1st Lecture on Medical Genetics (PDF)
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IUG
2023
Dr. Mohammed M. Laqqan, Raghad Kashkash
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Summary
This document is lecture notes on Medical Genetics for students, focusing on single-gene inheritance patterns. It explains the processes of meiosis, which results in genetic variety. This document is suitable for a undergraduate level course.
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pawn Medical Genetics Prepared by Dr. Mohammed M. Laqqan Rewritten by: Raghad Kashkash Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 1 Chapter 7...
pawn Medical Genetics Prepared by Dr. Mohammed M. Laqqan Rewritten by: Raghad Kashkash Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 1 Chapter 7 Patterns of Single-Gene Inheritance Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 5 Ew Ew i 11 Spermatogenesis Jiya gametes say In heploit23 23 teploid 46 a Eh e I 23chromosomes not46 as skin 25 (2323965,546 46.xx 44 XX 22 2 + Normalfemale Normalmale tow sister chromatite, Chromosome jointw ith centromere anaphase (15. ) < chromatide DNA Histones chromatine compact)156, condensations), 2xs.n.tonormalfemales activechromosomes xx Infertile 46.4 w by j XO nd y Jj A inactive I at active Infertile 46.4 w Eg n.IXXYN.IQ Jj A 47 XXXim E a É I c s locimeans positionof the gene -(55953155. S5) 981,I form 11 n.ISXYJ I homologous y J1, X /15) completly different i homologous N.IXX 4 a in WEE a Y Y 44 win Ed e T.FI Sister a W U um Ib 1 pi I I WIT DNA Locus plural loci a specific fixedposition on a chromosomewhere a particular located gene orgeneticmarker is A ta x I I Was homologous banding be meiosis to 44 É I ty chromosomehas prophase I every a special banding we at Jj's 4443 8 to a 1813, I = d15.5, giveit that a · J É L Aid uniquepicture NI homologous J E I I m a - Di b sUI - I e p W M GID over crossing btw I Ew ow a 1 crossing over 5.5.1 5. 51 S 31 m 64J I 8 E L I entical it T Xs a s É ii usage regions o.o ii as ysi X s a identicalgenes wid w w wa x s y EY s 1 1 w y crossingovers p a identicals a w Eww Ew bi si y I N Fi Y J X J m crossingover I of I Pseudo regionsJ autosomal n6 I e It w t É W https://youtu.be/2CgG7TYRJDM ingamates occurs Somaticcells jp 151454 dem 944in males u m IIa EI I 4,2464 sew j 94th J somaticcells Jia j É i I 54 6 Hi o Polarbodies Meiosis Is polarbidiess intraphaseYts 4 04 prophases am Msu s jtr.to 1 y i Did bake gwiewxidtw.at -4,61=8155 S 9 quantity 2 cells different 110M Id i I Meiosis is the type of division thatproducesgametes Meiosis is brokendown into 2 stages ofcell division u v ↓ 19 5115 Meiosis Meiosis iscalled reduction is called mitosis eachhas 4stages u v Prophase Prophase Metaphase Metaphase Anaphase Anaphase Telophase Telophase Prophase starts with a diploid cell its chromatin contains 2 uncoiled spread outsets of chromosomes one fromeach parent AftertheDNA in thecromatin replicates it condensesinto the more familiar X shaped chromosomes X The replicated DNA is the same in the identical sister chromatides of each chromosome In a process called synapsis each chromosome pairs up with and binds to its corresponding homologous chromosome forming a tetrad A tetrad is the group of 4sisterchromatids in paired homologous chromosomes The chromosomes contain genetic information called these were genes genes inherited from each parent and different versions of the samegene on each chromosome are called Alleles In a process called 8 Crossing over chromatids from each homologous chromosome exchange segments ofalleles alsocalled recombination resulting in differentgene chromosome Crossing over randomly happens on every combinations This explains why everygamete isgenetically different from every othergamete Crossing over results ingeneticvariety in offspring andthis is whychildren are differentfrom their biological parents as wellas fromtheir biological siblings Bach to Prophase 8 Nuclear membrane disappears The centrioles move to opposite endsof thecell Spindle fibers fanout fromthem Metaphase 8 The homologous chromosomes line up at the equator and attach to spindle fibers from opposite poles i a phase 8 Spindlefibersseparatethe homologous chromosomes in each tetrad and pullthem tooppositepoles ofthecell Telophase 8 Thecell entersthisphase with 1 chromosomefromeach homologous pairat separate poles However eachchromosome still consists of sister chromatids keep inyourmind that each chromosome'ssister