Medical Genetics Lecture Notes 2023/2024 PDF

Medical Genetics UDS School of Medicine Department of Biochemistry and Molecular Medicine Jennifer Suurbaar (+233248263912) 2023/2024  Lecture 1 & 2 Introduction to the field of genetics Introduction to...

Medical Genetics UDS School of Medicine Department of Biochemistry and Molecular Medicine Jennifer Suurbaar (+233248263912) 2023/2024  Lecture 1 & 2 Introduction to the field of genetics Introduction to medical genetics Overview of the History of Genetics Physical basis of genetics (Cells, Chromosomes and some terminologies) Cell division Cell cycle in brief Mitosis Meiosis Gametogenesis Sex determination  Introduction to medical genetics It involves the studying of the role of genes in health and disease. It focuses on understanding genetic factors contributing to various medical conditions identifying genetic disorders exploring ways to diagnose treat and prevent genetic diseases Medical genetics analyze the role of genes in health and work towards improving patients care through genetic interventions and personalized medicine  Overview of the history of genetics Before 1860: Is the discovery of the cell and the nucleus Events that occurred: Nicholas Hartsoeher (1694) theorized a miniature human in the head of a sperm (Homonculus) William Harvey, the theory of epigenetics Robert Hooke (1665), observed the cell structure under light microscope Anton Van Leeuwenhoek (1674 – 1683), the master lens maker; single lens microscope Jan Purkinje (1830), first described the nucleus within cell Robert Brown (1831), coined the term nucleus; Brownian motion of microscopic particles; gymnosperm vrs angiosperm Hugo von Mohl (1835 – 1839), mitosis in a cell and the first to use the term protoplasm Rudolf Virchow (1858) –summarized the concept of cell theory (All cells come from preexisting cells; “Omnis cellula e cellula”  History of genetics continues 1860 – 1900 : Mendelian traits and observation of Chromosomes Gregor Mendel (1856-1860), an Australian Monk; Classical hybridization experiments with pea plants; statistical patterns of heritable phenotypes. Oscar Hertwig(1875), German embryologis; fusion of sperms and egg Zygote Walther Flemming(1879 – 1885) , a Physician; newly stnthesised aniline dyes to view and describe chromosomes. Theodor Boveri, Karl Rabl and Edouard van Beneden (1880) – hypothesized that Chromosomes are individual stratctures with continuity from one generation. August Weismann (1885) - inheritance of traits is based exclusively in the nucleus; Meiosis (1887) Hetwig and Boveri (1890) described the process of Miosis in details  History of genetics continues 1900 – 1944 Chromosome theory and sex linkage Thomas Hunt Morgan (1900) Introduced Drosophila melanogaster as a model genetic system Walter Sutton (1902), explained Mendel’s rules of inheritance Thomas Hunt Morgan (1911), genes producing white eyes, yellow body and miniature wings in Drosophila and located on the X chromosome Lewis Stadler and Hermann Muller (1927), genes can be mutated artificially by X-Rays Silvador Luria and Max Delbruck (1943), demonstrated that bacteria have genetic system and phenotypes that could be studied  History of genetics continues 1944 – Present: DNA, RNA and Molecular Genetics Oswald Avery (1944), Alfred Hershey and Martha Chase (1952), DNA was the genetic material James Watson and Francis Crick (1953) worked out the structure of DNA Paul Berg (1972) was first to constract a recombinant DNA molecule containing parts of DNA from different species. In 1995 Haemophilus influenzae was the first organism to have its complete genome sequenced The human Genome Project (1990 – 2003), an international effort sequenced the entire human genome, providing a comprehensive map of the human genes Advancement in genomic Medicine (21st Century); Rapid advancement in DNA sequencing, CRISPR gene editing, and personalized medicine which enabled targeted therapies.  