妊高征易感基因的研究进展

妊高征具有明显的遗传倾向,其发病机理尚不清楚。本文综述了妊高征易感基因的研究进展,讨论了与高血压、内皮细胞损害、免疫反应失调相关基因和妊高征的关联,并论述了这些基因突变或多态性对妊高征的影响。 Abstract:The etiology and pathogenesis of pregnancy induced hypertension (PIH) remain still unknown.In recent years an increasing amount of evidence supports the concept that PIH is a complex genetic susceptibility disease.The progress in susceptibility gene for PIH is reviewed.The associations between the genes for hypertension,endothelial?cell dysfunction.,immune maladaptation?interaction and PIH have been recently investigated.Meanwhile,the paper evaluates the influences of mutations and polymorphism at the genes on PIH.     

Evidence for association of D1S249 locus on human chromosome 1 with the susceptibility to essential hypertension in Han Chinese

Essential hypertension (EH) is thought to result from the interaction of environmental and genetic factors. The molecular genetics of EH has witnessed considerable progress during the past few years. However, the number of genes involved, their chromosomal location and the magnitude of their effect on EH susceptibility are unknown. We conducted the present study to screen susceptibility genes to essential hypertension using a genome-wide scanning method in a group of Han people from Fangshan district located in the southwest of Beijing. A case-control study and affected sibpair were performed. Genotyping was carried out using a fluorescence-based semiautomated technique on automated DNA sequencer (ABI 377, PE). The basis for the genome-screen was the ABI prism linkage mapping sets of 400 microsatellite markers (version 2, PE, Co.). PCR for amplification of markers was carried out as multiplex reactions with Ampli Taq gold (PE, Co.) following protocols developed in our laboratory. Data were exported as a     

Association of the Late Cornified Envelope-3 Genes with Psoriasis and Psoriatic Arthritis:A Systematic Review

Psoriasis(Ps)and psoriatic arthritis(Ps A)are genetically complex diseases with strong genetic evidence.Recently,susceptibility genes for Ps and Ps A have been identified within the late cornified envelop(LCE)gene cluster,especially the cluster 3(LCE3)genes.It is noteworthy that the deletion of LCE3B and LCE3C(LCE3C_LCE3B-del)is significantly associated with these two diseases.Gene-gene interactions between LCE3 genes and other genes are associated with Ps and Ps A.LCE3 genes also have pleiotropic effect on some autoimmune diseases,such as rheumatoid arthritis,atopic dermatitis and systemic lupus erythematosus.Further studies need to focus on the potential function of LCE3 genes in the pathogenesis of Ps and Ps A in the future.     

Analyses of Sexual Reproductive Success in Transgenic and/or Mutant Plants

The pistil, the female reproductive organ of plants, is a key player in the success of sexual plant reproduction. Ultimately, the production of fruits and seeds depends on the proper pistil development and function. Therefore, the identification and characterization of pistil expressed genes is essential for a better understanding and manipulation of the plant reproduction process. For studying the function of pistil expressed genes, transgenic and/or mutant plants for the genes of interest are used. The present article provides a review of methods already exploited to analyze sexual reproductive success. We intend to supply useful information and to guide future experiments in the study of genes affecting pistil development and function.     

影响动物肉质性状主要候选基因的研究进展

随着分子生物学在动物遗传育种中的应用,对数量性状主效基因的研究成为必然。本文对影响肉质的脂肪酸结合蛋白基因、肥胖基因、leptin 基因、黑素皮质受体基因、脂蛋白脂酶基因、激素敏感脂酶基因的国内外研究状况加以综述。 Progress in Candidate Genes Influencing Meat Quality Traits in Chickens QIU Xue-mei1,3,LI Ning1,DEND Xue-mei2,WU Chang-xin2 1.The National Laboratories for Agrobiotechnology,China Agricultural University,Beijing 100094,China; 2.College of Animal Science and Technology,China Agricultural University,Beijing 100094,China; 3.College of Animal Science and Technology,Heilongjiang August First Land Reclamation University,Mishan 158308,China Abstract:As the molecular biology has been applied in animal genetics and breeding,it is important that we research major genes on quantitative traits for animal breeding by transgenic technology.In this paper,the research advance of FABP genes,obese gene,leptin gene,MCRs genes,LPL gene,HSL gene affecting meat quality in animals are reviewed. Key words：animal; meat quality; candidate gene     

