山羊基因组与遗传变异图谱研究进展

高通量测序技术和生物信息学的发展极大的促进了山羊分子生物学研究。山羊参考基因组的不断完善以及基因组重测序技术的应用,在全基因组水平上发现了大量的遗传变异信息(SNP、Indel和CNV),丰富了山羊分子群体遗传学研究利用的分子标记。综述了山羊参考基因组组装和全基因组变异图谱的构建及其在山羊上的研究进展,以期为进一步利用分子遗传标记进行山羊的各种性状的遗传基础研究和遗传资源保护利用提供科学依据和参考。     

单核苷酸多态性技术在鸡遗传变异中的研究及应用

单核苷酸多态性(SNP)是继限制性片段长度多态性、微卫星标记之后的第三代分子标记,通常呈双等位基因多态。本文从SNP的特点、SNP的发现与检测、SNP数据库、SNP的频率及其与表型的关系等方面简述了SNP在鸡遗传变异中的研究及应用进展。     

拷贝数变异的全基因组关联分析

基因组拷贝数变异(copy number variations,CNVs)是指与基因组参考序列相比,基因组中≥1 kb的DNA片段插入、缺失和/或扩增,及其互相组合衍生出的复杂变异．由于其具有分布范围广、可遗传、相对稳定和高度异质性等特点,目前认为,CNVs是一种新的可以作为疾病易感标志的基因组DNA多态性,其变异引起的基因剂量改变可以导致表型改变．最近,一种基于CNVs的新的疾病易感基因鉴定策略——CNV全基因组关联分析开始出现,这一策略和传统的基于单核苷酸多态性的关联分析具有互补性,通过认识基因组结构变异可以认识复杂疾病的分子机制和遗传基础．     

基于全基因组SNP位点和性状特征解析我国野生肺形侧耳的遗传多样性

目的 探究我国野生肺形侧耳（Pleurotus pulmonarius）的遗传变异水平;以期为新品种选育提供优异亲本材料和数据支撑。 方法 利用全基因组重测序技术获得的SNP标记对37个野生肺形侧耳菌株进行遗传多样性分析;同时观测其菌丝培养特征和结实性等表型性状。 结果 在供试野生菌株中检测到的SNP数量范围在71 521-114 390个之间;菌株间遗传距离的平均值为0.180;聚类分析发现;大部分来自同一采集地点的菌株亲缘关系更为接近;与云南相比;采自陕西、四川、新疆地区的菌株亲缘关系较为接近。野生菌株在菌丝生长适宜温度、菌丝温度敏感性、菌丝恢复生长等培养特征上以及原基形成和分化、子实体成熟、菌盖颜色等结实特性方面呈现出丰富的表型多样性;基于表型特征的聚类分析结果表明;所有菌株在SM相似系数为0.52水平上能够按照原基能否正常分化分成两大组;这与主成分分析的类群划分结果高度一致。 结论 我国肺形侧耳野生种质资源遗传多样性丰富;具有良好的驯化利用潜力;野生菌株基因组水平上的遗传分化程度可能与其地理分布有关;与表型特征无明显相关性。     

Local effects drive heterozygosity–fitness correlations in an outcrossing long-lived tree

Heterozygosity–fitness correlations (HFCs) have been used to understand the complex interactions between inbreeding, genetic diversity and evolution. Although frequently reported for decades, evidence for HFCs was often based on underpowered studies or inappropriate methods, and hence their underlying mechanisms are still under debate. Here, we used 6100 genome-wide single nucleotide polymorphisms (SNPs) to test for general and local effect HFCs in maritime pine (Pinus pinaster Ait.), an iconic Mediterranean forest tree. Survival was used as a fitness proxy, and HFCs were assessed at a four-site common garden under contrasting environmental conditions (total of 16 288 trees). We found no significant correlations between genome-wide heterozygosity and fitness at any location, despite variation in inbreeding explaining a substantial proportion of the total variance for survival. However, four SNPs (including two non-synonymous mutations) were involved in significant associations with survival, in particular in the common gardens with higher environmental stress, as shown by a novel heterozygosity–fitness association test at the species-wide level. Fitness effects of SNPs involved in significant HFCs were stable across maritime pine gene pools naturally growing in distinct environments. These results led us to dismiss the general effect hypothesis and suggested a significant role of heterozygosity in specific candidate genes for increasing fitness in maritime pine. Our study highlights the importance of considering the species evolutionary and demographic history and different spatial scales and testing environments when assessing and interpreting HFCs.     

Integrative gene network analysis provides novel regulatory relationships, genetic contributions and susceptible targets in autism spectrum disorders

Autism spectrum disorders (ASDs) are a group of diseases exhibiting impairment in social drive, communication/language skills and stereotyped behaviors. Though an increased number of candidate genes and molecular interactions have been identified by various approaches, the pathogenesis remains elusive. Based on clinical observations, data from accessible GWAS and expression datasets we identified ASDs gene candidates. Integrative gene network and a novel CNV-centric Node Network (CNN) analysis method highlighted ASDs-associated key elements and biological processes. Functional analysis identified neurological functions including synaptic cholinergic receptor (CHRNA) families, dopamine receptor (DRD2), and correlations between social behavior and oxytocin related pathways. CNN analysis of genome-wide genetic and expression data identified inheritance-related clusters related to PTEN/TSC1/FMR1 and mTor/PI3K regulation. Integrative analysis identified potential regulators of networks, specifically TNF and beta-estradiol, suggesting a potential central role in ASDs. Our data provide information on potential disease mechanisms, and key regulators that may generate novel postulations, and diagnostic molecular biomarkers.     