Cell division When cell divides into two or more daughter cells with the potential of each develop into a fully functional organism The fundamental aspect of growth, development and tissue maintenance Mitosis Mieosis During cell division each daughter cell must have an exact compliment of the contents of the one mother cell Cytoplasm – No Problem Mother cell will replicate (Copy) the one mother BUT there is only one Nucleus nucleus into two – one for each daughter cell Nucleus contains the genome – DNA is copied  Each cell in our body contains the same genetic information (DNA) Nucleus Gene - Encodes for protein  Cell division continues (Recall prokaryotic cell and Eukaryotic cells) Cell division is complicated in Eukaryotic cells Dissolve the nucleus Replicate each chromosome Make sure each new cell gets only one of each copy New nuclei forms then divides Different eukaryotes have different number of chromosomes Humans have 46 Flies have 8 Yeast have 32 Most Eukaryotes have two sets of chromosomes One set from Mom and one set from Dad Resulting in an even number of chromosomes This is called DIPLOID  Chromosome in Cell division Chromosomes (#1)from mom is identical to chromosome (#1)from Dad. They each contain the same gene but often have different ALLELE Chromosomes that are of the same pair and carry the same set of genes are called homologous. Human chromosomes Humans have 23 pairs of chromosomes, 22 autosomes and 1 pair of sex chromosomes. The 22 autosomal chromosomes are numbered in order of decreasing length from 1 to 22. In sex cells (gamates; egg and sperm cell) are made by Mieosis and are HAPLOID meaning having half the chromosomes as diploid cells  Definition of some terms Chromatid: one of the two copies of a duplicated chromosome formed by DNA replication during S-phase. Chromatin: Complex of DNA, histones, and non-histones, proteins found in the nucleus of eukaryotic cell. Chromosome: Structure composed of DNA molecule and associated proteins that carries part (or all) of the hereditary information of an organism. Histones: One of a group of small abundant proteins, rich in arginine and lysine. Histones form the nucleosome cores around which DNA is wrapped. Gene: Region of DNA that is transcribed as a single unit and carries information for a discrete hereditary characteristic, usually corresponding to A single protein (or set of related proteins generated by variant post- translational processing) or A single RNA (or set of closely related RNAs) Genome: The totality of genetic information belonging to a cell or an organism; in particular, the DNA that carries this information 13 Mostly, chromosomes are lightly compacted, thin and nearly invisible Just after replication and just before cell division Chromosomes become tightly compacted, very dense and visible under microscope  Cell cycle &Mitosis The purpose is primarily involved in the growth and maintenance of somatic (Non- Cell cycle is essentially reproductive)cells the life of a single cell Responsible for tissue repair replacement of damaged cells and overall growth in multicellular organisms  Cell cycle continues G0 Phase – cell do all your cells stuff Lung cells – exchange oxygen for carbon dioxide Immune cells – fighting infection Neurons – transmit electrical impulses G1 Phase - prepare to copy your genome S Phase – copy your genome in preparation towards cell division G2 - prepare yourself for Mitosis M Phase - Do mitosis and divide Now you have become two cells Guess what each of those cells will do Do cell stuff…….copy their genome………. Hence CELL CYCLE  Cell cycle continues Things can go wrong during the life of a cell Viral infection Loss of ATP production DNA damage Cells do not progress if experiencing these There are checkpoints in the cell cycle where proteins in the cell monitor and verify that the cell is healthy Only then the cell is allowed through the checkpoints and further through the cell cycle Cell cycle is divided into two phases INTERPHASE When cell are doing every thing it does except dividing and this includes DNA replication M PHASE Mitosis and cytokinesis  Interphase: The phase before mitosis Extended period of growth and development between cell division It consist of three stages G1 - Phase S – Phase G2 - Phase Cell cycle starts with G1 phase – here the cell grows and makes the This is what the proteins/enzymes needed for DNA replication – it last 10 hours cells have done Then the cell must pass through G1/S checkpoint Next is S- phase (for synthesis) – here the genomes are copied (9 Hours) Then G2 (Preparing for mitosis and cytokinesis: 4 hours) The cell must go through G2/M checkpoint This check point primarily scan the genome for damage Interphase is done and the cell is ready for Mitosis  Mitosis After interphase, identical sister chromatids are formed and the sister chromatids are stuck to one another due to a protein called COHESIN Coupled chromosomes must be separated for the daughter cells; one for you…… and one for you……. Mitosis consist of five(5) stages and the sixth stage is cytokinesis First stage of mitosis Prophase: The DNA compacts and becomes visible to the microscope A pair of CENTROSOMES moves to the opposite sides of the cell; these