A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants

Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.     

A common allele on chromosome 9 associated with coronary heart disease

Coronary heart disease (CHD) is a major cause of death in Western countries. We used genome-wide association scanning to identify a 58-kilobase interval on chromosome 9p21 that was consistently associated with CHD in six independent samples (more than 23,000 participants) from four Caucasian populations. This interval, which is located near the CDKN2A and CDKN2B genes, contains no annotated genes and is not associated with established CHD risk factors such as plasma lipoproteins, hypertension, or diabetes. Homozygotes for the risk allele make up 20 to 25% of Caucasians and have a approximately 30 to 40% increased risk of CHD.     

A common variant on chromosome 9p21 affects the risk of myocardial infarction

The global endemic of cardiovascular diseases calls for improved risk assessment and treatment. Here, we describe an association between myocardial infarction (MI) and a common sequence variant on chromosome 9p21. This study included a total of 4587 cases and 12,767 controls. The identified variant, adjacent to the tumor suppressor genes CDKN2A and CDKN2B, was associated with the disease with high significance. Approximately 21% of individuals in the population are homozygous for this variant, and their estimated risk of suffering myocardial infarction is 1.64 times as great as that of noncarriers. The corresponding risk is 2.02 times as great for early-onset cases. The population attributable risk is 21% for MI in general and 31% for early-onset cases.     

Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes

The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.     

Erythropoietin Receptor Gene （EPOR） Polymorphisms are Associated with Sow Litter Sizes

The erythropoietin receptor (EPOR) has shown to play an important role in fetal survival by promoting the maturation of red blood cells in many studies of uterine capacity and litter size in swine. In this study, we screened the porcine EPOR gene for mutations and identified five single nucleotide polymorphisms (SNPs): g.705G＞T in intron 1, g.2 373C＞T in intron 4, and g.2 882C＞T, g.3 035A＞G, and g.3 132A＞T in intron 6. We then genotyped 247 Beijing Black (BB) sows and compared the polymorphism data with the litter sizes of 1 375 parities among the sows. At first parity, there was no association of g.2 882C＞T and g.3 132A＞T with litter sizes. However, the CT sows in g.2 882C＞T had 2.13 higher total number born (TNB) (P＜0.01) and 1.81 higher number bom alive (NBA) (P＜0.01) than the CC sows and the heterozygous sows in g.3 132A＞Thad the highest litter size when compared to the two homozygotes for the later parities (P＜0.05). In the g.3 035A＞G SNP,for the later parities, the TNB of the sows with the GG genotype was 3.81 higher (P＜0.01) and the NBA was 2.75 higher(P＜0.01) than that with the AA genotype but no difference at first parity. The G allele of the EPOR g.705G＞T SNP wasassociated with a greater litter size at both the first parity (P＜0.05) and later parities (P＜0.01). Furthermore, we determined the allele frequencies for this SNP among five Chinese indigenous pig breeds (Erhualian, Laiwu Black, Meishan, Min, and Rongchang) and three western commercial pig breeds (Duroc, Landrace, and Large White). The G allele of the EPOR g.705G＞T SNP was significantly more common in the more prolific Chinese breeds. These results indicated that the EPOR could be an important candidate gene for litter size and g.705G＞T can serve as a useful genetic marker for improving litter size in both first and later parities in swine.     

鸡催乳素受体基因多态性与就巢及产蛋性状的关联分析

【目的】揭示与繁殖性状关系密切的催乳素受体（prolactin receptor,PRLR）基因与中国地方鸡种的就巢性及产蛋性能的关系。【方法】本试验采用PCR-SSCP方法,以576只宁都黄鸡为材料,检测PRLR基因的多态性,并进行多态性与就巢和产蛋性状间的关联分析。【结果】证实了前人研究过的SNP1（T10862C,外显子3）和SNP2（T25670C,外显子6）均与就巢性状无显著关联（P＞0.05）;SNP2对300 d产蛋量影响显著（P＜0.05）;新发现的SNP3（G30716A,内含子8）显著影响开产日龄（P＜0.05）;新发现的SNP4（A31900G,外显子10）极显著地影响就巢率（P＜0.01）,显著影响就巢天数和300 d产蛋量（P＜0.05）。由4个SNPs构建的不同单倍型在开产日龄上的差异达到极显著水平（P＜0.01）,在其它性状上的差异不显著（P＞0.05）。【结论】PRLR基因的多态性与就巢和产蛋性状相关,SNP4的效应更为突出。     

