Mendelian Genetics
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Mendelian Genetics

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Mendelian Genetics Mendelian Genetics Document Transcript

  • Week 1, Hilary Term References for lectures 1 and 2 Mendelian Genetics • Texts: Biology Hon. Mods: Cells and Genes – Hartwell et al. Genetics: From Genes to Genomes. 2nd ed., McGraw Hill, 2000, 2004. Human Sciences Prelims: Genetics and Evolution • Chapters 1-4 – Griffiths et al. An Introduction to Genetic Analysis, 2000 • Chapters 1-4 • Homework tonight Lecturer: Rosalind Harding – Revise the process of meiosis email: rosalind.harding@zoo.ox.ac.uk • Lecture Notes: http://www.stats.ox.ac.uk/~harding – Weblearn – http://stats.ox.ac.uk/~harding/teaching.htm Overview of Genes I Overview of Genes I Molecular Genetics is the field of biology which • DNA and RNA: the basis for all processes and studies the structure and function of GENES, structures of life. GENOMES, and HEREDITY at the DNA and RNA level. The whole inherited (genetic) information of an organism is encoded in DNA or RNA and called the GENOME Molecular genetics explains the diversity and complexity of life in unifying terms of chemistry Genomes include both the GENES and the non- Underlying biochemical processes are incredibly similar in coding sequences the various diverse life forms The Human Genome: Molecular genetics provides many tools for genetic Genes: DNA that can be transcribed & translated into proteins (~1.5% of human genome) analysis and manipulation, with wide applications in Non-coding: DNA that may be transcribed into mRNA but biology is not translated; some is related directly to genes for splicing & regulation, but most is not; much is repetitive But genetic analysis has a much older history! Introduction to Genes II Variation is widespread in nature The study of GENES and HEREDITY at the phenotypic level has a long history. People have long puzzled over questions of inheritance Questions about resemblance: Why do children resemble their parents? How can diseases run in families? Questions about diversity within families and within animal or plant breeds: Are there rules about why How can two black labradors have a litter of variation appears and how it black, brown and tan puppies? is transmitted between generations?
  • The first applied genetic practice was artificial selection The modification of variation in plants and animals as domestication, allowed hunters and gatherers to settle in villages and survive as farmers and herders. Dogs were domesticated from maize wolves. Archaeological evidence for domestication traces back 14,000 years. By 1750: ~20 breeds By 1905: 76 breeds Now: 350 – 1000 breeds In 1837 Moravian sheep breeders A dilemma for a Moravian sheep had a problem… breeder Selective breeding He possesses an outstanding ram that would be practices had priceless produced “if its advantages are inherited by its offspring”, but, valuable flocks of “if they are not inherited, then it is worth no more than merino sheep the cost of wool, meat and skin.” that made large quantities of Which would it be? Breeding practices in 1837 offered soft, fine no definite predictions. wool. Merino Sheep But one person was thinking about the problem: Abbot Cyril Napp Some misconceptions of the Abbot Napp speaks to the sheep time breeders… Hypotheses then used to explain inheritance: Abbott Cyril Napp presided over the Augustinian monastery in Brunn, in the province of Moravia, in Austria (now Brno, Czech Republic), 1) One parent contributes more to an a centre of learning in the sciences and humanities. 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 and forever changed (like blue and yellow to make green) Nicolaas Hartsoeker The Augustinian 1692 monastery
  • What Abbot Napp said … Gregor Mendel Napp proposed that breeders 1843: Mendel, aged 21, entered the could improve their ability to Augustinian monastery in Brunn predict which traits would appear in their offspring if they Mendel (now called Gregor) sent by addressed three questions: Napp to University of Vienna to 1) What is study physics (with Doppler), maths, inherited? chemistry, botany, palaeontology & plant physiology 2) How is it Returned from Vienna in 1853, inherited? began genetics experiments in 3) What is the 1854, published results at age 1865 role of chance at the age of 43 in heredity? The monks had no answers for Abbot Napp’s questions. Born Johann Mendel in 1822 Gregor Mendel: …and a particular experimental Father of Genetics approach Many complex problems are most conveniently tackled using a model. “There are organisms that, because of their A brilliant mind… anatomy or physiology, provide easy access to the