Lecture 3 Non-Mendelian Inheritance Part I PDF

Non-Mendelian Inheritance CHAPTER 5 Non-Mendelian Inheritance ©John Mendenhall Institute for Cellular and Molecular Biology, University of Texas at Austin...

Non-Mendelian Inheritance CHAPTER 5 Non-Mendelian Inheritance ©John Mendenhall Institute for Cellular and Molecular Biology, University of Texas at Austin 2 Introduction 1 Genes that have a Mendelian inheritance pattern conform to four rules: 1. Expression of the genes in the offspring directly influences their traits 2. Genes are passed unaltered from generation to generation (except when rare mutations occur) 3. Genes obey Mendel’s law of segregation 4. When crosses involve more than one gene, the genes obey Mendel’s law of independent assortment 3 Introduction 2 This chapter discusses additional patterns of inheritance that deviate from a Mendelian pattern Maternal effect: breaks rule 1 ◦ Involve genes in the nucleus ◦ Genotype of offspring does not directly govern phenotype as predicted by Mendel Epigenetic inheritance: breaks rule 2 ◦ Involve genes in the nucleus ◦ Genes are modified (e.g., methylation) during ◦ Gametogenesis- genomic imprinting ◦ Early embryonic development – dosage compensation (X-chromosome inactivation 4  Introduction 3 Extranuclear inheritance: breaks rule 3 ◦ Involves genes in organelles other than the nucleus ◦ Mitochondria ◦ Chloroplasts Linkage (Chapter 6): breaks rule 4 ◦ Involves genes in the nucleus ◦ Two or more genes are close to each other on the same chromosome 5  5.1 Maternal Effect Maternal effect refers to an inheritance pattern for certain nuclear genes in which the genotype of the female parent directly determines the phenotype of the offspring Surprisingly, the genotypes of the male parent and offspring themselves do not affect the phenotype of the offspring This phenomenon is due to the accumulation of gene products that the female parent provides to developing eggs 6 Discovery of Maternal Effect Genes The first example of a maternal effect gene was discovered in the 1920s by A. E. Boycott Boycott was studying morphological features of the water snail, Limnaea peregra In this species, the shell and internal organs can be arranged in one of two directions Right-handed (dextral) Left-handed (sinistral) The dextral orientation is more common and dominant 7 Experiment Showing the Inheritance Pattern of Snail Coiling © McGraw-Hill Education. 5-8  Experiment Showing the Inheritance Pattern of Snail Coiling In the F1 generation: Reciprocal crosses produce offspring with same genotype, but different phenotype. In the F2 generation: A 3:1 phenotypic ratio would be predicted by a Mendelian pattern of inheritance. The 3:1 phenotypic ratio shows up in the F3 generation. © McGraw-Hill Education. 5-9  Experiment Showing the Inheritance Pattern of Snail Coiling The phenotype of the offspring depended solely on the genotype of the mother, NOT her phenotype ◦ DD or Dd mothers produce dextral offspring ◦ dd mothers produce sinistral offspring ◦ The genotypes of the father and offspring do not affect the phenotype of the offspring © McGraw-Hill Education. 5-10  Non-Mendelian Inheritance Pattern This non-Mendelian inheritance pattern can be explained by the process of oogenesis Maturing animal oocytes are surrounded by maternal cells that provide them with nutrients These nurse cells are diploid, whereas the oocyte becomes haploid The snail’s body plan curvature depends on the cleavage pattern of the egg immediately after fertilization If a female is heterozygous for the snail-coiling maternal effect gene The haploid oocyte can receive either the D or d allele in meiosis 11 The Mechanism of Maternal Effect in Snail Coiling (Figure 5.2a) (a) Transfer of gene products from nurse cells to egg The nurse cells express mRNA and/or protein from genes of the D allele (green) and the d allele (red) and transfer those products to the egg. © McGraw-Hill Education. 5-12 The Mechanism of Maternal Effect in Snail Coiling (Figure 5.2b) D gene products cause egg cleavage that promotes a right-handed body plan. (b) Maternal effect in snail coiling © McGraw-Hill Education. 5-13 The Mechanism of Maternal Effect in Snail Coiling Recessive d gene products cause egg cleavage that promotes a left-handed body plan. Even if the egg is fertilized by sperm carrying the dominant D allele, the sperm’s genotype is irrelevant because the expression of the sperm’s gene would be too late to change early embryonic development. © McGraw-Hill Education. 5-14 Coiling at the Cellular Level Remarkably, the orientation of the cleavage plane in the earliest stages of development carries through to the adult (c) An explanation of coiling direction at the cellular level © McGraw-Hill Education. 