"Mendelian Chromosomal Genetics Notes"
Mendelian (Classical) Genetics Gregor Mendel—the father of genetics Raised on a farm Studied math, physics and botany at the University of Vienna Monastery of St. Thomas in Brno Found indirect, but observable evidence of how parents transmit their genes to offspring. Mendel and the Garden Pea Earlier investigators had produced hybrid peas. There were a large number of true-breeding varieties available. (He examined 32 and then choose 7) Peas are small and easy to grow. Self-pollination in the Pea The normally self-pollinating peas can be manipulated for experimental crosses. Mendel’s Experiments Grew peas by self-pollination for several generations to prove true-breeding. Performed experimental crosses between alternative traits. Allowed self-pollination between hybrid forms. Counted all progeny to obtain quantitative data (no one had ever done that before). Mendel’s First Law Law of Segregation Parents transmit discrete information about traits (factors) Each individual has two factors for each trait The pair of factors in the parent will separate or segregate during gamete formation Other important concepts: Dominant—the factor that is always expressed Recessive—the factor that is “hidden” or “latent” in the F-1, but reappears in the F-2 generation Phenotype—the physical appearance of an organism with respect to a specific trait Genotype—the actual gene composition Homozygous (a pair of factors that are identical) Heterozygous (a pair of factors that are different) Mendel’s Second Law Law of Independent Assortment Any two genes located on different chromosome pairs will migrate independently of each other during gamete formation. The Product Rule The chance that any two independent events will both occur is the product of their individual probabilities. Non-Mendelian Inheritance include: Incomplete, Codominance, Multiple Alleles, Lethal Allele Combinations, Epistasis, Penetrance and Expressivity Epistasis In epistasis, a gene at one locus alters the phenotypic expression of a gene at a second locus For example, in mice and many other mammals, coat color depends on two genes One gene determines the pigment color (with alleles B for black and b for brown) The other gene (with alleles E for color and E for no color) determines whether the pigment will be deposited in the hair Penetrance & Expressivity Penetrance -the proportion of individuals carrying a particular variation of a that also express a particular trait Huntington disease has 95% penetrance, Expressivity-variations of a phenotype in individuals carrying a particular genotype Polydactyly may be expressed on both hands and feet or just hands or just 1 hand Polygenic Inheritance Quantitative characters are those that vary in the population along a continuum Quantitative variation usually indicates polygenic inheritance, an additive effect of two or more genes on a single phenotype Skin color in humans is an example of polygenic inheritance Chromosomal Genetics Chromosome Theory of Inheritance--History 1882—Walther Fleming (Ger.) first observed dividing and called mitosis (from Greek for thread + condition) 1902—Walter Sutton (US) and Theodor Boveri (Ger.) recognized that the behavior of Mendel’s factors paralleled the behavior of chromosomes during meiosis; but no real proof yet of genes were located on chromosomes 1905—Nettie Stevens discovered Y chromosome Since their initial discovery, chromosomes have proved to be present in all eukaryotic organisms. Some species have as few as 2 pair (Ascaris, a roundworm and a sunflower) Some ferns have more than 500 pairs Sex Chromosomes and Sex-Linkage—History 1909—Thomas Hunt Morgan used background information of X and Y chromosomes to explain sex determination and also discovered sex-linkage in fruit flies Crossed a wild-type red-eyed female fly with a mutant white-eyed male to obtain an F-1 that was 100% red-eyed. Obtained an F-2 that was 3:1 red-eyed to white-eyed but observed that all white-eyed flies were males Chromosomal Basis of Sex In humans and other mammals, there are two varieties of sex chromosomes: a larger X chromosome and a smaller Y chromosome Only the ends of the Y chromosome have regions that are homologous with the X chromosome The SRY gene on the Y chromosome codes for the development of testes Females are XX, and males are XY Each ovum contains an X chromosome, while a sperm may contain either an X or a Y chromosome Other animals have different methods of sex determination Chromosomal Determination of Sex Drosophilia Humans XX – female XX – female XY – male XY – male XXY – female XX Y – male X0 - male X0 – female Non-X or Y chromosomes are known as AUTOSOMES Karotypes Chromosomes within a species differ in size, shape, and location of centromeres. The particular array of chromosomes that an individual possesses is its karyotype. Karyotypes are often examined to detect genetic abnormalities. Human Female Karyotype—22 Autosomes and XX Human Male Karotype— 22 Autosomes and XY Non-disjunction The failure of a pair of chromosomes to migrate to opposite poles during meiosis. This failure can produce abnormal numbers of chromosomes within a species. Some genetic disorders caused by abnormal chromosome numbers include: Trisomic # 21--Down Syndrome XXY--Klinefelter’s Syndrome XO--Turner Syndrome X Inactivation in Female Mammals In mammalian females, one of the two X chromosomes in each cell is