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1、Chapter 1 绪论绪论 第一部分第一部分 Heredity： A procedure that living things duplicate themselves in a model similar to their parents Stability of living things Variability： The differences of individuals resulted from genetic recombination, environmental modification and genetic mutation Diversity of living th
2、ingsGeneticsA SCIENCE concerned with variation and heredity in living organisms Gene: The fundamental physical and functional unit of heredity, which carries information from one generation to the next Allele: One of the different forms of a gene pair. At each autosomal locus an individual possessed
3、 two alleles, one inherited from mum and one from dad. Genotype: The combination of alleles that an individual possesses. Phenotype : The physical characteristics of a cell or organism as defined by its genetic constitution Linkage: The association of genes on the same chromosome. Recombination : Th
4、e exchange of corresponding chromosome parts between homologous chromosomes by breakage and reunion 第二部分第二部分 Genes are arranged on chromosomes linearly. During meiosis Alleles locating in the same loci of the homologous will be segregated with the homologous moving to the different gametes. The gene
5、s in the different non-homologous are independently assorted. The genes in the same chromosomes are linked, which will move together. The non-alleles in the pair of the homologous might be recombined due to the cross-over occurring between the homologous. 第三部分第三部分The principle of segregation A physi
6、cal characteristic of a organism is determined by a pair of genetic factors, which is either dominant or recessive. The pair of factors segregate from each other during the gamete formation.The principle of independent assortmentThe factors determined for different characteristics will be independen
7、tly assorted during the gamete formation Principle of linkage and crossoverA group of genes are arranged on a chromosome linearly. They will move together with the chromosome and might be recombined due to the cross-over occurring between the pair of homologous chromosomes during meiosis. 第四部分第四部分 G
8、enetic disorder or inherited disease: The diseases caused by human chromosomal aberration or DNA mutation Chromosome disorders Duplication or deletion of the certain chromosomes or the certain chromosomal segments Number abnormality Structure abnormality Single-gene disorder Caused by single gene mu
9、tationMendel disease Transferred in pedigree Autosomal or sex chromosomal Dominant or recessive Mitochondrial genetic disorder The mutation is in the encoding regions of mitochondrial DNA Single gene mutation Transmit with mitochondrial DNA - Maternal transmittingPolygenic disorderResulting from com
10、plex functions of both multiple genes and multiple environmental factors Family history, but incidence is much lower than Mendels model Somatic cell genetic disorder Accumulating results of changes of multiple genes and environmental factors in a certain duration. Mutations normally limited in somat
11、ic cells Mutation transmitted by mitosisChapter 2 基因基因 Gene: a DNA segment,a basic unit of heredity Chemically: A specific DNA segment, containing the code for the amino acid sequence of of a polypeptide chain. In physics: Arranged on chromosome linearly, can be exchanged and transmitted to the next
12、 generation. Functionally: Controlling the expression of specific characteristics of a living organism. PromoterDNA sequences clustered around start site of transcription (5 region) specifically recognized by RNA polymerase and promoting the gene transcriptionEnhancer Promoter-specific- Tissue-speci
13、fic A DNA sequence enhancing the promoter function Located in either upstream or downstream of start site, 3Kb or moreBoth 53or 35dirctions Function on both the genes in upstream and downstream. Terminator The end of downstream of gene Terminate the transcription of RNAComposed of a reversed repetit
14、ive sequence and specific 5-AATAAA-3 Gene FusionTwo different genes are fused resulted from recombination of DNA fragments Genome Total genetic information in a living organism. Total genes in a haploidy set of chromosomes with the mitochondrial DNA.Structural geneGenes directing the synthesizing pr
15、oteins Chapter 3 染色体染色体Chromatin is the basic components in the cell nucleus Composed of DNA, histone and non-histone protein Euchromatin: Slightly and evenly stained, non- or low-repetitive DNA regions Heterochromatin: Darkly and unevenly stained, highly repetitive DNA regions Fluorescence In Situ
16、Hybridization（FISH） Using DNA probe labeled with a certain marker Hybridizing with DNA in chromosomes and nuclei on slides Probes hybridized with the fragment in chromosome are detected by signals from the labeled markers （Rapid mapping of genes and sequences in chromosome Detecting small fragment i
17、n interphase. Detecting cryptic rearrangements or small deletions Banding could not be detected 2 relatively common allelesGenotype: the set of alleles Phenotype: the observable expression of a genotypeHomozygote: a individual with identical allelesHeterozygote: a individual with different allelesHe