mechanisms that underlie interesting and important physiological and biochemical problems” Appropriate biological material… Hans Krebs (1975) J. Expt. Zool. 194: 221-226 The proper equipment Mendel’s model organism: Use a model organism for experiments Pisum sativa • Many economically important organisms are not ideal for genetic analysis – Long generation time – Difficult to create pure (true) breeding lines (due to high heterozygosity, out-breeding nature, inbreeding depression) – Reproductive biology not great - hard to mate, few progeny – Large size - difficult to maintain in reasonably-sized experiments (e.g., in a laboratory, or a garden) • Model organisms are amenable to genetic analysis: – Short generation time – Can be inbred – Simple reproductive biology – Small size – Large numbers of progeny Garden pea View slide
  • Why peas were a good choice… Why peas were a good choice… • They could be self-fertilised (selfed) - Advantages of simple reproductive allows inbreeding biology • There were pure-breeding lines - Stamens (produce pollen) always bred true, producing the same trait generation upon generation • They could be readily cross-fertilised to create hybrids between pure-breeding lines- carefully controlled matings and Pistil reciprocal crosses could rule out the effect of one parent versus the other • Mendel could grow large numbers of plants and progeny – allowing quantitative analyses that produced robust results which aided interpretation (statistics come later) well characterised, cultivated plant that grew well in the monastery monastery garden at Brno – excellent for an experimental approach. Ovule (several in peas) Why peas were a good choice Not just “antagonistic pairs” peas! Variation expressed as discrete, Green Yellow Pigment phenotypes in foxgloves Axial Terminal alternative Flowers Flowers forms of a trait Yellow Green is common in nature. Long Short Round Wrinkled Stems Stems Purple White Peas have clear-cut (discrete/qualitative) traits– Mendel could clear- traits– unambiguously distinguish between two alternative forms. (Contrast (Contrast these with continuous/quantitative trait variation.) A mouse litter from two parents heterozygous for the yellow coat colour allele. Antagonistic traits What did Mendel observe? The mating of parents with Inflated Pinched antagonistic traits produces hybrids. The hybrids of the seven Axial Terminal antagonistic traits chosen by Flowers Flowers Mendel resemble only one of the parents. Green Yellow The trait in an antagonistic Long Short pair that was manifest in the Stems Stems Purple White Yellow Green hybrid was known as dominant. Round Wrinkled View slide
  • Dominance Dominant traits Inflated Axial Flowers Green Long Stems Purple Yellow Reciprocal crosses revealed not only dominance, but also that the dominance of a trait was independent of the parent - “It is immaterial to the form of the hybrid which of Round the parental types are used in the cross” Mendel’s monohybrid crosses revealed Some classical genetics terminology for units of inheritance, now known as describing breeding experiments genes Terminology needed for Mendelian genetics • P - parental generation • F1 - first filial generation - the offspring derived from the • Locus - a genetically defined location - strictly speaking, we don’t know parental generation if it is the place of only one gene or not - but it is transmitted as a single • F2 - second filial generation - the offspring derived from the unit. F1 generation • Allele - alternative form at a given locus • Self - an inbreeding cross that involves individuals that are • Dominant - the allele that manifests itself regardless of the other allele genetically identical (e.g., a single plant with itself, or that is present - indicated by an upper-case letter (e.g., A) between full siblings derived from true breeding parents) • Recessive - an allele whose effect is “masked” when co-inherited with a • Hybrid – derived from two different parents dominant allele - indicated by a lower-case letter (e.g., a) • Monohybrid cross – experiment involving hybrids for a single • Homozygous - when both alleles at a given diploid locus are the same - trait i.e., AA or aa • Dihybrid cross – experiment involving hybrids for two traits • Heterozygous - when there is one dominant and one recessive allele present at a diploid locus i.e., Aa What did Mendel figure out? What did Mendel figure out? Every individual carries two copies of Reappearance of each gene – one from recessive trait in each parent. These F2 generation segregate during disproves gamete formation. blending. A pure-breeding line carries two identical alleles and is homozygous. Hybrids carry two different alleles and are heterozygous.