chromatids are no longeridentical becauseof that happenedduring crossing over Thenspindlefibersdisappearand thenuclear membranearound the chromosomes Finally cytokinesis occurs Meiosis end with 2 geneticallydifferent haploid daughter cells Each haploid cell contains only asetof consistingofpairedsister chromosomes chromatids Meiosis 8 Unlike meiosis DNAdoesn't replicatebeforemeiosis begins Prophase 8 Nuclear membrane disappears and spindlefibers fanout fromthe 2 setsof paired centrioles Metaphase 8 The chromosomes in eachcelllineup at the equator and attachtospindlefibersfrombothpoles i a phase 8 The sister chromatids ofeachchromosome separate and move to opposite poles Once the sister chromatids separate they're called chromosomes Telophase 8 The spindlefibers disappearandnuclear membranes reform and both cells cytokinesisoccurs in I 2 ·mitosis-amiosis & 51, 5.0 695's female)19,5 = =J, s male 11* -gacs gits Itunesissessi Short Summary. s. I - Sw Is b i s differentformsofthesamegenes (s, SIC 15s Ii III Gas w NTwi a y(136859 [dE EH 2W EI i I ACATG it Np tips ok Jo At 44 If I 56 5 a S Home 11. $181s? s A sequences) isdeep investigation it 5 5 wir o 6mi pm I j w XY J i ni a e 3J I J nd 522 u u É im XX rt homozygous of JJ A onlyin hemizygous exists males xx https://youtu.be/GKgH3wkIu84 Ii j sheterozygous Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 13 Difference between sister chromatids and homologous chromosomes 8 Before a cell divide it must replicate itsDNA So we can get a complete copy of DNA A full set of sister chromatids are created during the centromere replication portion of the S phase of interphase Sisterchromatids Homologus chromosomes are a set of one paternal and one maternal chromosome that pair up with each other inside the cell meiosis during I i i Polymorphism: When a specific site on a chromosome has multiple alleles in the population, it is said to be polymorphic (many forms). Normal isi Hi I mutation]. - * (1 s5 SNP J1S Sequence Iucleotide Single polymorphism - SNP 6413 II c Deletion EH Mutations Subtitution I im I Translocation t sign as Its crossing over pointmutation Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 14 From Molecular Biology, Translation Chapter The three types v u v Silent mutation Missense mutation Nonsense mutation of EMI 0.2 am I III ut www.w.WIU.to wa É b go I Did I t wi ou I it mutations a 2d b 3,04 Js's 151 I n.I.im o4W 5 Is É 311 rWW I It if u j 6 im mutations I m y sb JWsi truncatedprotein my my j 2 categories J 2 categories Jim tip Missense mutation u v Conservative Non Conservative a It w Ut g ti wa um ay w wit IT it i t.tt It it is I si w w w y si 23 si w w w p w si in i go it is Jim i n I Insertion or Deletion I s b I EITI m Ji si ab removal i addition bi 44 IT vi b w it s I a sin s r sequenceJ ji Gui Chi t go.si b www.I 31,564 Ga i th T Inframemutation sequences Forexample I s okay od's aminoacidsequences 3 J Eww I shd Go i th nd frameshiftmutation Forexample Mutations: A mutation is an alteration in DNA sequence (thus, mutations produce new alleles). When mutations occur in cells giving rise to gametes, the mutations can be transmitted to future generations. Missense mutations result in the substitution of a single amino acid in the polypeptide chain (e.g., sickle cell disease is caused by a missense mutation that produces a substitution of valine for glutamic acid in the β-globin polypeptide). u Gy halflifes In N na 120 ji Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 15 Éti bi ni wi se e okon I I = Nonsense mutations produce a stop codon, resulting in premature termination of translation and a truncated protein. : S - is t I id ni If conservative - Functionis I i I nonconservative - SdI In Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 16 Nucleotide bases may be inserted or deleted. When the number of inserted or deleted bases is a multiple of 3, the mutation is said to be in-frame. w III b w same If not a multiple of 3, the mutation is a frameshift, which alters all codons downstream of the mutation, typically producing a truncated or severely altered protein product. - 3 I1. Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG E 17 ⑭ yawn M Nw6 Mutations can occur in promoter and other regulatory regions or in genes for transcription factors that bind to these regions. This can decrease or increase the amount of gene product produced in the cell. Mutations can also be classified according to their phenotypic effects. Nonsensemutation 61 YG Mutations that cause a missing protein product or cause decreased activity of the protein are termed loss-of-function. Those that produce a protein product with a new function or increased activity are termed gain-of-function. proofreadingsystem b 8.6 wDNA a cDNAJ JiRNAs a mutationJ Genetics (2022-2023-1) t b onDr.bRNAI I Laqqan-IUG Mohammed m o Ji FI of multiplication transcription It18 Single gene disease: Any genetic disorder caused by a change affecting only one gene. There are thousands of single-gene diseases including Achondroplasia, it Cystic fibrosis, Hemophilia, Huntington disease, Muscular dystrophy, and Sickle cell disease. Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 19 For example, individuals with a mutation in the VHL gene X -genesingledisorder can have hemangioblastomas (hemangio-blastomas). S A hemangioblastoma is a benign tumor, it grows from the cells in the lining of a blood vessel, usually in the brain, spinal cord or the tissue at the back of the eye (retina). Common symptoms include headache, loss of coordination, imbalance, nausea, and vomiting. Brainstem and spinal cord hemangioblastomas may cause loss of motor function (weakness), loss of sensation in the extremities, or impaired bowel and bladder function. ay c Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG a I m Diarrhea gonna 20 Serious single-gene disorders affect 1 in 300 neonates and are responsible for an estimated 7% of pediatric hospitalizations. Although less than 10% of single-gene disorders manifest after puberty, and only 1% occur after the end of the reproductive period. Single-gene diseases usually follow simple Mendelian patterns of inheritance “autosomal dominant, an autosomal oh e numberofautosomal recessive, or an X-linked”. mutant genes 44622pairs É ti d chromosomes III stipe Xia a mutant genes Single gene diseases are opposed to polygenic diseases which are caused by a combination of two or more genes. Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 21 58 45,0X 47,XXX. xyy xy. Three individuals carry the same disease-causing mutation; two suffer from the disease but exhibit different symptoms, while the third is completely unaffected. Why? É Im v Penetrance andExpressivity M w Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 22 pw u T I may i p pi 4 I 5 II I s y mutation pi 51 o Kim Penetrance and Expressivity These findings are the basis for the concepts of penetrance and expressivity. a big u ti ga Penetrance: Is measure the number of individuals in the population who carry the allele that causing disease and express the phenotype related to a disease. Severityofthedisease Expressivity: Is the degree to which trait expression differs among individuals. It occurs when a phenotype is expressed but to a different degree among individuals (vary in their severity) with the same genotype. Penetrance n W lo pi É 100 J Genetics (2022-2023-1) Expressivity Dr. Mohammed Laqqan-IUG w w 51 my 964 mWi23 5 MY M w w pta Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 24 veriable u iz 44 M.be 65J cabb d c wit wa at g 9W w w tm penetrance entrance Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 25 Penetrance Retinoblastoma is a cancer of the retina that primarily affects children and is caused by mutations in the Rb gene. E Interestingly, not all people who carry this mutation suffer from retinoblastoma. KID on ab w W on 46 t I's1,5.5) is The Rb protein is a tumor suppressor, which plays a central role in the negative control of the cell cycle and in tumor progression. It has been shown that Rb protein is responsible for 664 si dos IA A major G1 checkpoint, D W scirepairW SphasesJas by Blocking S-phase entry and cell growth. ti b e ab m cancerwprognosis E SnegativecontrolontumorPrognosis I Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 26 cancers at i T w og Ado mutation y Additionally, Rb interacts with other proteins to influence cell survival, the self-destruction of cells (apoptosis), and the process by which cells mature to carry out special functions samsignalt cell..'s (differentiation). RB RBI gene are the same Mutations in the RB1 gene appear to be inherited in an autosomal dominant pattern. In the case of retinoblastoma, because not all individuals who carry the mutation are affected by the disease, this condition is said to display incomplete or reduced penetrance. Other diseases with incomplete penetrance include Huntington's disease and Breast cancer. Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 27 In contrast to these examples, a disease shows complete penetrance if all of the individuals who carry the related gene are affected by the disease. For example, the inheritance of a specific point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene always results in the disorder achondroplasia, which is N g characterized by abnormal bone growth and dwarfism. M NUJ mutantallels UH Yak 5 is 551 I growth hormone j -8 Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 28 Severity I m Expressivity While the expressivity refers to variation in phenotypic expression when an allele is penetrant. For example, an individual with a certain mutation can exhibit differences in disease severity, they can also show differences in many other aspects of their phenotypes, such as their age of onset of disease symptoms. Some diseases, such as Huntington's disease, may have an earlier onset with more severe symptoms in subsequent generations. This type of variable expressivity is called anticipation. His Ji I a generationJey severity a ow s Genetics (2022-2023-1) i ti i n Jie Dr. Mohammed Laqqan-IUG 29 Mi ki A Tak diva Bothare completepenetrance Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 30 Why Do Phenotypes Show Differences in Penetrance and Expressivity? Nonetheless, research has shown that variable phenotypes can be caused by a number of factors, including the following: Modifier genes, 055,54 w U m Allelic variation, Genomic imprinting, Environmental factors, life style Modifier genes are defined as genes that affect the phenotypic and/or molecular expression of other genes. Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 31 Genetic modifiers can affect penetrance, dominance, P sI - 2,55!/5- expressivity, and pleiotropy. 44 112413,0 it pleiotropy Modifier genes can affect transcription and alter the next gene transcript expression. 24421W Éj t.LI igc H For example, patients with thalassemia (autosomal recessive), a disorder caused by defective beta-globin synthesis, have diverse clinical characteristics and variable expressivity. Patients with severe cases have profound anemia and require regular blood transfusions, while other individuals who carry the same allele have mild and undetectable symptoms. 2B 2am NIC PIATTI Genetics (2022-2023-1) adults fetal two c Abf Dr. Mohammed Laqqan-IUG Hba HbAz wed 32 i adult Splicing removing Alternative splicing ofintronintrons Alternative splicing is a molecular mechanism that modifies It's a normal pre-mRNA constructs prior to translation. process This process can produce a diversity of mRNAs from a single gene by arranging coding sequences (exons) from recently spliced RNA transcripts into different combinations. The mRNA transcripts created from alternative splicing can translate into varying amino acid sequences that produce protein isoforms with different functions. Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 33 Ya 4 Ur Ya g U É m joy Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 34 The most common types of alternative splicing.* Exon skipping: This process involves the removal of certain exons and their adjacent introns from mRNA constructs prior to translation. Alternate 5’ or 3’ splicing: Alternative splicing can also be mediated by the joining of exons at alternative 5’ or 3’ splice sites. Intron retention: This type happens when non-coding I'M I portions of a gene are retained in the final mRNA transcript. mRNAs 23SWmRNAJ Jo ow 6 s 4 It Erm Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 35 Nonfunctionalprotein introns Some of the most common types of alternative splicing. Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 36 Examples on the alternative mRNA splicing: Duchenne Muscular Dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by mutations in the dystrophin gene. cells muscle NI o ads i musclesize reductions $ Duchenne muscular dystrophy is a severe muscle-wasting u fordystrophinprotein different disease arising from defects in the dystrophin gene, typically ypesof utations eadto nonsense or frame-shift mutations that prevent the synthesis ifferent diseases of a functional protein. mi É www Becker muscular dystrophy generally arises from in-frame deletions that allow synthesis of a shorter but still semi- functional protein. Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 37 u maleJ I Ed J Genetics (2022-2023-1) Dr. Mohammed Laqqan-IUG 38 functional 2copiess