Frontier of therapeutic antibody discovery:The challenges and how to face them

Therapeutic monoclonal antibodies have become an important class of modern medicines.The established technologies for therapeutic antibody discovery such as humanization of mouse antibodies,phage display of human antibody libraries and transgenic animals harboring human IgG genes have been practiced successfully so far,and many incremental improvements are being made constantly.These methodologies are responsible for currently marketed therapeutic antibodies and for the biopharma industry pipeline which are concentrated on only a few dozen targets.A key challenge for wider application of biotherapeutic approaches is the paucity of truly validated targets for biotherapeutic intervention.The efforts to expand the target space include taking the pathway approach to study the disease correlation.Since many new targets are multi-spanning and multimeric membrane proteins there is a need to develop more effective methods to generate antibodies against these difficult targets.The pharmaceutical properties of therapeutic antibodies are an active area for study concentrating on biophysical characteristics such as thermal stability and aggregation propensity.The immunogenicity of biotherapeutics in humans is a very complex issue and there are no truly predictive animal models to rely on.The in silico and T-cell response approaches identify the potential for immunogenicity;however,one needs contingency plans for emergence of antiproduct antibody response for clinical trials.     

Progress in TILLING as a tool for functional genomics and improvement of crops

Food security is a global concern and substantial yield increases in crops are required to feed the growing world population. Mutagenesis is an important tool in crop improvement and is free of the regulatory restrictions imposed on genetically modified organisms. Targeting Induced Local Lesions in Genomes（TILLING）, which combines traditional chemical mutagenesis with high‐throughput genome‐wide screening for point mutations in desired genes, offers a powerful way to create novel mutant alleles for both functional genomics and improvement of crops. TILLING is generally applicable to genomes whether small or large, diploid or evenallohexaploid, and shows great potential to address the major challenge of linking sequence information to the function of genes and to modulate key traits for plant breeding. TILLING has been successfully applied in many crop species and recent progress in TILLING is summarized below, especially on the developments in mutation detection technology, application of TILLING in gene functional studies and crop breeding. The potential of TILLING/EcoTILLING for functional genetics and crop improvement is also discussed. Furthermore, a small‐scale forward strategy including backcross and selfing was conducted to release the potential mutant phenotypes masked in M2（or M3） plants.     

The genetic basis of deafness in populations of African descent

Hearing loss is the most common sensorineural disorder worldwide and is associated with more than1000 mutations in more than 90 genes. While mutations in genes such as GJB2(gap-junction protein β 2)and GJB6(gap-junction protein β 6) are highly prevalent in Caucasian, Asian, and Middle Eastern populations, they are rare in both native African populations and those of African descent. The objective of this paper is to review the current knowledge regarding the epidemiology and genetics of hearing loss in African populations with a focus on native sub-Saharan African populations. Environmental etiologies related to poor access to healthcare and perinatal care account for the majority of cases. Syndromic etiologies including Waardenburg, Pendred and Usher syndromes are uncommon causes of hearing loss in these populations. Of the non-syndromic causes, common mutations in GJB2 and GJB6 are rarely implicated in populations of African descent. Recent use of next-generation sequencing(NGS) has identified several candidate deafness genes in African populations from Nigeria and South Africa that are unique when compared to common causative mutations worldwide. Researchers also recently described a dominant mutation in MYO3α in an African American family with non-syndromic hearing loss. The use of NGS and specialized panels will aid in identifying rare and novel mutations in a more cost-and timeeffective manner. The identification of common hearing loss mutations in indigenous African populations will pave the way for translation into genetic deafness research in populations of African descent worldwide.     

Progress in TILLING as a tool for functional genomics and improvement of crops

Food security is a global concern and substantial yield increases in crops are required to feed the growing world population. Mutagenesis is an important tool in crop improvement and is free of the regulatory restrictions imposed on genetically modified organisms. Targeting Induced Local Lesions in Genomes(TILLING), which combines traditional chemical mutagenesis with high‐throughput genome‐wide screening for point mutations in desired genes, offers a powerful way to create novel mutant alleles for both functional genomics and improvement of crops. TILLING is generally applicable to genomes whether small or large, diploid or evenallohexaploid, and shows great potential to address the major challenge of linking sequence information to the function of genes and to modulate key traits for plant breeding. TILLING has been successfully applied in many crop species and recent progress in TILLING is summarized below, especially on the developments in mutation detection technology, application of TILLING in gene functional studies and crop breeding. The potential of TILLING/EcoTILLING for functional genetics and crop improvement is also discussed. Furthermore, a small‐scale forward strategy including backcross and selfing was conducted to release the potential mutant phenotypes masked in M2(or M3) plants.     

