The VNTR polymorphism of the CLEC4M gene and susceptibility to HIV-1 infection in Han Chinese population

C-type lectin domain family 4, member M (CLEC4M, also known as DC-SIGNR) is a C-type lectin that functions as a transreceptor for human immunodeficiency virus-1 (HIV-1). The relationship between variable number tandem repeat (VNTR) polymorphism of the DC-SIGNR gene and susceptibility to HIV-1 infection has been under debate. In the present study, a cohort of 287 HIV-1 seropositive patients and 388 ethnically age-matched healthy controls from Han Chinese population were enrolled in order to determine the influence of host genetic factors on HIV-1 infection. A total of 11 genotypes and 5 alleles were found in our population. A cross-sectional comparison between HIV-1 seropostive patients and healthy controls did not reveal significant differences with regards to DC-SIGNR genotype distribution, allele frequencies and homozygotes proportion. In addition, previous studies showed that DC-SIGNR might play different roles in different HIV infection routes. We stratified the patients into two subgroups: sexual contact patients and intravenous drug abuser/blood transfusion patients. Our results showed the frequencies of DC-SIGNR genotypes/alleles in these two subgroups were similar. To our knowledge, this is the first study performed in Northern Chinese. Our findings suggested that DC-SIGNR neck region VNTR polymorphism was not directly associated with hosts’ predisposition for HIV-1 infection and not associated with the HIV-1 routes of infection. By lack of HIV-1 exposed seronegative (HESN) individuals and relative small sample size in present study made our conclusions not strong enough. In addition, the role of the DC-DIGNR neck region in different HIV-1 infection routes remains open for future study.     

Instability in the ATCT variable number tandem repeat locus VWF.VNTR I in intron 40 of the von Willebrand factor gene

The von Willebrand factor gene intron 40 variable number tandem repeat VWF.VNTR I exhibits 10 alleles making it highly polymorphic and useful for parentage and forensic testing. 45 unrelated families (210 meiotic events) were tested for VWF.VNTR I alleles. One spontaneous mutation was observed in a family member. Haplotype analysis demonstrated that this mutation was due to a gain of one motif repeat by a paternal allele. Sequence analysis confirmed the difference in the number of motif repeats between the proband and the alleles expressed by the parents. This instability emphasizes the importance of demonstrating exclusion in at least two separate loci in parentage testing.     

用Amp－FLP技术研究中国汉族群体D4S95和DXS52位点的遗传多态性

为研究中国汉族群体Ｄ４Ｓ９５和ＤＸＳ５２位点的遗传多态性，应用改进的Ｄ４Ｓ９５和ＤＸＳ５２位点的扩增片段长度多态性（Ａｍｐ－ＦＬＰ）分析技术，检测了中国汉族个体共２２２名。结果分别为，（１）Ｄ４Ｓ９５位点：在１０８名无关个体中发现了７个等位基因（片段长度为９１０～１１５０ｂｐ），１８种基因型，杂合性为０．７６，个人鉴别力为０．８７１（２）ＤＸＳ５２位点：在１１４名无关个体中（男性７０人，女性４４人）发现了１４个等位基因（片段长度为６９５～２４００ｂｐ），在４４名女性个体中发现了２２种基因型，杂合性为０．７７．个人鉴别力为男性０．８９，女性０．９３１检测了两个家系两代３口之家的两位点的基因型，证明该两位点的基因按Ｍｅｎｄｅｌ定律遗传，该技术在法医科学鉴定中具有重要的应用价值。     

D1S80 allele frequencies in a Chinese population

Allele frequencies for the VNTR locus D1S80 were determined in a Chinese population sample using the polymerase chain reaction and subsequent analysis of the amplified products by polyacrylamide gel electrophoresis and silver staining. A total of 18 nominal D1S80 alleles were observed in 105 unrelated Chinese. The data demonstrate that D1S80 is highly polymorphic in Chinese with a heterozygosity of 90.5%. The D1S80 frequency distribution meets Hardy-Weinberg expectations. This D1S80 data can be used in forensic analyses and paternity tests to estimate the frequency of a DNA profile in a Chinese population.     

