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Department of Biological and Environmental Sciences
Genetics
 Dr. David A. Johnson
Biol 333

Mutation I

When you have mutants you're better off that when you don't.
--Salvador E. Luria

A mutation is defined as any permanent change to the genetic material. Mutation can be classified according to several criteria. (There are also non-permanent changes to the genetic material called epigenetic changes, like methylation of DNA bases. See "What is Epigenetics" below.)
  • Origin of the Mutation: Mutations can be either spontaneous or induced.
    • Spontaneous Mutations: Mutations occur naturally, but at a very low rate. We will explore the chemical nature of some of these spontaneous mutations later. The rate for spontaneous mutations varies from organisms to organism (10-4 to 10-8).
    • Induced Mutations and Mutagens: Mutations can be induced by various outside factors, called mutagens.
      • Chemical Mutagens: Numerous chemicals can alter DNA by reacting with it or creating other molecules that react with DNA. Again, we will study some examples later.
      • Mutagenic Radiation: Certain types of radiation damage DNA.
        • Ionizing Radiation: Some radiation creates radicals or ion pairs as it passes through tissue. These are very reactive and can chemically modify DNA.
          • X rays: X rays are an example of ionizing radiation. In 1927, H. J. Muller first showed that X rays cause mutations.
          • Others: γ rays, β and α particles, neutrons are other examples of ionizing (therefore mutagenic) radiation.
        • Ultraviolet Radiation: Although some UV can cause ionization, it is usually mutagenic due to its ability to create covalent bonds between adjacent thymine bases in DNA (thymine dimers, more later).
  • Site of the Mutation: In multicellular organisms, mutations can be classified as either germ-line mutations or somatic mutations:
    • Germ-Line Mutations: These are mutations in gametes or cells destined to become gametes. They can be passed along to future generations.
    • Somatic Mutations: There are mutations in the somatic cells and cannot be passed along.
      • Carcinogenesis and Mutagenesis: One class of somatic mutations are those that turn a normal gene into a cancer gene (oncogene). We will look at this process briefly later in this course.
  • Chromosome Mutation vs. Gene Mutation: Mutations can be classified as either chromosome mutations or gene mutations.
    • Chromosome Mutation: These mutations change the chromosome number or chromosome structure, but may not have any detectable effect on the individual genes. Rather, the dosage and/or locus of a gene is changed.
      • Changes in Chromosome Number: Many chromosome mutations change the number of chromosomes.
        • Euploidy: This is the addition or subtraction of a whole haploid set (genome). 
          • Haploidy: This is the 1n condition in an organism that is normally 2n and is very rare.
          • Polyploidy: This is the gain of one or more genomes (3n, 4n, 5n, etc.). Polyploidy is common in many plants and some lower animals. It may sexual or asexual.
            • Autopolyploidy: Autopolyploidy involves the gaining of a duplicate genomes from the same species. This may occur spontaneously or may be induced by microtubule blockers like colchicine.
            • Allopolyploidy: Allopolyploidy is polyploidy by adding genomes of different species.
        • Aneuploidy and Nondisjunction: Aneuploidy is gaining or losing single (or several) chromosomes. It is the main cause of spontaneous abortions (35% of all) and is the main cause of mental retardation. Aneuploidies are also extremely common in cancer tumors (causative or not?). Aneuploidy most commonly occurs by a mistake of meiosis called nondisjunction, which usually occurs at anaphase I. This is the failure of homologous chromosomes to segregate.
          • Trisomy: A trisomic individual has gained one  chromosome.
            • Down Syndrome: Also called trisomy 21, this is a common aneuploidy in humans. It usually occurs by nondisjunction in oogenesis, with the rate increasing with maternal age (average frequency = 1/700; age 25 = 1/1400; age 35 = 1/350; age 40 = 1/100).


