Mendelian Genetics: Patterns of Inheritance PDF

Titu Maiorescu University Faculty of Dental Medicine Specialization: Dental Medicine Genetics, year 2 Mendelian Genetics: Patterns of Inheritance and Single-Gene Disorders Inheritance Patterns  Many diseases are caused or influenced by genetic...

Titu Maiorescu University Faculty of Dental Medicine Specialization: Dental Medicine Genetics, year 2 Mendelian Genetics: Patterns of Inheritance and Single-Gene Disorders Inheritance Patterns  Many diseases are caused or influenced by genetics.  Genes, through the proteins they encode, determine how efficiently foods and chemicals are metabolized, how effectively toxins are detoxified, and how vigorously infections are targeted.  Genetic diseases can be categorized into three major groups: single-gene, chromosomal, and multifactorial.  Changes in the DNA sequence of single genes, also known as mutations, cause thousands of diseases.  A gene can mutate in many ways, resulting in: an altered protein product that is unable to perform its normal function. The altered protein product may still retain some reduced normal function, or the protein may be totally disabled by the mutation or gain an entirely new, but damaging, function.  The outcome of a particular mutation depends not only on how it alters a protein’s function, but also on how vital that particular protein is to survival.  Other mutations, called polymorphisms, are natural variations in DNA sequence that have no adverse effects and are simply differences among individuals.  The basic laws of inheritance are useful in understanding patterns of disease transmission. Titu Maiorescu University Faculty of Dental Medicine Specialization: Dental Medicine Genetics, year 2  Single-gene diseases are usually inherited in one of several patterns, depending on the location of the gene (e.g., chromosomes 1-22 or X and Y) and whether one or two normal copies of the gene are needed for normal protein activity.  Six basic modes of inheritance for single-gene diseases exist: autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, Y-linked and mitochondrial.  The way in which traits are passed from one generation to the next-and sometimes skip generations-was first explained by Gregor Mendel.  By experimenting with pea plant breeding (Pisum sativum), Mendel developed three principles of inheritance that described the transmission of genetic traits, before anyone knew genes existed. Mendel`s laws of inheritance 1. LAW OF SEGREGATION – alleles segregate, offsprings acquire one allele from each parent; 2. LAW OF DOMINANCE – alleles can be dominant/ recessive; Domninat traits appear when ≥ one dominant allele is present. 3. LAW OF INDEPENDENT ASSORTMENT – separate genes assort independently. Les gènes situés sur des chromosomes di érents sont hérités indépendamment les uns des autres. En d’autres termes, la transmission d’un certain caractère (comme la couleur des yeux) n’in uence pas la transmission d’un autre caractère (comme Glossary of Terms la taille) si ces caractères sont contrôlés par des gènes situés sur des chromosomes di érents. HYBRID = offsprings that are the result of mating between two genetically different kind of parents; F1 GENERATION = the first offspring (or filial) generation. MONOHYBRID CROSS = cross between parents differing in only one trait or in which only one trait is being considered; DIHYBRID CROSS = cross between parents in which two pairs of contrasting characters are studied simultaneousley for the inheritance pattern. LAW OF DOMINANCE In a cross of parents that are pure for contrasting traits, only one form of the trait will appear in F1 generation. All offsprings will be hybrid for a trait and will have only the dominant trait express the phenotype. The phenotype trait which is not expressed in the hybrid is called recessive. LAW OF SEGREGATION According to this principle, the "particles" (or alleles as we now know them) that determine traits are separated into gametes during meiosis and meiosis produce equal numbers of egg or sperm cells that contain each allele. Titu Maiorescu University Faculty of Dental Medicine Specialization: Dental Medicine Genetics, year 2 Fenotipic ratio: 3:1 Genotipic ratio: 1:2:1 Limitations of Mendel’s Law of Dominance 1. CO-DOMINANCE = the mechanism of dominance seen in some alleles where both alleles of a gene in a heterozygote lack the dominant and recessive relationship