BMS/GNA2042 Lecture 4 - Extensions to Mendelian Inheritance II - Monash University PDF

BMS/GNA2042 Lecture 4 Extensions to Mendelian Inheritance II Gene and environmental interactions References: Klug 12th ed, Chapter 4 Strachan & Read 4th ed, Chapter 3 © 2017 Pearson Education, Ltd. Associate Professor Francine Marques @FZMarques Acknowledgement of Country I wish to acknowledge t...

BMS/GNA2042 Lecture 4 Extensions to Mendelian Inheritance II Gene and environmental interactions References: Klug 12th ed, Chapter 4 Strachan & Read 4th ed, Chapter 3 © 2017 Pearson Education, Ltd. Associate Professor Francine Marques @FZMarques Acknowledgement of Country I wish to acknowledge the people of the Kulin Nations, on whose land we are gathered today, and pay my respects to Elders, past, present, and emerging. I would also like to ask that we all reflect on the impact of policies and research in creating such different health outcomes for Aboriginal and Torres Strait Islander Peoples. What we will learn today: • • • • • • • Complementary gene action Epistasis Duplicate genes Sex-influenced and sex-limited traits Environmental influence Genetic imprinting Mitochondrial inheritance Tools & Technology Lesson A Lesson B Lesson C Lesson D Problem identification & solution LECTURE 4 PART A Associate Professor Francine Marques F J'd Autosomal dominant Affected: Aa Unaffected: aa © 2017 Pearson Education, Ltd. only females only carriers X-linked recessive Affected X^aY or XaY Carriers: X^AX^a or XAXa Unaffected: X^AY or XAY, X^AX^_ or XAX_ https://www.researchgate.net/publication/13759773_Dystrophin_gene_abnormalities_in_two_patients_with_idiopathic_dilated_cardioyopathy/figures?lo=1 I skip © 2017 Pearson Education, Ltd. Autosomal recessive Affected: aa Carriers: Aa Unaffected: A_ generations If a father has type O blood and his son has type A blood, what are the possible blood types of his son’s mother? a) b) c) d) e) type O type A type B types A, B, or O any blood type Father iOiO Son iAiO Mother needs to have at least one iA allele vatffressivity You are studying an autosomal dominant disease. Symptoms include the formation of lesions on the skin. Symptoms range from t mild to severe, but all individuals with the dominant allele show symptoms. This is an example of: a) incomplete penetrance and variable expressivity b) full penetrance and variable expressivity c) incomplete penetrance and uniform expressivity d) full penetrance and uniform expressivity e) incomplete penetrance and incomplete dominance Since all individuals who have the variant show the phenotype, penetrance is 100%. The severity of symptoms varies so expressivity is variable. The genes that Mendel worked with were__________________ a) Variable in penetrance and expressivity b) Variable in penetrance only c) Variable in expressivity only d) 100% penetrant with 100% expressivity The 7 sets of pea genes that Mendel worked with showed 100% penetrance and 100% expressivity. Due to this the dominant and recessive genes always expressed the different phenotype to the full degree of expression. Extensions to Mendel 2: Gene-gene and gene-environmental interactions Many traits are genetically heterogeneous – they are controlled by multiple genes e.g. deafness in humans When genes interact in pathways, variants of >1 gene can produce exactly the same phenotype  locus heterogeneity When two genes affect different traits, a dihybrid cross gives an F2 9:3:3:1 phenotypic ratio = dihybrid ratio. However, most traits are controlled by two or more genes, therefore we need to consider gene interactions. 