中国医科大学七年制遗传重点.docx

98期七年制Human Development and Geneticsmade by 98k73b题型：1. 单选题 20题，每题1分，共20题单项选择题（只有一个答案），比较简单2. 填空题20空，每空0.5分，共10分E.g.非整倍体形成的原因_, _遗传异质性包括_、多基因病的几条需要背会一级亲属发病率计算从ppt上找原话填空3. 概念题10题，每题2分，共20分每章重点 单体型的概念4. 简答题4题，每题5分，共20分基因治疗的策略、Lyon假说的5. 综合分析题3题，每题6、6、8分，共20分e.g. 间接基因诊断的方法（pku血友病）、系谱分析（给描述画图给系谱让你分析）（分析遗传类型、为什么是这种遗传类型、写基因型、算发病率、）用所学过的知识解释某个现象，镰状细胞贫血，设计实验方案找出变异，甲和乙都是聋哑但后代没有解释为什么，肿瘤二次突变（视网膜母细胞瘤为什么又遗传性和非遗传型），结肠息肉到结肠癌 （多阶段多步骤）6. 整合分析题1题，每题10分，共10分染色体病遗传学、生殖内分泌、胚胎发育三个角度解释这种症状Chapter 1 头两个很重要Definition: medical genetics, genetic disorder医学遗传学（概率大）遗传病Characteristics and classification of genetic disorders 分几类 每一类要能写出几种病Landmarks in medical genetics 选择题知道名字 比较重要的Aim of Human Genome Project 填空题基因组测序的两种技术的名字Two genome-sequencing strategiesImportant events in HGPChina Contribution to HGPChapter2 第一页ppt 考点多Definition: gene, genome, gene family, pseudogene, split gene, GT-AG rule, flanking sequence, cis-acting element, trans-acting element, mutation, frameshift mutation, dynamic mutation, probe, recombinant DNA, vector, DNA libraryClassification of chromatinX-chromatin and Y-chromatine.g.XY都在哪 内缘、里面 怎么检测 几个X几个Y X兼性异染色质（易考X）Regulation mechanism of epigeneticsChapter 2 第二页pptNuclear genome and mitochondrial genome Basic structure of DNA and its biological significanceClassification of repetitive sequenceCharacteristic of eukaryotic structural geneRNA processingTypes of gene mutationMethods of probe labelingSouthern Blotting, Northern Blotting, ASO真核生物结构基因的特点 （简答）DNA结构特征和生物学意义（简答）基因突变的类型探针标记有一年考过简答 方法Southern等技术考名字Chapter2 第三页pptRestriction endonuclease: nomenclature, recognition sequence, restriction fragmentsCharacteristic of vector and common cloning vectorFour essential steps of cell-based DNA cloningMain types of DNA libraryPCR: principle, steps, reaction system, application, advantage and disadvantagePrinciple of Sanger sequencing载体 片段的长度 谁大谁小 大的用谁小的用谁细胞DNA克隆四步 选择题 考顺序DNA文库的主要类型 基因组文库和cDNA 文库PCR是给案例考方法测序的原理Chapter3Definition: meiosis, Homologous chromosome, SynapsisGenetic affairs in Meiosis ISignificance of MeiosisSpermatogenesis and oogenesis减数分裂 所发生的遗传事件和细胞遗传学基础 相当于减数分裂的意义和I期的重要遗传事件第六章 生殖内分泌 两个概念都考Definition: Decidua, Disorder of sex development (DSD)Fetal MembranesPlacenta: Development, component, circulation, function and anomalySources of Amniotic FluidChromosomal basis of sex determinationEmbryology of the reproductive systemCommon types of disorders of sex developmentChapter7 重点看Definition: karyotype, Robertsonian translocation, X-chromation, Y-chromatin, marker chromosomeChromosome morphology and Chromosome bandingChromosome nomenclature and karyotype descriptionFISH and its probesEuploidy (triploid and tetraploid) and aneuploidyStructural abnormality: symbols and abbreviationsAutosomal chromosome disorders (Down syndrome, Edwards syndrome, Patau syndrome, Cri du Chat syndrome): names, clinical features, karyotypesSex chromosome disorders (Klinefelter Syndrome, Turner Syndrome, Fragile X Syndrome): names, clinical features, karyotypesLyon hypothesis: Key points and exceptions结构异常 知道符号都代表什么意思数目异常产生的原因 整倍体非整倍体产生的原因染色体 21三体 性染色体综合征clinyfea 和Turner综合征 年年都考知道临床表现、核型分类、嵌合型 怎么诊断、 （做核型分析）Leon假说简答题第八章 Definition: single-gene disorders, locus, alleles, homozygote, heterozygote, compound heterozygote, double heterozygote, genotype, phenotype, pedigree, proband, codominance, multiple allele, penetrance, variable expressivity, genetic