  • Mendel’s Law of Segregation explains how genes are transmitted Mendel’s results reflect basic rules of probability Prob (gamete is Y) = ½ • Each member of a gene Prob (gamete is y) = ½ pair segregates from each Product rule for independent events other into the gametes, so occurring together that one-half of the gametes Prob (event 1 AND event 2) = carry one member of the Prob (event 1) x Prob (event 2) pair and the other one-half e.g. ½ x ½ =¼ of the gametes carry the Prob (progeny are YY) = ¼ other member of the pair Sum rule for independent, • The alleles unite at random, mutually exclusive events one from each parent, at Prob (event 1 OR event 2) = fertilisation Prob (event 1) + Prob (event 2) e.g. 1/4 + 1/4 =½ Prob (progeny are Yy ) =½ Prob (progeny are yellow) =¼+½ Further crosses confirm ratios predicted by the Law of Segregation A a A a A A Aa aA a a genotype 1 2 1 phenotype 3 1 Look at the phenotypic ratios in the progeny for Is there a better way to keep track of all the possible genotype combinations and these two different crosses. their proportions? Because dihybrid crosses will be more complicated than this! Dihybrid crosses reveal Mendel’s Law of Independent Assortment A a a Genes for pea colour (green or A yellow alleles) and pea shape (round or wrinkled alleles) assort A AA Aa independently. A a a Aa a a New combinations in F2 compared with P Genotypic ratio 1 AA: 2 Aa: 1 aa Phenotypic ratio 3 A_ : 1 aa A visual summary of the cross is provided by the Punnet Square.
  • The Law of AaBb Independent Assortment AB A b a B a b • During gamete formation the A B AABB AABb AaBB AaBb segregation of alleles at one locus is independent of the AaBb segregation of alleles of another A b AABb AAbb AaBb Aabb locus. • Results in predictable ratios of a B AaBB AaBb aaBB aaBb phenotypes in the F2 generation as shown by a Punnett square • Follows basic laws of probability a b AaBb Aabb aaBb aabb Phenotypic ratio: 9 A_B_: 3 A_bb: 3 aaB_: 1 aabb Mendel published in 1865 After Mendel So then what happened? • 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 Mendel’s work sat dormant Mendel’ commissioned by the Royal Horticultural Society and for 34 years - untested, which led to the coining of the words “genetical” and unconfirmed and unapplied… unapplied… “genetics” to Mendel’s frustration for 18 Mendel’ of those years Mendelian Genetics What do we now know about genes? How do we Genes are DNA sequences. reconcile the laws that DNA sequences are organised into chromosomes Mendel proposed with what we now 1 cm = 103 mm know about 106 μm genes? 109 nm http://www.gla.ac.uk/cancerpathology/ genemech/awest/research1.htm
  • For many species chromosomes come The chromosomal in pairs basis of heredity Chromosomes 1902 – chromosome theory of come in pairs inheritance proposed called homologues. based on microscopic One of each pair is observations of segregation of transmitted from homologous chromosome pairs each parent. during gamete formation chromosomes parallel the One pair of behaviour of Mendel’s units of chromosomes inheritance and so it was determines an inferred that they carried the individual’s sex. genetic material (genes) Meiosis Q. What was this lecture about ? Meiosis consists of one round of chromosome A. The basic Mendelian principles of replication and two rounds of nuclear division how phenotypes are inherited by the transmission of genes from parent to Meiosis produces gametes. offspring Next lecture Alleles of a gene, carried on Genetic polymorphism the homologous chromosomes, segregate during gamete formation.