Genetics - Ch. 13 Gene Mutations, Transposable Elements, & DNA Repair

About ______% of the human genome consists of sequences derived from transposable elements, although most of these elements are now inactive and no longer capable of transposing. A comparison of human and chimpanzee genomes suggests that almost 11,000 transposition events have occurred since these two species diverged about 6 million years ago.

45%

___________________ ______________ are chemicals that donate alkyl groups, such as methyl and ethyl groups, to nucleotide bases. For example, ethyl-methylsulfonate (EMS) adds an ethyl group to guanine, producing O^6-ethylguanine, which pairs with thymine. Thus, EMS produces C-G to T-A transitions. EMS is also capable of adding an ethyl group to thymine, producing 4-ethylthymine, which then pairs with guanine, leading to a T-A to C-G transition. Because EMS produces both C-G to T-A and T-A to C-G transitions, mutations produced by EMS can be reversed by additional treatment with EMS.

Alkylating agents

One of the most common transposable elements in the human genome is ________. Every human cell contains more than 1 million related, but not identical, copies of Alu in its chromosomes. Alu sequences are similar to the gene that encodes the 7S RNA molecule, which transports newly synthesized proteins across the endoplasmic reticulum. Alu sequences create short flanking direct repeats when they insert into DNA and have traits that suggest that they have transposed through an RNA intermediate.

Alu

Expanding nucleotide repeats have been found in numerous human genetic diseases. Most of these diseases are caused by the expansion of a set of three nucleotides (called a trinucleotide), most often ___________, where N can be any nucleotide. However, some diseases are caused by repeats of four, five, and even twelve nucleotides. The number of copies of the nucleotide repeat often correlates with the severity or age of onset of the disease. The number of copies of the repeat also corresponds to its instability: when more repeats are present, the probability of expansion to even more repeats ______________.

Expanding nucleotide repeats; CNG; increases

__________-_________ mutations arise in cells that ultimately produce gametes. These mutations can be passed to future generations, producing individuals that carry the mutation in all their somatic and germ-line cells. Generally, "mutations" in multicellular organisms refers to germ-line mutations.

Germ-line

When pyrimidine dimers block replication, cell division is inhibited and the cell often dies; for this reason, UV light kills bacteria and is an effective sterilizing agent. For a mutation to occur, the replication block must be overcome. Bacteria can sometimes circumvent replication blocks produced by pyrimidine dimers and other types of DNA damage by means of the _________ system. This system allows replication blocks to be overcome, but in the process, it makes numerous mistakes and greatly increases the rate of mutation. Indeed, the very reason that replication can proceed in the presence of a block is that the __________ in the SOS system do not strictly adhere to the base-pairing rules. The trade-off is that replication can continue and the cell survives, but only by sacrificing the normal accuracy of DNA synthesis.

SOS; enzymes

_____________ mutations arise in somatic tissues, which do not produce gametes; when a somatic cell with a mutation divides (by mitosis), the mutation is passed on to the daughter cells, leading to a population of genetically identical cells (a clone). The _____________ in development that a somatic mutation occurs, the larger the clone of cells will be that contain the mutation.

Somatic; earlier

A recent version of the test (called ______ _____) uses several auxotrophic strains that detect different types of base-pair substitutions. Other strains detect different types of frame-shift mutations. Each strain carries a his^- mutation, which renders it unable to synthesize the amino acid histidine, and the bacteria are plated on medium that lacks histidine. Only bacteria that have undergone a reverse mutation of the histidine gene (his^- to his^+) are able to synthesize histidine and grow on the medium, which makes these mutations easy to detect. Different dilutions of a chemical to be tested are added to plates inoculated with the bacteria and the number of mutated bacterial colonies that appear on each plate in compared with the number that appear on control plates with no chemical (those that arose via spontaneous mutation). Any chemical that significantly increases the number of colonies appearing on a treated plate is mutagenic and probably also carcinogenic.

Ames II

In 1974, Bruce Ames developed a simple test for evaluating the potential of chemicals to cause cancer. The _______ ______ is based on the principle that both cancer and mutations result from damage to DNA, and the results of experiments have demonstrated that 90% of known carcinogens are also mutagens. Ames proposed that mutagenesis in bacteria could serve as an indicator of carcinogenesis in humans.

Ames test

_________________ mutations are expressed only under certain conditions. For example, some of these mutations affect the phenotype only at elevated temperatures. Another type of mutation is a ____________ mutation, one that causes premature death.

Conditional; lethal

Some transposable elements transpose as DNA (instead of being first copied into RNA, as retrotransposons are) and are referred to as ________ _______________ (aka Class II transposable elements). Other transposable elements transpose through an RNA intermediate. In this case, RNA is transcribed from the transposable element (DNA) and is then copied back into DNA by a special enzyme called reverse transcriptase. Elements that transpose through an RNA intermediate are called __________________ (aka Class I transposons). Most transposable elements found in bacteria are DNA transposons. Both DNA transposons and retrotransposons are found in eukaryotes, although retrotransposons are more common.