contain MICROTUBULES ( these are kind of cellular cables) Then the MITOTIC SPINDLE forms; this is an organized array of microtubules Prometaphase: It is marked by the disintegration of the nuclear membrane. This allows the spindle microtubules to directly attach to the chromatids Typically, a microtubule from one centrosome will attach to the Kinetochore of one chromatid while a microtubule from the other centrosomes attaches to the other chromatid The microtubule lengthens and shortens playing tug-of- war with the chromosome in the center Eventually each microtubules wins because the chromosomes splits in half  Metaphase: Before the chromatid separates, all this pulling and tugging results in the chromosomes been aligned at the center of the cell at the metaphase plate the centrosomes are on both sides This alignment is checked by making sure there is equal tension on each chromatid Without equal tension, cells are not allowed to continue on with Mitosis Assume equal tension………………  Anaphase: Equal tension across our spindle; we made it to anaphase …….. Holding the sister chromatids together breaks down and the chromatid separates Because of the tugging of the microtubules, the two identical chromatids are pulled to the opposite sides of the cell This means there is identical set of identical chromosomes now on the exact opposite sides of the cell  Telophase: Once the chromosomes arrive at the SPINDLE POLES (the opposite sides of the cell) telophase is next, the last stage of Mitosis A nuclear membrane forms around each set of chromosomes resulting in two distinct nuclei The chromosomes decompact and become no longer visible in the light microscope And in many cells cytokinesis occurs simultaneously  After mitosis each new daughter cell should have a genome that is exactly identical to the mother cell before division No DNA is lost  MEIOSIS Meiosis is crucial for sexual reproduction as it ensures genetic diversity among offspring for survival. It reduces the chromosome number by half, producing haploid cells (gametes) from diploid cells (somatic cells) Evolution depends upon genetic variability – differences between us_ “survival of the fittest” requires that some will be more fit than others Sex shuffles genetic information of two parents, creates a total new novel and unique genome and gives rise to a brand new human being A human being more fit than others and less fit than some Here Father contributes half of his genome to the offspring and mother contributes half of hers Meiosis is similar to mitosis Similarities Both goes through cell cycle interphase ensuring that each resulting gamete has a full set of genetic information Cytokinesis follows mitosis, Cytokinesis occurs after both meiosis I and meiosis II, resulting in the production of four haploid daughter cells (gametes) Miosis I – is called reductive division cells divide but they do so without separating chromatid Meiosis II - Separate the sister chromatids cells divides, four non-identical haploid gametes. Prophase 1: First division of meiosis Chromosomes compact and dense and visible under the microscope Homologous chromosomes line up next to each other and its called SYNAPSIS Each chromosome duplicates and remains closely associated (forming TETRAD; four chromatids) During synapsis CROSS-OVER occurs Crossing-over - refers to the exchange of genetic material or chromosome segments between non- sister chromatids (homologous chromosomes) Crossing over is the basis of Recombination- genome reshuffling Metaphase 1: Homologous chromosomes align at the equatorial plate. Microtubules attach to each chromosome Anaphase 1: Homologous pairs separate with sister chromatids remaining together Telophase 1: New nuclei is formed Two daughter cells are formed with each daughter containing only one chromosome of the homologous pair Interkinesis: This is a brief interphase-like stage between meiosis I and meiosis II. DNA replication doesn't occur during interkinesis. Phases of Meiosis II: Prophase II: Chromosomes re-condense, and a new spindle apparatus forms in each haploid cell Metaphase II: Chromosomes align at the metaphase plate in both haploid cells Anaphase II: Centromeres split, and sister chromatids move to opposite poles (cohesion dissolves) Telophase II: Nuclear membranes reform around the separated chromatids. cytokinesis occurs, resulting in four haploid daughter cells  Independent Assortment provides genetic variability refers to the random distribution of different pairs of alleles (gene variants) during the formation of gametes It ensures that different