imprinting, anticipation, carrier, consanguinity, coefficient of relationship, genetic heterogeneity, cross inheritance, hemizygote, holandric inheritance, functional cloning, positional cloningPedigree analysisFeatures of AD, AR, XR and XD inheritanceAtypical patterns of AD inheritanceABO blood groupReasons for irregular dominanceDelayed dominance, anticipation, genetic imprinting and dynamic mutationConsanguineous matingTypes of genetic heterogeneity系谱分析 最容易考显性遗传病种类 填空 延迟显性、动态突变、早现遗传、遗传印记 密不可分不规则显性的原因遗传异质性概念常隐 近亲婚配 亲缘系数算发病率第九章Definition:1. Molecular disease：disease caused by abnormality of protein quantity or protein quality due to gene mutation.分子病是基因突变导致蛋白质分子质和量差异，从而引起机体功能障碍的一类疾病。2. Hemoglobinpathy：disease caused by abnormality of globin structure or synthetic quantity due to gene mutation or deletion. disorders of the structure or synthesis of hemoglobin (Hb)血红蛋白病 是指由于珠蛋白分子结构或合成量异常所引起的疾病。3. abnormal hemoglobinpathy：structural disorders of hemoglobin (Hb) due to mutation of globin gene.异常血红蛋白病：是指由于珠蛋白基因突变导致珠蛋白肽链结构异常。4. thalassemia：diseases of hemoglobin synthesis in which mutations reduce the synthesis or stability of either the -chain or -chain, resulting in imbalance in the ratio of the : chains and hemolytic anemia地中海贫血，由于珠蛋白基因缺失或突变导致某种珠蛋白的链合成障碍，造成链和链合成失去平衡而导致的溶血性贫血。Types, developmental expression and genetic control of hemoglobin1.Types:见下图2. developmental expression:3. genetic control：Molecular basis of abnormal hemoglobinpathy 异常血红蛋白的分子基础1. Individual base substitution 单个碱基置换2. Frameshift mutation 移码突变3. Insertion and deletion of codon密码子的缺失和插入4. Fusion gene 融合基因*Types and clinical features of a-thalassemiaSilent静止型 aa-thalassemia ，delete 1 aa- geneMild 轻型aa-thalassemia， delete 2 aa- geneHb H 血红蛋白H病， delete 3 aa- geneHb Barts hydrops fetalis syndrome Hb Barts胎儿水肿综合征，delete 4 a- gene*Molecular basis of b -thalassemia b地中海贫血的分子基础1. Coding region mutation编码区突变2. Non-coding region mutation非编码区突变3.Promoter region mutation启动子区突变4.RNA cleavage signal mutation RNA裂解信号突变5.Cap site mutation 加帽位点单个碱基突变Inborn errors of metabolism: names, enzymes, inherit patternDiseaseEnzymeinheritanceamino acid metabolismPhenylketonuria, PKUPhenylalanine, PAHARAlcaptonuriaHomogentisic acid oxidasecarbohydrate metabolismGalactosemiaGPUTGlycogen Storage DiseasesGSD-1G6PLipid storage diseasesGaucher DiseaseglucocerbrosidaseTay-Sachs DiseaseHexasaminidase Apurine metabolismLesch-Nyhan syndromeHGPRTXRreceptor proteinsFamilial Hypercholesterolemia , FHLDL receptor on cell membraneADG6PD deficiencyG6PDFunctional types of LDLR mutation1.synthesis2.transfer from ER to Golgi3.binding of LDL4.clustering in coated pits5.recyclingHb A, Hb F, Hb H, Hb M, Hb S组成见前面特殊的五个血红蛋白 原因 临床表现 基因型 后代发病的可能是多少 分离率和自由组合率新陈代谢缺陷糖脂和氨基酸代谢 病的名称、缺什么、遗传方式第十章 Definition: 1. Population, group of organisms of the same species living in the same geographical area.2. Population genetics, study of distribution of genes in populations and of the factors that maintain or change the frequency of genes and genotypes from generation to generation.3. Consanguinity, marriage between blood relatives who have at least one common ancestor no more remote than a great-great-grandparent.近亲婚配：即有共同祖先血缘关系的亲属之间的婚配。4. Inbreeding coefficient, the probability that a son or a daughter has inherited two same alleles from a common ancestor.近婚系数：近亲婚配中的二人，他们可能从共同祖先继承到同一基因，婚后又可能把同一基因传递到他们子女，这样，子女的这一对基因就是相同的。近亲婚配使子女得到这样一对相同基因的概率，称为近婚系数。