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关键词： 尖嘴魟   种群遗传学   大银鱼   基因组学   系统进化树  

摘要： 软骨鱼类是起源于4亿年前较原始的鱼类，在其进化过程中历经了海洋环境变迁和数次生物大灭绝，是大尺度研究海洋生物地理学的理想物种。本研究选取广泛分布在西北太平洋地区具有典型代表意义的软骨鱼类尖嘴魟（Telatrygon zugei）为研究对象，采用线粒体和微卫星两种分子标记开展种群遗传学研究，为该类群多样性保护、资源可持续利用以及渔业管理等方面提供科学依据。本研究对来自中国沿海、日本海、泰国湾和安达曼海8个种群244尾尖嘴魟遗传多样性进行分析，结果显示1812bp线粒体序列发现了209个变异位点共定义115个单倍型，所有样本单倍型多样性(h)为0.975，核苷酸多样性(π)为0.017。微卫星遗传多样性结果显示期望杂合度(HE)为0.951和观测杂合度(Ho)为0.803，该物种具有较高的遗传多样性水平。尖嘴魟线粒体单倍型在进化上分为明显的两支（A枝和B枝），A枝来自中国沿海和日本海个体，B枝来自安达曼海和泰国湾个体，A、B两枝的分歧时间在2.5-1.6个百万年前(Mya)。AMOVA与STRUCTURE结果均支持将尖嘴魟种群分成日本种群(JP)、泰国湾种群(TLD)、安达曼海种群(ADM)和中国沿海种群(CHN)4个遗传单元。FST结果显示这4个遗传单元之间存在较大的遗传差异。分析认为种群遗传分化的原因与更新世气候变化和尖嘴魟底栖的生活习性密切相关。中性检测和BSP分析结果显示尖嘴魟群体经历过更新世群体扩张事件。基于微卫星数据模拟种群历史动态结果显示，所有的尖嘴魟种群在全新世出现了种群数量下降的趋势。尖嘴魟种群数量的下降与人类活动和气候变化密切相关。因此保护它们的繁育生境和防止过度捕捞对种群的恢复十分重要。　　随着测序技术的不断发展，越来越多的鱼类基因组得到解析。鱼类基因组数据为研究鱼类的进化、生物学特征、性别分化、生长发育、免疫等提供了重要的基础数据。大银鱼(Protosalanx chinensis)为银鱼科重要的经济鱼类，也是东亚地区特有的一年生小型鱼类。该物种具有幼态持续特征表现为体色透明、身体小型化、软骨无鳞、终生具有脊索。为揭示大银鱼短寿和幼态持续特征的分子和遗传机制，对大银鱼开展了基因组和转录学研究。本研究采用二代和三代相结合的测序方法进行de novo测序，组装得基因组大小为484.10M，contig N50长度为103.01Kbp，scaffold N50长度为5.10Mbp，注释得到23，645个蛋白编码基因，获得了高质量大银鱼基因组数据。物种进化分析发现，大银鱼与大西洋鲑鱼和白斑狗鱼的分歧时间为185.5百万年前。与其它硬骨鱼比较，大银鱼大部分基因家族发生收缩，收缩的基因家族主要富集在免疫信号通路上。特别是免疫基因家族MHCⅠ、MHCⅡ、补体C3家族、NOD-like受体基因数量少于其它硬骨鱼类。获得性免疫T细胞介导的免疫应答过程缺少大量的细胞因子。大银鱼CD4+T细胞系中还缺少两个重要的与MHCⅡ类分子识别有关的细胞膜结合蛋白CD4和CD40L。因此认为大银鱼获得性免疫系统尚不完善。研究发现，大银鱼基因组中与骨骼钙化密切相关的SCPP家族基因部分发生缺失，其中scpp1基因为假基因，与鳞片形成密切相关的EDAR基因缺少信号肽结构。分析认为SCPP基因的缺失和EDAR基因变异有可能与大银鱼软骨无鳞的生物学特征密切相关。本研究对大银鱼四个发育时期转录组进行分析，发现甲状腺激素受体基因在受精卵和仔鱼期低表达而在成鱼期高表达，这与其它硬骨鱼类甲状腺激素受体基因的表达模式刚好相反。推测大银鱼甲状腺激素受体基因在受精卵和仔鱼期低表达模式有可能导致大银鱼不能完成从仔鱼期到幼鱼期变态发育，使得大银鱼终生保持幼体时的状态。至今，银鱼科在分类和系统进化研究存在较大分歧，本研究对银鱼科9种银鱼进行重测序，基于全基因组SNP数据构建系统进化树，明确了银鱼科物种间的进化关系。大银鱼基因组数据和转录组数据为今后研究鱼类的遗传进化、分子育种和资源保护提供有价值的遗传信息。