combinations of alleles are distributed randomly into gametes during meiosis. This randomness contributes to the genetic variability observed among individuals within a population Here every single possible Maternal - Orange combination is possible Paternal - Blue 8,388,608 possible combination, not accounting for crossing-over Meiosis in Animals (Human) Production gametes is termed Gametogenesis All gametes arise from primordial germ cells (PGCs), a small population of cells set aside from other cell lineages very early in embryonic life in most animal species Germ cells are the stem cells of the species, since they give rise to organisms 1st Polar rather than organs Body They are the means by which species form 2ndPolar Body and change in evolution In humans (as well as other animals), they are also the vehicles for inherited diseases  Sex Determination Sex of offspring is determined at moment of fertilization 1. Female mammal has 2 x chromosomes (XX) 2. Male mammal has 1 x chromosome (XY) After meiosis, all egg cells have X chromosome Only 1/2 of sperm cells have X chromosome and the other half is a Y-chromosome So, sex of animal is determined by male parent. Easily shown in Punnett square Sex determination in human There are few syndromes that highlights Turner Syndrome these concepts NORMAL MALE Turner Syndrome Normal intelligence Usually sterile Underdeveloped sexual X’teristics Klinefelter syndrome Small testis and reduced facial hair Tall and sterile Usually normal intelligence Triple X syndrome Often undiagnosed, normal appearance and physiology  Lecture 3 & 4 Basic Principles of Heredity Mendelian Genetics History of Gregor Mendel Basic genetic terminologies Monohybrid crosses Using genetics to predict offspring of the parent  History of Gregor Mendel Gregor Johann Mendel (1822 – 1884) was an Austrian monk and scientist who was in charge of the monastery garden Mendel studied garden peas and did that with no knowledge on DNA How traits are passed to offspring in peas We will tie this concept on what we know about DNA, gene etc….. Linking the concept will help in a better understanding  Mendel’s data revealed patterns of inheritance Mendel made three key decisions in his experiments Use of purebred plants Control over breeding Observation of seven “either-or” traits Pea plants happened to be a good choice to study because: Easy to cultivate They are self-pollinating He had different pea plants that were true-breeding. True-breeding - means that they are homozygous for that trait (Pure breeding strains) If the plants self-pollinate they produce offspring identical to each other and the parents  Mendelian genetics In breeding experiments between 1856 and 1865 Inheritance patterns of certain traits in pea plants Gametes: reproductive cells produced by sexually reproducing organisms. Two types: male gametes = sperm In plants: contained in pollen Female gametes = eggs In plants: contained in ovules Gregor Johann Mendel Ovules contained in carpels  (P) Parental Generation (true breeding) Original cross F1 Generation (offspring) Cross pollination F2 Generation (Cross of F1 Generations)  Mendel’s Pea Plant experiments Fertilization: fusion of egg and sperm Self-fertilized & Cross fertilized Produced hybrids F1: first generation F2: second generation Modified to today’s vocabulary Genes: the hereditary information that determines a single trait Alleles: alternate forms of a gene When an organism inherits two identical alleles for a trait: homozygous for the trait. When an organism inherits to different alleles for one trait: heterozygous for the trait. His experiments showed that they obeyed simple statistical (probability) rules Used mathematical analysis in his studies. Mendel concluded: For each character, there are 2 possible traits Alleles: Different versions of the same gene Remember, genes are used to make proteins Each allele contains the DNA that codes for a slightly different version of the same protein This gives us the different characteristics for each trait  Mendelian’s laws of inheritance 1.Law of Dominance: - In a cross of parents that are pure for contrasting traits, only one form of the trait will appear in the next generation. - Offspring that are hybrid for a trait will have only the dominant trait in the phenotype. 2. Law of Segregations: - During the formation of gametes (eggs or sperm), the two factors (alleles; hereditary units) responsible for a trait separate from each other. - Alleles for a trait are then "recombined" at fertilization, producing the genotype for the traits of the offspring. 