            • Others: There are other human trisomies that are not as common as Down Syndrome, including trisomy 18 (Edwards Syndrome) (1/8,000) and trisomy 13 (1/20,000).
          • Monosomy: This is the loss of a single chromosome.
          • Aneuploidy of Sex Chromosomes: These are common aneuploidies of sex chromosomes in humans.
            • Klinefelter Syndrome: In humans, an XXY male individual has this syndrome (1/500). (Other rare Klinefelter individuals may be XXXY, XXYY, XXXXY, or even XXXXXY. They have more severe symptoms.)
            • Turner Syndrome: In humans, an XO female has this syndrome (1/2,500). Other Turner individuals may be missing only a portion of the X chromosome. (See NIH info site)
            • Others: XXX, XYY and other aneuploidies are possible.
          • A Hypothesis for the Mechanisms of Aneuploidy: Aneuploidy may produces a plethora of effects but it has been postulated from work originally in yeast (confirmed in mammals) that aneuploidy creates stress on the proteasome mechanism of cells. Proteasomes are cellular complexes that include proteases (protein-destroying enzymes). These destroy unneeded or damaged (misfolded) proteins. Thereby they help regulate the relative concentration of proteins, which is important in assembling proteins with tertiary structure. Having an extra chromosome increases the concentration of proteins made by genes on that chromosome. This put stress on the mechanism that keeps the relative concentration of proteins correct (proteasomes). In fact, it appears that the higher the ploidy, the lesser the effect of adding a single chromosome. (A 1n yeast cell with and extra chromosome is more defective than a 2n cell with an extra chromosome, presumably because the relative concentration of proteins is further off in the 1n cell.) Targeting cells with aneuploidies with drugs presents a novel way of attaching cancer cells, since aneuploidy is common in tumors. (Amon, GSA 2012)
      • Changes in Chromosome Structure: Chromosomal segment may change their copy number or location.
        • Duplication: If a segment is duplicated, it can be in one of three configurations.
          • Tandem Duplications: These have the duplicated segment in the original order and next to it.
            • Unequal Crossing Over: This mistake of meiosis I can cause both tandem duplications and deletions. (Duplications and deletions may occur by other mechanisms also.)
              • Homologous Unequal Crossing Over: This is a secondary event that occurs as a result of the presence of a previous tandem duplication, as illustrated by the Bar mutation in Drosophila.
              • Nonhomologous Unequal Crossing Over: This is the original event that creates a tandem duplication and deletion.

