KIZ CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases

Kunming, China

KIZ CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases

Kunming, China
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Chen H.Y.,Chinese University of Hong Kong | Huang W.,Peking Union Medical College | Leung V.H.K.,Chinese University of Hong Kong | Fung S.L.M.,Chinese University of Hong Kong | And 4 more authors.
Human Mutation | Year: 2013

A CA-repeat microsatellite in insulin-like growth factor 1 (IGF1) promoter was associated with interindividual variation of circulating IGF1 level. Previously, we reported that such association was due to variation of haplotype unit in a linkage disequilibrium block composed of microsatellite and single-nucleotide polymorphisms (SNPs), suggesting the presence of an interaction between them. In this study, reporter assays were performed to investigate the regulatory effect and interaction of genetic variants on gene expression. We used an in vitro system to compare the transcriptional activities of haplotypes (rs35767:T>C, the CA-repeat microsatellite, rs5742612:T>C, and rs2288377:T>A) in evolutionarily conserved region of IGF1 promoter. In haplotype C-T-T, a longer microsatellite had a lower transcriptional activity (17.6 ± 2.4-fold for 17 repeats and 8.3 ± 1.1-fold for 21 repeats), whereas in haplotype T-C-A, such trend could not be observed, as the microsatellite with 21 repeats had the highest transcriptional activity (17.5 ± 2.3-fold). Because the microsatellite and SNPs affected the transcriptional activity of each other, there may be an interaction between them in the regulation of IGF1 expression. For the first time, we demonstrated that a noncoding microsatellite polymorphism could act as a functional unit and interact with SNPs in the regulation of transcription in human genome. © 2013 WILEY PERIODICALS, INC.


Ji L.-D.,CAS Kunming Institute of Zoology | Ji L.-D.,KIZ CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases | Ji L.-D.,Ningbo University | Qiu Y.-Q.,KIZ CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases | And 12 more authors.
Molecular Biology and Evolution | Year: 2012

Research into the mechanisms of human adaptation to the hypoxic environment of high altitude is of great interest to the fields of human physiology and clinical medicine. Recently, the gene EGLN1, from the hypoxia-inducible factor (HIF) pathway, was identified as being involved in the hypoxic adaptation of highland Andeans and Tibetans. Both highland Andeans and Tibetans have adapted to an extremely hypoxic habitat and less attention has been paid to populations living in normoxic conditions at sea level and mild-hypoxic environments of moderate altitude, thus, whether a common adaptive mechanism exists in response to quantitative variations of environmental oxygen pressure over a wide range of residing altitudes is unknown. Here, we first performed a genome-wide association study of 35 populations from the Human Genome Diversity-CEPH Panel who dwell at sea level to moderate altitude in Eurasia (N = 691; 0-2,500 m) to identify the genetic adaptation profile of normoxic and mild-hypoxic inhabitants. In addition, we systematically compared the results from the present study to six previously published genome-wide scans of highland Andeans and Tibetans to identify shared adaptive signals in response to quantitative variations of oxygen pressure. For normoxic and mild-hypoxic populations, the strongest adaptive signal came from the mu opioid receptor-encoding gene (OPRM1, 2.54 × 10-9), which has been implicated in the stimulation of respiration, while in the systematic survey the EGLN1-DISC1 locus was identified in all studies. A replication study performed with highland Tibetans (N = 733) and sea level Han Chinese (N = 748) confirmed the association between altitude and SNP allele frequencies in OPRM1 (in Tibetans only, P < 0.01) and in EGLN1-DISC1 (in Tibetans and Han Chinese, P < 0.01). Taken together, identification of the OPRM1 gene suggests that cardiopulmonary adaptation mechanisms are important and should be a focus in future studies of hypoxia adaptation. Furthermore, the identification of the EGLN1 gene from the HIF pathway suggests a common adaptive mechanism for Eurasian human populations residing at different altitudes with different oxygen pressures. © 2012 The Author.