Germline Chromothripsis Driven by L1‐Mediated Retrotransposition and Alu/Alu Homologous Recombination

Chromothripsis (CTH) is a phenomenon where multiple localized double‐stranded DNA breaks result in complex genomic rearrangements. Although the DNA‐repair mechanisms involved in CTH have been described, the mechanisms driving the localized “shattering” process remain unclear. High‐throughput sequence analysis of a familial germline CTH revealed an inserted SVA_E retrotransposon associated with a 110‐kb deletion displaying hallmarks of L1‐mediated retrotransposition. Our analysis suggests that the SVA_E insertion did not occur prior to or after, but concurrent with the CTH event. We also observed L1‐endonuclease potential target sites in other breakpoints. In addition, we found four Alu elements flanking the 110‐kb deletion and associated with an inversion. We suggest that chromatin looping mediated by homologous Alu elements may have brought distal DNA regions into close proximity facilitating DNA cleavage by catalytically active L1‐endonuclease. Our data provide the first evidence that active and inactive human retrotransposons can serve as endogenous mutagens driving CTH in the germline.     

Association between VNTR polymorphism in promoter region of prodynorphin (PDYN) gene and heroin dependence

Within the core promoter region of prodynorphin (PDYN), a 68-bp sequence was found to occur as a polymorphism element, either singular or as tandemly repeated two, three or four times. We report the sequence of a novel allele (5-repeats). Our study revealed the existence of an ancestral nucleotide (A) at 29th position of the VNTR in human. In total, 442 heroin addicts and 799 controls were included in this study. The present findings revealed a male-limited association between VNTR polymorphism and heroin dependence risk.     

Association between endothelial nitric oxide gene intron 4a4b VNTR polymorphism and plasma homocysteine concentrations in Tunisian male patients with myocardial infarction

Many studies have shown that hyperhomocysteinemia may be an independent risk factor for coronary artery disease. However, not all prospective studies support an association between elevated plasma homocysteine levels and coronary artery disease. Nitric oxide (NO) plays a relevant role in various events during atherogenesis, and in vitro data suggest that NO may modulate total homocysteine (tHcy) concentrations, whereas polymorphisms of the endothelial nitric oxide (NOS3) gene have been reported to be related to an increased risk of myocardial infarction (MI) and hyperhomocysteinemia, but the results have been controversial. We hypothesized that the NOS3 synthase 4a4b VNTR polymorphism is a determinant of tHcy concentrations and tested this in 310 patients with MI and 250 controls. The NOS3 gene intron 4a4b VNTR polymorphism was analyzed by polymerase chain reaction analysis. There was no significant difference in the homocysteine levels between patients with MI and controls. The frequencies of the NOS34b4b, 4b4a, and 4a4a genotypes in the MI group were significantly different from those in the control group. In patients with MI, plasma tHcy concentrations were significantly different among the NOS3 genotypes (13.5 ± 4.5, 18.5 ± 3.9, and 20.4 ± 2.1 μmol/L for 4b4b, 4a4b, and 4a4a genotypes, respectively; P < .001). However, no significant difference was observed for tHcy concentrations in the control group. In conclusion, the NOS34a4b gene polymorphism (presence of 4a allele) is associated with MI and influences plasma tHcy concentrations in patients with MI in the Tunisian male population.     