and each allele is capable of some degree of phenotypic expression (the phenotype will be a blend of the two alleles); 2. INCOMPLETE DOMINANCE = the dominant allele does not entirely overcome the phenotypic expression of the recessive allele and there occurs an intermediate phenotype in the Co-dominance : Les deux allèles s’expriment pleinement et séparément heterozygote. dans le phénotype, sans mélange. Dominance incomplète : Les deux allèles contribuent au phénotype, mais de manière partielle, créant un résultat intermédiaire ou « fusionné ». LAW OF INDEPENDENT ASSORTMENT  Mendel observed that, when peas with more than one trait were crossed, the F1 generation did not always match the parents.  This is because different traits are inherited independently – this is the principle of independent assortment.  He cross-bred pea plants with round, yellow seeds and plants with wrinkled, green seeds. Only the dominant traits (yellow and round) appeared in the F1 progeny, but all combinations of trait were seen in the self-pollinated F2 generation. Titu Maiorescu University Faculty of Dental Medicine Specialization: Dental Medicine Genetics, year 2  The traits were present in a 9:3:3:1 ratio (round, yellow: round, green: wrinkled, yellow: wrinkled, green). Observable Human Characteristics o Earlobe attachment o Dimples o Freckles o Hairline shape Autosomal Dominant Single-Gene Diseases  Examples: Huntington`s disease - a progressive neurodegenerative disorder, myotonic dystrophy - a progressive muscle atrophy and weakness, familial hypercholesterolemia - it causes LDL (bad) cholesterol level to be very high, neurofibromatosis - increased risk of developing tumors, polycystic kidney disease - clusters of cysts grow in the body, mainly in the kidneys etc. Autosomal Recessive Single-Gene Diseases  Examples: phenylketonuria - mutations in the gene that encodes the enzyme phenylalanine hydroxylase (PAH) - unable to break down the amino acid phenylalanine, cystic fibrosis- causes severe damage to the lungs, digestive system and other organs in the body - it affects the cells that produce mucus, sweat and digestive juices, sickle-cell anemia - it affects the shape of red blood cells - an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells, occulocutaneous albinism - reduction or complete lack of melanin pigment in the skin, hair and eyes etc. X Chromosome–Linked Dominant Single-Gene Diseases  Examples of X chromosome-linked dominant diseases are rare, but several do exist: hypophosphatemic rickets - a disorder of bone mineralization, Rett syndrome - a neurodevelopmental disease; symptoms include impairments in language and coordination, and repetitive movements. Those affected often have slower growth, difficulty walking, and a smaller head size. X Chromosome–Linked Recessive Single-Gene Diseases  Examples: hemophilia A - hemorrhagic disorder resulting from a congenital deficit of factor VIII that manifests as protracted and excessive bleeding either spontaneously or secondary to trauma, Duchenne muscular dystrophy - progressive muscle fiber degeneration and weakness, red/green colorblindness (daltonism) - the decreased ability to see color or differences in color. Titu Maiorescu University Faculty of Dental Medicine Specialization: Dental Medicine Genetics, year 2 Y Chromosome–Linked Single-Gene Disease  It makes no difference whether the Y chromosome-linked mutation is dominant or recessive, because only one copy of the mutated gene is ever present; thus, the disease-associated phenotype always shows.  Examples: hairy ear (auricular hypertrichosis) - excessive hair growth on or in your outer ear, the part of your ear you can see. Mitochondrial Single-Gene Disease  Mitochondrial disorders impair the function of mitochondria; depending on which cells have fewer or lower-functioning mitochondria, different symptoms may occur.  Examples: Leber hereditary optic neuropathy (LHON) - form of vision loss (blurring and clouding of vision), MELAS syndrome - = Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes - predominantly affects the nervous system and muscles. CONCLUSIONS  Gregor Mendel, through his work on pea plants, discovered the fundamental laws of inheritance.  He deduced that genes come in pairs and are inherited as distinct units, one from each parent.  Mendel tracked the segregation of parental genes and their appearance in the offspring as dominant or recessive traits.