Tang N.L.S.,Chinese University of Hong Kong | Tang N.L.S.,Li Ka Shing Institute of Health science | Tang N.L.S.,KIZ CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases | Liao C.D.,Chinese University of Hong Kong | And 8 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2013

Background: Breast cancer patients regularly undergo adjuvant chemotherapies following surgery. However, these treatments are largely associated with chemotherapeutic toxicities ranging from nausea to severe myelosuppression. In this investigation, we examined the effects of four SNPs in NR1I2, CYP3A4 and CYP3A5 genes on chemotherapy-induced severe neutropenia in 311 female Chinese breast cancer patients undergoing a standard adjuvant chemotherapy regimen. Methods: Patients were monitored for adverse reactions throughout the treatment, then divided into "none or mild" (80 %) or "severe" (20 %) toxicity groups according to whether they suffered grade 4 neutropenia defined as having an absolute neutrophil counts (ANC) of less than 0.5 × 109/L anytime during the treatment. DNA was extracted from patients' peripheral blood samples, then genotyped using allele-specific Tm-shift PCR and melting analysis. Results: Logistic regression revealed that rs776746 or CYP3A53 strongly associated with grade 4 neutropenia (OR = 2.56, P = 0.023) after adjustment for covariates, one of which more significant factor was baseline ANC (OR = 0.68, P = 0.020). Although univariate analysis in all patients did not reveal any association at first, further analysis indicated that rs776746 is significantly associated with severe neutropenia in subgroup of breast cancer patients with normal baseline ANC (≥2.0 × 109/L). These carriers of A-allele have 3.14-fold increased risk of developing severe neutropenia (P = 0.004). Conclusion: Our results suggested that polymorphisms in CYP3A5 might be useful pharmacogenetic markers for the prediction of severe neutropenia during chemotherapy, however, only after screening patients by their baseline ANC in the presence of gene-environmental interaction. We demonstrate an approach of pharmacogenetic analysis, in which the genetic data should be analyzed in the perspective of other clinical parameters. © 2012 Springer-Verlag Berlin Heidelberg.


Peng M.-S.,CAS Kunming Institute of Zoology | Peng M.-S.,KIZ CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases | Peng M.-S.,University of Chinese Academy of Sciences | Zhang Y.-P.,CAS Kunming Institute of Zoology | And 2 more authors.
PLoS ONE | Year: 2011

Background: Extensive studies in different fields have been performed to reconstruct the prehistory of populations in the Japanese archipelago. Estimates the ancestral population dynamics based on Japanese molecular sequences can extend our understanding about the colonization of Japan and the ethnogenesis of modern Japanese. Methodology/Principal Findings: We applied Bayesian skyline plot (BSP) with a dataset based on 952 Japanese mitochondrial DNA (mtDNA) genomes to depict the female effective population size (Nef) through time for the total Japanese and each of the major mtDNA haplogroups in Japanese. Our results revealed a rapid Nef growth since ~5 thousand years ago had left ~72% Japanese mtDNA lineages with a salient signature. The BSP for the major mtDNA haplogroups indicated some different demographic history. Conclusions/Significance: The results suggested that the rapid population expansion acted as a major force in shaping current maternal pool of Japanese. It supported a model for population dynamics in Japan in which the prehistoric population growth initiated in the Middle Jomon Period experienced a smooth and swift transition from Jomon to Yayoi, and then continued through the Yayoi Period. The confounding demographic backgrounds of different mtDNA haplogroups could also have some implications for some related studies in future. © 2011 Peng, Zhang.


He Y.-H.,CAS Kunming Institute of Zoology | He Y.-H.,KIZ CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases | Lu X.,CAS Kunming Institute of Zoology | Lu X.,KIZ CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases | And 9 more authors.
Neurobiology of Aging | Year: 2014

Mitochondrial DNA (mtDNA) content plays an important role in energy production and sustaining normal physiological function. A decline in the mtDNA content and subsequent dysfunction cause various senile diseases, with decreasing mtDNA content observed in the elderly individuals with age-related diseases. In contrast, the oldest old individuals, for example, centenarians, have a delayed or reduced prevalence of these diseases, suggesting centenarians may have a different pattern of the mtDNA content, enabling them to keep normal mitochondrial functions to help delay or escape senile diseases. To test this hypothesis, a total of 961 subjects, consisting of 424 longevity subjects and 537 younger control subjects from Hainan and Sichuan provinces of China, were recruited for this study. The mtDNA content was found to be inversely associated with age among the age of group 40-70 years. Surprisingly, no reduction of mtDNA content was observed in nonagenarians and centenarians; instead, these oldest old showed a significant increase than the elderly people aged between 50 and 70 years. The results suggest the higher mtDNA content may convey a beneficial effect to the longevity of people through assuring sufficient energy supply. © 2014 Elsevier Inc.


