Chromosomal Mutations

7 Key excerpts on "Chromosomal Mutations"

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  eBook - ePub

  Advanced Molecular Biology

  A Concise Reference

  • Richard Twyman(Author)
  • 2018(Publication Date)
  • Garland Science

    (Publisher)

  Chapter 4

  Chromosome Mutation

  Fundamental concepts and definitions

  • A chromosome mutation (or chromosome aberration) is a mutation involving a large segment of the genome. Such a mutation usually affects many genes and is often observable at the cytogenetic level, i.e. it can be seen with a light microscope.
  • Chromosome mutations are numerical if they involve a deviation from normal chromosome number, and structural if they involve breakage and rearrangement of chromosome segments. Numerical mutations often result from chromosome segregation errors caused by structural mutations, but may also reflect aberrant replication or errors at fertilization. Structural mutations result from the faulty repair of broken chromosomes or from nonallelic recombination events. In mammals and in Drosophila, subtle structural mutations can be detected because they disrupt chromosome banding patterns (q.v.). Structural mutations are balanced if DNA is rearranged but there is no loss or gain of material, or unbalanced if DNA is lost or gained. All numerical mutations are unbalanced.
  • There are four consequences of chromosome mutations disruption, fusion, position and dosage effects. Disruption and fusion effects occur in structural mutations and reflect the nature of the chromosome breakpoints before and after mutation (e.g. a breakpoint can interrupt a gene or separate a gene from its promoter, resulting in loss of gene function, and fusion can join two genes, allowing a composite product to be synthesized, perhaps with novel functions). Position effects also occur in structural mutations and reflect global influences on gene expression conferred by chromatin structure (e.g. a translocation may bring a normally active gene adjacent to a region of heterochromatin causing transcriptional repression; q.v. chromatin domain, position-effect variegation). Dosage effects occur in both structural and numerical mutations and concern the number of copies of each gene in the cell. The dosage levels of many autosomal genes are flexible, but, others demonstrate haploinsufficiency (q.v.), which is one type of dosage effect. Unbalanced chromosome mutations, especially full aneuploidies, alter the dosage of many genes at the same time, and therefore generate multiple dosage effects. A change in dosage of many contiguous genes, especially an entire chromosome, is termed chromosome imbalance.

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  Genetic Theory and Analysis

  Finding Meaning in a Genome

  • Danny E. Miller, Angela L. Miller, R. Scott Hawley(Authors)
  • 2023(Publication Date)
  • Wiley

    (Publisher)

  Genetic Theory and Analysis: Finding Meaning in a Genome, Second Edition. Danny E. Miller, Angela L. Miller, and R. Scott Hawley. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc. 1 A mutation is a stable and potentially heritable change in a DNA sequence. Mutations may occur in the soma of an organism, affecting only a particular cell or lineage of cells, or they may occur in the germline of an organism and be passed to all of that organism’s offspring. Mutations that occur within or near a gene may create a phenotype different from that normally expressed by the wildtype allele of that gene. A number of different types of mutations have been found to cause changes in phenotype. These mutations can be changes in individual base pairs, such as substitutions (e.g. C →T), insertions or deletions of DNA, or they may be chromosomal aberrations such as inversions, translocations, or copy number variants near or within genes. Because this book is fundamentally about mutational analysis, we need to spend some time considering the types of mutations that can occur, both at the molecular level and in terms of the effects they can have. We also need to review the various systems that exist to classify mutations. Such a review is all the more critical because the nomenclature systems that geneticists have developed are keyed to the structure and effects of the mutants they name. Thus, the things themselves – and our names for them – are inextricably intertwined. 1.1 Types of Mutations Most introductory genetics texts classify mutations simply as recessive or dominant. A mutation (m1) is said to be recessive if m1/m1 organisms display a mutant phenotype, but m1/+ organisms are wildtype. (Note: the symbol “+” denotes the wildtype, or normal, allele of a given gene.) Conversely, a mutation (M2) is said to be dominant if M2/+ organisms display a mutant phenotype while +/+ organisms are normal.

