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1/24/13 Gene*cs Principles 23 January 2013 Rebecca Lowdon Outline • Inheritance / Transmission gene*cs – Mendel & classical gene*cs • Meiosis: mechanism that unites inheritance and chromosomes – Chromosomal theory of inheritance, Walter SuLon • Muta*on – Morgan and Muller • Characteris*cs of Phenotypes and Non-‐Mendelian Inheritance – Non-‐Mendelian inheritance – Gene*cs vs epigene*cs • Popula*on gene*cs: study of gene*c varia*on in popula*ons 1 1/24/13 Outline • Inheritance / Transmission gene*cs – Mendel & classical gene*cs • Meiosis: mechanism that unites inheritance and chromosomes – Chromosomal theory of inheritance, Walter SuLon • Muta*on – Morgan and Muller • Characteris*cs of Phenotypes and Non-‐Mendelian Inheritance – Non-‐Mendelian inheritance – Gene*cs vs epigene*cs • Popula*on gene*cs: study of gene*c varia*on in popula*ons Mendel’s Aims 1. Characterize hybrid phenotypes. 2. Determine pedigrees for hybrids. 3. Quan*fy phenotype ra*os. 2 1/24/13 Mendel • Deduced paLerns of inheritance from breeding experiments. – Dominance: an allele masks expression of the second allele for a trait/at a locus. – Recessivity: an allele/phenotype that is only expressed in the homozygote. • Gene: the unit of heredity. • Homozygote: an individual has two of the same alleles for a locus. • Heterozygote (hybrid): an individual has two different alleles at a locus. Mendel’s Principles of Inheritance • Law of Segrega8on: For autosomal traits, there is a 50% chance of passing on either maternal/paternal allele. • Law of Independent Assortment: Genes for different traits are inherited independently. 3 1/24/13 Mendelian Probabili*es • PunneL Square incorporates independent assortment and segrega*on. • Fisher’s issue with Mendel’s results? P Pp Pp – They were too close to expecta*on • Illustra*on of Mendel’s results – Coin-‐flip simula*on, repea*ng the experiment 1000 *mes. • Ques*on #4: 1. Unconscious bias 2. Exclusion due to assumed experimental error 3. Coun*ng done by students. Hieracium • Why was Hieracium a poor model system for studying inheritance? • Its seed are purely maternal, there is no meiosis or fer*liza*on, so no recombina*on or segrega*on of alleles. 4 1/24/13 Variega*on and Soma*c Muta*on • Variega*on was a source of confusion when sor*ng out segrega*on paLerns (de Vries, Correns, figured out by Emerson). 1. Posi*on effect variega*on 2. Variega*on due to soma*c muta*on – Barbara McClintock discovered transposable elements while studying chromosome breakage at Cold Spring Harbor in the 1950’s. Transposable elements are mobile regulatory elements • Dissociator locus is under the control of Ac+vator. • Mobiliza*on of Ds out of the colored gene results produces clones with pigmenta*on. • Transposable element mobiliza*on has phenotypic consequences. – Soma*c mosaicism McClintock, 1951 h1p://old.weedtowonder.org/mcclintock/ds_jumps.html 5 1/24/13 Consequences of soma*c mosaicism • Random X-‐inac*va*on • Cancer • Variable expressivity Outline • Inheritance / Transmission gene*cs – Mendel & classical gene*cs • Meiosis: mechanism that unites inheritance and chromosomes – Chromosomal theory of inheritance, Walter SuLon • Muta*on – Morgan and Muller • Characteris*cs of Phenotypes and Non-‐Mendelian Inheritance – Non-‐Mendelian inheritance – Gene*cs vs epigene*cs • Popula*on gene*cs: study of gene*c varia*on in popula*ons 6 1/24/13 Walter SuLon: Evidence for Mendel’s Principles • Chromosomal theory of inheritance: chromosomes are the physical basis of gene*c inheritance. • Evidence: – Boveri: chromosomes are required for development to occur in sea urchins. – SuLon: chromosomes appear in matched pairs in grasshoppers. • “… the associa*on of maternal and paternal chromosomes in pairs and their separa*on in the reduc*on division may cons*tute the physical basis of heredity.” • Described how random assortment fulfills Mendel’s law, and can explain observed varia*on in traits. Meiosis 7 1/24/13 Remember Meiosis • Synapsis: close pairing of homologous chromosomes to form a bivalent; during prophase I when crossing over occurs. • Meiosis I: reduc8on division, separa*on of… • Meiosis II: separa*on of… Meiosis is where heritable gene*c varia*on is generated • Ques*on 8: What is parental purity? • Meiosis explains Mendel’s laws of inheritance. • Meiosis is where inherited muta+ons occur. • Ques*on 9: What is Su1on talking about on p8? 8 1/24/13 Nondisjunc*on • Discovered by Calvin Bridges. • Evidence for chromosomal theory. Outline • Inheritance / Transmission gene*cs – Mendel & classical gene*cs • Meiosis: mechanism that unites inheritance and chromosomes – Chromosomal theory of inheritance, Walter SuLon • Muta*on – Morgan and Muller • Characteris*cs of Phenotypes and Non-‐Mendelian Inheritance – Non-‐Mendelian inheritance – Gene*cs vs epigene*cs • Popula*on gene*cs: study of gene*c varia*on in popula*ons 9 1/24/13 T.H. Morgan’s Fly Room • Originally an embryologist, became interested in the debate over the physical basis of inheritance. • Established Drosophila as a gene*cs model system at Columbia. The Fly Room at Columbia T.H. Morgan and gene*c linkage • Breed flies with spontaneous muta*ons to study their inheritance paLerns. • By breeding the white eyed mutant males, Morgan confirmed the chromosomal theory of inheritance and the existence of sex chromosomes. • Discovered “linked” genes. – Linkage: the close physical proximity of two or more genes. – Linkage disequilibrium: the tendency for two (or more) alleles to be inherited together. 