Mapping and identifying genes for asthma and psoriasis

Susceptibility genes for complex diseases are characterized by reduced penetrance, caused by the influence of other genes, the environment or stochastic events. Recently, positional cloning efforts have yielded several candidate susceptibility genes in different complex disorders such as Crohn's disease and asthma. Within a genetic locus, however, the identification of the effector gene may pose further challenges and require functional studies. I review two examples of such challenges: the cloning of GPR154 (GPRA) and AAA1 on chromosome 7p14 at a susceptibility locus for atopy and asthma, and the study of HLA-Cw6, CCHCR1 (HCR) and CDSN on chromosome 6p21 at PSORS1, the major susceptibility locus for psoriasis. The susceptibility locus for atopy and asthma contains two genes and only one of them is protein coding. We studied its isoform-specific expression in bronchial biopsies and in a mouse model of ovalbumin-induced inflammation of bronchial epithelia. In the PSORS1 locus, strong linkage disequilibrium between genes has made it difficult to distinguish the effects of the three nearby genes. We engineered transgenic mice with either a HCR non-risk allele or the HCR*WWCC risk allele controlled by the cytokeratin-14 promoter. The results suggested that the overexpression of HCR in mouse skin was insufficient to induce a psoriasiform phenotype, but it appeared to induce allele-specific gene expression changes that were similar to those observed in psoriatic skin.     

Recent advances in the genetics of allergy and asthma.

Asthma is a common condition that results from the interaction of an unknown number of genes with environmental factors. About 10% of children have asthma, usually as part of a syndrome of atopy, which is characterized by the presence of allergy, asthma, seasonal rhinitis and eczema, and tends to occur in familial clusters. The incidence of asthma is lower in adults (5%) and a significant proportion is seen without an atopic background. The prevalence of asthma has increased substantially over the past decades, particularly in the western world. Allergy and asthma are not inherited as single-gene disorders and do not show a simple pattern of inheritance. Environmental and genetic factors interact in a complex fashion to produce disease susceptibility and expression. Here, we describe the recent advances in the understanding of the inherited susceptibility to asthma and atopy and discuss their potential implications.     

Asthma: a major pediatric health issue

Asthma and associated phenotypes are complex traits most probably caused by an interaction of multiple disease susceptibility genes and environmental factors. Major achievements have occurred in identifying chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma, atopic dermatitis, IgE levels and response to asthma therapy. The aims of this review are to explain the methodology of genetic studies of multifactorial diseases, to summarize chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma and associated traits, to list genetic alterations that may alter response to asthma therapy, and to outline genetic factors that may render individuals more susceptible to asthma and atopy due to environmental changes.     

Interactions between genes and environmental factors in asthma and atopy: new developments

Asthma and associated phenotypes are complex traits most probably caused by an interaction of multiple disease susceptibility genes and environmental factors. Major achievements have occurred in identifying chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma, atopic dermatitis, IgE levels and response to asthma therapy. The aims of this review are to explain the methodology of genetic studies of multifactorial diseases, to summarize chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma and associated traits, to list genetic alterations that may alter response to asthma therapy, and to outline genetic factors that may render individuals more susceptible to asthma and atopy due to environmental changes.     

Interleukin-4 receptor alpha gene variants and allergic disease

The interleukin-4 (IL-4) signalling cascade has been identified as a pathway potentially important in the development of asthma. Genetic variants within this signalling pathway might contribute to the risk of developing asthma in a given individual. A number of polymorphisms have been described within the IL-4 receptor α (IL-4Rα) gene. In addition polymorphism occurs in the promoter for the IL-4 gene itself. This commentary accompanies a paper by C Oberet al describing the contribution of IL-4Rα polymorphism to susceptibility to asthma and atopy in the Hutterite population and other outbred populations collected during the collaborative studies on the genetics of asthma (CSGA) programme.     

V75R576 IL-4 receptor alpha is associated with allergic asthma and enhanced IL-4 receptor function

Asthma is a complex polygenic disease. Many studies have implicated the importance of IL-4R alpha in the development of allergic inflammation and its gene has been implicated in the genetics of asthma and atopy. In this study, we examined the functional consequences of two of the human IL-4R alpha allelic variants that have been found to associate with asthma and atopy. We examined the effects of each variant alone and in combination on IL-4-dependent gene induction. We found that neither the Q576R nor the I75V variants affected IL-4-dependent CD23 expression. However, the combination of V75R576 resulted in expression of an IL-4R alpha with enhanced sensitivity to IL-4. We next examined the genetics of five of the known IL-4R alpha allelic variants in asthmatic and nonatopic populations. Strikingly, the association of V75/R576 with atopic asthma was greater than either allele alone and the association of R576 with atopic asthma was dependent on the coexistence of V75. A haplotype analysis revealed a single IL-4R alpha haplotype that was associated with allergic asthma, VACRS, further confirming the importance of the V75 and R576 combination in the genetics of asthma. This is the first report demonstrating that a functional alteration in IL-4R alpha requires the coexistence of two naturally occurring single nucleotide polymorphisms (snps) in combination; neither snp alone is sufficient. These data illustrate the importance of studying snps in combination, because the functional significance of a given snp may only be evident in a specific setting of additional snps in the same or different genes.     