猪TBG基因多态性突变位点的检测

通过直接测序的方法,对猪TBG基因进行全基因组扫描,鉴别TBG基因在合作猪、长白猪和华特B系猪中的SNPs.结果显示共发现10个SNPs,分别是T733A,T740C,867和3135的A→T,926的G→A,1006的C→T,1106,1449和2371的A→G,1509的C→T分别位于第1(733,740,867,926,1006,1106,1449和1509)、第2(2371)和第3(3135)内含子内;且还发现TBG基因的3130(A)和3131(A)位之间以及3131(A)和3132(A)之间在合作猪中存在T,而长白和华特B系猪中不存在,与GenBank公布的TBG基因(AY550250)全序列进行比对,在3130(A)和3131(A)位之间以及3131(A)和3132(A)不存在T碱基;同样在3135(T)和3136(A)之间,合作猪中存在AC两个碱基的插入,而在华特B系猪和长白猪中则没有,因此在合作猪中存在插入或在长白猪、华特B系猪中存在缺失的突变.通过TBG基因在各猪种中突变位点的识别,可见合作猪种存在丰富的遗传多样性.     

猪精子黏合分子1(SPAM1)基因在白色杜洛克×二花脸F2资源群体中的遗传变异及其与母猪产仔数的关联性

 【目的】猪精子黏合分子1(SPAM1)基因在精卵结合过程中发挥重要作用,是影响产仔数的重要候选基因。本试验分析SPAM1基因的遗传变异及其与母猪产仔数的相关性。【方法】以305头白色杜洛克×二花脸资源群体F2母猪为材料,记录连续3胎的产仔性状,利用PCR-RFLP检测intron1 g298 C＞T 、intron1 g357 C＞T 和intron3 g380 C＞T共3个SNP位点在F2群体中的多态性,构建单倍型,分析各SNP基因型和单倍型与母猪产仔数、产活仔数、产死胎数的相关性。【结果】intron1 g298 C＞T位点CC型母猪的总产仔数显著低于CT、TT型母猪（P＜0.05）,CT基因型母猪产死胎数显著多于TT型（P＜0.05）。intron1 g357 C＞T位点CT基因型母猪产死胎数显著多于CC、TT基因型（P＜0.05）。intron3 g380 C＞T位点CC基因型母猪产活仔数显著低于CT型,产死胎数显著高于CT型（P＜0.05）。在6种单倍型中,TTT单倍型母猪的总产仔数和产活仔数明显高于其它5种（P＜0.05）;TCT、TTC单倍型母猪产死胎数显著低于CTC、TTT和TCC（P＜0.05）。【结论】SPAM1基因与母猪产仔数存在显著相关性。     

金定鸭FSHR基因第1～7外显子的克隆及SNP位点的筛查

动物的繁殖活动主要受内分泌生殖激素的调控,FSHR存在于卵泡颗粒细胞膜上,属于G蛋白偶联受体家族,对动物卵巢细胞的发育、成熟和排卵具有重要的作用。本研究以高产和低产金定鸭基因组为模板,通过PCR扩增、目的基因片段克隆和测序等方法,获取金定鸭FSHR基因1~7外显子序列,并对基因序列进行比对分析。结果显示,序列a包含第1外显子(185bp)的完整序列,第1内含子(145bp)的部分序列;序列b包含第2(75bp)、3外显子(75bp)、第2内含子(463bp)的完整序列,第1(40bp)、3内含子(47bp)的部分序列;序列c包含第4外显子(75bp)的完整序列,第3(180bp)、4内含子(55bp)的部分序列;序列d包含第5外显子(78bp)的完整序列,第4(232bp)、5内含子(56bp)的部分序列;序列e包含第6(69bp)、7外显子(75bp)、第6内含子(117bp)的完整序列,第5(133bp)、7内含子(146bp)的部分序列。根据基因序列特征,对获取的5段金定鸭FSHR基因序列进行扩增序列测序比对。结果发现:在外显子1第50bp处存在A/G突变;在外显子2第30bp处存在A/G突变;在外显子4第33bp处存在C/T突变;在外显子5第45bp处存在A/G突变,第19bp处可能存在A/T突变,33bp处可能存在C/T突变。金定鸭FSHR基因序列的克隆及SNP突变位点的发现可为后续开展FSHR基因的多态性与金定鸭产蛋性能的相关研究奠定一定的基础。     

密穗小麦高分子量谷蛋白亚基组成分析密穗小麦高分子量谷蛋白亚基组成分析

采用十二烷基硫酸钠 -聚丙烯酰胺凝胶电泳 ( SDS- PAGE)方法 ,分析了 32份密穗小麦的高分子量谷蛋白亚基 ( HMW- GS)组成。在 3个位点上一共检测到 12种不同的亚基类型。在 Glu- B1位点上 ,密穗小麦的高分子量谷蛋白亚基组成具有其明显的组成特点 ,表现为 2 1和 13+16亚基出现频率较高 ,分别为 34 .83%和 18.75% ,而这 2种亚基在普通小麦和斯卑尔脱小麦中为极稀有亚基 ;密穗小麦在 Glu- A1和 Glu- D1位点上的主要亚基变异形式与普通小麦相似 ,即以 null( Glu- A1)、2 +12和 5+10 ( Glu- D1)为其主要变异形式。另外 ,本研究还筛选出了 7份具有 5+10优质亚基的材料 ,这将为提高密穗小麦与普通小麦种间杂交种的品质杂种优势提供了材料基础。最后讨论了密穗小麦的起源     

A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity

Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.     