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  Introducing Genetics

  From Mendel to Molecules

  • Alison Thomas(Author)
  • 2014(Publication Date)
  • Garland Science

    (Publisher)

  The genetic information of a diploid organism is delicately balanced in both content and location. Different genes are found at specific sites on specific chromosomes. Two copies are generally present at corresponding sites on the two homologs. The various alleles of a gene correlate with different phenotypes and some are less efficient than others, occasionally even lethal. It is hardly surprising, therefore, that major changes to a chromosome (e.g. rearranging the genetic layout of a region), or even changing the number of chromosomes, can have a dramatic impact on an organism’s phenotype, to the extent of preventing its normal development. Any change to the num-ber or arrangement of chromosomes is known as a chromosome mutation or chromosome aberration . This chapter considers chromosome aberrations from two perspectives: • How they arise • Their genetic and phenotypic consequences Variation in Chromosomal Number and Structure 8 CHAPTER 113 Aneuploidy 8.1 Changes in chromosome number: terminology When an organism or cell has one or more complete sets of chromosomes it is said to be euploid . Thus, eukaryotic organisms such as mice and humans, which are normally diploid, can also be referred to as euploid. Likewise, any polyploid species with multiple chromosome sets is euploid. Mutations can occur that reduce or increase the number of chromosomes of a set. Any organism or cell with a chromosome number that is not an exact multiple of the haploid number of chromosomes is described as aneuploid (Figure 8.1). 8.2 Aneuploidy The most frequent examples of aneuploidy are cases when a single chromosome is either lost from or added to a normal diploid set (i.e. monosomy or trisomy ). The extra or lacking chromosome can be an autosome or a sex chromosome.

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  Animal Genetics for Chemists

  • Ralph G Wilkins(Author)
  • 2017(Publication Date)
  • Royal Society of Chemistry

    (Publisher)

  CHAPTER 4 DNA Mutations and Their Impact on Human and Animal Phenotypes

  4.1 INTRODUCTION

  This is a very important chapter encompassing all the varied changes that DNA can undergo and thereby produce faulty (mutant) genes and protein products. At the center of genetics, a mutation involves a functional change in the genetic material of a cell, specifically a change in the DNA or RNA sequences, and thus affects the sequence of amino acids in the resulting protein. If the change does not affect this sequence, it is a natural variant. A mutation is not necessarily irreversible, but if it involves somatic cells (acquired mutations), these will disappear when the owner dies. However, if the mutation involves the reproductive cells (germline mutation), an offspring may inherit the mutation in all its cells and have a hereditary ailment (inherited mutation). If after conception, growth and development of an embryo, only some cells have the mutation, mosaicism results.

  The frequency of mutations is rare and may be inherited or acquired during a person’s lifetime. Only a very small percentage of mutations cause genetic disorders, usually by altering or removing a critical encoded protein. The animal affected by the mutation (the mutant) may have discernible changes in the resulting phenotype, that is in its appearance, behavior or traits (disorders or diseases) compared with the wild-type animal, which has the phenotype most common in nature. The intensity of the phenotype change is likely to depend on the magnitude of the mutation, namely how much the DNA is changed or the chromosome involved. The mutation may arise as a random event during the formation of the egg or sperm, or in the early embryo (see Section 5.3 in Chapter 5 ), in which case there will have been no history of the disease in the family. Alternatively, it may be inherited from an affected parent.

  4.2 TYPES OF MUTATION

  There is a wide range of types of alterations in DNA that lead to a mutation. Slight changes, involving only one or a few nucleotides, can only be detected by full sequencing techniques. On the other hand, whole chunks of DNA, involving millions of base pairs and even entire genes, may be lost or moved around within a chromosome or between chromosomes. These may be detected using karyotype patterns or by spectroscopic techniques (see FISH and SKY in Section 1.4.3 in Chapter 1

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  Genetics and Genomics in Medicine

  • Tom Strachan, Anneke Lucassen(Authors)
  • 2022(Publication Date)
  • CRC Press

    (Publisher)

  Section 7.5 together with other types of chromosome abnormality resulting from errors in chromosome segregation and recombination.

  As initially considered in Chapter 5 , the link between deleterious mutations and disease phenotype is often not straightforward. A deleterious mutation that might be expected to result in a single-gene disorder, according to the principles described in Chapter 5 , may produce different degrees of disease severity, or no disease at all. We examine factors that complicate the link between genetic variation and disease phenotype, beginning in Section 7.6 with the tiny mitochondrial genome: it has just 37 genes but is nevertheless important in disease, and has unique properties that complicate the molecular pathology. Then in Section 7.7 we go on to describe factors affecting phenotypes that result from variation in the nuclear genome.