randomly inactivated during embryonic development The inactive X condenses into a Barr body If a female is heterozygous for a particular gene located on the X chromosome, she will be a mosaic for that character Gene Linkage Linked genes tend to be inherited together because they are located near each other on the same chromosome Each chromosome has hundreds or thousands of genes Genes located on the same chromosome that tend to be inherited together are called linked genes How Linkage Affects Inheritance T. H. Morgan did additional experiments with fruit flies to see how linkage affects inheritance of two characters Morgan crossed flies that differed in traits of body color and wing size He took wild type gray body, normal winged flies and crossed them with black body, vestigal winged flies. Morgan found that body color and wing size are usually inherited together in specific combinations (parental phenotypes) He noted that these genes do not assort independently, and reasoned that they were on the same chromosome However, nonparental phenotypes were also produced which were recombinant types such as the black body, normal winged or gray body, vestigal winged flies Recombination of Linked Genes: Crossing Over Morgan discovered that genes can be linked, but the linkage was incomplete, as evident from recombinant phenotypes Morgan proposed that some process must sometimes break the physical connection between genes on the same chromosome That mechanism was the crossing over of homologous chromosomes Chromosome Map In 1093, Alfred Sturtevant, one of Morgan’s students, constructed the first genetic map, an ordered list of the genetic loci along a particular chromosome Sturtevant predicted that the farther apart two genes are, the higher the probability that a crossover will occur between them and therefore the higher the recombination frequency Linkage Map A linkage map is a genetic map of a chromosome based on recombination frequencies (the units between genes are now called morgans) The Final Proof 1931 Barbara McClintock and Harriet Creighton—connection between a region on the chromosome with a physical trait (when genes appeared to cross-over so did chromosomal material) McClintock’s Transposons (jumping genes) Breakage of a chromosome can lead to four types of changes in chromosome structure: Deletion removes a chromosomal segment Duplication repeats a segment Inversion reverses a segment within a chromosome Translocation moves a segment from one chromosome to another Changes in Chromosome Structure Deletions—loss of a part of a chromosome Deletion of short arm of # 5 causes a disorder known as Cri-du-chat Discovered by Jerome Lejuene in 1963 1 in 20,000-50,000 live births Translocations—the shift of one part of a chromosome to another non-homologous chromosome Translocation of a proto-oncogene on tip of # 8 next to an antibody enhancer gene on # 14 causes Burkitt’s lymphoma (very rare in US, <100 cases year; more common in Africa where immuniodeficiency and EBV are implicated) Translocation of #9 to # 22 results in Philadelphia chromosome which causes chronic myeloma leukemia (Ph chromsome is found only in tumor cells) HumanGenetic Disorders Pedigree Analysis Patterns for Human Traits-single gene pair Recessive Traits Parents are generally unaffected 25% chance of an affected child Two affected parents always have affected offspring Dominant Traits Trait appears every generation 50% chance of an affected child Two affected parents can produced unaffected offspring Examples of Autosomal Recessive Traits Albinism—absence of pigmentation Sickle-cell anemia—severe tissue damage Phenylketouria (PKU)—mental retardation Galactosemia—brain, liver, eye damage Cystic Fibrosis—lung, digestive tract damage Congenital deafness—loss of hearing Tay-Sachs—progressive, irreversible neurological degeneration (onset at 6 months) Methemoglobinemia—cytochrome b5 reductase absent in only rbc or in all cells Autosomal Dominant Traits Huntington’s Disorder—progressive, irreversible neurological degeneration (onset 40-50 years) Achondroplasia—a type of dwarfism Polydactyly—extra digits Progeria—premature aging Compodactyly—rigid, bent little fingers Achondroplasia Polydactyly Progeria Sex-Linked (X-linked) Hemophilia A—deficient blood clotting Complete Androgen Insensitivity Syndrome (CAIS); formerly Testicular Feminizing Syndrome—absence of male organs, sterility Duchenne’s Muscular Dystrophy—muscular degeneration Red-Green Colorblindness—varying inability to detect shades of red and green Duchenne Muscular Dystrophy Exceptions to the standard chromosome theory There are two normal exceptions to Mendelian genetics One exception involves genes located in the nucleus (genomic imprinting), and the other exception involves genes located outside the nucleus (extra-nuclear genes) Genomic Imprinting In the mouse gene for insulin-like growth factor, only the paternal allele is expressed. Genomic imprinting silences one allele of certain genes, either of the maternal or paternal chromosome. Imprinting affects only a small fraction of mammalian genes, but those known are important for embryonic development Cytoplasmic Genes Mitochondria and plastids contain small circular loops of DNA with a number of genes since the organelles are self-reproducing, they transmit their genes to daughter organelles Inheritance of mitochondrial or plastid DNA depends solely on the maternal parent