关键词： 遗传病   眼白化病   GPR143   高通量测序   基因组序列比对   Perl   家系分析  

摘要： 遗传多样性是个体表型多样性的基础,也决定了个体是否存在缺陷。很多关键基因因遗传物质变异而导致功能的改变,可能会在一个家族中导致遗传病。由于亲代所遗传的致病基因或遗传物质受到外界物理、化学因素的影响发生改变所导致的疾病,称之为遗传病。本研究观察了一个来自中国云南的大型先天性眼白化病1型家系,家系中有六代人共113个成员,在该家系中每代直系成员中均有少量患有遗传病的个体出现,患者最为突出和一致的表型是眼球震颤和眼底色素沉积减少,是典型的家族遗传病模型。通过高通量测序技术、全基因组序列比对和Perl编写脚本筛选突变的方法,系统深入地分析了该家族中患病者和携带者的全基因组,寻找该家族中引起眼白化病的遗传变异。通过比较患病者、携带者与健康人的基因组以及一代测序验证,在一个重要基因GPR143上所有患病者和携带者都发现了同一个长片段的功能缺失。该缺失长74bp位于基因GPR143的第一外显子上,而无累及家系成员中没有发现该缺失。功能分析表明,这个缺失导致基因GPR143的蛋白翻译提前终止,突变后基因GPR143不能翻译出正常功能的蛋白质。正常基因GPR143编码有404个氨基酸的蛋白质,而突变后的基因GPR143编码的蛋白质只有74个氨基酸。基因GPR143是眼球发育、眼底色素沉着过程中的关键基因,编码的蛋白质靶向色素细胞中的黑素体并参与细胞内的信号传导。基因GPR143功能的丧失很有可能引起眼球发育和眼底色素沉着的异常,很多研究结果也表明基因GPR143上的变异是导致眼白化病的原因。在本研究中,通过高通量测序技术获取该家系人员的全基因组信息;通过全基因组序列比对的方式寻找样本基因组的异常突变,再根据孟德尔遗传定律为基础用Perl编写脚本筛选比对的突变;通过功能分析确定在该家系中的致病变异;最后对整个家系所有样本进行变异位点测序分析,确定携带个体与无受累个体上该基因的变异情况。针对家系所有成员的基因突变与家系图谱中致病和受累者的关系分析,发现基因型和表型完全吻合。综合各方面的实验证据,可以确定所发现的位于基因GPR143上的大片段缺失就是在该家系中导致遗传病的直接原因。结论:在所观察的先天性眼白化病家系中,发现的这个位于基因GPR143上的大片段缺失可引起一种变异形式的眼球白化并且伴随着眼球震颤,给患病者造成严重的视力障碍。该功能性的变异在全球眼白化患病者中是首次被发现,该研究结果不仅丰富了基因GPR143的突变谱,更加强调了基因GPR143对于眼球发育、眼低色素沉积的重要作用。对于未来的功能研究,临床诊断,鉴别诊断和遗传咨询提供了重要的家系遗传学数据。

关键词： 生物   遗传学   致死现象   归类分析  

摘要： 从遗传学两大规律入手,分析高中生物遗传学中各种致死现象的类型和本质,帮助学生梳理完善遗传规律知识体系,建立分析问题的基本框架,掌握解决遗传学致死现象的必备知识和关键能力,提高在有限的时间里解决问题的能力,树立起攻克遗传题的信心。

关键词： Analyses of large multi-omics datasets help describe genetics of type 2 diabetes   type 2 diabetes   epigenome   transcriptome   eQTL   genome   Thesis  

