Flipped lesson 1 - inheritance patterns-3.pdf

Inheritance patterns MD210 – GGE – Flipped Lesson 1 1 Essential Learning Outcomes By the end of this lesson you should be able to: • Recognise and describe dominant and recessive inheritance patterns • Understand the concepts of penetrance and expressivity • Understand the concept of incomplete d...

Inheritance patterns MD210 – GGE – Flipped Lesson 1 1 Essential Learning Outcomes By the end of this lesson you should be able to: • Recognise and describe dominant and recessive inheritance patterns • Understand the concepts of penetrance and expressivity • Understand the concept of incomplete dominance 2 Some terminology… Genome: • All of the hereditary information that an organism has encoded in its DNA (or for some viruses RNA) Chromosome: • A threadlike structure of DNA and protein (chromatin) found in the nucleus of most living cells. Each chromosome has many genes, which carry genetic information. Human cells have 23 pairs of chromosomes. 3 Some terminology… • Gene: • a unit of heredity which is transferred from a parent to offspring and is responsible for a character/trait of the offspring • or a DNA sequence associated with a particular property / encoding for a particular protein h h HH Hh h H • Allele • each of two or more alternative forms of a gene that arise by mutation and are found at the same place (locus) on a chromosome • Homozygous: • Refers to a gene with identical alleles on both homologous chromosomes • Heterozygous: • Refers to a gene with different alleles on each homologous chromosome 4 Phenotype / Genotype Phenotype: • The observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences Genotype of an Organism: • The (entire) set of alleles in an organism that determines the expression of its characteristic(s) or trait(s) (phenotype) 5 Trait/Character • A specific part/relatively discrete element of the total phenotype Dichotomous Characters • Yes/No • Extra Fingers, Presence or absence of a disease Quantitative/Continuous Characters • Height/IQ Apparent: Eye colour Non-apparent: Expression of Glucose-6phosphate dehydrogenase 6 Mendelian Characters • Specific identifiable characters/traits (normal or pathological) that show a (fairly) clear cut pattern of inheritance • We now understand as Monogenic • The specific character/trait depends (mostly) on genotype at a single gene locus That is To Say: • Given an otherwise normal genetic & environmental background one allele at one specific locus determines the character • Invisible “heritable factors” providing for visible traits in predictable ways - “Experiments in plant hybridization” 1866 7 Monogenic Inheritance Mendelian Characters:  ~10,000 described Mendelian characters  https://www.omim.org/  MIM ♯143100 Huntington Disease  Gene Map Locus 4p16.3 8 Punnett Square Father A mother is heterozygous for the H allele, which has a dominant pattern of inheritance for the monogenic Huntington’s disease character Mother The father is homozygous for the h allele, which has a recessive pattern of inheritance for the non HD character H h h h Hh Hh Huntington disease Huntingto n disease hh hh Normal Normal We can fill in the Punnett Square to predict the genotypes and phenotypes of their 4 children 9 Mendelian patterns of inheritance • Dominant: one abnormal allele (from one parent) is enough to manifest the character – heterozygotes for mutation affected • Recessive: need two abnormal alleles (usually from both parents) to manifest the character – only homozygotes for mutation affected • Terms generally refer to pattern of inheritance of the character (phenotype) rather than to the gene • Terms describe the functional relationship of two different alleles of the same gene in a (compound) heterozygous organism H h Huntington’s Disease (dominant) c c Cystic Fibrosis (recessive) 10 Dominant Genetic Characters Individuals with the character typically have a parent with the character e.g. Huntington Disease (exceptions – new mutations and incomplete penetrance) 11 Recessive Genetic Characters Affected individuals typically have unaffected parents e.g. Cystic Fibrosis 12 Penetrance • The extent to which the phenotype/trait is manifest when the appropriate genotype is present • If a condition is fully penetrant, the clinical phenotype is manifested in 100% of the offspring with the appropriate genotype – e.g. Huntington Disease • Incomplete/reduced penetrance refers to when the clinical phenotype is not observed among all individuals who carry the disease-associated genotype – e.g. breast cancer in carriers of BRCA1 and BRCA2 genes • Penetrance is a complex continuum influenced by other (modifier) genes and non-genetic factors (environment, lifestyle, age, epigenetics) 13 Expressivity • Expressivity describes the differences in the degree that the clinical phenotype is manifest in individuals with the condition • Variable expressivity is the norm, for example in Cystic Fibrosis, where even siblings with the same mutation have varying degrees of lung and pancreas dysfunction Variable expressivity in Neurofibromatosis Type 1: Café-au-lait spots in a 6 year old, multiple hyperpigmented macules and neurofibromas in an adult woman. 14 Incomplete Penetrance vs Variable Expressivity Incomplete penetrance Variable expressivity • Penetrance = probability of a genotype/trait being expressed • Incomplete = phenotype only expressed in a fraction (%) of the population with the genotype • Variation in phenotypic expression when penetrance is complete • A range of symptoms displayed in individuals with the same fully penetrant genotype BB x bb BB x bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Bb Incomplete penetrance for blue phenotype Variable expressivity for blue phenotype 15 Incomplete Dominance • A form of intermediate inheritance in dominant disorders in which one allele is not completely expressed over its paired allele – “blending of traits” ff Wild-type • Clinical phenotype of most dominant genetic traits in heterozygotes (Aa) is in-between that of wild-type (aa) and mutant homozygotes (AA) • Homozygosity for a disease causing mutation (AA) with dominant pattern of inheritance often results in much more severe clinical phenotype Ff Achondroplasia • Example = Achondroplasia • Heterozygosity for FGFR3 mutation (Ff) = short limbed dwarfism • Homozygosity for FGFR3 mutation (FF) = stillborn/early death due to respiratory failure (underdeveloped rib cage) Image sources: By suzi-pratt.com - Nikolaj Coster-Waldau at HBO's "Game Of Thrones" Season 3 Seattle Premiere at Cinerama, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=31943921 By Uploaded by TAnthony, https://en.wikipedia.org/w/index.php?curid=43279864 Death pre or early post natal FF 16 Things to Remember 1. A trait/character is a phenotypic feature that may be inherited in a dominant or recessive pattern Dominant characters: individuals with the character typically have a parent with the character Recessive characters: the parents typically don’t have the character 2. Penetrance = the fraction of the population in which (or probability that) the phenotype/trait is expressed when the appropriate genotype is present 3. Variable expressivity = a range of phenotypic symptoms displayed in individuals with the same fully penetrant genotype 4. Incomplete dominance: the clinical phenotype of most dominant genetic traits in heterozygotes (Aa) is in-between that of wild-type (aa) (normal) and mutant homozygotes (AA) (most severe) 19