Mendelian Inheritance Patterns PDF

Mendelian Inheritance s2c1 Patterns Paul Dunn Learning Objectives Explain the principles of Mendelian 1 inheritance Explain Mendel’s laws of segregation & 2 independent assortment & how they relate to human genetics Define features of diseases &...

Mendelian Inheritance s2c1 Patterns Paul Dunn Learning Objectives Explain the principles of Mendelian 1 inheritance Explain Mendel’s laws of segregation & 2 independent assortment & how they relate to human genetics Define features of diseases & traits that are 3 inherited by: dominant, recessive & X-linked modes of inheritance 4 Identify the mode of inheritance from pedigrees  Gregor Mendel (1823-1884)  Mendel had no knowledge of chromosomes or genes  Proposed the theories of inheritance  Developed the concept of dominant & recessive units, which exist in pairs  These hereditary units are now referred to a genes  Alleles & Zygocity  Genes can have alternative forms that differ in sequence, called alleles  Homologous Chrs with identical alleles for a given gene are referred to as homozygous  Homologous Chrs with different alleles for a given gene are referred to as heterozygous  Dominant/Recessive Alleles  Take a single gene with 2 possible alleles: Allele 1 = A; Allele 2 = a  In a diploid cell there are 4 possibilities = AA, Aa, aA, aa  Dominant phenotype  The trait is expressed in both the: - homozygote (AA) - heterozygote (Aa)  Recessive phenotype  The trait is only expressed in the homozygote (aa) - Recessive homozygote  Monohybrid Cross Phenotypes: Phenotypes: tall tall tall dwarf Genotypes: AA X aa Genotypes: Aa X Aa Gamete formation Gamete formation AA aa Aa Aa Gametes: A X a Gametes: A a X A a Fertilisation: Fertilisation: Genotypes: Genotypes: AA Aa A aa Aa a Phenotypes: tall Phenotypes: tall tall tall dwarf Zygocity: Heterozygous Zygocity: Homozygou Heterozygous Heterozygous Homozygou s s Mendel’s First Three Principles 1. Unit factors are inherited in pairs Genetic characters are controlled by unit factors existing in pairs in individual organisms 2. Dominance/Recessive When two unlike unit factors responsible for a single character are present in a single individual, one unit factor is dominant to the other, which is said to be recessive 3. Law of Segregation During meiosis the 2 alleles for any given gene separate so that each ends up in different gametes Each gamete contains only one homologous Chr & therefore only one allele for each gene  Punnett Square tall tall A a Aa X Aa GenotypePhenotype AA Aa 1 AA A 3/4 tall tall tall 2 Aa Gamete formation Aa Aa 1 aa 1/4 dwarf a Aa aa tall dwarf 1:2:1 3:1 A a A a Genotype 1:2:1 Phenotype 3:1  Punnett Square Convention  Female (♀) alleles on the top ♀  Male (♂) alleles on the left  Dominant allele in upper case (D) ♂  Recessive allele in lower case (d)  Dominant allele is always written before the recessive (Dd)  Mendel’s 4th Principle of Inheritance Mendel’s Dihybrid Cross Experiment  Law of Independent Assortment  During meiosis the 2 alleles for any given gene separate independently of other alleles for other genes - Not true if the 2 genes found on same Chr (i.e. linked) Chromosomal Theory of Inheritance Law of Segregation Law of Independent Assortment Klug, Concepts of Genetics Fig. 3-1  Independent Assortment & Gamete Diversity  There are >8.3 million (223) unique ways to arrange the 23 pairs of Chr by independent assortment https:// www.youtube. com/watch? v=5I8Bnmdzo S8 ​ Pedigrees  Family Studies  Controlled humans breeding experiments are not possible/unethical  Also relatively few offspring are available for study  Traditionally we use pedigrees (family trees) to study modes of inheritance  Look for the presence/absence of specific traits in each family member of each generation  Why?  Mode of inheritance  Risk factors  Pedigree Conventions ug, Concepts of Genetics Fig. 3-12; 3-13  General Modes of Inheritance 1. Autosomal Dominant 2. Autosomal Recessive 3. Sex-linked Dominant 4. Sex-linked Recessive  Autosomal Dominant (AD)  Only requires one copy of mutant gene to show phenotype (disease symptoms)  Gain-of-function  One affected parent or sporadic mutation  Statistically 50% of offspring affected  Vertical pedigree pattern  Less severe than recessive disorders  May show variable expressivity  May show ‘anticipation’ - earlier age of onset with increased severity in successive generation  Gain-of-Function Mutations Alberts, Essential Cell Biology, Fig. 19-26  Autosomal Dominant DAD HAS THE DISEASE MUM DOES NOT HAVE THE DISEASE d ♀ d D Dd Dd ♂ D d d d Affected Affected dd dd d UnaffectedUnaffected