PL1003 Lecture 3.5 - Inheritance PDF

Inheritance Dr. Gemma Barron [email protected] This Photo by Unknown Author is licensed under CC BY-NC Today’s Learning Outcomes At the end of today’s class, you should be able to: Understand how genetic information is passed from parent to offspring. Desc...

Inheritance Dr. Gemma Barron [email protected] This Photo by Unknown Author is licensed under CC BY-NC Today’s Learning Outcomes At the end of today’s class, you should be able to: Understand how genetic information is passed from parent to offspring. Describe the characteristic patterns of inheritance and related conditions. This Photo by Unknown Author is licensed under CC BY-NC Inheritance Offspring inherits two sets of chromosomes, one from each parent. Offspring becomes predisposed to characteristics of parent. Passage of hereditary traits from one generation to the next: important clinically in both health and disease Genotype: refers to the actual nucleotide sequence of genes: this is what is passed on from parent to offspring on chromosomes. Inheritance Phenotype Observable and/or measurable physical characteristic of an organism Examples: hair and eye colour, height etc Dictated by the genotype (expression of the gene) But does maps imperfectly onto genotype For a given characteristic (e.g., Alleles 2 of each chromosome: one from each parent So, two copies of each gene (exception: sex chromosomes) These are called alleles May have the same nucleotide sequence = Homozygous Or different nucleotide sequences = Heterozygous Principle of Segregation Also known as the first law of inheritance A pair of alleles will segregate during the production of gametes, so that each gamete gets one allele (one copy of the gene). When fertilization occurs, the cells of the organisms will Bioninja have two alleles for each gene: one from each parent.  Gametes Principle of Segregation produced by parent 1 For example gene ‘A’ and its allelic variant ‘a’ Two heterozygous parents. Parents can produce gametes carrying either the ‘A’ or ‘a’ allele. Offspring will inherit either ‘A’ or ’a’ from parent 1… And either ‘A’ or ’a’ from parent 2… Gametes Genotypes of offspring produced We can represent this in a Punnett by parent 2 square. Principle of Dominance Physical characteristic of one of the alleles would be observed, while the other would not. Expressed phenotype = dominant. Non-expressed phenotype = recessive. Test Crosses If an individual expresses a dominant phenotype, they have two possible genotypes. How can we distinguish them? Perform a test cross (or ‘recessive backcross’) with a homozygous recessive organism (genotype is known). Homozygous – all offspring show dominant phenotype. Heterozygous – mixed phenotypes on Principle of independent assortment The alleles of one gene are segregated into gametes (and therefore inherited) independently of the alleles of another gene. In practice, this means that we can see different combinations of two characteristics in offspring – e.g. yellow smooth, yellow wrinkled, green smooth and green wrinkled. Exception: genes located near one another may show some linkage and tend to be inherited together. X-linked inheritance The Y chromosome is smaller than the X chromosome. Individuals that carry XY chromosomes only have one copy of several genes. Recessive disease-causing alleles: Will cause disease in XY individuals, as no ’healthy’ allele to compensate. In XX individuals, it is far less likely that two copies of the disease-causing allele will be inherited  heterozygous carriers. E.g., Red-green colour blindness, Duchenne muscular dystrophy. Polygenic inheritance and genetic predisposition More than one gene contributes to the phenotype. Physical traits: skin colour, height. Susceptibility to conditions such as atherosclerosis and Type II diabetes. Clinical Significance Clinical Significance: What you need tothe Understand know. difference between conditions arising from mutations in single genes (“monogenic”) and conditions influence by multiple genes (“polygenic”). For monogenic inheritance, there are >10,000 mutations recognized to cause disease: Dominant (one mutant allele results in disease phenotype) Recessive (two mutant alleles needed for disease phenotype) X-linked (gene located on X chromosome) Autosomal (gene located on non-sex chromosome) You need to be able to explain the pattern of inheritance in each of these situations. Autosomal Dominant Huntington’s disease Neurodegenerative disorder affecting both motor and cognitive function. Onset in middle age. Mild cognitive and behavioural disturbances progressing to dementia and involuntary body movements (chorea). Mean life expectancy: 20 years from onset. Autosomal Dominant Mutation in the gene encoding Huntingtin. Normally contains a tri- nucleotide repeat sequence – CAG Number of repeats is higher in affected individuals. CAG encodes glutamine, so extra glutamine residues in resulting protein. Autosomal recessive Cystic Fibrosis Mutation in the CFTR gene – encodes an ion channel. Thick secretions at epithelial surfaces e.g. mucus in lungs. Many different mutations, all inherited recessively. Children will be affected if they inherit mutant alleles from both parents (usually heterozygous carriers). Personalised/Stratified medicine ~1000 identified. CFTR isn’t produced (premature STOP codon), traffics incorrectly, doesn’t function properly, in produced in smaller amounts, or is degraded faster. Different drugs might be used to correct these different defects. E.g. Ivacaftor can increase CFTR- mediated chloride transport, and is Can Respir J. 2015 Sep-Oct; 22(5): 257–260. approved for use in patients with class III “gating” mutations (channel function impaired). Using ”mini-guts” to predict patient responses to novel therapies. Patient intestinal stem cells can be used to generate “mini-guts” that can be maintained in culture in the lab. A patient’s response to different drugs can then be evaluated. Swelling of the organoid indicates increased Mini-guts in clinical decision making Autosomal recessive Phenylketonuria Mutation in gene encoding a hepatic enzyme, phenylalanine hydroxylase Phenylalanine is not broken down normally and is converted to phenylketone. Build up causes neurological damage Treated by excluding phenylalanine from the diet. Heel prick test at birth. X-linked Duchenne Muscular Dystrophy Progressive muscle weakness, beginning before age 5. Mutation in the dystrophin gene on the X- chromosome Should we call this “recessive”? Carriers may have some Incomplete dominance Heterozygote Sickle cells? Normal cells? Halfway house! Complicated But if we take the ‘phenotype’ as being ‘disease’, then we have a new phenotype (less severe) Co-dominance Both alleles are fully expressed A and B O – absence of antigens This is very important in transfusion Will be covered in much more detail as part of the immunology section of this module Pharmacogenomics Study of how an individual’s genetic make-up will influence how they respond to drugs Combines traditional pharmaceutical sciences with molecular genetics Can tell us why some patients respond to drugs and others don’t Can explain adverse effects Stratified medicine Anti-coagulation: Warfarin Extrinsic Intrinsic X Thromboplastin Factor cascade Xa Prothrombin Thrombin XIIIa Fibrinogen Fibrin Clot  Anti-coagulation: Warfarin Intrinsic and extrinsic converge on common pathway (drug target) Activation: carboxylation Vitamin K – changed; needs to be recycled Warfarin blocks this Prevents clot formation Personalised medicine Metabolised by CYP2C9 Makes it polar for renal excretion CYP2C9 polymorphic variants are inefficient Get build up Low dose Monitor INR closely Cures for Genetic Diseases? Some conditions can be managed by drugs Knowing the genetic mutation may or may not influence treatment. Gene therapy Lots of interest in using CRISPR – Nobel prize in 2020. Stem cells Bone marrow transplants to treat leukaemia Gene edited stem cells Summary You need to be able to describe how genetic information is passed from parents to offspring. You also need to be able to describe the characteristic patterns of inheritance and related conditions. Ideas for further reading and discussion will be uploaded to the PL1003 Moodle page.