10 1/24/13 Muller and Muta*on • Discovered that X rays increase muta*on rate. • Exploited use of the X chromosome to es*mate the rate of lethal muta*ons. • Two sugges*ons: – Muta*ons might be primarily due to background radia*on. • Stadler reported that muta*on rate was 8x treated seeds compared to the control. • Hanson & Heys extended this: studying radium they discovered that ioniza*on is responsible for muta*ons. – The rela*on between dosage and muta*on rate might be exponen*al instead of linear. • Stadler reported that muta*on rate increased linearly with dosage. • Confirmed by Oliver who showed that by varying the dose/dura*on of exposure gave a linear curve rela*ng dosage to muta*on rate. Muller and Muta*on • What new class of mutagen arose in the late 40’s? What sparked its study? Why was its use in research delayed for so long? – Mustard gas was discovered as a mutagen by Auerbach and Robson in 1941. They found similari*es between phenotypes of those exposed to mustard gas and irradia*on. The work could not be published un*l 1946 when WWII was over because it was considered classified. 11 1/24/13 Outline • Inheritance / Transmission gene*cs – Mendel & classical gene*cs • Meiosis: mechanism that unites inheritance and chromosomes – Chromosomal theory of inheritance, Walter SuLon • Muta*on – Morgan and Muller • Characteris*cs of Phenotypes and Non-‐Mendelian Inheritance – Non-‐Mendelian inheritance – Gene*cs vs epigene*cs • Popula*on gene*cs: study of gene*c varia*on in popula*ons Characteris*cs of Phenotypes • Phenotype: a measurable trait. • Penetrance: the percentage of individuals of a given genotype that display a phenotype. – BRCA1/BRCA2 • Expressivity: the degree to which a phenotype is displayed in individuals of a given genotype. – “Hemingway cat”: Polydactyly in cats is highly penetrant but has variable expressivity. 12 1/24/13 Mendelian Inheritance can give rise to complex phenotypes • Incomplete/semi-‐ dominance: when the phenotype of the heterozygote is intermediate to the phenotypes of each homozygote – Snapdragon petal color • Codominance: contribu*ons from both alleles visible in the phenotype. – E.g. blood type alleles in human. Mendelian Inheritance can give rise to complex phenotypes • Polygenic traits (complex traits) – Mul*ple genes contribute to a phenotype. – If penetrance or expressivity is < 100% other genes/modifiers may be involved. • Genes involved in the phenotype usually follow Mendelian inheritance, but create complexity by different interac*ons that result from allelic varia*on. 13 1/24/13 Sex-‐linked traits Mitochondrial Inheritance • Once circular, 16kb “genome” per mitochondria. – 13 protein-‐coding genes (for oxida*ve phosphoryla*on system). – Muta*on rate is 100x higher than the nuclear genome. – Heteroplasmy: many heterogeneous mtDNA genomes per cell. • Non-‐Mendelian inheritance – Inherited strictly maternally, through the oocyte. – Disease muta*ons tend to affect *ssues with high-‐energy demands. • E.g. Leber hereditary op*c neuropathy (LOHN): loss of vision, due to mtDNA muta*on. 14 1/24/13 Non-‐Mendelian Inheritance • Ques*on 10: What are Bateson’s three types of non-‐Mendelian inheritance? • Blended inheritance or con*nuous varia*on: mul*ple genes influence a trait. • First crosses that breed true: All gametes of a self-‐ fer*lizing species are iden*cal due to absence of the reduc*on division (no separa*on of homologous chromosomes). • False hybrids: Loss of one set of parental chromosomes in the offspring, resul*ng in a haploid organism (parthenogenesis). Epigene*c Inheritance • Epigene*cs: the ensemble of mechanisms that concurrently modify the chroma*n to stably or dynamically modulate gene expression without affec*ng DNA sequence. • Epigene*c features transmiLed across genera*ons. Imprin8ng: DNA methyla*on marks preserved across genera*ons. Templa8ng: DNA methyla*on and histone marks preserved across cell division. 15 1/24/13 Epigene*c vs. Gene*c Inheritance • Gene8cs – both the use of muta*ons and muta*onal analysis to study a given biological process and the study of the hereditary process itself. • Epigene8cs – the study of molecular mechanisms that mediate environmental influences on gene produc*on or regula*on whose effects persist (are inherited mito*cally and/or meio*cally) when the environmental s*mulus is removed. Outline • Inheritance / Transmission gene*cs – Mendel & classical gene*cs • Meiosis: mechanism that unites inheritance and chromosomes – Chromosomal theory of inheritance, Walter SuLon • Muta*on – Morgan and Muller • Characteris*cs of Phenotypes and Non-‐Mendelian Inheritance – Non-‐Mendelian inheritance – Gene*cs vs epigene*cs • Popula*on gene*cs: study of gene*c varia*on in popula*ons 16 1/24/13 Popula*on Gene*cs • The science of the mechanisms responsible for microevolu+on, or the study of gene*c varia*on in popula*ons. • Phenotype: a measurable trait of an individual, which emerges from the interac*on of a genotype and its environment. – Physical – Gene*c Either can cause variable expressivity or penetrance. Popula*on Gene*cs • Study of varia*on in reproduc*ve success – Game*c – Environmentally-‐induced • Evolu8on: change in allele frequencies in a popula*on over *me. 17 1/24/13 Compara*ve Gene*cs/Genomics • Synteny: conserva*on of blocks of order within two chromosomes that are being compared, usually between species. QUESTIONS? 18