5. Biological fitness (f) , the ability of an individual who can survive and transmit genes to the next generation in a population. It is often measured by relative fertility.适合度：是指一定环境条件下，某一基因型个体能够生存并将基因传给后代的相对能力。6. Selection coefficient (s), a measure of the loss of fitness and is defined as 1-f.选择系数 指在选择作用下适合度降低的程度，用s表示。S反映了某一基因型在群体中不利于存在的程度，因此s=1-f7. Heterozygote advantage, for some AR disorders, heterozygotes show a slight increase in biological fitness compared with unaffected homozygotes.杂合子优势：对于某些常染色体隐性遗传病，杂合子比正常纯合子具有更高的适合度，称之为“杂合子优势”。8. founder effect, high frequency of a particular allele in a population because the population is derived from a small number of founders, one or more of whom carried that allele.建立者效应：可能由于某种偶然因素使该小群体存在某些隐性突变基因携带者，在逐代传递中该基因的频率高于原来的整个群体；也可能出于偶然，某等位基因不可传递而消失，仅有另一等位基因，这种机制称为建立者效应。9. Genetic shift, random fluctuations in gene frequencies, most evident in small populations.在小群体中可能出现后代的某基因比例较高，在一代代传递中基因频率明显改变，破坏了Hardy-weinberg平衡，这种现象称之为随机遗传漂变。10. Gene flow, gradual diffusion of genes from one population to another, as a result of migration and intermarriage.基因流：等位基因跨越种族或地界的渐近混合称之为基因流。11. Genetic load, the relative decrease in the average fitness due to the existence of deleterious gene in a population.n Mutation load the relative decrease in the average fitness due to the deleterious or lethal gene mutation.n Segregation load the relative decrease in the average fitness due to the homozyous offspring (aa) of two heterozygous parents (Aa).遗传负荷是由群体中导致适合度下降的所有有害基因构成，遗传负荷主要有突变负荷和分离负荷，受近亲婚配和环境因素影响。*12. Genetic polymorphism: the existence of two or more variants (alleles, phenotypes, sequence variants, chromosomal variants) at significant frequencies in the population, and the rarest ones could not be maintained by mutation alone.遗传多态性：指在一个群体中存在由遗传决定的两种或两种以上的基因型或变异型，其中频率最低的形式也远远高于依赖突变所能维持的频率。对于同一基因座上的两个或两个以上的等位基因，等位基因频率至少为0.01，携带该等位基因的杂合子频率大于2%，则认为该基因座具有多态性。*Hardy-Weinberg equilibrium: condition, content and application简答题1. Hardy-Weinberg equilibrium contentA fundamental principle in population genetics stating that the genotype frequencies and gene frequencies of a large, randomly mating population remain constant provided immigration, mutation and selection do not take place.在一个大群体中，如果是随机婚配，没有突变，没有自然选择，没有大规模迁移及基因流，群体中的基因频率和基因型频率在一代代传递中保持不变。2. Conditions 条件Large population 大群体Random mating 随机婚配No selection 没有自然选择No new mutation 没有突变No migration 没有大规模迁移3. Application 应用 出小的计算题 书上Determine whether a population is in Hardy-Weinberg Equilibrium or not.Determine allele frequency and heterozygote carrier frequency in a population for which the frequency of a trait is known.*Factors that disturb Hardy-Weinberg equilibrium(1) Nonrandom mating (2) Selection(3) Mutation(4) Small populations(5) Gene flow (migration)*Calculate the inbreeding coefficient, Biological fitness (f) and selection coefficient (s)Types of genetic load 遗传负荷的种类1. Mutation load-the relative decrease in the average fitness due to the deleterious or lethal gene mutation.突变负荷是遗传负荷的主要部分，是由于基因的有害或致死突变而降低了适合度，给群体带来的负荷。突变负荷的大小取决于突变率（）和突变基因的选择系数（s）。2. Segregation load-the relative decrease in the average fitness due to the homozyous offspring (aa) of two heterozygous parents (Aa).分离负荷是指由于杂合子（Aa）和杂合子（Aa）之间的婚配，后代中有1/4为纯合子（aa），其适合度降低，因而导致群体适合度的降低，造成遗传负荷增加；如果纯合子（aa）的选择系数大，适合度降低越明显，群体遗传负荷的增加越显著。