2.1. Complementary gene action Distinguished by a 9:7 F2 dihybrid ratio Example: Colour in sweet peas. Normally purple, but Bateson and Punnett had several true breeding white varieties. Crossed two together and all F1 were purple. F2 had purple: white in a 9:7 ratio. Brooker Fig 4.20 2.1. Complementary gene action Need a dominant allele for each gene to produce the trait Gene C Gene P C_ P_ Two genes: C dominant to c, P dominant to p If either cc or pp will be white. Need a dominant allele for both genes to get purple. F2 9 : 7 purple : white C_;P_ : C_;pp or cc;P_ or cc;pp © 2017 Pearson Education, Ltd. Gene P Gene C Colourless precursor 1 Colourless precursor 1 Colourless precursor 1 Colourless precursor 1 F2 Colourless precursor 2 C_ C_ cc cc Colourless precursor 2 Colourless precursor 2 Colourless precursor 2 P_ pp P_ pp Purple Pigment? Purple Pigment? Purple Pigment? Purple Pigment? 9 : 7 purple : white C_;P_ : C_;pp or cc;P_ or cc;pp LECTURE 4 PART B Associate Professor Francine Marques Extensions to Mendel II: 2.2 Epistasis Klug 10, Chapter 4 2.2 Epistasis The phenotype produced by a variant of one gene (called the epistatic allele) blocks or masks the phenotype produced by alleles of another gene. Usually occurs because genes act in the same pathway for producing trait. No new phenotypes are produced, but fewer than four phenotypes expected by two separate genes Recessive epistasis - distinguishing F2 ratio is 9:3:4 A recessive epistatic allele blocks or masks phenotypic effects of alleles of other genes only when it is homozygous. e.g. Recessive epistasis Coat colour in Labrador retrievers, ee is epistatic to B gene. t yellow E gene brown B gene black Hartwell Fig 3.13a yellow yellow E gene E_ dom yellow E_ dom yellow ee reves brown brown brown brown B gene B_ dom bb reees B_ am black black black X black I yellow eeZ recessive brown bb red's black X 9 B_E_ (black) 3 bbE_ (brown) 4 __ee (yellow) The case of Charlie Chaplin’s paternity suit Joan Berry O A AB Carol Ann Question: Was he the father? Changed paternity laws in California Bombay phenotype India 1:10,000 European ancestry 1:250,000 What is wrong with this pedigree? Hartwell Fig 3.13b Bombay phenotype explained • H substance – One or two terminal sugars are added – O blood types (ii) only have the H substance protruding from red blood cells • In 1952, a female in Bombay was found to be homozygous for FUT1 at the fucosyl transferase locus, which masks expression of IA and IB alleles – Prevented her from producing H substance – No substrate to make A or B antigens – Resulted functionally in type O Dominant epistasis • Dominant allele at one loci masks an allele at second loci • Ratio 12 : 3 : 1 • Example: Summer squash fruit colour – Dominant allele B  White fruit • Regardless of second loci allele – Absence of B allele  Yellow fruit • Genotypes bb, Aa, AA  yellow fruit • Genotype aa  green LECTURE 4 PART C Associate Professor Francine Marques Extensions to Mendel II 2.3 Duplicate genes Distinguished by 15:1 F2 dihybrid ratio Either A or B is required e.g. fruit shape in Shepherd’s purse (weed) - two genes, each with two alleles - dominant allele of either  triangular shape. 15 T - ; - - or - - ; V – 1 tt;vv Brooker Fig 4.24 http://www.uaex.edu/yard-garden/images/weed_id/shepherds_purse_fruit.jpg Extensions to Mendel II 2.4 Effect of environment on phenotype The environment can affect the phenotypic expression of a genotype Examples: 1. Temperature e.g. Coat colour in the arctic fox 2. Chemicals e.g. Phenylketonuria (PKU) in humans Loss of enzyme to metabolize amino acid phenylalanine (Phe) Severe problems unless low-Phe diet Alter physical environment by removal of phenylalanine from diet Temperature-sensitive variants: Siamese cats • Temperature-sensitive allele is responsible for pigment production. • They work as conditional variants. • Variant in tyrosinase (that makes melanin) in Siamese cats causes it work best at room temperature. • Thus, body extremities that are closer to room temperature have darker hair colour compared to body regions that are warmer. Phenylketonuria (PKU) Autosomal recessive, PAH gene Affects 1:15,000 in Australia (20-25 babies a year, tested at birth) Phenylalanine hydroxylase Neurotoxic, leading to intellectual disability https://wiki.ubc.ca/File:How_does_PKU_occur%3F.png Congenital lactase deficiency (variant in the LCT gene, AR) • Also called