人microRNA相关的遗传变异与肿瘤

微RNA(microRNA,miRNA)是新发现的一类进化上高度保守的重要的转录后调控因子,通过调节基因的表达而参与调控细胞凋亡、增殖及分化等生理过程,同时与肿瘤等疾病的发生发展密切相关。近年来研究发现,miRNA、miRNA生物合成通路基因及miRNA的靶基因结合位点的遗传变异(例如单核苷酸多态性和拷贝数变异等)可影响miRNA调控功能的发挥,并产生显著的遗传学效应。文章主要综述了miRNA相关的遗传变异与肿瘤易感性和临床转归等的研究进展。     

Delineation of the frequency and boundary of chromosomal copy number variations in paediatric neuroblastoma

Neuroblastoma, the most common solid tumour in early childhood, is characterized by very frequent chromosomal copy number variations (CNVs). While chromosome 2p amplification, 17q gain, 1p and 11q deletion in human neuroblastoma tissues are well-known, the exact frequencies and boundaries of the chromosomal CNVs have not been delineated. We analysed the publicly available single nucleotide polymorphism (SNP) array data which were originally generated by the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, defined the frequencies and boundaries of chromosomes 2p11.2 – 2p25.3 amplification, 17q11.1-17q25.3 gain, 1p13.3-1p36.33 deletion and 11q13.3-11q25 deletion in neuroblastoma tissues, and identified chromosome 7q14.1 (Chr7:38254795-38346971) and chromosome 14q11.2 (Chr14:21637401-22024617) deletion in blood and bone marrow samples from neuroblastoma patients, but not in tumour tissues. Kaplan Meier analysis showed that double deletion of Chr7q14.1 and Chr14q11.2 correlated with poor prognosis in MYCN gene amplified neuroblastoma patients. In conclusion, the oncogenes amplified or gained and tumour suppressor genes deleted within the boundaries of chromosomal CNVs in tumour tissues should be studied for their roles in tumourigenesis and as therapeutic targets. Focal deletions of Chr7q14.1 and Chr14q11.2 together in blood and bone marrow samples from neuroblastoma patients can be used as a marker for poorer prognosis and more aggressive therapies.     

Evaluation of 16 loci to examine the cross‐species utility of single nucleotide polymorphism arrays

Large collections of single nucleotide polymorphisms (SNPs) have recently been identified from a number of livestock genomes. This raises the possibility that SNP arrays might be useful for analysis in related species for which few genetic markers are currently available. To address the likely success of such an approach, the aim of this study was to examine the threshold number and position of flanking mutations which act to prevent genotype calls being produced. Sequence diversity was measured across 16 loci containing SNPs known either to work successfully between species or fail between species. In pairwise comparisons between domestic and wild sheep, sequence divergence surrounding working SNP assays was significantly lower than that surrounding non‐functional assays. In addition, the location of flanking mismatches tended to be closer to the target SNP in loci that failed to generate genotype calls across species. The magnitude of sequence divergence observed for both working and non‐functional assays was compared with the divergence separating domestic sheep from European Mouflon, African Barbary, goat and cattle. The results suggest that the utility of SNP arrays for analysis of shared polymorphism will be restricted to closely related pairs of species. Analysis across more divergent species will, however, be successful for other objectives, such as the identification of the ancestral state of SNPs.     

Genetic approaches for studying transgene inheritance and genetic recombination in three successive generations of transformed tobacco

Transgene integration into plant genomes is a complex process accompanied by molecular rearrangements. Classic methods that are normally used to study transgenic population genetics are generally inadequate for assessing such integration. Two major characteristics of transgenic populations are that a transgenic genome may harbor many copies of the transgene and that molecular rearrangements can create an unstable transgenic locus. In this work, we examined the segregation of T1, T2 and T3 transgenic tobacco progenies. Since transfer DNA (T-DNA) contains the NptII selectable marker gene that confers resistance to kanamycin, we used this characteristic in developing a method to estimate the number of functional inserts integrated into the genome. This approach was based on calculation of the theoretical segregation ratios in successive generations. Mendelian ratios of 3:1, 15:1 and 63:1 were confirmed for five transformation events whereas six transformation events yielded non-segregating progenies, a finding that raised questions about causal factors. A second approach based on a maximum likelihood method was performed to estimate recombination frequencies between linked inserts. Recombination estimates varied among transformation events and over generations. Some transgenic loci were unstable and evolved continuously to segregate independently in the T3 generation. Recombination and amplification of the transgene and filler DNA yielded additional transformed genotypes.