3. Law of Independent Assortment: - For a pair of contrasting characters, the factors will assort independently in the gametes (Alleles for different traits are distributed to sex cells (& offspring) independently of one another). Since that time many more complex forms of inheritance have been demonstrated Read more on this as revision Nature and Nurture Some traits (Like Mendel’s) are largely nature while others are largely Nurture Allelles and genotypes are passed on in families With Human Free will Good choices Common sense Can do wonders in managing some genetic predisposition Using genetics to predict offspring of the parent  Probability and Genetics Punnett square and probability laws are used to determine the probability. The likelihood that a particular event will occur is called probability The principles of probability can be used to predict the outcomes of genetic crosses. The inheritance of a trait is by chance. Probability laws apply when calculating the chance of an offspring inheriting a specific genotype The probability is the likelihood of an event to occur.  Punnett squares The Punnett square is a grid system for predicting all possible genotypes resulting from a cross. The axes represent the possible gametes of each parent The boxes show the possible genotypes of the offspring 1 2 1 The Punnett square yields 𝐴𝐴 = 4 𝐴𝑎 = 4 = 2 the ratio of possible genotypes and 1 𝑎𝑎 = phenotypes 4  Probability Probability ranges from zero to one (0 – 1) Value of 1 means the event is certain to occur, and a value of 0 means the event is certain not to happen Some events are mutually exclusive – one event occurring makes all other possibilities impossible in the same event The sum of the probabilities of all possible events will always equal one THE SUM RULE (OR) The PRODUCT RULE (AND) states that the probability of independent events occurring together is the product of the probabilities of the individual events. Heredity patterns can be calculated with probability Probability is the likelihood that something will happen Probability predicts an average number of occurrences, not an exact number of occurrences number of ways a specific event can occur Probability = number of total possible outcomes Probability applies to random events such as meiosis and fertilization. Punnett Square is easy in one trait but difficult in two or more trait Monohybrid Dihybrid  Eg: If two parents are heterozygous for a genetically inherited dominant trait, what is the probability that they will have a child together who has this trait in his or her phenotype? a) 25% b) 50% c) 75% d) 100%  AaBbCcDdEe Vrs AaBbCcDdEe A team of scientists are looking into 5 different genes (A, B, C, Aa Vrs Aa D, E) responsible for 5 different traits in a rare species of wild rabbits. In case they cross a rabbit that is heterozygous for all 5 A a genes with another rabbit that has an identical genotype, what A AA Aa is the probability of having an offspring with the following Aa aa genotype: AABbCCddEe a A) 1/128 B) 1/4 C) 1/256 D) 1/16 E) 1/64  Mendelian inheritance Dominant vs. Recessive Allele Dominant: an allele that is expressed whenever it is present Recessive: an allele that is masked whenever the dominant allele is present. Dominant and recessive alleles influence an organism’s phenotype Using Punnett Squares to Predict the Inheritance of Sickle Cell Anemia Given parents’ genotypes, you can predict offspring’s genotypes and phenotypes HbS/ HbS = homozygous recessive results in sickle cell anemia Both HbA/ HbS (heterozygous) and HbA/ HbA (homozygous dominant) are normal. Try this: Predict the possible inheritance (genotypic and phenotypic) outcome given that both parents are normal phenotypically. Pedigree Analysis A pedigree is a genetic family tree that shows how prevalent a trait is in a family unit from generation to generation. They are often used to track the expression of genetic conditions and disorders Geneticists Often Use Pedigrees To Study the Inheritance of Characteristics in Humans Pedigree Analysis Horizontal line between two symbols of man and woman indicated mating (–) Person from whom the pedigree is initiated is called Proband two assumptions in analyzing Pedigree Charts These are: Complete Penetrance — an individual in the pedigree will be affected (express the phenotype associated with a trait) when the individual carries at least one dominant allele of a dominant trait, or two recessive alleles of a recessive a trait. Rare-in-Population — generally, the trait in question is rare in the general population. Modes of Inheritance