Liu Y.-W.,CAS Kunming Institute of Zoology | Liu Y.-W.,KIZ CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases | Liu Y.-W.,University of Chinese Academy of Sciences | He Y.-H.,CAS Kunming Institute of Zoology | And 8 more authors.
Neurobiology of Aging | Year: 2014

A673T, a rare variant in the amyloid-β precursor protein gene, shows a protective potential against Alzheimer's disease (AD) and age-related cognitive decline in an Icelandic population. Although A673T was observed independently in a Finnish population, this variant was absent in 8721 Asian subjects. The conflicting observations suggest that the contribution of A673T may be confined to Europeans and Americans rather than Asians. Nevertheless, A673T confers a protective function against AD and thus may be observed only in longevity subjects; thus it is not surprising to see its absence when the general populations or the patient cohorts were considered. To test whether the A673T contributes to the Chinese population, 1237 healthy longevity subjects (mean age 96.9 years) and 1404 matched younger controls (mean age 44.2 years) were genotyped for the variant. Our study failed to observe this variant in either the longevity subjects or the controls. Given the previous observation from Asians, our results suggest that the A673T variant is not involved in longevity in Chinese individuals; some other protective mechanisms may contribute to a lower incidence of AD in Chinese nonagenerians and centenarians. © 2014 Elsevier Inc..


Wang C.-Y.,CAS Kunming Institute of Zoology | Li H.,CAS Kunming Institute of Zoology | Hao X.-D.,CAS Kunming Institute of Zoology | Hao X.-D.,University of Chinese Academy of Sciences | And 9 more authors.
PLoS ONE | Year: 2011

In the past decade, a high incidence of somatic mitochondrial DNA (mtDNA) mutations has been observed, mostly based on a fraction of the molecule, in various cancerous tissues; nevertheless, some of them were queried due to problems in data quality. Obviously, without a comprehensive understanding of mtDNA mutational profile in the cancerous tissue of a specific patient, it is unlikely to disclose the genuine relationship between somatic mtDNA mutations and tumorigenesis. To achieve this objective, the most straightforward way is to directly compare the whole mtDNA genome variation among three tissues (namely, cancerous tissue, para-cancerous tissue, and distant normal tissue) from the same patient. Considering the fact that most of the previous studies on the role of mtDNA in colorectal tumor focused merely on the D-loop or partial segment of the molecule, in the current study we have collected three tissues (cancerous, para-cancerous and normal tissues) respectively recruited from 20 patients with colorectal tumor and completely sequenced the mitochondrial genome of each tissue. Our results reveal a relatively lower incidence of somatic mutations in these patients; intriguingly, all somatic mutations are in heteroplasmic status. Surprisingly, the observed somatic mutations are not restricted to cancer tissues, for the para-cancer tissues and distant normal tissues also harbor somatic mtDNA mutations with a lower frequency than cancerous tissues but higher than that observed in the general population. Our results suggest that somatic mtDNA mutations in cancerous tissues could not be simply explained as a consequence of tumorigenesis; meanwhile, the somatic mtDNA mutations in normal tissues might reflect an altered physiological environment in cancer patients. © 2011 Wang et al.


Xiao F.-H.,CAS Kunming Institute of Zoology | Xiao F.-H.,KIZ CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases | Xiao F.-H.,University of Chinese Academy of Sciences | He Y.-H.,CAS Kunming Institute of Zoology | And 8 more authors.
PLoS ONE | Year: 2015