5-15  5.2 Epigenetic Inheritance Epigenetic inheritance refers to a pattern in which a modification occurs to a nuclear gene or chromosome that alters gene expression ◦ However, the expression is not permanently changed over the course of many generations ◦ That is because the DNA sequence does not change Epigenetic changes are caused by DNA and chromosomal modifications ◦ These can occur during oogenesis, spermatogenesis or early embryonic development We will look at Dosage Compensation and Genomic Imprinting © McGraw-Hill Education. 5-16 Dosage Compensation The purpose of dosage compensation is to offset differences in the number of active sex chromosomes Dosage compensation has been studied extensively in mammals, Drosophila and Caenorhabditis elegans Depending on the species, dosage compensation occurs via different mechanisms ◦ Refer to Table 5.1 © McGraw-Hill Education. 5-17 TABLE 5.1 Mechanisms of Dosage Compensation Among Different Species Sex Chromosomes in: Species Females Males Mechanism of Compensation Placental XX XY One of the X chromosomes in the somatic cells of mammals females is inactivated. In certain species, the X chromosome from the male parent is inactivated, and in other species, such as humans, either of the two X chromosomes is randomly inactivated throughout the somatic cells of females. Marsupial XX XY The X chromosome from the male parent is inactivated mammals in the somatic cells of females. Drosophila XX XY The level of expression of genes on the X chromosome melanogaster in males is doubled. Caenorhabditis XX* X0 The level of expression of genes on each X elegans chromosome in hermaphrodites is decreased to 50% of the level occurring on the X chromosome in males. *In C. elegans, an XX individual is a hermaphrodite, not a female. 18 Dosage Compensation in Birds In birds, the sex chromosomes are the ◦ Z, a large chromosome containing many genes ◦ W, a micro chromosome containing few genes ◦ Males are ZZ; females are ZW It appears that the Z chromosome in males does not undergo condensation and dosage compensation like one of the X chromosomes in female mammals. Some Z-linked genes may be dosage compensated. © McGraw-Hill Education. 5-19  Dosage Compensation in Birds ◦ Different studies have shown variation in gene expression of some Z- linked genes in male and female birds  Example: Males express twice as much of an enzyme, aconitase, as females ◦ May lack a general mechanism, but some compensation may occur on specific genes © McGraw-Hill Education. 5-20 Dosage Compensation in Mammals In 1949, Murray Barr and Ewart Bertram identified a highly condensed structure in the interphase nuclei of somatic cells in female cats but not in male cats ◦ This structure became known as the Barr body (Figure 5.3a) In 1960, Susumu Ohno correctly proposed that the Barr body is a highly condensed X chromosome In 1961, Mary Lyon proposed that dosage compensation in mammals occurs by the inactivation of a single X chromosome in females © McGraw-Hill Education. 5-21  Dosage Compensation in Mammals Dosage Compensation in Mammals Occurs by Chromosome Condensation (left) a Barr body in a human nucleus after staining with a DNA-specific dye (right) the same nucleus stained with a yellow fluorescent probe that recognizes the X chromosome © McGraw-Hill Education. 5-22 Dosage Compensation-Chromosome Condensation The mechanism of X chromosome inactivation (XCI), also known as the Lyon hypothesis, is schematically illustrated in Figure 5.4 Example: A white and black variegated coat color found in certain strains of mice Mouse with patches of black and white fur © McGraw-Hill Education. 5-23  Dosage Compensation-Chromosome Condensation A female mouse has inherited two X chromosomes: ◦ One from its mother that carries an allele conferring white coat color (Xb) ◦ One from its father that carries an allele conferring black coat color (XB) © McGraw-Hill Education. 5-24  The Mechanism of X-chromosome Inactivation Figure 5.4 Random X inactivation occurs early in development. © McGraw-Hill Education. 5-25  The Mechanism of X-chromosome Inactivation During X chromosome inactivation, the DNA becomes highly compacted ◦ Most genes on the inactivated X cannot be expressed When this inactivated X is replicated during cell division- ◦ Both copies remain highly compacted and inactive ◦ X inactivation is passed along to all future somatic cells © McGraw-Hill Education. 