Genetics Lecture 1 PDF

Genetics Dr. Zainab waleed aziz Lecture I 26/10/2023 Objectives: At the end of the lectures students should have a good knowledge and comprehension on the following topics: ✔ The mechanisms of transmission of mendelian traits and the relative physical and molec...

Genetics Dr. Zainab waleed aziz Lecture I 26/10/2023 Objectives: At the end of the lectures students should have a good knowledge and comprehension on the following topics: ✔ The mechanisms of transmission of mendelian traits and the relative physical and molecular basis ✔ The mechanisms of mutations ✔ The mechanisms of the more frequent molecular diseases ✔ Medical genetics diagnostic techniques Introduction: Human diseases in general can be classified into three categories: 1. Those are genetically determined. 2. Those are environmentally determined. 3. And those to which both contribute. Gene NORMAL FEMALE 46, XX  Genome: The genetic material within an organism. Genomics: The science that aims to understand the entire genetic information of an organism.  DNA: Deoxyribonucleic acid, is the molecule that carries genetic information for the development and functioning of an organism. – It is made of two linked strands — a shape known as a double helix. – Each strand has a backbone made of alternating sugar (deoxyribose) and phosphate groups. – Attached to each sugar is one of four nitrogen bases: adenine (A), cytosine (C), guanine (G) or thymine (T). – These three components form a structure called……………….. ? – The human genome contains some 3.2 billion of nucleotides. – Trinuceliotide base= codon – The human genome contains 64 codons, 61codons encoding for amino acid synthesis, 3 codons called stop codons. – The human has 20 amino acids  Gene: Sequence of nucleotides. – within the genome there are only about 20,000 protein-encoding genes, constituting just 1.5% of the genome. Exons: as expressed (Coding)sequences of the gene. Introns: intervening (Non-coding) sequences in the gene.  Locus: location of the gene in a chromosome. P53 gene 17p13.1  Genotype: The genetic material passed between generations. Phenotype: appearance or traits of an organism.  Hereditary disorders can be derived from parents, are transmitted in the gametes through the generations, and therefore are familial. Congenital simply implies “present at birth.” But not all genetic disorders are congenital.  Classification of Genetic disorders: 1. Classical Genetic Diseases: a. Chromosomal disorders. b. Single gene disorders (Mendelian Disorders). c. Multifactorial disorders. 2. Non-Classical Diseases "or the single gene disorders with atypical pattern of inheritance": a. Diseases caused by mutations in mitochondrial genes. b. Triplet repeat mutations. c. Uniparental disomy. d. Genomic imprinting. e. Gonadal mosaism. 1. Classical Genetic Diseases: A. Chromosomal Disorders: - It is estimated that about 1 of 200 newborn infants has some form of chromosomal abnormality. The figure is much higher in fetuses that do not survive to term. - Cytogenetic disorders may result from alterations in the number or structure of chromosomes and may affect autosomes or sex chromosomes. So, they could either be Numerical or Structural. I. Numerical Abnormalities in Chromosomes: Euploidy: is the state where the chromosome count is an exact multiple of the haploid number (n). It represents the normal condition. Aneuploidy: Aneuploidy occurs when there is a gain or loss of one or more individual chromosomes. It results from errors in chromosome segregation during cell division. – Polyploidy: Polyploidy involves a gain of entire sets of chromosomes. Common examples are triploidy (3n) and tetraploidy (4n). Polyploidy often leads to developmental abnormalities and spontaneous abortions. – Trisomy: a specific type of aneuploidy where there is an extra copy of a single chromosome. For example, Down syndrome is caused by trisomy 21, where there are three copies of chromosome 21 instead of the normal two. – Monosomy: a specific type of aneuploidy where there is only one copy of a specific chromosome in an otherwise diploid cell or organism. For example, Turner Syndrome where females have only one X chromosome (45,X) instead of the usual two (46,XX). Causes of Aneuploidy: 1. Non-disjunction, where homologus chromosomes fail to separate properly during cell division(meiosis), leads to gametes with an extra chromosome (n+1) or one less chromosome (n-1). Fertilization of these gametes results in trisomic (2n+1) or monosomic (2n-1) zygote 2. Anaphase lag , where a chromosome or chromatid lags behind during division. It leads to one normal cell and one cell with monosomy  Mosaicism: – Mosaicism occurs when an individual has two or more distinct cell populations with different chromosome numbers within their body.  1. post-zygotic mitotic chromosome errors 2. pre-existing paternal aneuploidy of meiotic origin Chromosomal Mosaicism: Origins and Clinical Implications in Preimplantation and Prenatal Diagnosis. Prenat Diagn. 