RCSI Mendelian Genetics (AD, AR, Genetic Heterogeneity) FFP1 PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in MENDELIAN GENETICS Éirinn (AD, AR, GENETIC BAHRAIN HETEROGENEITY) Module : Fou...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in MENDELIAN GENETICS Éirinn (AD, AR, GENETIC BAHRAIN HETEROGENEITY) Module : Foundations for Practice 1 FFP1 Class: Med year 1 semester 1 Lecturer : Paul O’Farrell Date : 17 October 2024 Learning objectives Identify inheritance models in genetic disease from pedigrees Describe autosomal dominant inheritance and explain exceptions in pedigrees Explain how a mutation at a single gene can cause a disease phenotype Describe autosomal recessive inheritance Explain genetic heterogeneity, distinguishing: i) allelic and ii) locus heterogeneity). Illustrate using examples of PKU and retinitis pigmentosa Basics Genome : all the genetic material, 3 billion bp The genome is organised into individual DNA molecules called chromosomes Humans have 22 pairs of homologous autosomes 1 pair of heterologous sex chromosomes Diploid : 2 sets of chromosomes (n=46) Haploid : 1 set of chromosomes (n=23) ALLELES Most cells are diploid ie two homologous copies of each chromosome – (one maternal + one paternal) (gametes are haploid) 2 copies of each gene, one per chromosome Each gene copy is called an allele Alleles can vary slightly in their DNA sequence, so there can be different alleles of a gene Eg A & a Genes with two or more alleles in the population: genetic polymorphism GENOTYPES Different alleles combine to produce different genotypes – AA or aa Homozygote – Aa Heterozygote Genotype = genetic make-up Phenotype = physical appearance » The visible or otherwise measureable physical and/or biochemical characteristic of an organism, resulting from the genotype and its interaction with the environment* Phenotype is (largely) determined by genotype If A determines phenotype, it is said to be dominant; a is therefore said to be recessive Simple mendelian inheritance Eg. Recessive trait in peas Phenotype : round or wrinkled Alleles R and r R is round and is dominant Genotype of offspring 1:2:1 r = wrinkled and is recessive Phenotype of offspring 3:1 Heterozygote cross Rr x Rr R r – Gametes R and r – Independent assortment leads to 4 possible R RR Rr arrangements of wrinkled parental alleles in the r Rr rr offspring MENDELIAN INHERITANCE PATTERNS Autosomal dominant Autosomal recessive Y-linked X-linked dominant X-linked recessive (mitochondrial) Identified in families by pedigree analysis Standard symbols in pedigree analysis Strachan and Read 4.1 proband Note: When multiple siblings are displayed in a pedigree, the convention is to arrange them in order of age, with the oldest to the left An Autosomal Dominant mutation can cause disease when only one copy of the gene is affected AD traits expressed in homozygotes AA and Heterozygotes Aa Most cases of AD disease will be heterozygous Why? - homozygotes will be at a selective disadvantage compared to heterozygotes and frequently die before reproductive age Allele frequencies in AD disease are usually low How does a mutation of a single copy of the gene cause a disease phenotype? Or, what makes a dominant mutation dominant? Haploinsufficiency Where Normal Physiology requires > 50% gene product Structural proteins Transcription factors Receptors Enzymes loss 50% normal activity of a protein = disease Eg LDL receptor (familial hypercholesterolaemia) Dominant Negative Effect Abnormal protein produced Interferes with the function of the product of the normal allele Eg collagen disorders (eg osteogenesis imperfecta – brittle bone disease)_ Gain of Function Function of Mutant protein enhanced e.g. Achondroplasia e.g. Huntington disease: novel function is toxic to the cell (mutant protein forms aggregates) Loss of Heterozygosity Dominantly Inherited Cancers Tumour suppressor genes : Inherited copy of mutant gene and random loss of normal allele, even in only a few cells, renders those cells cancerous Eg Retinoblastoma, Familial Adenomatous Polyposis Examples of AD inheritance Familial hypercholesterolaemia – Reduced ability to remove LDL cholesterol from the bloodstream: atherosclerosis, MI at young age Huntington’s disease – Mutant huntingtin protein damages neurons Osteogenesis imperfecta – Abnormal collagen leads to bone fragility Neurofibromatosis – Loss of neurofibromin protein allows uncontrolled cell growth (NF type 1) Familial adenomatous polyposis – Damage to APC protein allows development of colorectal tumours AD pedigree Autosomal Dominant inheritance pattern Characteristic pattern is ‘vertical’ – “phenotype is seen in every generation” – Every affected individual will have an affected parent Both sexes have equal probability of being affected Approximately 50% of the offspring of an affected parent will be affected Most common AD mating type Aa + aa –Generally, the frequency of A in the population will be low A a a Aa aa a Aa aa Apparent exceptions to AD inheritance pattern Mutation Sporadic cases may arise within families by mutation Variable expressivity Expressivity refers to the nature and severity of the phenotype; (but people with the genotype show the phenotype to some degree) Reduced penetrance – Penetrance refers to the proportion of individuals with a given genotype who show the associated phenotype Reduced penetrance AD pedigree An autosomal recessive mutation will only show a disease phenotype when both copies of the gene are affected Symptoms only seen in homozygotes : aa Heterozygotes (Aa) are “carriers” Carriers are not at a selective disadvantage – even if affected individuals do not breed, the mutation can become widespread AR diseases are more common than AD AR pedigree AR inheritance pattern Affected individuals tend to be in a single sib-ship and disease does not occur in multiple generations - A ‘horizontal’ pattern Both sexes affected with equal probability When 2 carriers mate: ¼ affected ½ carrier ¼ normal Strachan and Read 4.2 EXAMPLES OF AR INHERITANCE Cystic fibrosis 1/1600 (USA)(1/20 is a carrier) Phenylketonuria 1/12000 Albinism Sickle-cell anaemia α and β thallassaemia Most common AR mating type Carrier x Carrier Aa x Aa ¼ AA - normal ½ Aa - carrier ¼ aa - affected A a A AA Aa a Aa aa Less common AR mating types carrier x affected: Aa x aa Normal x affected: AA x aa ½ Aa – carrier all Aa – carrier ½ aa – affected A A A a a Aa Aa a Aa aa a Aa Aa a Aa aa What to look for.. When families are small, AR disease can appear as a single case and may be dismissed as sporadic Multiple affected siblings within large sib-ships Parental consanguinity Demonstration of a partial defect in obligate heterozygotes Newborn Screening Eg for PKU General Problems in pedigree analysis Uncertain parentage Small human family size Accurate information about relatives De novo mutation Reduced penetrance / variable expressivity Genetic heterogeneity Disease Complexity: Genetic heterogeneity Genetic heterogeneity can create difficulties in understanding genetic disease Genetic heterogeneity : Where different genetic defects produce identical or similar clinical phenotypes Allelic heterogeneity: different mutations in the same gene Locus heterogeneity: mutations in different genes often involve complex pathways – pathway can be interrupted at many points with the same result Allelic heterogeneity Example : Phenylketonuria (PKU) Phenylalanine hydroxylase (PAH) converts Phe to Tyr; this is part of the degradation pathway for phenylalanine. A defect causes a build up of phenylalanine and phenylketones and can lead to mental retardation A number of different mutant versions of PAH are known – which lead to PKU of varying degrees of severity Allelic heterogeneity The level of enzyme activity of many of these different mutants is known: Activity Mutation