5-26  The Lyon Hypothesis Put to the Test Experiment 5A In 1963, Ronald Davidson, Harold Nitowsky and Barton Childs set out to test the Lyon hypothesis at the cellular level To do so they analyzed the expression of a human X-linked gene ◦ The gene encodes glucose-6-phosphate dehydrogenase (G-6-PD), an enzyme used in sugar metabolism © McGraw-Hill Education. 5-27 Individuals Vary with Regard to the G-6-PD Enzyme This variation can be detected when the enzyme is subjected to gel electrophoresis ◦ One G-6-PD allele encodes an enzyme that migrates very quickly The “fast” enzyme ◦ Another allele encodes an enzyme that migrates more slowly The “slow” enzyme The two types of enzymes have minor differences in their structures These do not significantly affect G-6-PD function © McGraw-Hill Education. 5-28 Individuals Vary with Regard to the G-6-PD Enzyme (Figure 5.5) Heterozygous adult females produce both types of enzymes Hemizygous males produce either the fast or the slow type © McGraw-Hill Education. 5-29  The Hypothesis According to the Lyon hypothesis, an adult female who is heterozygous for the fast and slow G-6-PD alleles should express only one of the two alleles in any particular somatic cell and its descendants, but not both Testing the hypothesis ◦ Refer to Figure 5.6 © McGraw-Hill Education. 5-30  Figure 5.6 1. Mince the tissue to separate the individual cells. 2. Grow the cells in a liquid growth medium and then plate (sparsely) onto solid growth medium. Each cell divides to form a clone of many cells. 3. Take nine isolated clones and grow in liquid cultures. (Only three are shown here.) 4. Take cells from the liquid cultures, lyse cells to obtain proteins, and subject to gel electrophoresis. (This technique is described in the Appendix.) Note: As a control, lyse cells from step 1, and subject the proteins to gel electrophoresis. The control is derived from several small skin samples from a heterozygous woman. © McGraw-Hill Education. 5-31 (photo): © Lutz Slomianka © McGraw-Hill Education. 5-32 The Data Adapted from Ronald G. Davidson, Harold M. Nitowsky, and Barton Childs (1963) Demonstration of two populations of cells in the human female heterozygous for glucose-6-phosphate dehydrogenase variants, PNAS, 50(3): 481–485, Fig. 2. Access the text alternative for slide images. 33 Interpreting the Data All nine clones expressed one of the two types of G-6-PD enzyme, not both. Clones 2, 3, 5, 6, 9 & 10 expressed only the slow type Clones 4, 7 & 8 expressed only the fast type © McGraw-Hill Education. 5-34 Interpreting the Data These results are consistent with the hypothesis that ◦ X inactivation has already occurred in any given epithelial cell AND ◦ This pattern of inactivation is passed to all of the cell’s progeny © McGraw-Hill Education. 5-35 Mammalian Cells Allow a Single X to Remain Active Researchers have found that mammalian cells can count their X chromosomes and allow only one of them to remain active ◦ Additional X chromosomes are converted to Barr bodies Phenotype Sex Chromosome Number of Composition Barr bodies Normal female XX 1 Normal male XY 0 Turner syndrome (female) X0 0 Triple X syndrome (female) XXX 2 Klinefelter syndrome (male) XXY 1 © McGraw-Hill Education. 5-36 X-chromosome Inactivation X-chromosome inactivation in mammals depends on the X-inactivation center and Xist The genetic control of inactivation is not entirely understood at the molecular level However, a short region on the X chromosome termed the X-inactivation center (Xic) plays a critical role For inactivation to occur, each X chromosome must have a Xic region This process will be further explained in Chapter 16 37 The Function of the Xic during X-chromosome Inactivation Nucleation: Occurs during embryonic development. The number of X-inactivation centers (Xics) is counted and one of the X chromosomes remains active and the other is targeted for inactivation. Spreading: Occurs during embryonic development. It begins at the Xic and progresses toward both ends until the entire chromosomes is inactivated and becomes a Barr body. Maintenance: Occurs from embryonic development through adult life. The inactivated X chromosomes is maintained as such during subsequent cell divisions. 38 The function of the Xic during X-chromosome inactivation. Access the text alternative for slide images. 