2021 Mar 22;41(5):631–641. doi: 10.1002/pd.5931 II. Structural abnormalities in Chromosomes: In this case, the cell has a normal number of 46 chromosomes but they are morphologically abnormal. Structural abnormalities usually result from chromosomal breakage followed by loss or rearrangement of material. 1. Deletion: -Structural abnormality where a portion of a chromosome is missing or deleted. Types: a. Terminal, in which, there is one break in the chromosome and the portion distal to this break is lost. This lost piece could be carrying important genes, and its loss results in signs and symptoms related to the lost genes products b. Interstitial, where the piece of a chromosome between two breaks is lost resulting in a chromosome that is shorter than the original with the same consequences e.g. Cri du chat (loss of arm of chromosome 5)  Ring chromosome is a variant of a deletion, after loss of segments from each end of the chromosome, the arms unite to form a ring, because of the adhesive nature of the exposed DNA, will stick together forming a ring or a circle chromosome. It usually results in serious consequences.  Ring chromosome 20 syndrome – the genetics of inheritance and the main symptom:.seizures 2. Duplication involves the presence of an extra copy of a chromosome segment. Consequences: Duplications can result in an overabundance of certain genes, might causing genetic disorders or variations. 3. Inversion Structural rearrangement where a chromosome segment is flipped or reversed in orientation. Consequences: Inversions may disrupt genes or regulatory sequences but often have milder effects compared to deletions or duplications. Example: Pericentric inversion involves the centromere, while paracentric inversion does not. 4. Translocation Two non-homologous chromosomes exchange segments of genetic material. Types: a. Reciprocal Translocation: – Exchange of chromosome segments between two non-homologous chromosomes. – Can be balanced (no loss or gain of genetic material) or unbalanced (results in loss of genetic material). – Example: Philadelphia chromosome in chronic myeloid leukemia (CML), involving chromosomes 9 and 22. b. Robertsonian Translocation: – Involves the fusion of two acrocentric chromosomes (those with a very short arm). – Results in a single, larger chromosome and a smaller fragment. – seen in Down syndrome (trisomy 21) due to a translocation between chromosomes 14 and 21. Consequences: Reciprocal translocations can exchange genetic material between chromosomes, potentially leading to genetic disorders or carrier states. Example: The Philadelphia chromosome, resulting from a translocation between chromosomes 9 and 22, is associated with chronic myeloid leukemia (CML). 5. Isochromosome is an abnormal chromosome with two identical arms, typically formed due to an error in chromosome division. Consequences: Isochromosomes can lead to genetic disorders, often involving sex chromosomes. Example: Turner syndrome (45,X) may result from an isochromosome of one X chromosome.  Clinical examples of Some chromosomal Abnormalities: I. Disorders of Autosomal Chromosomes: - Trisomy (21, 18, 13) (Down’s syndrome, Edward's syndrome, Patau syndrome) - Deletion (Cri du chat syndrome which involves chromosome 5). Trisomy 21 (Down’s syndrome): It is the most common chromosomal disorder. Cytogenetic types of Down’s syndrome: 1. Regular Down's Syndrome (Trisomy 21): – Accounts for 95% of cases. – Typically caused by non-disjunction. – In 95% of cases, the extra chromosome comes from the mother. – Not influenced by paternal age. – Incidence strongly linked to maternal age (1 in 1550 for women < 20, 1 in 25 for women > 45). 2. Translocation Down's Syndrome: – Represents 4% of cases. – Involves extra chromosomal material attached to chromosome 22 or 14, 15. – Often familial in nature. 3. Isochromosome '21': – Very rare, but can result in Down's syndrome. – Involves duplication of the long arm of chromosome 21. 4. Mosaic Down's Syndrome: – Approximately 1% of trisomy 21 cases are mosaic. – Individuals have a mix of 47 and 46 chromosomes. – Symptoms vary in severity depending on the proportion of abnormal cells.  II. Abnormalities of Sex Chromosomes: Klinefelter syndrome(47,XXY): ✔ Sex chromosome abnormality that occurs in males with two or more X chromosomes (typically XXY, rather than the genetic male norm of XY) ✔ Syndrome is not inherited (passed from parent to child); rather, it is caused by a cell division error in utero. Because it is not genetic, prenatal testing is not a useful tool to predict the likelihood of having a male child with Klinefelter. Turner syndrome (45,X0): is a genetic condition that affects females and is characterized by a missing or partially missing second X chromosome. TS results in one out of 2,000 female births and 10% of miscarriages.