DNA transposons; retrotransposons

_________-_____-___________ mutation causes the cell to produce a protein or gene product whose function is not normally present. The result could be an entirely new gene product or one produced in an inappropriate tissue or at an inappropriate time in development. For example, a mutation in a gene that encodes a receptor for a growth factor might cause the mutated receptor to stimulate growth all the time, even in the absence of the growth factor. These mutations are frequently dominant in their expression because a single copy of the mutation leads to the presence of a new gene product.

Gain-of-function

Mutations are important to the study of genetics and many other biological fields, because many studies focus on how genetic variations produced by mutation are inherited and mutations are useful for examining fundamental biological processes. ______________ ______________, in which mutations are found or created to analyze the effects that can often lead to an understanding of the system, is a valuable source of insight into biological processes.

Genetic dissections

____________________ is a very specific base-modifying mutagen that adds a hydroxyl group to cytosine, converting it into hydroxylaminocytosine. This conversion increases the frequency of a rare tautomer that pairs with adenine instead of guanine and leads to C-G to T-A transitions. Because hydroxylamine acts only on cytosine, it will not generate T-A to C-G transitions; thus, hydroxylamine will not ______________ the mutations that it produces.

Hydroxylamine; reverse

_________________ in the number of nucleotide repeats can produce several disease symptoms in different ways. In several diseases, such as Huntington disease, the nucleotide expansion occurs within the ______________ part of a gene, producing a toxic protein that has extra glutamine residues (the amino acid encoded by CAG). In other diseases, the repeat is outside the coding region of a gene and affects its expression. In fragile-X syndrome, the additional copies of the nucleotide repeat cause the DNA to become methylated, which turns off the transcription of an essential gene.

Increases; coding

_________-______-__________ mutations cause the complete or partial absence of normal protein function. This mutation alters the structure of protein so much that the protein no longer works correctly, or occurs in regulatory regions that affect the transcription, translation, or splicing of the protein. These mutations are the same mutations that cause cystic fibrosis: these mutations produce a nonfunctional form of the cystic fibrosis transmembrane conductance regulator protein, which normally regulates the movement of chloride ions into and out of the cell.

Loss-of-function

An inherited change in genetic information.

Mutation

________________ rates vary among genes and species, but you can draw several general conclusions about mutation rates. First, spontaneous mutation rates are low for all organisms studied. Typical mutation rates for bacterial genes range form about 1 to 100 mutations per 10 billion cells. The mutation rates for most eukaryotic genes are higher, from about 1 to 10 mutations per million gametes. These higher values in eukaryotes may be due to the fact that the rates are calculated per _____________, and that several cell divisions are required to produce a gamete, whereas mutation rates in prokaryotic cells are calculated per __________ _______________.

Mutation; gamete; cell division

Small insertions and deletions can arise spontaneously in replication and crossing over. ___________ ____________ can occur when one nucleotide strand forms a small loop. If the looped-out nucleotides are on the newly synthesized strand, an _______________ results. At the next round of replication, the insertion will be replicated and both strands will contain the insertion. If the looped-out nucleotides are on the template strand, then the newly replicated strand will have a _______________, and this deletion will be perpetuated in subsequent rounds of replication.

Strand slippage; insertion; deletion

______________ ______________ - DNA sequences that can move about in the genome - are often a cause of mutations. They are found in the genomes of all organisms and are abundant in many: for example, they make up at least 45% of human DNA. Most of these are able to insert themselves at many different locations in the genome, relying on mechanisms that are distinct from homologous recombination. They often cause mutations, either by inserting into a gene and disrupting it or by promoting DNA rearrangements such as deletions, duplications, and inversions.

Transposable elements

_______ light has less energy than ionizing radiation and does not eject electrons, but is nevertheless highly mutagenic. Pyrimidine bases readily absorb UV light, resulting in the formation of chemical bonds between adjacent pyrimidine molecules on the same strand of DNA, which create pyrimidine ______________. Pyrimidine dimers consisting of two thymine cases (called thymine dimers) are most frequent, but cytosine dimers and thymine-cytosine dimers can also form. These dimers are bulky lesions that distort the configuration of DNA and often block replication. Most pyrimidine dimers are immediately repaired, but some escape repair and inhibit replication and transcription.