清远麻鸡VIPR-1基因C1704887T、C1715301T位点与繁殖性状的关联性分析

家禽繁殖内分泌调控机制和血管活性肠肽I型受体(vasoactive intestinal peptide receptor-1,VIPR-1)基因的体内体外表达实验证明,VIPR-1基因参与了繁殖行为的调控。研究以鸡VIPR-1基因的C1704887T与C1715301T位点作为繁殖性状的候选标记,对512只清远麻鸡进行基因型检测并分析其与繁殖性状的相关性。研究表明:位于内含子6的位点C1704887T与40周龄、43周龄以及54周龄的总产蛋数和总正常蛋数显著相关(P<0.05),等位基因C有利于产蛋;位于内含子8的位点C1715301T与30周总畸形蛋数显著相关(P<0.05);这2个位点组成的二倍型与开产日龄呈显著的相关性(P<0.05),但这2个位点与开产性状无显著相关。研究结果提示:位点C1704887T可作为产蛋量的标记辅助选择的潜在分子标记。     

Variable occurrence of the nrdB intron in the T-even phages suggests intron mobility

The bacteriophage T4 nrdB gene, encoding nucleoside diphosphate reductase subunit B, contains a self-splicing group I intervening sequence. The nrdB intron was shown to be absent from the genomes of the closely related T-even phages T2 and T6. Evidence for variable intron distribution was provided by autocatalytic 32P-guanosine 5'-triphosphate labeling of T-even RNAs, DNA and RNA hybridization analyses, and DNA sequencing studies. The results indicate the nonessential nature of the intron in nrdB expression and phage viability. Furthermore, they suggest that either precise intron loss from T2 and T6 or lateral intron acquisition by T4 occurred since the evolution of these phages from a common ancestor. Intron movement in the course of T-even phage divergence raises provocative questions about the origin of these self-splicing elements in prokaryotes.     

Bayesian inference towards the resolution of molecular evolution:application to the "Trichoderma harzianum sensu lato" clade

The Hypocrea lixii/Trichoderma harzianum species aggregate contains a group of taxa (H. lixii /T. harzianum, T. aggressivum, T. tomentosum, T. cerinum, T. velutinum, H. tawa) of which some (e.g. T. harzianum) are important for biocontrol of plant pathogenic fungi in agriculture, whereas others are aggressive pathogens of Agaricus spp. and Pleurotus spp. in mushroom farms (T. aggressivum), or opportunistic pathogens of immunocompromised mammals including humans (T. harzianum). We ch…     

杜洛克猪生长性状全基因组关联分析

对猪全基因组高密度SNP基因型数据及生长性状表型数据进行全基因组关联分析,以期找到影响这些性状的候选基因,更准确地了解这些生长性状的遗传基础。利用Illumina猪60KSNP芯片对191头杜洛克猪进行基因型检测,使用R语言环境下GenABEL 软件包提供的单标记回归分析模型,对体重达100 kg 日龄(D100)、活体背膘厚(BFT)和活体眼肌面积(LMA)3个生长性状的表型分别进行全基因组关联分析。在D100和LMA2个性状中分别检测到1个基因组水平和6个染色体水平显著关联的SNP,均位于5号染色体;没有检测到与BFT显著相关的SNP。生物信息学分析表明,BTG1和EFCAB6可能是影响生长性状的重要候选基因,但其功能有待进一步研究确认。关键词猪;全基因组关联分析;候选基因;生产性状。     

A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels

Several studies have shown that healthy individuals with fasting plasma glucose (FPG) levels at the high end of the normal range have an increased risk of mortality. To identify genetic determinants that contribute to interindividual variation in FPG, we tested 392,935 single-nucleotide polymorphisms (SNPs) in 654 normoglycemic participants for association with FPG, and we replicated the most strongly associated SNP (rs560887, P = 4 x 10(-7)) in 9353 participants. SNP rs560887 maps to intron 3 of the G6PC2 gene, which encodes glucose-6-phosphatase catalytic subunit-related protein (also known as IGRP), a protein selectively expressed in pancreatic islets. This SNP was associated with FPG (linear regression coefficient beta = -0.06 millimoles per liter per A allele, combined P = 4 x 10(-23)) and with pancreatic beta cell function (Homa-B model, combined P = 3 x 10(-13)) in three populations; however, it was not associated with type 2 diabetes risk. We speculate that G6PC2 regulates FPG by modulating the set point for glucose-stimulated insulin secretion in pancreatic beta cells.     

