ژنتیک 1

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What Is Medical 22222?Genetics Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders, counselling people with genetic disorders, gene therapy, personalized medicine and predictive medicine. 

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NH, 9 1 c N Ave Wy \ HH ¢ cia An ‏وت‎ ‎" "۷ Guanine 8 HAN Thymine (DNA) Pyrimidines © Late 1800s: Albrecht Kossel determines that DNA contains the four nitrogenous bases: adenine, guanine, cytosine, and thumina 4 é S AN EN, wee SG Hc2 , SCH ‏ما‎ 9 ‏سید‎ N N "۷ ۳ Pyrimidine Purine 

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©» 1920s: Phoebus Aaron Levine discovers that DNA consists of repeating units, Purine or each consisting of a sugar, a phosphate, ee ‏ا‎ and a nitrogenous base. pyrimidine Pentose 

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OH H OH H OH H ‏به‎ Nucleotide: Deoxyadenylate Deoxyguanylate Deoxythymidylate Deoxycytidylate (deoxyadenosine (deoxyguanosine (deoxythymidine (deoxycytidine 5'-monophosphate] 5/-monophosphate) 5'-monophosphate) 5'-monophosphate) Symbols: A, dA, dAMP G, dG, dGmP 7 ۵7, ۴ > ‏فال‎ ‎Nucleoside: Deoxyadenosine Deoxyguanosine Deoxythymidine Deoxycytidine Deoxyribonucleotides 

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OH OH Cytidylate (cytidine 5’-monophosphate) c, CMP Cytidine OH OH Uridylate (uridine 5’-monophosphate) u, UMP Uridine OH OH Guanylate (guanosine 5’-monophosphate) G, GMP Guanosine Ribonucleotides OH OH Nucleotide: Adenylate (adenosine 5’-monophosphate) ‘Symbols: A, AMP Nucleoside: Adenosine 

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Determining the 3-dimmensional structure of DNA 1947: William Ashbury begins studying DNA structure using X-ray diffraction. 1951-1953: Rosalind Franklin, working in Maurice kins’ lab, obtains higher resolution James D.' Watson Francis Crick; lg ER 0 exes ee Adel of DNA structure. Deduced the structure DNA using evidence from Chargaff, Franklin, and others. Proposed a double helix olecule has a diameter of 2nm and makes a icture 

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Aform Bform Zform 

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Left handed ~18A 12 37A 7 0-2 endo for pyrimidines; 0-3 endo for purines Anti for pyrimidines; syn for purines Right handed ~20 10.5 34A 6 0-2 endo Right handed ~26 11 2.68 20 06-3 endo Helical sense Diameter Base pairs per helical turn Helix rise per base pair Base tilt normal to the helix axis Sugar pucker conformation Glycosyl bond conformation 

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RNA 5’ End DNA s' End وحم Phospho- diester -"O—P—O linkage { 4 

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Thymine Cytosine 

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‘Life cycle of humans | 28 ۳ = Male 2 5 46, XX ‎Kee‏ سانا ‎۱ ‎meiosis ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎meiosis L ۳ mitosis 1 5 ‏د‎ n zygote n @) fertilization ‎ ‎ ‎ ‎ ‎ ‎ 

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Cell division » The cell cycle is a sequence of cell growth and division. > The cell cycle is the period from the beginning of one division to the beginning of the next. lls divide when they reach a certain size hromosomal packaging of DNA allows efficient distribution of genetic material during cell division > Life cycle requires two distinct types of cell division processes: mitosis and meiosis 

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Eukaryotic cell cycle | Stages in cell cycle ‏موم سح‎ Interphase First gap phase (G1) 61 = Growin Synthesis phase (S) 9 17 Mitfsis (involves division of the mitosis chfomosomes) Cytokinesis (involves division of --- Gg = DNA supercoils. e cytoplasm) condense: “machinery” s of mitosis assemble S= DNA ‏م سس‎ replicated 

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Interphase Chromatin » Chromosomes are not clearly discerned in the nucleus, Centrioles although a dark spot called the (Two Pare nucleolus may be visible. e cell may contain a pair of centrioles, both of which are organizational sites for 1 microtubules. 5-5-2 > The cell is engaged in = ‏سم‎ ‎metabolic activity and = performing its prepare for mitosis. Nuclear Envelope 

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Interphase Q Interphase is the longest phase of the cell cycle. Interphase takes 21 ~ hours to complete. rowth of cells) In this part of interphase, a high amount of protein synthesis occur: d the cell grows (to about double jts original size) - more organelles are produced and the volume of the cytoplasm increases. If the cell is not to divide again, it will enter GO nerve, skeletal muscle and red blood lls), G1 takes about 9 hours. 