Types of genetic polymorphism 遗传多态现象的类型*(1) DNA polymorphism(SNP、RFLP、VNTR)RFLP (Restriction fragment length polymorphism)VNTR (variable number of tandem repeat)SNP (single nucleotide polymorphism)(2) Chromosome polymorphism(3) Protein polymorphism transferrin (4) Enzyme polymorphismisoenzyme (5) Antigen polymorphism HLA相对。选择系数 出填空、选择 近婚系数会算多态和基因诊断在一起第十一章Definition: 1. Susceptibility: genetic factors which influence the development of a multifactorial disorder.在多基因遗传病中，若干作用微小但有累积效应的致病基因构成了个体患某种病的遗传因素，这种由遗传基础决定一个个体患病的风险称为易感性。2. Liability: genetic and environmental factors which influence the development of a multifactorial disorder together.由遗传因素和环境因素共同作用并决定一个个体是否易患某种疾病的可能性则称为易患性。3. Heritability: the proportion of the total liability that is caused by additive genetic factors.遗传度：是指多基因的累加效应对疾病易患性的作用大小，一般用百分率表示。4. Threshold: minimal liability which cause a multifactorial disorder.这种由易患性决定的多基因遗传病发病的最低限度称为阈值。Characteristics of quantitative trait and qualitative trait多基因遗传的性状由多个基因和多个环境因素相互作用而产生的，通常为数量性状（quantitative），而不是质量性状(qualitative)，在群体连续分布，常近似正态分布（normal distribution）Common polygenic diseaseHypertensionDiabetes mellitus SchizophreniaAsthma Autism Parkinson diseaseThe liability/threshold model易感性、易患性、遗传度、阈值的定义及阈值模式的相关分布图。*Predictions regarding recurrence risks for polygenic disease多基因遗传病再发风险的预测 （易考简答）1.The recurrence risk for polygenic inheritance is related to the heritability. 多基因遗传病的发病风险与遗传度密切相关2. Recurrence risks represent average risks and will vary among different families. 再发风险代表平均风险，在不同家庭中各不相同3. The recurrence risk is higher if more than one family member is affected.患病风险岁受累亲属数目的增加而增高4. If the expression of the disease in the proband is more severe, the recurrence risk is higher. 多基因病患者的并且越重，其亲属患病风险越高5. If the population incidence is much lower, the recurrence risk is much higher. 某种疾病随着群体发病率的降低，患者亲属的患病风险增加6. The recurrence risk is higher if the proband is of the less commonly affected sex.当某种多基因病的发病率有性别差异时，发病率低的性别，其后代发病的风险相对较高；发病率高的性别，其后代发病的风险相对较低。第十二章Definition: 1. Oncogene, is an activated proto-oncogene that contributes to neoplastic transformation.癌基因是指能够使细胞发生癌变的一类基因。2. proto-oncogene, is the normal cellular homologue of an oncogene that is generally involved in the control of cell growth.原癌基因是正常细胞生产发育所必需的，并具有使细胞癌变的潜能。3. tumor suppressor gene, （TSG） are a class of genes that control cell division and thus help to prevent tumors.肿瘤抑制基因是指在正常细胞中存在的，对细胞的生长、分裂和发育起负调控作用的一类基因。4. double minutes, amplified segments of DNA existing outside of the chromosome as separate small fragments. DMs当扩增的DNA片段从染色体上被释放为独立的小片段并连在一起时常形成双点样形状叫做双微体。5. homogeneously staining region, a cytogenetically detectable expanded region in a chromosome resulting from many fold amplification of a discrete segment of DNA.当扩增的DNA插入一条染色体时，则形成均质染色区。6. loss of heterozygosity, loss of one allele in a tumor cell from a chromosomal region for which the individuals normal cells are heterozygous.肿瘤细胞的杂合性等位基因（或遗传多态标记）中的一个丢失，称作杂合性丢失。