Meta-analysis of genome-wide linkage studies of asthma and related traits

Background

Asthma and allergy are complex multifactorial disorders, with both genetic and environmental components determining disease expression. The use of molecular genetics holds great promise for the identification of novel drug targets for the treatment of asthma and allergy. Genome-wide linkage studies have identified a number of potential disease susceptibility loci but replication remains inconsistent. The aim of the current study was to complete a meta-analysis of data from genome-wide linkage studies of asthma and related phenotypes and provide inferences about the consistency of results and to identify novel regions for future gene discovery.

Methods

The rank based genome-scan meta-analysis (GSMA) method was used to combine linkage data for asthma and related traits; bronchial hyper-responsiveness (BHR), allergen positive skin prick test (SPT) and total serum Immunoglobulin E (IgE) from nine Caucasian asthma populations.

Results

Significant evidence for susceptibility loci was identified for quantitative traits including; BHR (989 pedigrees, n = 4,294) 2p12-q22.1, 6p22.3-p21.1 and 11q24.1-qter, allergen SPT (1,093 pedigrees, n = 4,746) 3p22.1-q22.1, 17p12-q24.3 and total IgE (729 pedigrees, n = 3,224) 5q11.2-q14.3 and 6pter-p22.3. Analysis of the asthma phenotype (1,267 pedigrees, n = 5,832) did not identify any region showing genome-wide significance.

Conclusion

This study represents the first linkage meta-analysis to determine the relative contribution of chromosomal regions to the risk of developing asthma and atopy. Several significant results were obtained for quantitative traits but not for asthma confirming the increased phenotype and genetic heterogeneity in asthma. These analyses support the contribution of regions that contain previously identified asthma susceptibility genes and provide the first evidence for susceptibility loci on 5q11.2-q14.3 and 11q24.1-qter.     

Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations

After a genomewide screen in the Hutterites was completed, the IL4RA gene was examined as the 16p-linked susceptibility locus for asthma and atopy. Seven known variants and one novel variant, representing all nonsynonymous substitutions in the mature protein, were examined in the Hutterites; on the basis of studies in the Hutterites, outbred white, black, and Hispanic families were genotyped for selected markers. All population samples showed evidence of association to atopy or to asthma (P values.039-.0044 for atopy and. 029-.0000061 for asthma), but the alleles or haplotypes showing the strongest evidence differed between the groups. Overall, these data suggest that the IL4RA gene is an atopy- and asthma-susceptibility locus but that variation outside the coding region of the gene influences susceptibility.     

A major susceptibility gene for asthma maps to chromosome 14q24

Asthma is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. Numerous loci and candidate genes have been reported to show linkage and association to asthma and atopy. Although some studies reporting these observations are compelling, no gene has been mapped that confers a sufficiently high risk of asthma to meet the stringent criteria for genomewide significance. Using 175 extended Icelandic families that included 596 patients with asthma, we performed a genomewide scan with 976 microsatellite markers. The families were identified by cross-matching a list of patients with asthma from the Department of Allergy/Pulmonary Medicine of the National University Hospital of Iceland with a genealogy database of the entire Icelandic nation. We detected linkage of asthma to chromosome 14q24, with an allele-sharing LOD score of 2.66. After we increased the marker density within the locus to an average of one microsatellite every 0.2 cM, the LOD score rose to 4.00. We designate this locus "asthma locus one" (AS1). Taken together, these results provide evidence of a novel susceptibility gene for asthma on chromosome 14q24.     

Genetics of asthma and atopy

The genetics of asthma and atopy has made tremendous progresses over the last couple of years. It has been known for ages that allergies and asthma are concentrating within families. Modern genetics has pinpointed some gene areas such as 5q31.1, 6p21.3, 11q13, 12q15, 14q11.1 and 16p12. Much of the information available today has been fragmentary and not always confirmed. Alleles at multiple loci are likely to be involved and the ultimate picture is most likely determined by many genetic and environmental factors.