牦牛DGAT1基因多态性及其与乳质性状关联分析

【目的】检测牦牛DGAT1基因多态性,评估基因突变对牦牛乳品质性状的影响,以期丰富牦牛重要经济性状的分子遗传研究基础。【方法】采用PCR-SSCP方法,检测甘南牦牛、天祝白牦牛、青海牦牛及野血牦牛DGAT1基因intron5-exon7和intron15-exon17区突变,分析基因突变对乳品质性状的影响。【结果】牦牛DGAT1基因intron5-exon7区发现c.562+32_c.562+33ins CCGCCC的插入/缺失,等位基因M、基因型MM频率最高为优势等位基因和基因型,各类群牦牛PIC0.5属中度或低度多态;intron15-exon17区检测到c.1249-23CT和c.1336CT的突变,其中exon17发现的c.1336CT突变导致编码氨基酸p.Arg447Cys转变,等位基因A频率最高为优势等位基因,甘南牦牛、天祝白牦牛和青海牦牛中基因型AA为优势基因型,野血牦牛基因型AB为优势基因型,各类群牦牛0.25PIC0.5属中度多态;两区域3处突变位点构建出6种单倍型和11种单倍型组合,突变位点间存在连锁关系且接近于连锁平衡。关联分析表明,甘南牦牛intron5-exon7区基因型与乳质性状无显著相关;intron15-exon17区基因型BB个体乳品质性状最低,且乳蛋白率、乳脂率、总固体物质含量中显著低于其他基因型个体(P0.05);携带等位基因A的个体乳蛋白率、乳脂率、总固体物质含量及无脂固体含量显著高于未携带者(P0.05),携带等位基因C的个体乳脂率也显著高于未携带者(P0.05),而携带等位基因B的个体乳脂率、总固体物质含量显著低于未携带者(P0.05);单倍型组合H1H3个体的乳蛋白率、乳脂率、总固体物质含量和无脂固体物质含量均较高,且乳脂率及总固体物质含量显著高于其他单倍型组合(P0.05),而H2H2单倍型组合个体则较低,除乳糖率以外的其他乳品质性状均显著低于其他7种单倍型组合(P0.05)。【结论】牦牛DGAT1基因intron5-exon7和intron15-exon17区为低度和中度多态,intron6存在c.562+32_c.562+33ins CCGCCC的插入/缺失,intron15和exon17分别检测到c.1249-23CT突变和c.1336CT的非同义突变。intron15-exon17区突变影响甘南牦牛乳品质性状,选留携带等位基因A的个体和淘汰携带等位基因B的个体、或选留H1H3单倍型组合及淘汰H2H2单倍型组合个体,均可显著改善后代群体的乳品质。     

低氧适应相关基因及其研究策略的思考

目的筛选藏绵羊血红蛋白基因和EPAS1基因的低氧正选择位点,并解析位点遗传效应,揭示两基因在藏绵羊低氧适应中的作用。方法以血红蛋白、EPAS1为候选基因,筛选藏绵羊的优势SNP位点,并扩大样本检测3个海拔梯度(1 500、2 500和3 500 m)绵羊的海拔趋势位点和血液生理指标,进行基因型与血液生理指标关联分析。结果藏绵羊血红蛋白、EPAS1基因分别检测到6个和12个SNPs。血红蛋白6个SNPs均为同义突变,其基因频率均未呈现海拔趋势。EPAS1基因第8内含子C871T位点突变等位基因(T)频率呈现明显海拔趋势,该位点TT基因型具有增加血红蛋白含量(HGB)、红细胞平均血红蛋白含量(MCH)和血液黏稠度的遗传效应(P<0.05);通过转录因子结合位点预测,发现该突变导致 GATA (造血调控因子)结合位点丢失。EPAS1基因第9外显子G1001A为非同义突变VAL352MET,但突变等位基因频率仅为0.34,此位点3种基因型与各血液生理指标之间差异均不显著(P>0.05);通过蛋白结构同源预测,未发现蛋白结构功能变化。结论藏绵羊EPAS1基因第8内含子C871T位点突变等位基因(T)的频率随海拔升高而升高,其TT型能显著提高血红蛋白质量浓度14.14 g/L,是藏绵羊高血红蛋白浓度的潜在关联位点。