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Interphase QOS phase (Copying of the DNA) This part of interphase takes roughly 10 hours. OQ G?phase (Preparation for fivision) er the replication of the DNA, e cell resumes its growth in reparation for division. The itochondria divide and the ell continues to grow until itosis begins. In total this part nternhase takes about 2 

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1 = Prophase ° Chromatin in the nucleus begins to | condense and becomes visible in the light microscope as chromosomes. opposite ends of the cell and fibers exjend from the centromeres. me fibers cross the cell to form the totic spindle. 

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۱ Prometaphase | | © The nuclear membrane dissolves, marking the beginning of prometaphase. ° Proteins attach to the centromeres creating the kimetochores. icrotubules attach at the inetochores and the hhromosomes begin moving. 

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1 Metaphase |e Spindle fibers line the chromosomes along the middle of the cell nucleus. This line is referred to as the metaphase ©» Polay’ microtubules extend from the pole to the equator, and ically overlap netochore microtubules tend from the pole to the inetochores is organization helps to ensure t in the next phase, when the 

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i Anaphase The paired chromatids separate at the kinetochores and move to opposite sides of the cell. omatids are pulled by the kinetochore microtubules to the poyes and form a "V" shape otion results from a combination f kinetochore movement along the pindle microtubules and through e physical interaction of polar icrotubules. 

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Telophase | © Chromatids arrive at opposite poles of cell, and new membranes form around the daughter nuclei. © The chromatids disperse and fe no longer visible under the ight microscope. The spindle fibers disperse, and cytokinesis will start. 

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ms ite ۰ Telophase Anaphase Cytokinesis Vesicles filled Vesicles fuse to with cell wall form a growing components cell plate into #Wo uauyuce: ccs, cau with one nucleus. n plant cells, synthesis of new ell wall between two daughter lis rather than cleavage row in cytoplasm. 

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Meiosis ۰ Diploid cells undergo meiosis to form haploid cells. | Two successive nuclear divisions occur, Meiosis I (Reduction) and Meiosis II (Division). 2 I reduces the ploidy level from 2n to n (reduction) while is II divides chromatids of chromosomes in a mitosis-like profess (division). meiosis, homologous chromosomes and chromatids are separated to different daughter cells sis I and meiosis II each include prophase, metaphase, anaphase, 

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The spindle appears. Nuclear envelopes disappear. The DNA of the chromosomes begin to twist and condense, making the DNA visible to the microscope. The two replicated homologous pairs find each other (synapse). The structure formed is referred to as a ‘tetrad’ or ‘bivalent’ (four chromatids). Each bivalent consists of one maternal homologue, and one paternal homologue. The point at which the two non-sister chromatids intertwine is called a chiasma. Sometimes a process known as crossing over occurs at this point. This is where two non-sister chromatids exchange genetic material. This exchange does not become evident, however, until the two homologous pairs separate. رس ۱ 1 Nera ‘The chromosomes condense, and the nuclear envelope breaks down, Crossing-over occurs. 

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jomolog chromatids Crossover point (chiasma) سح Centromere Homologous | (a) 

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=a © © 5 Cantromeres divide. Anuclear envelope forms around Chromatids move to the each set of chromosomes. opposite poles of the cells. The cytoplasm divides. Anew spidle forms around Metaphase Il chromosomes. the chromosomes. line up at the equator. 

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netic terms you need to know 4 Gene. e-untiotheneditys Homologous Chromosomes, * Genome - the entire set 0 Genes, and Alleles att eles - multiple forms 0 = * Chromosome pair: ‏یر‎ ‎۱ ۲ ۲ ~ “homologous ۳ and give rise to differen chromosomes” ‏ا تا هن‎ 1 * pair has genes at the ‏اسر تن‎ referred to as alleles (Wild ‏اما موی‎ — “alleles” * Locus - a fixed location o — may be the same or different ome mooi? 5059 its alleles is located. goneat oss Seinen ‏موس‎ * Homozygous -having ide. particular characteristic. 

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netic terms you need to know * Heterozygous - having two different genes for a particular characteristic. jominant - the allele of a gene that masks or suppresses the expression of an alternate allele; the trait appears in the heterozygous condition. Recessive - an allele that is masked by a dominant allele; does not appear in the heterozygous condition, only in homozygous. Genotype - the genetic makeup of an organisms. 

