Lecture 2: Mendelian Genetics PDF

HMB265: Human & General Genetics Lecture 2: Mendelian Genetics Dr. Maria Papaconstantinou  Lecture Outline Early theories of inheritance Gregor Mendel August Krogh Principle and Genetic Models Basic Genetic Terminology Mendel’s Experiments-Antagonistic Pairs, Dominance, Te...

HMB265: Human & General Genetics Lecture 2: Mendelian Genetics Dr. Maria Papaconstantinou  Lecture Outline Early theories of inheritance Gregor Mendel August Krogh Principle and Genetic Models Basic Genetic Terminology Mendel’s Experiments-Antagonistic Pairs, Dominance, Testcross, Monohybrid Cross, Laws of Segregation and Independent Assortment Reading: Goldberg et al. 8th US edition, Chapter 1 (emphasis on pages 1-12) We can observe traits being inherited, but can we predict how they are inherited at all? Steve & Liv Tyler Charlie & Martin Sheen  We can observe traits being inherited, but can we predict how they are inherited at all? Goldie Hawn & Kate Hudson Katie Holmes & Suri Cruise How about similar traits appearing in unrelated people? Sarah Palin & Tina Fey We can observe traits being inherited, but can we predict how they are inherited at all? Merino Sheep Moravian sheep breeders in 1837… Selective breeding practices had produced valuable flocks of merino sheep that made large quantities of soft, fine wool, but what now? Breeder’s dilemma: “I possess a ram that would be priceless if its advantages are inherited by its offspring, but, if they are not inherited, then it is worth no more than the cost of wool, meat and skin. What should I do?” Why Moravian sheep breeders had a dilemma in 1837 Two hypotheses to explain inheritance: 1) One parent contributes more to an offspring’s inherited traits - e.g., Aristotle contended that it was the male and that a fully formed homunculus was inside the sperm 2) Blended inheritance - the traits of the parents are blended in their offspring (like blue and yellow to make green) - explained single offspring, but not siblings, or the next generation Nicolaas Hartsoeker 1692  What Abbot Napp said… Abbott Cyril Napp presided over the Augustinian monastery in Brunn, in the province of Moravia, in Austria (now Brno, Czech Republic) Napp proposed that breeders could improve their ability to predict what traits would appear in their offspring if they addressed three questions: What is inherited? How is it inherited? What is the role of chance in heredity? Gregor Mendel Born Johann Mendel in 1822 Entered the Augustinian monastery in Brunn in 1843 at age 21 Napp sent Mendel (now called Gregor) to University of Vienna to study physics (with Doppler), maths, chemistry, botany, palaeontology and plant physiology Returned from Vienna in 1853, began genetics experiments in 1854, published results in 1865 at the age of 43  Gregor Mendel: Augustinian Monk, Father of Genetics Appropriate The right mind… biological material… The proper equipment…  The August Krogh Principle “For many problems there is a model on which it can easily be most conveniently studied” “There are organisms that, because of their anatomy or physiology, provide easy access to the mechanisms that underlie interesting and important physiological and biochemical problems” Hans Krebs (1975) J. Expt. Zool. 194: 221-226  Following from the Krogh Principle... Need to identify organisms that are more amenable to genetic analysis- model organisms: Short generation time Can be inbred (self-fertilize) Simple reproductive biology Small size (easy to grow/breed) Large numbers of progeny Genetic Models  Why Pisum sativum was a good choice… Well characterized, cultivated plant, grew well in Brno Could be self-fertilized (selfed) - pollen from the plant could be used to pollinate its own flowers - allows inbreeding Could obtain and maintain pure-breeding lines - these always bred true producing the same trait generation upon generation Could be readily cross-fertilized to create hybrids between pure-breeding lines - could have carefully controlled matings and reciprocal crosses - to rule out the effect of one parent versus the other Could examine clear-cut (qualitative/discrete) traits where there were 2 forms of the trait- “either-or” choices - unambiguously distinguish forms of the trait Could have a large number of plants and progeny, so could subject the data to statistical analysis - Mendel did quantitative analyses that produced robust results and aided interpretation  Taking advantage of the simple reproductive biology of plants… Goldberg et al. (2024) Genetics: From Genes to Genomes  Taking advantage of the simple reproductive biology of plants… Traits that Mendel investigated - “antagonistic pairs” -axial -terminal Goldberg et al. (2024) Genetics: From Genes to Genomes  Dominance One of the two traits in an antagonistic pair was dominant and would always be manifest in the F1 hybrid  Dominance -axial Goldberg et al. (2024) Genetics: From Genes to Genomes  Dominance Reciprocal crosses revealed that not only were traits dominant but also that this was independent of the parent - “It is immaterial to the form of the hybrid which of the parental types are used in the cross” Some classical genetics terminology Locus - a genetically defined location - strictly speaking, we don’t know if it is only one gene or not - but it behaves like a single gene (more on this in future lectures) Allele - alternative form at a given locus Dominant - the allele that manifests itself regardless of the other allele that is present - indicated by an upper- case letter (e.g. A) - the trait that is manifest in a hybrid Recessive - an allele whose effect is “masked” when the dominant allele is present - all alleles at a locus must be recessive in order for the recessive allele to manifest itself - indicated by a lower-case letter (e.g. a) Some classical genetics terminology Homozygous – when both alleles at a given diploid locus are the same – i.e. AA or aa Heterozygous – when there is one dominant and one recessive allele present at a diploid locus– i.e. Aa Homozygote – an individual who is homozygous at the locus in question Heterozygote – an individual who is heterozygous at the locus in question Hybrid – derived from two different parents Monohybrid – one hybrid locus Dihybrid – two hybrid loci True-breeding - homozygous at the loci/locus in question Some classical genetics terminology P – Parental generation F1 – first filial generation – the offspring derived from the parental generation F2 – second filial generation – the offspring derived from the F1 generation Self - an inbreeding cross that involves individuals that are genetically identical (e.g. a single plant with itself, or between full siblings derived from true breeding parents)  Reappearance of the recessive trait completely disproves “blending” and uniparental inheritance Monohybrid Cross Goldberg et al. (2024) Genetics: From Genes to Genomes Further crosses confirm predicted ratios The Law of Segregation was inferred from these crosses Goldberg et al. (2024) Genetics: From Genes to Genomes  The Law of Segregation explains how genes are transmitted Two members of a gene pair segregate from each other into the gametes, so that one-half of the gametes carry one member of the pair and the other one-half of the gametes carry the other member of the pair The alleles unite at random, one from each parent, at fertilization Goldberg et al. (2024) Genetics: From Genes to Genomes  The Law of Segregation explains how genes are transmitted Goldberg et al. (2024) Genetics: From Genes to Genomes Equal segregation 1 : 2 :1 YY : Yy : yy Equal segregation 3 : 1 yellow : green Mendel’s First Law incorporates the fact that his results reflected basic rules of probability  Rules of Probability Reginald Punnett William Bateson (1875-1967) (1861-1926)  Genotypes & Phenotypes Genotype – pair of alleles present in an individual Phenotype – observable characteristic of an organism Genotypes versus Phenotypes Goldberg et al. (2024) Genetics: From Genes to Genomes  How to discriminate between dominant homozygotes (e.g. YY) and heterozygotes (e.g. Yy)? Testcrosses reveal unknown genotypes Testcross = unknown genotype X homozygous recessive Goldberg et al. (2024) Genetics: From Genes to Genomes  Dihybrid crosses reveal: The Law of Independent Assortment Goldberg et al. (2024) Genetics: From Genes to Genomes The Law of Independent Assortment During gamete formation, the segregation of alleles at one locus is independent of the segregation of alleles at another locus Results in predictable ratios of phenotypes in the F2 generation as shown by a Punnett square Follows basic laws of F1 22 probability Goldberg et al. (2024) Genetics: From Genes to Genomes F2  The Law of Independent Assortment F1 F2 Hartwell et al. (2017) Genetics: From Genes to Genomes The Law of Independent Assortment Goldberg et al. (2024) Genetics: From Genes to Genomes Laws of probability for multiple genes Laws of probability for multiple genes Punnet Square method - 24 = 16 possible gamete combinations for each parent Thus, a 16 × 16 Punnet Square with 256 genotypes That’s one big Punnet Square! Imagine that we want to know the likelihood of particular genotypes appearing in a particular cross, with this many loci... e.g. What is the probability of obtaining the genotype RrYyTtss? Loci Assort Independently - So we can look at each locus independently to get the answer.  Rules of Probability Independent events - probability of two or more events occurring together What is the probability that both A and B will occur? Solution = determine probability of each and multiply them together (product rule). Laws of probability for multiple genes (cont) Laws of probability for multiple genes (cont) What is the probability of obtaining a genotype that is either RRYYTTSS or rryyttss?  Rules of Probability Mutually exclusive events - probability of one or another event occurring What is the probability of A or B occurring? Solution = determine the probability of each and add them together (sum rule). Laws of probability for multiple genes (cont) What is the probability of obtaining a genotype that is either RRYYTTSS or rryyttss? Summary of Mendel’s 1865 Paper Inheritance is particulate - not blending (Point 1) There are two copies of each trait in a germ cell (Point 2) Gametes contain one copy of the trait (Point 3) Alleles (different forms of the trait) segregate randomly (Point 4) Alleles are dominant or recessive - thus the difference between genotype and phenotype (Point 5) Different traits assort independently (Point 6) Mendel’s 1865 Paper Points 1 & 2 Point 3 Point 4 Point 5  So then what happened? Mendel’s work sat dormant for 34 years - untested, unconfirmed and unapplied… to Mendel’s frustration for 18 of those years 1900 - 16 years after Mendel’s death - his work was “rediscovered” by three researchers: - Carl Correns - Hugo de Vries - Erich von Tschermak Shortly thereafter, William Bateson and R.C. Punnett used Mendel’s work as the basis of investigations into why hybrid flowers were “unstable” - work that was commissioned by the Royal Horticultural Society and which led to the coining of the words “genetical” and “genetics” 1) A mouse has the following genotype: A/A; B/B; c/c; D/d. This mouse is characterized as what type of individual based on that genotype? A) monohybrid B) dihybrid C) trihybrid D) tetrahybrid 2) For the following cross: A/a; B/b; C/c X A/a; B/b; C/c What proportion of the progeny will have the dominant phenotype for A, and the recessive phenotype for B and C? A) 9/64 B) 1/16 C) 3/16 D) 3/64 3) A female guinea pig with genotype Aa; Bb; cc; DD; Ee is crossed with a male guinea pig with genotype aa; Bb; Cc; dd; Ee. What proportion of the progeny will be phenotypically identical to the female parent? A) 9/128 B) 9/64 C) 3/128 D) 3/32