7. mismatched repair gene错配修复基因 编码一类检测DNA复制过程中发生的碱基错误配对并将其纠正的修复系统，这些基因的异常大大提高而基因的突变率Cancer family and familial carcinoma 癌家族和家族性癌1. Cancer family: 癌家族High incidence Higher incidence in a special tumor Multiple tumorsEarlier ageAD inheritancee.g. Lynch Syndrome Li-Fraumeni Syndrome2. Familial carcinoma: 家族性癌Same carcinoma in members of a familyHigher genetic susceptibility to carcinomaHigher incidence in first degree relativesUncertain inheritance patternFamilial tendency*Examples of chromosome instability syndromes染色体不稳定性综合征的例子, hereditary cancer 遗传性肿瘤and hereditary precancerous lesion 遗传性癌前病变1.Chromosome instability syndromes: 染色体不稳定性综合征的症状 AR inheritance 常染色体隐性遗传病 Defects in DNA repair system DNA修复系统缺陷 Chromosome instability 染色体不稳定 Predisposition to leukemia 易患白血病Examples: Fanconi Anemia Fanconi 贫血Bloom syndrome Bloom 综合征Ataxia Telangiectasia 毛细血管扩张性共济失调Xeroderma Pigmentosum 着色性干皮病2. Hereditary cancer: 遗传性肿瘤的特征 bilateral双侧发生 multiple多发 Derived from nervous or embryonic tissue Earlier age Malignant tendency AD inheritance Examples: Retinoblastoma视网膜母细胞瘤Nephroblastoma 肾母细胞瘤Neuroblatoma 神经母细胞瘤3.Hereditary precancerous lesion: 遗传性癌前病变的特征AD inheritance 常染色体显性遗传病Malignant tendency 癌变趋势Examples: Familial Polyposis Coli 家族性结肠息肉 FPCNeurofibromatosis I型神经纤维瘤Basal Cell Nerves Syndrome 基地细胞痣综合征*Ph 1 chromosome and 14q+ chromosome 费城染色体和14q+染色体的形成和临床意义1.Ph染色体Ph染色体是22号染色体长臂缺失形成的，缺失的部分易位至9号染色体长臂末端，是一种相互易位。约95%慢性粒细胞白血病患者具有Ph染色体，可作为该病的诊断依据。有时Ph染色体先于临床症状出现，可用于产前或症状前诊断。Ph1 chromosome: Found in CML patient (95%) G group chromosome acrocentric chromosome found in Philadephiat(9;22)(q34;q11)Chimeric BCR-ABL protein transforming activity ABL (Abelson) proto-oncogene on 9qBCR (breakpoint cluster region) on 22q2.14q+染色体长臂增长的14号染色体即14q+，是8q24和14q32相互易位的结果。14q+染色体可作为Burkitt淋巴瘤的诊断依据。14q+ chromosome: Found in BL patient (75%) longer 14q t(8;14)(q24;q32) MYC proto-oncogene on 8qImmunoglobulin heavy-chain locus on 14qActivating overexpression of the MYC gene by the enhancer (E) of COncogenes: functional classification, activation mechanism癌基因功能的分类和原癌基因激活机制1.癌基因的功能分类Types of oncogene growth factor growth factor receptor Intracellular signal transduction factors DNA-binding nuclear protein Cell-cycle factors*2.原癌基因激活机制Activation Mechanism of Oncogene1）Promoter insertion2）Point mutation3）Amplification Double minutes Homogeneously staining region4）Chromosome translocation Chromosomal rearrangement creating a novel chimeric gene Translocation to a region of transcriptionally active chromatinDiscovery of tumor suppressor genes1.细胞融合实验Cell fusion2.家族性视网膜母细胞瘤的研究Familiar Retinoblastoma3.杂合性丢失Loss of heterozygosity (LOH)4. Familial Cancers *Tumor and cell cycle dysregulation 肿瘤发生与细胞周期调控1.肿瘤细胞经历细胞周期的过程易受G1-S检查点、G2-M检查点和纺锤体检查点(G1-S checkpoint, G2-M checkpoint, Spindle checkpoint)Progression through the cell cycle is controlled by cyclins and cyclin dependent kinases (CDKs) and regulated at a series of checkpoints.2.三个关键的肿瘤抑制基因RB、TP53和CDKN2A在肿瘤发生中处于核心地位Three Key TSGs (RB, P53 and CDKN2A) Control Events in G1Single clone origin hypothesis*随肿瘤的发展也可以演变为多克隆，其中占主导地位的克隆，就构成干系（stem line），干洗的染色体数目称为众数（modal number）。占非主导地位的克隆称为旁系（side line）。干系和旁系的地位可以相互转变。*Knudsons two-hit hypothesis 为什么同一种肿瘤有遗传型和非遗传型之分Familial tumor: germline mutation + somatic mutationSporadic tumor: somatic mutation + somatic mutation*很重要！Multi-stage evolution of a tumor (colon cancer)1. Loss of the APC gene transforms normal epithelial tissue lining the gut to hyperproliferating tissue. 2. Hypomethlyation of DNA (which can cause genomic instability and up-regulate proto-oncogenes), activation of the KRAS proto-oncogene, and loss of the DCC gene are involved in the progression to a benign adenoma. 3. Loss of the TP53 gene and other alterations are involved in the progression to malignant carcinoma and metastasis.*肿瘤发生因素1.肿瘤发生的环境因素Environmental factor化学致癌物Chemical Carcinogens:Cigarette smoking lung cancerAflatoxin