congenital alactasia, is a disorder in which infants are unable to break down lactose in breast milk or formula. • The LCT gene provides instructions for making the lactase enzyme. • Variants that cause congenital lactase deficiency are believed to interfere with the function of lactase, causing affected infants to have a severely impaired ability to digest lactose in breast milk or formula. https://www.gbhealthwatch.com/Trait-Lactose-Intolerance.php Extensions to Mendel II 2.5 Sex-influenced and sex-limited traits • Sex influences the inheritance and expression of genes in a variety of ways • Sex-chromosome influenced characteristics – Inherited characteristics that are conditioned by the sex of the individual – Example: baldness behaves as an autosomic dominant condition in XY carriers, and as a recessive in XX carriers • Sex-chromosome limited characteristics – Characteristic only appears (or develops) in one of the sexes – Example: Ovary development and milk yield in XX; sperm development in XY Pattern of baldness in the Adams family line John Adams (father) Brooker Fig 4.15 John Quincy Adams Charles Francis Adams (son) (grandson) Henry Adams (great-grandson) Sex-influenced does not mean trait is sex-linked!! Allele B behaves dominant in males and recessive in females In BB genotype in females, phenotype is less pronounced Brooker Fig 4.16 LECTURE 4 PART D Associate Professor Francine Marques Extensions to Mendel II 2.6 Genomic (parental) imprinting • For some human genes, one of the alleles is transcriptionally inactive (no mRNA is produced), depending upon the parent from whom the allele was received. • This process of gene silencing is known as imprinting, and the transcriptionally silenced genes are said to be imprinted. • Imprinted alleles tend to be heavily methylated or have modifications in chromatin of specific histone types (epigenetic changes). • Selective gene silencing impacts phenotypic expression. • Silencing depends on parental origin of genes and occurs in early development. Example: deletion of chromosomal region 15q11-q13 Inheritance of the deletion from the father produces Prader-Willi syndrome (PWS) (paternally expressed genes SNRPN and NDN) Inheritance of the deletion from the mother produces Angelman syndrome (maternally expressed gene UBE3A) Inheritance pattern of this deletion and the activation status of genes in the critical region Extensions to Mendel II 2.7 Cytoplasmic inheritance • Inheritance of parental characters through non-chromosome DNA. • Mitochondrial DNA is cytoplasmically inherited since the information is not segregated at mitosis. • Inheritance is matrilineal (XX) only and can be initially seen as autosomal dominant because affects either sex. mitochondria have sperm doesn't any that can be • Human mitochondrial genome is small (16.5kb). inherited • These encode only 37 genes that are important in mitochondrial development. Mitochondrial genes • The mitochondria, which produce ATP, have their own unique DNA. • Mitochondrial DNA is maternally inherited and has a high mutation rate. • A number of diseases are known to be caused by mutations in mitochondrial DNA. Homoplasmy: every mitochondrial genome carries the causative mutation Heteroplasmy: contain a mixed population of normal and mutant genomes in each cell Maternal haplogroup • U5a1b (1 in 270 23andme customers), 8,500 years old Learning outcomes • Explain how complementary gene action works • Describe epistasis and the Bombay phenotype • Explain the impact of gene duplication in inheritance patterns • Describe interaction of genes with environment, and give examples • Understand the concept of genetic imprinting and sex-chromosome influenced/limited traits • Identify a pedigree affected by mitochondrial DNA mutation If you are thinking… “I have questions” or “I would love to talk to you” Post Questions: please post them on Moodle Chat Private chats about the lectures, careers in genetics and genomics, or mental health – book via Moodle