele was significantly associated with decreased concentrations of plasma triglycerides (P=0.0003). Direct genotyping of 1455 individuals from Africa, Asia and Oceania showed that the triglyceride-lowering H allele was found at quite low frequencies (0.00-0.16) in most of the populations examined. The exceptions were some Central Asian populations, including Mongolians, Tibetans and Uyghurs, which exhibited much higher frequencies of the H allele (0.21-0.26). The high prevalence of the H allele in Central Asia implies that the Q241H variant of MLXIPL might have been significant for utilization of carbohydrates and fats in the common ancestors of these populations, who successfully adapted to the environment of Central Asia by relying on nomadic livestock herding.

Triglyceride-rich lipoproteins (TGRLs) and low-density-lipoprotein (LDL) cholesterol are independent risk factors for coronary artery disease. We have previously proposed that the very low-density-lipoprotein (VLDL) receptor is one of the receptors required for foam cell formation by TGRLs in human macrophages. However, the VLDL receptor proteins have not been detected in atherosclerotic lesions of several animal models. Here we showed no VLDL receptor protein was detected in mouse macrophage cell lines (Raw264.7 and J774.2) or in mouse peritoneal macrophages in vitro. Furthermore, no VLDL receptor protein was detected in macrophages in atherosclerotic lesions of chow-fed apolipoprotein E-deficient or cholesterol-fed LDL receptor-deficient mice in vivo. In contrast, macrophage VLDL receptor protein was clearly detected in human macrophages in vitro and in atherosclerotic lesions in myocardial infarction-prone Watanabe-heritable hyperlipidemic (WHHLMI) rabbits in vivo. There are species differences in the localization of VLDL receptor protein in vitro and in vivo. Since VLDL receptor is expressed on macrophages in atheromatous plaques of both rabbit and human but not in mouse models, the mechanisms of atherogenesis and/or growth of atherosclerotic lesions in mouse models may be partly different from those of humans and rabbits.

Genes of the immunoglobulin superfamily (IgSF) have a wide variety of cellular activities. In this study, we investigated molecular evolution of IgSF genes in primates by comparing orthologous sequences of 249 IgSF genes among human, chimpanzee, orangutan, rhesus macaque, and common marmoset. To evaluate the non-synonymous/synonymous substitution ratio (ω), we applied Bn-Bs program and PAML program. IgSF genes were classified into 11 functional categories based on the Gene Ontology (GO) database. Among them, IgSF genes in three functional categories, immune system process (GO:0002376), defense response (GO:0006952), and multi-organism process (GO:0051704), which are tightly linked to the regulation of immune system had much higher values of ω than genes in the other GO categories. In addition, we estimated the average values of ω for each primate lineage. Although each primate lineage had comparable average values of ω, the human lineage showed the lowest ω value for the immune-related genes. Furthermore, 11 IgSF genes, SIGLEC5, SLAMF6, CD33, CD3E, CEACAM8, CD3G, FCER1A, CD48, CD4, TIM4, and FCGR2A, were implied to have been under positive selective pressure during the course of primate evolution. Further sequence analyses of CD3E and CD3G from 23 primate species suggested that the Ig domains of CD3E and CD3G underwent the positive Darwinian selection.

The objectives of this study were to detect effective genetic polymorphisms of bovine growth hormone (bGH) gene associated with calf weight in Japanese Black cattle. Fifty-eight sires and 47 breeding cows were used to detect the polymorphisms in exons by single-strand conformation polymorphism (SSCP). Four homozygous and six heterozygous SSCP genotypes were identified in exon 5. Although each single nucleotide polymorphism (SNP) had been reported, these genotypes were caused by three SNPs at the nucleotide positions 2141, 2277 and 2291. Four haplotypes C-C-A, G-C-A, C-C-C and G-T-A were newly identified. It was suggested that other haplotypes not detected in this study may not exist, considering the allele frequencies reported in Bos taurus and Bos indicus, and the migrating process of native Japanese cattle. Thereafter, we examined associations between the detected polymorphic sites in exon 5 by PCR - restriction fragment length polymorphism and calf weight using 53 breeding dams and 135 calves. The birth weights of calves with haplotype G-C-A are significantly lighter and calves' weights produced by cows with such haplotype are also lighter at 30 days old, using regression analysis. Although further research is necessary, these results may serve as a useful criterion to select breeding stocks, especially in maternal abilities.