摘要： Type 2 diabetes (T2D) is a complex disease that affects an estimated 415 million people worldwide. Genome wide association studies (GWAS) have identified >240 genetic signals that encode predisposition to this disease and related traits. However, the underlying biological mechanisms driving this predisposition are largely unknown, which is a serious impediment in designing precision therapeutic strategies. The focus of my research is to untangle the genetic complexity of T2D to better understand the biological mechanisms of how disease predisposition is encoded in our DNA. Specifically, I aim to understand how T2D genetic risk variants modulate gene expression in orchestrating disease mechanisms. I utilize high throughput molecular profiling data in human pancreatic islets and other diverse tissues along with human and rodent cell line model systems and employ computational and experimental approaches to map functional signatures of genetic variants associated with T2D. First, I compared gene regulatory annotations defined using diverse epigenomic data across 4 cell types to compare their cell specificities and genetics of gene expression regulation. I observed that genetic variants in genomic regions with more cell type-specific enhancer chromatin have lower effects on gene expression than variants in genomic regions with more ubiquitous promoter chromatin. However, genetic variants in cell type-specific enhancer regions have higher effects in chromatin accessibility than those in less cell type-specific promoter regions. Second, I integrated GWAS data with various -omics data in islets to nominate biological mechanisms. I observed that T2D risk variants confluently disrupt DNA binding motifs of the transcription factor (TF) regulatory factor X (RFX) in accessible regions. Third, I describe large scale expression quantitative trait locus (eQTL) mapping efforts along with integration of epigenomic data to describe molecular regulatory mechanisms. Utilizing such larg

关键词： 精准医疗思维融入医学遗传学教学中的价值评价  

摘要： 社会方方面面技术的发展使得人们对疾病的认知程度也在不断加深,人们对医学的要求也在不断增高,这就出现了精准医学.医学遗传学是将基础和临床连接在一起的学科,也是与精准医疗理念联系最为密切的学科之一.将精准医疗思维应用于临床中可显著提升治疗效果,应用价值高;将精准医疗思维应用于医学教学活动中,通过优化教学内容、改进教学方法以培养病患的思维创新能力,培养更加适应新时期发展医护需求的新型精准医疗人才.

关键词： Biology   Plant sciences   Biochemistry  

摘要： How cells respond to light or time is a fundamental question in biology. Cryptochromes (CRYs) are evolutionarily conserved blue light receptors or key components of the circadian oscillator found in major evolutionary lineages, from bacteria to human and have been intensively studied. However, the structure-function relationship of CRYs from evolutionary perspective is unclear. In this thesis, I interrogated the evolutionary roles of universally conserved residues (UCRs) of Arabidopsis thaliana cryptochrome 2 (CRY2) (Chapter 2) and developed optogenetic tools by engineering CRY2 using continuous directed evolution techniques (Chapter 3). UCRs are invariable amino acids evolutionarily conserved among members of a protein family across diverse kingdoms of life. UCRs are considered important for stability and/or function of protein families, but it has not been experimentally examined systematically. In Chapter 2, I experimentally analyzed 51 UCRs of Arabidopsis CRY2 that are universally conserved in eukaryotic cryptochromes from Arabidopsis to human. Surprisingly, I found that UCRs required for stable protein expression of CRY2 in plants are not similarly required for stable protein expression of human hCRY1 in human cells. Moreover, 74% of the stably expressed CRY2 proteins mutated in UCRs retained wild-type-like activities for at least one of the photoresponses I analyzed. My finding suggests that the evolutionary mechanisms underlying conservation of UCRs or that distinguish UCRs from non-UCRs determining the same functions of individual cryptochromes remain to be investigated. CRY2 mainly regulates plant photomorphogenesis through blue-light-specific interactions with numerous protein partners. Such blue-light-specific interactions have been exploited in optogenetics to manipulated biological events in a timely and precisely manner. Chapter 3 focused on the development of a novel pair of blue-light-dependent interacting proteins: CRY2-BIC1 (Blue-light Inhibitor of