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Telomere. “iy Centromere X Metacentric ‏سس ار‎ A Acrocentric A Telocentric Qai Telomere: Sister chromatid 

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ereditary Material 2 ( ۰ ۰ ) ew, off ۱ ۲ 1 va 1234 5 6 7 8 9 10111213 1415 16 17 18.19 2021 29 way bos 9,895 ٩ ‏سس‎ ‎a ( a) 1 1 1 * pystfophiit )2: 2141955 ‏م خا‎ ae x (hau ۱ 6 5 SRY (900 bases, 1 exon) ۰ ّ ۱ ‏مسا‎ NAS (= ~60bases,texon) , 1# 41 4 ۷ ٩۸ ‏ب‎ — 2 

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Transcription. mRNA Translation Protein ncRNA Non-coding RNA (98% of the genome) Function Function 

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Regulatory sequence Regulatory sequence Enhancer /silencer Operator Promoter 5'UTR ORF ORF /silencer 1 5 y= = Transcription Protein codingregion Protein coding region Polydstronicoperon سسوم === ‘Translation. Protein 

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Gregor Johann Mendel 160 pEheolegyation > Born in 1822, Son of farn@® ere he studied went to the university of Vienna botany all selfpollination and leammed:thenSientific bt. a So Bani Gears, In forked with putd fake 4 > He tried to-repeat Tid trk in anctild@! Stent, but didn’t work because the plant reproduced asexually! > Work was largely ignored for 34 years, until 1900, when 3 independent botanists rediscovered Mendel’s 

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Mendels Laws of Inheritance Three Laws of Inheritance: 1( The Law of Unit Inheritance. ii) The Law of Segregation. iii) The Law of Independent Assortment. 

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The Law of Unit Inheritance The characteristics (traits i.e. genes) do not blend (mix), but are inherited as units, which might not be expressed in the first generation off-springs, but may appear unaltered in later generations. First Generation Second Generation AR tt L SK Tt Tt pe ‏بي “بمب قب‎ [a Tt TT Tt Tt tt All tall in the first generation. 75% Tall and 25% short in 2"* generation. 

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The Law of Segregation Gamete, Gamete Zygot The two members of a single trait (gene) i.e. alleles, are never found in the same gamete, but ys segregate and to different The failure of two alleles to segregate due to chromosome non- 

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e Law of Independent Assortment * Members of different gene pairs (traits) assort to the gametes independently of one another i.e. random recombination of maternal and paternal chromosomes occur in (3 4 Maternal Paternal Crossing-over ametes 

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e Law of Independent Assortment The exceptions to Law of Independent Assortment (not recognized by Mendel) are closely “linked” genes on the same chromosome, which do not assort independently. 0 ) 0 Maternal Paternal Crossing-over Gametes 

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Pedigr ee A pedigree is a diagram made up of a set of symbols that identify males and females, individuals affected by the trait being studied, and family relationships. 

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Standard symbols used in pedigrees oO Marriage or union Femate Divorced Consanguinity ko - ‏ی>‎ sex unspecified EO 21 ‏ی دق‎ CEP] ‏موس مو‎ SO SR ان اج یت ‎vroct01‏ © هر Twins of unknown zygosity 2 Pedigree with ' LAO | CC aenerations ana = iMdiwviduals numbered امندهناهط مدع ع 8 ‎TE]‏ ‎Miscarriage‏ عل امصتصسيع ‎١‏ عو ومع ‎Adopted inte tamity TCO‏ [50] ‎ID] Adopted out of tamity ‏مب‎ 0 ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ 

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Standard symbols used in Female Sex unknown Individual Affected individual Two or more conditios Muliple individuals Deceased individual 5 ۵۱9۱۱0 ۱5۱ ل له نه لو اؤذلوة وروی و = Stillbirth I م نار ‎Consultant‏ Proband ‏اقا‎ eo ES 

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Standard symbols used in pedigrees Relationship line Breakage Sibship line \ \ \ Line of descent 1 Individua''s line => 

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Organising the pedigree chart Generations are identified by Roman numerals I 0 1 be VU ۳ om 1 ل 

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Organising the pedigree chaxt in each generation are identified by Arabic numerals, numbered from the left. Therefore the affected individuals are II3, IV2 and IV3. 0 0 © ۱۲ 1 Ir 

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Mutations * Permanent changes in the DNA of an organism. * Mutations in the somatic cells (Somatic Mutations) are not transferred to the progeny but are important in the causation of cancer and some congenital diseases. * Germ Cell Mutations Occur in an organism’s germ cells (gametes)- only affect offspring. 