18、mizygote: a individual with an allele on X chromosome, but no corresponding loci on the Y chromosome.Pedigree: A simplified diagram of a familys genealogy that shows family members relationships to each other and how a particular trait or disease has been inherited.Proband: The family member who fir
19、st bring a family to the attention of an investigator is probandCarrier: a person who has a recessive mutated gene, together with its normal allele. Carriers do not usually develop disease but can pass the mutated gene on to their children.Pleiotropy（多效性）（多效性）: one gene, more than one effect Genetic
20、 heterogeneity 异质性异质性: the same phenotypic changes resulted from different mutations at the same locus(allelic ) or mutation at the different loci(locus ) Expressivity（表现度）（表现度）: the severity of phenotype expressionPenetrance（外显率）（外显率）: the probability of a gene expressionConsanguineous marriage （近亲
21、婚配）（近亲婚配）: couple with common one or more ancestorGenetic imprinting（基因印记）（基因印记）: a gene expression depends on whether the allele has been inherited from the father or from the mother Anticipation（遗传早现）：（遗传早现）：increasing severity or decreasing onset age of the genetic disorders in successive generat
22、ions Other factors affecting pedigree patterns Onset age Pleiotropy: one gene, more than one effect Genetic heterogeneity Expressivity and penetranceCoefficient of relationship and consanguineous marriage Sex-limited phenotypes and sex-influenced phenotypesgenetic imprinting Anticipation X inactivat
23、ionAutosomal Dominant The trait appears in every generation Any child of an affected person has a 50 percent risk of inheriting the trait. Unaffected family members do not transmit the trait to their children The occurrence and transmission of the trait are not influenced by sex Autosomal RecessiveT
24、he trait characteristically appears only in sibs, not in their parents. Offspring or other relatives.On the average, one fourth of the sibs of the proband are affected; in other words. The recurrence risk is one in four for each birth.The parents of affected child may be consanguineous. Males and fe
25、males are equally likely to be affected.There are many small groups in which the frequency of certain rare recessive genes is quite different from that in the general population. X-linked Recessive- The trait is passed from an affected man through all his daughters to, on the average, half their son
26、s.The incidence of the trait is much higher in males than in females.The trait is never transmitted directly from father to son.The trait may be transmitted through a series of carrier females; if so, the affected males in a kindred are related to one another through females.Carriers show variable e
27、xpression of the trait. X-linked dominant inheritance Affected males have no normal daughters and no affected sons. Affected heterozygous females transmit the condition to half their children of either sex. Affected females are more common than affected males, but as they are almost always heterozyg
28、otes they usually have milder (but Variable) expression. Y-linked Disorders they are always passed from father to son, and they never appear in females Chapter 5 多基因病多基因病Qualitative trait (discrete trait): A genetic disease trait that either present or absent Monogenic disease, Blood types Quantitat
29、ive trait (continued variation ): are measurable characteristics such as height, blood pressure, serum cholesterol, and body mass index Characteristics of Inheritance of Complex Diseases Not single-gene disorders and do not demonstrate a simple Mendelian pattern of inheritance Demonstrate familial a
30、ggregation, because relatives of an affected individual are not likely to have disease-predisposing alleles in common with the affected person than are unrelated individuals Pairs of relatives who share disease-predisposing（疾病倾向的）（疾病倾向的）genotypes at relevant（相关）（相关）loci may still be discordant（不一致）（
31、不一致）for phenotype (show lack of penetrance) because of the crucial(至关紧要的至关紧要的) role of nongenetic factors in disease causation(原因原因). The most extreme examples of lack of penetrance despite identical genotypes are discordant monozygotic twins (MZ) The disease is more common among the close relatives
32、 of the proband and becomes less common in relatives who are less closely related. Greater concordance for disease is expected among MZ versus dizygotic twins (DZ) Linkage Analysis is more difficult in multifactoral conditions than in single-gene disorders: A,Variants in more than 1 gene are likely
33、to contribute to the disorderB,The number of affected persons within a family is likely to be fewer than for a single-gene disorders C,The mode of inheritance is usually uncertain D,Some multifactorial disorders are likely to have more than 1 etiology(病因，病源病因，病源) E,Many multifactorial conditions hav
34、e a late age of onsetChapter 6 群体遗传学群体遗传学Mendelian populationAn interbreeding population of sexually reproducing individuals sharing a common gene pool. Gene pool : the genetic constitution of a population of a given organism.(All the genes of all the individuals in population make up the gene pool.