关键词： 急性间歇性卟啉病   胆色素原脱氨酶   δ-氨基γ-酮戊酸   胆色素原  

摘要： 目的:卟啉病是血红素合成过程中酶活性异常导致的代谢性疾病,多由遗传突变引起。急性间歇性卟啉病(acute intermittent porphyria AIP)是其中一种,由于编码胆色素原脱氨酶(Porphobilinogen deaminase PBGD),或称羟甲基胆素合成酶(Hydroxymethylbilance synthase HMBS)的基因发生突变,酶活性降低乃至缺失引起的一种常染色体显性遗传病。该病临床罕见,易误诊误治,目前国内对其研究甚少。本文旨在寻找中国AIP患者HMBS基因突变的特点,总结基因突变规律,并探讨其可能的功能危害。方法:参与本研究的AIP患者均来自卟啉关爱中心。采用问卷形式收集患者一般资料(包括患者性别、年龄、婚育史、有无吸烟饮酒史等)、发病诱因、发病频次等。采集静脉血,采用二代测序、一代验证方法查找基因突变位点。对本研究发现的4个新发突变基因(c.597dup C、c.673＿674del、c.653G>A、c.1045＿1046del AA)所编码的蛋白质进行亚细胞定位研究及空间结构预测。利用含FLAG标签的野生型HMBS质粒、突变型HMBS质粒转染He La细胞,24小时后,通过免疫荧光染色检测突变蛋白在细胞中的定位。在SWISS-Mode网站分别输入HMBS野生型和各突变体的氨基酸序列进行同源建模,利用PDB-Viewer软件分析比较蛋白质的三级结构变化。并同时参照相关文献对部分突变进行功能预测。结果:一般情况:本研究含女性48例,男性8例,发病年龄在17-38岁之间。女性常见诱因:月经>劳累>情绪波动;男性最常见诱因为劳累。基因检测结果:本研究共包含56个AIP家系,基因检测结果发现了35种基因突变,其中14种为文献中未见报道的新发突变。35种基因突变中含14个错义突变(40%),8个剪接突变(23%),9个框移突变(26%),4个无义突变(11%)。35种基因突变分别是c.673C>T(R225X)(13%,发生在7个家系),c.517C>T(R173W)(11%,发生于6个家系中),c.973C>T(p.R325X),(5%,发生于3个家系中),c.267-1G>C,(5%,发生于3个家系中),c.76C>T、c.77G>A、c.331G>A、c.445C>T、c.806C>G,这5种突变各发生于2个家系中,c.92C>T、c.88-1G>C、c.160+3G>T、c.181G>A、c.229T>G、c.469A>T等25种突变各发生于1个家系中。突变最常发生的外显子依次是12>10,第12号外显子(出现9种基因突变占31%)>第10号外显子(出现4种基因突变占11%)>第3、5、7、9、15外显子,第4、14号内含子(均出现2种基因突变)>第8、14号外显子,第6、7、12号内含子(均出现1种基因突变)。亚细胞定位结果:该4种新发突变均不影响蛋白质的亚细胞定位。转染质粒后HMBS在细胞质中均有表达,野生型在细胞质中分布相对均匀,而突变型HMBS在细胞质中易于形成聚集现象。空间结构预测结果:本次研究发现c.653G>A(P.G218E)编码的蛋白质空间结构较野生型无明显改变。c.597dup C导致氨基酸编码至200位时发生改变,并在改变后的第8个氨基酸处提前终止,c.673＿674del导致氨基酸编码至225位开始发生改变,并在232位时提前终止,这两种突变缺失氨基酸较多,因此对酶结构影响较大。c.1045＿1046del AA导致氨基酸编码至第349位时发生改变,并在358位时提前终止,该种突变缺失氨基酸较少,因此该突变对酶空间结构影响相对较小。结论:本次研究中最常见的外显子依次是12号(31%)>第10号(19%),第7号外显子与其他外显子共同居第3位,与国外基本一致。而c.517C>T是本次研究中次常见的突变基因型,也是多个国家最常见的突变。不同的是,c.673C>T作为本次研究中最常见的突变基因型,目前尚未作为国外最常见的突变基因型被报道。