脉冲场凝胶电泳和多位点串联重复序列分析 应用于中国鼠伤寒沙门菌分型能力的评价

目的 比较脉冲场凝胶电泳(PFGE)和两种国际多位点串联重复序列分析(MLVA)分型方法用于我国鼠伤寒沙门菌分子分型的能力,并初步确定适用于我国鼠伤寒沙门菌MLVA分型中的VNTR位点。 方法 根据国际PulseNet公布的沙门菌PFGE分型方案、MLVA分型方案(包含7个VNTR位点,简称MLVA_PN)及欧洲食源性疾病监测网公布的鼠伤寒沙门菌MLVA分型方案(包含5个VNTR位点, 简称MLVA_EU),对来自我国5个省(直辖市)的175株鼠伤寒沙门菌进行分子分型分析,并结合流行病学资料,评价这三种分型方法对我国分离的鼠伤寒沙门菌的分型能力。 结果 175株鼠伤寒沙门菌经XbaⅠ酶切,PFGE后,获得56种带型,其分辨能力(D值)为0.8823。对其中的主优势带型JPXX01.CN0001菌株55株进一步用第二种内切酶BlnⅠ酶切后,获得6种带型。用MLVA_EU分型,获得96种型别,D值为0.9758。应用MLVA_PN分析,获得98种型别, D值为0.9763。 两种MLVA分型方法对菌株的分辨能力几乎相同,且分型结果具有较高的一致性。对流行病学调查显示为鼠伤寒沙门菌暴发患者和食物来源的菌株进行PFGE双酶切及MLVA分型,三种分型方法获得一致性结果,均显示这些菌株具有明显的聚集性。 结论 两种MLVA分型方法的分辨能力均高于PFGE,在确认鼠伤寒沙门菌引起的暴发事件时,采用需时较短,操作更方便的5个VNTR位点的MLVA分型方法可满足菌株聚集性分析。     

MAO A VNTR polymorphism and amygdala volume in healthy subjects

The X-linked Monoamine Oxidase A (MAO A) gene presents a well known functional polymorphism consisting of a variable number of tandem repeats (VNTR) (long and short variants) previously associated with altered neural function of the amygdala. Using automatic subcortical segmentation (Freesurfer), we investigated whether amygdala volume could be influenced by this genotype. We studied 109 healthy subjects (age range 18-80 years; 59 male and 50 female), 74 carrying the MAO A High-activity allele and 35 the MAO A Low-activity allele. No significant effect of the MAO A polymorphism or interaction effect between polymorphism × gender was found on amygdalar volume. Thus, our findings suggest that the reported impact of the MAO A polymorphism on amygdala function is not coupled with consistent volumetric changes in healthy subjects. Future studies are needed to investigate whether the association between volume of the amygdala and the MAO A VNTR polymorphism is influenced by social/psychological variables, such as impulsivity, trauma history and cigarette smoking behaviour, not taken into account in this work.     

Recent molecular genetic studies and methodological issues in suicide research

Suicide behavior (SB) spans a spectrum ranging from suicidal ideation to suicide attempts and completed suicide. Strong evidence suggests a genetic susceptibility to SB, including familial heritability and common occurrence in twins. This review addresses recent molecular genetic studies in SB that include case-control association, genome gene-expression microarray, and genome-wide association (GWA). This work also reviews epigenetics in SB and pharmacogenetic studies of antidepressant-induced suicide.SB fulfills criteria for a complex genetic phenotype in which environmental factors interact with multiple genes to influence susceptibility. So far, case-control association approaches are still the mainstream in SB genetic studies, although whole genome gene-expression microarray and GWA studies have begun to emerge in recent years. Genetic association studies have suggested several genes (e.g., serotonin transporter, tryptophan hydroxylase 2, and brain-derived neurotrophic factor) related to SB, but not all reports support these findings. The case-control approach while useful is limited by present knowledge of disease pathophysiology. Genome-wide studies of gene expression and genetic variation are not constrained by our limited knowledge. However, the explanatory power and path to clinical translation of risk estimates for common variants reported in genome-wide association studies remain unclear because of the presence of rare and structural genetic variation. As whole genome sequencing becomes increasingly widespread, available genomic information will no longer be the limiting factor in applying genetics to clinical medicine. These approaches provide exciting new avenues to identify new candidate genes for SB genetic studies. The other limitation of genetic association is the lack of a consistent definition of the SB phenotype among studies, an inconsistency that hampers the comparability of the studies and data pooling.In summary, SB involves multiple genes interacting with non-genetic factors. A better understanding of the SB genes by combining whole genome approaches with case-control association studies, may potentially lead to developing effective screening, prevention, and management of SB.