35、) Genotypes: the genetic constitution of a single individual. Gene frequency (allelic frequency): the frequencies of the members of a pair of allele genes in a population. Phenotype frequencyHardy Weinberg EquilibriumStates the relationships between the frequency of alleles at a locus, and the genot
36、ypes resulting from these alleles. Hardy-Weinberg equilibrium implies that gene and genotype frequencies are constant from generation to generation. If disequilibrium occurs, equilibrium will be reestablished after one generation of random mating. H-W law rests on several assumptions: 1.large popula
37、tion 2.random mating 3.no mutations 4.no migration between populations 5. no selection - all genotypes reproduce with equal success Exceptions to Hardy Weinberg Assumptions A Migration introduction / loss of alleles B Mutations may occur at different frequency in different populations C Small popula
38、tion size- genetic isolate / founder effect D Non-random mating 1- consanguinity 2-assortative mating(=non-random mating) Hardy-Weinberg equilibrium lawIf two alleles at a gene - A and a 1. frequency of the A allele = p 2. frequency of the a allele = q 3. The two fractions add up to totality p + q =
39、 l 4. the proportions of the three genotypes: AA, Aa and aa are p2: 2pq : q2 5. Hardy-Weinberg formula: p2 (AA) + 2pq (Aa) + q2 (aa) = 1 Changes in Allele Frequency Can be caused by: mutation (source of genetic variation) selection (phenotypes differ in biological fitness)(deleterious mutations may
40、be removed by early death / lack of reproduction) migration (movement in or out) F(Fitness) - the ability to contribute to the gene pool of the next generationS(selective coefficient) Heterozygote Advantage eg. Sickle cell anemia. Mutant allele has a high frequency despite reduced fitness in affecte
41、d individuals. Heterozygote has increased fitness over both homozygous genotypes Genetic DriftFluctuation in allele frequency due to chance in a small population. Founder Effect if an original member of a sub-population has a rare allele, it may become common in the sub-population (high carrier freq
42、uency), resulting in high frequency of rare disease. Consanguinity/Inbreeding when an individuals parents have one or more common ancestors, identifiable from a pedigree (or archival records)- because of genetic isolate, cultural practice, assortative mating-Increased likelihood of q 2Chapter 7 线粒体基
43、因遗传线粒体基因遗传Mitochondrial genome +Small (16.5 kb) circular DNA +1 gene/0.45 kb +Very few repeats +Heavy and Light strands +No introns +93% coding Special features of mitochondrial genetics +Maternal Inhertance +Heteroplasmy +Replicative Segregation +Threshold Expression +High Mutation Rate Homoplasmy
44、originally, it studies the effect exerted on drug ADMET (absorption, distribution, metabolism, excretion, repairing DNA damage and maintaining genomic integrity. LOH (loss of heterozygosity)杂合性丢失杂合性丢失Loss of a normal allele from a region of one cs of a pair,allowing a defective allele on the homolog
45、ous cs to be clinically manifest.A feature of many cases of retinoblastoma,breast cancer,and other tumors due to mutation in a TSG. “Two-hit” hypothesis: Knudson,1971. This explains why hereditary retinoblastoma usually has an earlier age of onset and exhibits bilateral（双侧性）（双侧性） or multifocal（多发性）（
46、多发性） occurrence more often than sporadic retinoblastoma. “You are only one and they are so many. You must work day and night, or else you will be crushed like a roach!” -Gunter Blobel (1999) The best prescription is knowledge !Chapter 12 遗传诊断遗传诊断 RE : recognize specific base sequences in double-heli
47、cal DNA and cleave at specific places.PCR3 steps:Denature, renature (annealing), extension Recombinant DNAAny DNA molecule formed in vitro by joining DNA fragments from different sources. Commonly produced by cutting DNA molecules with restriction enzymes and then joining the resulting fragments fro
48、m different sources with DNA ligase. Plasmid:质粒质粒 Small,circular extrachromosomal DNA molecule capable of autonomous replication in a cell. A library is a set of cloned fragments together representing the entire genome (genomic library) or all the expressed genes (cDNA library).DNA microarrays (gene chips)with the appropriate computerized software allow rapid,automated high-throughput DNA sequencing and mutation detection.Prenatal Diagnosis