关键词： Botany   Systematic biology  

摘要： Grammitids are a large monophyletic group of primarily epiphytic ferns in Polypodiaceae. Genera Oreogrammitis, Radiogrammitis and Themelium (ORT) formed a clade in grammitid phylogeny where three genera are polyphyletic in the ORT clade. A study was conducted to delineate the phylogenetic relationships of the ORT group by using intensive taxon sampling and with nine genetic markers from both nuclear and chloroplast genomes. Gene sequences were analyzed in maximum likelihood and Bayesian algorithms. Nuclear gene trees and nuclear and plastid gene trees were summarized to construct species trees under multi-species coalescent method in ASTRAL program. All the analyses with higher number of species and data revealed that the three genera are polyphyletic. Thus, taxonomic revisions are suggested. Oreogrammitis must be redefined to include Radiogrammitis and Themelium. Oreogrammitis hookeri is an endemic Hawaiian grammitid fern. It is one of the three Hawai‘i endemic Oreogrammitis species. Oreogrammitis hookeri can be found in all the major islands in Hawaiian archipelago whereas the other two species have limited distribution. Some populations of O. hookeri contain unique alleles and the species may have been undergoing incipient speciation or represent cryptic species complex. Current study was conducted to investigate the population structure of O. hookeri with populations sampled from all the major islands except Lanai. Double Digest Restriction Site Associated DNA sequencing (ddRADseq) technique was used to generate genomic data. Analysis of 176 loci in STRUCTURE program showed that there are two genotypes in O. hookeri. Populations collected from Kauaʻi and Mauna Loa, Hawai‘i is one genotype and Oʻahu and Kilauea, Hawai‘i is another genotype. Maui and Molokaʻi contain both genotypes. Incipient speciation or existence of cryptic species of O. hookeri can be ruled out because Maui-Molokaʻi genetic cluster contain both genotypes thus it supports the idea that individu

关键词： life sciences   human genetics   genetics  

ISBN: (数字)9780128142608 ISBN: (纸本)9780128142592

摘要： This volume provides comprehensive information on how mapping an individual’s epigenome can be medically relevant and holds the potential to improve preventive medicine and precision therapeutics at an early-stage (prior to disease onset). In order to advance clinical adoption of the recently developed epigenetic approaches, it is necessary for translational scientists, clinicians, and students to gain a better understanding about epigenetic mechanisms that are associated with a particular disorder; and to be able to effectively identify biomarkers that can be applied in drug development and for better diagnosis and prognosis of diseases. Prognostic Epigenetics is the most-inclusive volume to-date specifically dedicated to epigenetic markers that have been developed for prognosis of diseases, recent advances in this field, the clinical implementation of this research, and the future outlook.

关键词： Bio informatics   Genetics   Genome resequencing   Quantitaive trait loci   Quantitative genetics  

摘要： We are using whole genome resequencing to identify chromosomal regions associated with resistance or susceptibility to ascites, a form of pulmonary hypertension syndrome, meat-type chickens. Previous Genome Wide Association Studies (GWAS) based on Single Nucleotide Polymorphisms (SNPs) have identified regions on chromosomes 2, 9 and Z. Despite several GWAS and further genotyping, there are no reliable or potential markers for ascites phenotype. We have completed screening of Copy Number Variations (CNVs) and Single Nucleotide Polymorphisms in ascites resistant and susceptible birds from the relaxed, REL, line derived from a commercial elite broiler line. DNA samples from resistant and susceptible birds were purified, quantified and pooled in two pools of 10 DNAs from each phenotype for both genders. Eight pools (2 pools x 2 phenotypes x 2 genders) were generated. Each pool was submitted for bar-coded library generation, and 2x125 paired end reads on Illumina HiSeq 2500 and with 66X genome coverage. The sequence reads were mapped onto Galgal5 using Bowtie for initial CNV mapping *** (R package). Further mapping to chromosomes were done using NGen and ArrayStar (DNAStar ver 13). So far, we have identified two potential regions for CNVs and 31 regions for SNPs with potential association with ascites phenotype. CPQ gene on chromosome 2 and LRRTM4 gene on chromosome 22 have been validated for containing ascites QTLs. However, their exact role in ascites is yet to be discovered. Further, we screened the regions from REL line in DNAs from an unrelated commercial broiler line using WGR.