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O Nucleotide Insertions and deletions (Indel) ” Triplet Repeats (Dynamic mutation, include umf ao [une ۳ unequal s: Fragile X ste A (PARI) Kennedy disease (AR) Spinocerebellar ataxia 1 (A Spinocerebeller ataxia 2 (A Machado-Joseph disease/S Spinocerebellar ataxia 6 (C Spinocerebellar ataxia 7 (A Spinocerebellar ataxia 8 (A Spinocerebellar ataxia 10 ( Spinocerebellar ataxia 12 ( ] 17 ( ga 3 Friadreich atasla (XNT) Intron 1 Fragile X site E (AFF2) L_met | arg | tou | stop | [| Promoter ctlopharyngeal muscular, 7# Coding TR, Unvansated rgb. 

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Mutations in Noncoding DNA Y Mutations in promoter sequences, enhancers or other regulatory regions can affect the level of gene expression. 2 Eukaryote promoter Transcribed sequence TRs “Transcription pen eading frame 5 ‏سب لد‎ 3 ‏ات فل‎ - _ t t 1 ~~ See 7 35 ‏مق‎ CAAT—GGGCGG-—— TATAAAA, 

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Splicing Mutations Y Mutations of the highly conserved splice donor (GT) and splice acceptor (AG) sites usually result in aberrant splicing. Y This can result in the loss of coding sequence (exon ipping) or retention of intronic sequence, and may lead to frameshift mutations. Y Cryptic splice sites Y Base substitutions resulting in apparent silent, missense, and nonsense mutations can cause aberrant splicing through mutation of exon splicing enhancer sequences. 

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Sinale chromosome mutations ZWK99024 KEY * Variation in Chrom (aneuploidy, polypl * Chromosome Abno ” Deletions ¥ /Duplications 2» TInversions ” Insertion Y Translocations 

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7 Normal chromosomes 14 t4 210 21 ۴ 8 Fragments lost grea 1414/01 21 Possible gametes 14/21 14/21 21 14 14721 Outcome Normal Normal Down Lethal ‏لان نا‎ balanced rearrangement 

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Pericentric Inversions duplication and deletion risk of approximately 5% to10% for having a child’with viable imfalance. aracentric Inversions acentric or dicentric likelihood that a balanced paracentric inversion will result in the birth of an abnormal aby is extremely low. 

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} FIGURE 3.24 Partial karyotype showing a ring chromosome 9. (Courtesy Meg Heath, City Hospital, Nottingham.) Ring Chromosomes Aring chromosome is formed when a break occurs on each arm of a chromosome leaving two ‘sticky’ ends on the central ortion that reunite as a ring. The two distal chromosomal fragments are lost so that, if the involved chromosome is an autosome, the effects are usually serious. 

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2 18 7 8 1 1 وی ‎Soe‏ 3 as i a 19 Isochromosomes An isochromosome shows loss of one arm with duplication of the other. ost probable explanation for the’formation of an isochromosome ‎that the centromere has divided‏ مز ‎transversely rather than‏ ‎longitudinally. ‎46,X,i(Xq) ‎up to 15% of all cases of Turner 

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Functional Effects of Mutations on the Protein allele), it is often ‏و‎ an amorph or amorphic mutation in the Muller's morphs schema. Phenotypes associated with such mutations are most often recessive. Exceptions are when the organism is haploid, or when the reduced dosage of a normal gene product is 20 Snares for a normal SON and sensory neuropathy type 1, Increased expression levels), (Tumors, timing or tissue specificity). > Dominant negative mutations (antimorphic mutations) Have an altered gene product that acts antagonistically to the wild-type allele. Dominant-negative mutations are particularly common in proteins that are dimers or multimers, for instance structural proteins such as the 

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. Multiple Sclerosis (MS) . Psoriasis . Behcets Syndrome (BS) . Ankylosing Spondylitis . Rheumatoid arthritis . Systemic lupus Erythematosus (SLE) . Celiac disease . Type 1 diabetes mellitus هايح اضر ين بم ان م ف . Narcolepsy 10.Sjogren Syndrome 11.Graves-Basedow disease 12.Myasthenia gravis 13.Hashimotos thyroiditis (chronic lymphocytic thyroiditid) Skotte Aldrich Syndrome (WAS) Chediak Higashi Syndrome (CHS) . X-linked Proliferative Syndrome (XLP) . Bare Lymphocyte Syndrome (BLS) immunodeficiency with increased IgM) 10.Chronic granulomatouse disease (CGD) 11.Leukocyte adhesion disease (LAD) . CVID (common variable immunodeficiency) 2. SCID (Severe combined immunodeficiency) Di George/Sedlakova . Ataxia Telangiectasia (AT) . Hyper IgM Syndrome (X-Linked 12.Hereditary angioedema (HAE)