  In Section 7.8 we examine downstream effects at the protein structure level, notably how altered protein folding, and protein aggregation contribute to disease phenotypes. Finally, in Section 7.9 we consider the difficulties in correlating genotypes and phenotypes, and we give examples of how the phenotype of a monogenic disorder can be influenced by various factors including genetic variation at other gene loci and environmental factors.

  7.1 AN OVERVIEW OF HOW GENETIC VARIATION RESULTS IN DISEASE

  The great majority of variation in our DNA appears to be without consequence. For the most part, that happens because just a small percentage of our genome is functionally important (the great majority of nucleotides within introns and in extragenic DNA can be changed by small mutations without any obvious effect on the phenotype). A second, and minor, reason is genetic redundancy: some genes are present in multiple, almost identical copies—an inactivating mutation in a single ribosomal RNA gene in nuclear DNA has no effect because each type of cytoplasmic rRNA is made by hundreds of extremely similar gene copies.

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  Characterization of Biomaterials

  • M Jaffe, W. Hammond, P Tolias, T Arinzeh(Authors)
  • 2012(Publication Date)
  • Woodhead Publishing

    (Publisher)

  These are rearrangements to the chromosomes that are either balanced or unbalanced. In balanced changes, the genetic material has been displaced but the amount of genetic information has remained intact. In unbalanced changes, there is either a gain or loss of genetic material. Both events can have severe clinical significance since they basically disturb the amount or correct orientation of the genes located on the chromosomes. Table 7.1 illustrates some of the more common structural changes that have been identified. Table 7.1 Common chromosomal abnormalities Type of abnormality Definition Monosomy One chromosome absent Trisomy One chromosome extra Deletion Part of a chromosome missing Duplication Part of a chromosome present twice Inversion Segment of a chromosome reversed Translocation Two chromosomes join long arms or exchange parts Ring chromosome A chromosome that forms a ring due to deletions in telomeres, which cause ends to adhere Isochromosome A chromosome with identical arms Aneuploidy An extra or missing chromosome Polypoidy Extra chromosome sets While it is easy to see how deletions or duplications of the chromosomes can cause dramatic phenotypic effects because of the loss or gain of genes, reciprocal translocations, even when they appear balanced, can have important consequences. Reciprocal translocations are exchanges between two or more chromosomes that result in recombinant chromosomes that have structures that are composed of the exchanged chromosomes. Sometimes these translocation events cause the gene structure or expression of the gene to be disturbed and can result in serious phenotypic consequences for the carrier individual

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  Evolution

  • Mark Ridley(Author)
  • 2009(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  The old and new copies will have different numbers of repeats. They may be repaired to create a mutant DNA (with two or four repeats) or to restore the original number of three repeats. Sections of DNA with many repeats of a similar sequence may be particularly vulnerable to slippage. . . . frameshift mutations . . . . . . slippage . . . . . . transposition . . . chromosome, or to another place on the same chromosome, or be inverted. Whole chromosomes may fuse, as has happened in human evolution; chimps and gorillas (our closest living relatives) have 24 pairs of chromosomes whereas we have 23. Some or all of the chromosomes may be duplicated. The phenotypic effects of these Chromosomal Mutations are more difficult to generalize about. If the break-points of the mutation divide a protein, that protein will be lost in the mutant organism. But if the break is between two proteins, any effect will depend on whether the expression of a gene depends on its position in the genome. In theory, it might not matter whether a protein is transcribed from one chromosome or another; though in practice gene expression is probably at least partly regulated by relations between neighboring genes and a chromosomal mutation will then have phenotypic consequences. 30 PART 1 / Introduction .. (a) Transposition (by reverse transcription) (b) Unequal crossing-over Reverse transcription A B A B A A B B Target Transposable element RNA (a) (b) A B C D E F G H A E F G H F G H F G H A B C D E A B C D E F G H A B C D E N O P Q R A B C D E F G H A E D C B F G H A B C O N E D P Q R Deletion Duplication Inversion Reciprocal translocation (c) (d) Figure 2.6 Transposition and unequal crossing-over are mutation mechanisms that affect stretches of DNA longer than one or two nucleotides. They duplicate DNA laterally through the genome. (a) Transposition can occur by more than one mechanism. Here transposition occurs via an RNA intermediate that is copied back into the DNA by reverse transcription.

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