Autosomal dominant Autosomal recessive X-linked dominant X-linked recessive Y-linked inheritance  Pedigrees Autosomal Dominant Traits Both sexes can transmit these traits Does not skip generation Most people with the trait are heterozygous Homozygous Achondroplasia, which causes death during infancy Example: Achondroplasia is a common form of dwarfism. Short stature and bowed legs. Fibroblast growth factor 3 (FGFR3) gene at 4p16 (chromosome 4, p arm, region 1, band 6) encodes a receptor protein. This protein influences how cells divide, mature, and form structures, such as bones Autosomal recessive traits Equal frequency between both sexes- if uncommon most parents of affected offspring are unaffected and are carriers skips generation when recessive trait is rare most people outside families are Example: Phenylketonuria (PKU) – Individuals with homozygous for normal allele phenylketonuria (PKU) have a mutation in recessive trait more likely to appear the PAH gene at 12q24 (chromosome 12, q arm, with inbreeding/consanguinity- tay region 2, band 4), which encodes an enzyme that sachs breaks down phenylalanine into tyrosine called Phenylalanine hydrolase (PAH). Making tyrosine an essential amino acid.  Tay Sachs disease It's caused by the absence of an enzyme that helps break down fatty substances. These fatty substances, called gangliosides, build up to toxic levels in the brain and spinal cord and affect the function of the nerve cells. Tay- Sachs disease happens when both parents have a mutated HEXA gene. X-linked recessive traits traits appear more frequently in male cause they are hemizygous affected males are usually born into Colour Blindness: Red-green color blindness means that a person cannot unaffected mothers who carry the distinguish shades of red and green allele (usually blue-green), but their ability to see is normal. tends to skip generations hemophilia A- is a disorder where the not passed from father to son blood cannot clot properly due to a deficiency of a clotting factor called Factor All daughters of affected male will VIII. F8 gene at Xq28 (X chromosome, q arm, region 2, band 8), internal and be carriers external bleeding can’t be stopped. X-linked dominant traits Affected parents does not skip generation affected men pass to their daughters cannot pass from father to son female can receive trait from either parent Example: Fragile x syndrome — The FMR1 gene at Xq21 (X chromosome, q arm, region 2, band 1) encodes a protein needed for neuron development. Y-linked traits Only males are affected, trait is passed from father to son does not skip generations traits acquired through patrilineal inheritance Apart from sex-determining genes (SRY genes, AZF genes) there are also other genes that y An example is the Hypertrichosis of chromosome bear. One of them is the SOX21 ears wherein the trait characterized by gene, which codes for the transcription factor having hairy ears is passed on from the SOX-21 protein. This protein is associated with father to the male offspring baldness or hair loss. The pedigree below represents a monogenic disease in an affected family. After analyzing the pedigree, what is the likely inheritance pattern of this disease? Miscarriage or still birth A. Autosomal recessive B. Autosomal dominant C. X-linked recessive D. X-linked dominant E. Y-Linked Exceptions in Mendel’s inheritance From Mendel’s experiment: you might imagine that all genes control a single characteristic and affect some harmless aspect of an organism’s appearance (such as color, height, or shape) Those predictions are true for some genes, but definitely not all of them! The exceptions A human genetic disorder called Marfan syndrome is caused by a mutation in one gene, a set of seemingly unrelated symptoms, includes usually tall height Thin fingers and toes Dislocation of the lens of the eye Heart problems Pleiotropy, or one gene affecting multiple characteristics Beyond Mendelian Genetics Multiple Allelic Traits This occurs when a gene has many allelic forms or alternative expressions. ABO Blood Types a. The ABO system of human blood types is a multiple allele system. b. Two dominant alleles (IA and IB) code for presence of A and B glycoproteins on red blood cells. c. This also includes a recessive allele (iO) coding for no A or B glycoproteins on red blood cells. d. As a result, there are four possible phenotypes (blood types): A, B, AB, and O e. This is a case of codominance, where both alleles are fully expressed. The Rh factor is inherited independently from the ABO system; the Rh+ allele is dominant.