39 Some Genes May Escape Inactivation Some genes on the inactivated X chromosome are expressed in the somatic cells of adult female mammals Pseudoautosomal genes Dosage compensation in this case is unnecessary because these genes are located on both the X and Y chromosomes Up to a quarter of X-linked genes in humans may escape full inactivation The mechanism is not understood May involve loosening of chromatin in specific regions 40  5.3 Genomic Imprinting Genomic imprinting is a phenomenon in which a segment of DNA is marked and the effect is maintained throughout the life of the organism inheriting the marked DNA Depending on how the genes are “marked”, the offspring expresses either the maternally-inherited or the paternally-inherited allele Not both This is termed monoallelic expression 41 Mouse Igf2 Gene as an Example of Genomic Imprinting The Igf2 gene codes a growth hormone called insulin-like growth factor 2 A functional Igf2 gene is necessary for a normal size Imprinting results in the expression of the paternal but not the maternal allele The paternal allele is transcribed into RNA The maternal allele is not transcribed Igf 2− is a loss-of-function allele that does not express a functional Igf2 protein This may cause a mouse to be small size depending on whether it inherits the mutant allele from its male or female parent 42 An example of genomic imprinting in the mouse Dr. Argiris Efstratiadis Reciprocal cross: Offspring genotypes are identical; phenotypes different Access the text alternative for slide images. 43 Stages of Imprinting 1 At the cellular level, imprinting is an epigenetic process that can be divided into three stages: 1. Establishment of the imprint during gametogenesis 2. Maintenance of the imprint during embryogenesis and in the adult somatic cells 3. Erasure and reestablishment of the imprint in the germ cells 44 Genomic imprinting during gametogenesis Access the text alternative for slide images. 45 Stages of Imprinting 2 Establishment of the imprint In this example, imprinting occurs during gametogenesis in the lgf2 gene, which exists in the lgf2 allele from the male and the Igf2- allele from the female. This imprinting occurs so that only the paternal allele is expressed. Maintenance of the imprint After fertilization, the imprint pattern is maintained throughout development. In this example, the maternal Igf2- allele will not be expressed in somatic cells. Note that the offspring on the left is a female and the one on the right is a male; both are normal in size. 46 Stages of Imprinting 3 Erasure and reestablishment In the germ-line cells, the Imprint is erased. The female mouse produces eggs in which the gene is silenced. The male produces sperm in which the gene can be transcribed into mRNA. 47 Genomic Imprinting Occurs in Several Species Genomic imprinting occurs in several species including insects, mammals and flowering plants It may involve A single gene A part of a chromosome An entire chromosome Even all the chromosomes from one parent It can be used for X inactivation in some species 48 Imprinting and DNA Methylation Genomic imprinting must involve a marking process At the molecular level, the imprinting of several genes is known to involve an imprinting control region (ICR) located near the imprinted gene The ICR is methylated either in the oocyte or sperm ◦ Not both The ICR contains binding sites for one or more transcription factors that regulate the imprinted gene For most genes, methylation causes inhibition of transcription 49 Pattern of Methylation In figure 5.10, each parent inherits one methylated and one unmethylated gene, which is maintained in somatic cells. Methylation is removed in gamete forming cells 50 The pattern of methylation from one generation to the next Access the text alternative for slide images. 51 Imprinting in Human Disease 1 Prader -Willi syndrome (PWS) PWS is characterized by Reduced motor function Obesity Small hands and feet Angelman syndrome (AS) AS is characterized by Hyperactivity and thinness Unusual seizures Repetitive symmetrical muscle movements Cognitive impairment 52 Imprinting in Human Disease 2 Most commonly, PWS and AS involve a small deletion in chromosome 15 If it is inherited from the male parent, it leads to PWS If it is inherited from the female parent, it leads to AS 53  Imprinted Genes Cause AS or PWS 1 Researchers have discovered that this region contains closely linked but distinct genes These are maternally or paternally imprinted AS results from the lack of expression of a single gene, UBE3A UBE3A codes a protein that regulates protein degradation The paternal copy is silenced 54 Imprinted Genes Cause AS or PWS 2 PWS appears to result from the lack of expression of several genes: SNRNP codes a small nuclear ribonucleoprotein polypeptide N which is part of a complex that controls gene splicing NDN codes a protein that functions as a growth suppressor for neurons A cluster of genes that code snoRNAs The maternal copy of each of these genes is silenced 55 The role of imprinting in the development of Angelman or Prader-Willi syndrome Access the text alternative for slide images. 56