It is recognized that genetic factors contribute to human longevity. Besides the hypothesis of existence of longevity genes, another suggests that a lower frequency of risk alleles decreases the incidence of age-related diseases in the long-lived people. However, the latter finds no support from recent genetic studies. Considering the crucial role of epigenetic modification in gene regulation, we then hypothesize that suppressing disease-related genes in longevity individuals is likely achieved by epigenetic modification, e.g. DNA methylation. To test this hypothesis, we investigated the genome-wide methylation profile in 4 Chinese female centenarians and 4 middle-aged controls using methyl-DNA immunoprecipitation sequencing. 626 differentially methylated regions (DMRs) were observed between both groups. Interestingly, genes with these DMRs were enriched in age-related diseases, including type-2 diabetes, cardiovascular disease, stroke and Alzheimer' s disease. This pattern remains rather stable after including methylomes of two white individuals. Further analyses suggest that the observed DMRs likely have functional roles in regulating dis-ease-associated gene expressions, with some genes [e.g. caspase 3 (CASP3)] being down-regulated whereas the others [i.e. interleukin 1 receptor, type 2 (IL1R2)] up-regulated. Therefore, our study suggests that suppressing the disease-related genes via epigenetic modification is an important contributor to human longevity. © 2015 Xiao et al.


Liu J.,CAS Kunming Institute of Zoology | Liu J.,KIZ CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases | Liu J.,University of Chinese Academy of Sciences | Wang L.-D.,Zhengzhou University | And 11 more authors.
Molecular Biology and Evolution | Year: 2012

In accordance with the hypothesis that cancer formation is a process of somatic evolution driven by natural selection, signature of positive selection has been detected on a number of cancer-related nuclear genes. It remains, however, controversial whether a similar selective pressure has also acted on mitochondrial DNA (mtDNA), a small molecule in mitochondrion that may play an important role in tumorigenesis by altering oxidative phosphorylation. To better understand the mutational pattern on cancerous mtDNA and decipher the genetic signature left by natural selection, a total of 186 entire mitochondrial genomes of cancerous and adjacent normal tissues from 93 esophageal cancer patients were obtained and extensively studied. Our results revealed that the observed mutational pattern on the cancerous mtDNAs might be best explained as relaxation of negative selection. Taking into account an additional 1,235 cancerous (nearly) complete mtDNA sequences retrieved from the literature, our results suggested that the relaxed selective pressure was the most likely explanation for the accumulation of mtDNA variation in different types of cancer. This notion is in good agreement with the observation that aerobic glycolysis, instead of mitochondrial respiration, plays the key role in generating energy in cancer cells. Furthermore, our study provided solid evidence demonstrating that problems in some of the published cancerous mtDNA data adequately explained the previously contradictory conclusions about the selective pressure on cancer mtDNA, thus serving as a paradigm emphasizing the importance of data quality in affecting our understanding on the role of mtDNA in tumorigenesis. ©2011 The Author.


Ma L.,CAS Kunming Institute of Zoology | Ma L.,University of Chinese Academy of Sciences | Wu D.-D.,CAS Kunming Institute of Zoology | Ma S.L.,Chinese University of Hong Kong | And 7 more authors.
Journal of Psychiatric Research | Year: 2014

CREB1 is a cAMP responsive transcriptional factor which plays a key role in neural development. CREB1 signal pathway (CSP) has been implicated repeatedly in studies of predisposition for schizophrenia. We speculated that CSP has undergone positive selection during evolution of modern human and some genes that have undergone natural selection in the past may predispose to schizophrenia (SCZ) in modern time. Positive selection and association analysis were employed to explore the molecular evolution of CSP and association with schizophrenia. Our results showed a pan-ethnic selection event on NRG1 and CREB1, as confirmed in all 14 ethnic populations studied, which also suggested a selection process occurred before the "Out of Africa" scenario. Analysis of 62 SNPs covering 6 CSP genes in 2019 Han Chinese (976 SCZ patients and 1043 healthy individuals) showed an association of two SNPs (rs4379857, P = 0.009, OR [95% CI]: 1.200 [1.379-1.046]; rs2238751, P = 0.023, OR [95% CI]: 1.253 [1.522-1.032]) with SCZ. However, none of these significances survived after multiple testing corrections. Nonetheless, we observed an association of a rare CREB1 haplotype CCGGC (Bonferroni corrected P = 1.74 × 10-5) with SCZ. Our study showed that there was substantial population heterogeneity in genetic predisposition to SCZ, and different genes in the CSP pathway may predispose to SCZ in different populations. © 2014 Elsevier Ltd.

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