          • Palindromes: This is a repeat that is in reverse order compared to the original segment.
          • Displace Duplications: This is a duplication in which the duplicated segment is not adjacent to the original segment.
          • Human Duplications:
            • Hb Lepore syndrome: Normal adult hemoglobin (Hb) has two α globins and two β globins: α2β2). The rare genetic syndrome called Hb Lepore syndrome results when a person has one mutant Lepore β Hb allele and one normal β allele (that is, they are heterozygotes). They are usually asymptomatic. However, homozygotes for the Lepore β allele have β-thalassemia. (β-thalaseemia is a general term for severe anemia in which there is decreased production of the β chain.) The Lepore allele most likely arose by homologous unequal crossing over between the δ and β globin genes on chromosome 11, resulting in a δ/β fusion gene which codes for the altered Hb called Hb Lepore , which is a polypeptide that is a fusion of the amino end of the δ polypeptide and the carboxyl end of the β polypeptide. [Non-homologous unequal crossing over is believed to have given rise to the δ allele in the human evolutionary past. Homologous unequal crossing over is believed to be the origin of the δ/β fusion allele.]
            • Huntington Disease: This is an autosomal dominant trait (involving the HTT gene on chromosome 4) with incomplete penetrance that is due to a trinucleotide repeat (CAG)n, encoding multiple glutamines in the huntingtin protein (the protein coded for by the mutant HTT allele). The normal number of repeats is between 9 and 36. Persons with 36-39 repeats show the reduce penetrance describe in the Mendel Revisited outline (McNeil SM et al. 1997, Hum Mol Genet. 6:775). Juvenile-onset Huntington disease (onset before age 20) is usually inherited from the father and affected individuals have 60 or more repeats. However, "a substantial proportion of the variance in age of onset in Huntington disease is due either to variation in genes other than HTT or in the environment" (Wexler et al. 2004. Proc Natl Acad Sci USA 101:3498). The function of huntingtin in the cell is unknown..." as of 2012 (http://www.ncbi.nlm.nih.gov/pubmed/22482451), but it is known to have its effect on brain cells.
            • Fragile-X Syndrome: A fairly common, X-linked dominant genetic disorder, it also involves extra copies of a trinucleotide repeat, like Huntington Disease. Read and know explanation in this link of fragile-X. Know the info under Description, Frequency, Genetic Changes, and Inheritance Pattern: https://ghr.nlm.nih.gov/condition/fragile-x-syndrome#inheritance
        • Deletions: Like tandem duplications, deletion (also called deficiencies) can also be caused by unequal crossing over (and other mechanisms). (Cri-du-chat, first documented human deletion). Duplications and deletions may be referred to as copy number variants (CNVs).
        • Inversions: Inversions involve reversing the orientation of a segment of a chromosome. Inversion may be paracentric or pericentric. Inversion heterozygotes have problems making functional gametes due to crossing over in the inverted segment.
        • Translocations: Translocations move a segment to a non-homologous chromosome. Just as with inversion heterozygotes, reciprocal translocation heterozygotes have reduced fertility.
          • Robertsonian Translocation (Robertsonian Fusion): A nonhomologous exchange between two acrocentric or telocentric chromosomes can result in a fused (metacentric) chromosome. (Reference: mechanisms may result in two closely adjacent centromeres and one acentric fragment, rather than as illustrated to the right. Here is a more recent article proposing how Robertsonian translocations  between two telocentric chromosomes may occur.)
      • Karyotyping and Chromosome Mutations: Karyotyping makes it possible to detect chromosome mutations. The human karyotype divides the chromosome into groups A, B, C, D, E, F, G, and sex chromosomes. (Arrange in size order, large to small; A group (3 pairs) = metacentric and submetacentric, B (2 pairs) group = submetacentric, C group (7 pairs) = metacentric, D group (3 pairs) = acrocentric, E group (3 pairs) = metacentric, F group (2 pairs), G group (2 pairs) = acrocentric, X chromosome = resemble a C group chromosome, Y chromosome = resembles a G group chromosome.)
    • Gene Mutations: (Next outline)
What Is Epigenetics? (from: http://www.zymoresearch.com/learning-center/epigenetics/what-is-epigenetics)
  "Epigenetics" refers to covalent modification of DNA, protein, or RNA, resulting in changes to the function and/or regulation of these molecules, without altering their primary sequences. In some cases, epigenetic modifications are stable and passed on to future generations, but in other instances they are dynamic and change in response to environmental stimuli. Nearly every aspect of biology is influenced by epigenetics, making it one of the most important fields in science.
Epigenetics and Me
  Why do some foods cause health problems and others make us healthy? How does stress impact our long-term well-being? Why is it that the older we get, the more likely it is that age-related illness will strike us? Unlocking the secrets behind these and other questions has the potential to revolutionize life as we know it. The emerging field of epigenetics is aiming to do just that.
  The importance of nature versus nurture has long been disputed. It cannot be denied that environment greatly influences how a child grows and develops, nor can it be denied that our DNA is the blueprint that makes us who we are. Epigenetics merges these two seemingly contradictory lines of thought to explain how environmental factors cause physical modifications to DNA and its associated structures, which result in altered functions.
  The most commonly known epigenetic modification is DNA methylation. Although many technologies have been developed in the past to characterize genomic DNA methylation, none of them has been able to efficiently determine DNA methylation patterns on a genomic scale. Until now.
More on Epigenetics
  Many cellular processes, including gene expression and DNA replication, are often regulated by mechanisms that fall into the category of "classical genetics." This generally means that they are controlled by elements such as promoters, enhancers, or binding sites for repressor proteins, that are present or absent in the DNA sequence.  An example of this type of regulation is the control of expression of a cellular oncogene.  In normal (non-cancer) cells, this gene would not be expressed. However, in a cancer cell, this gene could have acquired a mutation, which is a change to the DNA sequence, that allows the oncogene to be expressed, and thus can contribute to the progression of cancer.
  In addition to the regulatory mechanisms of classical genetics, nearly all cellular processes can also be regulated by epigenetic mechanisms.  Epigenetic mechanisms can be just as important to biological events as genetic mechanisms, and can also result in stable and heritable changes. However, the big difference between genetic and epigenetic regulation is that epigenetic mechanisms do not involve a change to the DNA sequence, whereas genetic mechanisms involve the primary DNA sequence and changes or mutations to this sequence.  Epigenetic regulation involves the modification of DNA and the proteins associated with DNA, which results in changes to the conformation of DNA and accessibility of other factors to DNA, without a change to the sequence of the DNA.
  The Greek prefix "epi" means "on top of" or "over", so the term "Epigenetics" literally describes regulation at a level above, or in addition to, those of genetic mechanisms. Common types of epigenetic regulation are DNA methylation and hydroxymethylation, histone modification, chromatin remodeling, and regulation by small and large non-coding RNAs. The field of epigenetics was given its name and a vague definition only ~50 years ago, but is now a dynamic and rapidly expanding discipline, challenging and revising traditional paradigms of inheritance.
  Through epigenetics, the classic works of Charles Darwin, Gregor Mendel, and Jean-Baptiste Lamarck and others are now seen in different ways. As more factors influencing heredity are discovered, today's scientists are using epigenetics to decipher the roles of DNA, RNA, proteins, and environment in inheritance. The future of epigenetics will reveal the complexities of cellular differentiation, embryology, the regulation of gene expression, aging, cancer, and other diseases.
Things I Learned at the Movies:
Radiation causes interesting mutations — not to your future children, but to you, right then and there.