D d D d d d d d Dd = 2/4 = 50% (Affected) dd = 2/4 = 50% (Unaffected) 0% CHILDREN HAVE THE DISEASE 50% CHILDREN DO NOT HAVE THE DISEASE AD Pedigree  Autosomal Recessive (AR)  Requires both copies of mutant gene to show phenotype (disease characteristics)  Loss-of-function mutation  Generally inherited from both parents who are usually unaffected carriers  Statistically 25% of offspring affected  Horizontal pedigree pattern  Typically more severe than dominant disorders  Less variable expressivity  Clustering of phenotype among siblings  Autosomal Recessive DAD IS A CARRIER (unaffected) MUM IS A CARRIER (unaffected) D ♀ d DD D Unaffected Dd ♂ D d D d Carrier Dd dd d Carrier Affected D D D d D d d d DD = 1/4 = 25% (Unaffected Dd = 2/4 = 50% (Carrier) 25% CHILDREN DO NOT HAVE 50% CHILDREN ARE CARRIERS 25% HAVE THE DISEASE dd = 1/4 = 25% (Affected) THE DISEASE  Loss-of-Function Mutations Alberts, Essential Cell Biology, Fig. 19-26 AR Pedigree  Sex-Linked Inheritance  Generally refers to genes inherited on X chromosome  X-linked pedigrees show NO male-to-male transmission  X-Linked Dominant  At least one parent affected  Males & females equally affected  Males display more severe forms  All females children of affected males are affected  X-Linked Recessive  Skips generations, more affected males  50% of sons of carrier females are affected  Hemizygocity  Males are hemizygous for most X-linked genes  single X Chr, very few of the same genes are on Y Chr  X-Linked Dominant (Affected Father) DAD HAS THE DISEASE MUM DOES NOT HAVE THE DISEASE X d ♀ X d X XDXd XDXd X X X ♂ Y D D d d Affected Affected Xd Y Xd Y X X X X X X Y UnaffectedUnaffected D d D d d Y d Y XDXd = 2/4 = 50% (Affected) XdY = 2/4 = 50% (Unaffected ALL SONS DO NOT HAVE LL DAUGHTERS HAVE THE DISEASE THE DISEASE  X-Linked Dominant (Affected Mother) DAD DOES MUM HAS THE X D ♀ X d NOT HAVE THE DISEASE DISEASE X XDXd Xd Xd ♂ d X X Affected Affected X Y d D d XDY Xd Y Y UnaffectedUnaffected X X X X X X D d d d D Y d Y XDXd = 1/4 = 25% (Affected) XdXd = 1/4 = 25% (Unaffected) XDY = 1/4 = 25% (Affected) 50% 50% DAUGHTERS DO NOT HAVE 50% SONS 50% SONS DO XdY = 1/4 = 25% (Unaffected) DAUGHTERS HAVE THE NOT HAVE HAVE THE THE DISEASE DISEASE THE DISEASE XLD Pedigrees  X-Linked Recessive (Carrier Mother) DAD DOES NOT MUM IS A X D ♀ X d HAVE THE CARRIER DISEASE (Unaffected) X XDXD XDXd ♂ D X X Unaffected Carrier X Y D D d XDY Xd Y Y Unaffected Affected X X X X X X D D D d D Y d Y XDXD = 1/4 = 25% (Unaffected) XDXd = 1/4 = 25% (Carrier) XDY = 1/4 = 25% (Unaffected) 50% DAUGHTERS DO NOT HAVE 50% DAUGHTERS 50% SONS DO 50% SONS XdY = 1/4 = 25% (Affected) NOT HAVE HAVE THE THE DISEASE ARE CARRIERS THE DISEASE DISEASE  X-Linked Recessive (Affected Father) DAD HAS THE DISEASE MUM DOES NOT HAVE THE DISEASE X D ♀ X D X XDXd XDXd X X X ♂ Y d d D D Carrier Carrier XDY XDY X X X X X X Y UnaffectedUnaffected D d D d D Y D Y XDXd = 2/4 = 50% (Carrier) XDY = 2/4 = 50% (Unaffected ALL DAUGHTERS ARE ALL SONS DO NOT HAVE CARRIERS THE DISEASE XLR Pedigree  Establishing Mode of Inheritance  Autosomal Dominant  X-Linked Dominant  Males & female affected in equal  Affected individuals in multiple proportions generations  Affected individuals in multiple  No male to male transmission generations  All daughters from an affected father  Transmission by individuals of both are also affected sexes  X-Linked Recessive  Only males usually affected  Autosomal Recessive  Transmitted through unaffected  Males & female affected in equal females proportions  Affected males cannot transmit the  Affected individuals usually only a disorder to their sons single generation  Transmission by individuals of both  Y-Linked  Affected males only sexes  Single Gene Disorders  Autosomal Dominant  Achondroplasia, Brachydactyly, Huntington disease, Marfan syndrome, Neurofibromatosis, von Willebrand disease  Autosomal Recessive  Albinism, Cystic fibrosis, Phenylketonuria, Sickle cell anemia, Tay-Sachs, Thalassemia  X-Linked Dominant  Hypophosphatemia, Aicardi Syndrome, Chokenflok Syndrome, Rett Syndrome  X-Linked Recessive  Colour blindness, Duchenne muscular dystrophy, Fragile X, G6PD deficiency, Haemophilia, Lesch-Nyhan syndrome  Resources & Animations  Punnett Square Basics  https://www.youtube.com/watch?v=PyP_5EgQBmE  Independent Assortment  https://www.youtube.com/watch?v=VAUE9YX1KOA  Mendelian Inheritance (Dolan Lab)  https://www.proprofs.com/quiz-school/story.php?title=pedigrees-quiz  Genial Pedigree Draw (web-based tool for drawing pedigrees)  http://www.progenygenetics.com/online-pedigree/  Texts:  Medical Genetics, Jorde, Chapters 4-5