UV; dimers

_____________________ __________________ is a rare autosomal recessive condition that include abnormal skin pigmentation and acute sensitivity to sunlight. Persons who have this disease also have a strong predisposition to skin cancer, with an incidence ranging from 1,000 to 2,000 times that found in unaffected people. Sunlight includes a strong UV component, so exposure to sunlight produces pyrimidine dimers in the DNA of skin cells. Most pyrimidine dimers in humans can be corrected by nucleotide-excision repair. However, the cells of most people with xeroderma pigmentosum are defective in nucleotide-excision repair, and many of their pyrimidine dimers remain uncorrected and may lead to cancer.

Xeroderma pigmentosum

One class of chemical mutagens consists of _________ _________, chemicals with structures similar to those of any of the four standard bases of DNA. DNA ________________ cannot distinguish these analogs from the standard bases, so if base analogs are present during replication, they may be incorporated into newly synthesized DNA molecules. For example, 5-bromo-uracil (5BU) is an analog of thymine; it has the same structure as thymine except that it has a bromine (Br) atom on the 5-carbon atom instead of a methyl group. Normally, 5-bromo-uracil pairs with adenine just as thymine does, but it occasionally mispairs with guanine, leading to a transition. Through mispairing, 5-bromo-uracil can also be incorporated into a newly synthesized DNA strand opposite guanine. In the next round of replication, 5-bromo-uracil pairs with adenine, leading to another transition. In the lab, mutations caused by base analogs can be reversed by treatment with the same analog or by treatment with a different analog.

base analogs; polymerases

In ______-___________ repair, a modified base is first excised and then the entire nucleotide is replaced. The excision of modified bases is catalyzed by a set of enzymes called DNA glycosylases, each of which recognizes and removes a specific type of modified base.

base-excision

Replication is amazingly accurate: less than one error in a _______________ nucleotides arises in the course of DNA synthesis. However, spontaneous replication errors do occasionally occur.

billion

People in industrial societies are surrounded by a multitude of artificially produced chemicals: more than 50,000 different chemicals are in commercial and industrial use today, and from 500 to 1,000 new chemicals are introduced each year. Some of these chemicals are potential ______________, and some natural products are also potentially _______________. One method for testing the cancer-causing potential of substances is to administer them to lab animals (rats or mice) and compare the incidence of cancer in the treated animals with that in control animals. Unfortunately, these tests are time-consuming and expensive. Furthermore, the ability of a substance to cause cancer in rodents is not always indicative of its effect on humans.

carcinogens; carcinogenic

In addition to its spontaneous occurrence, deamination can be induced by some _______________. For instance, nitrous acid deaminates cytosine, creating uracil, which in the next round of replication pairs with adenine, producing a C-G to T-A transition mutation. Nitrous acid also changes adenine into hypoxanthine, which pairs with cytosine, leading to a T-A to C-G transition. In addition, nitrous acid deaminates guanine, producing xanthine, which pairs with cytosine just as guanine does; however, xanthine can also pair with thymine leading to a C-G to T-A transition. Nitrous acid produces exclusively _____________ mutations, and because both C-G to T-A and T-A to C-G transitions are produced, these mutations can be reversed with nitrous acid.

chemicals; transition

Another spontaneously occurring chemical change that occurs in DNA is __________________, the loss of an amino group (NH2) from a base. This change may be spontaneous or may be induced by mutagenic chemicals.

deamination

In addition to spontaneous mutations that arise in replication, mutations also result from spontaneous chemical changes in DNA. One such change is ___________________, the loss of a purine base from a nucleotide. Depurination results when the covalent bond connecting the purine to the 1'-carbon atom of the deoxyribose sugar breaks, producing an ____________ site, a nucleotide that lacks its purine base. This site cannot act as a template for a complementary base in replication. In the absence of base-pairing constraints, an incorrect nucleotide (most often adenine) is incorporated into the newly synthesized DNA strand opposite the apurinic site, frequently leading to an __________________ error. The incorporated error is then transformed into a replication error at the next round of replication. Depurination is a common cause of spontaneous mutation; a mammalian cell in culture loses about 10,0000 purines every day. Loss of pyrimidine bases also occurs, but at a much lower rate than depurination.

depurination; apurinic; incorporated

Another type of DNA-repair mechanism is _________ ________, which does not replace altered nucleotides, but instead restores their original (correct) structures.

direct repair

Mutations in which the number of copies of a set of nucleotides increases are called _____________ _____________ ____________. This type of mutation was first found in 1991 in a gene called FMR-1, which causes fragile-X syndrome, the most common hereditary cause of intellectual disability. The disorder is called fragile-X because in specially treated cells from persons having the condition, the tip of each long arm of the X chromosome is attached by only a slender-appearing part of the chromosome. The normal FMR-1 allele has 60 or fewer copies of CGG, but with a mutation, the allele may harbor hundreds or thousands of copies.

expanding nucleotide repeats

Short _____________ ___________ ___________ from 3 to 12 bp long are present on both sides of most transposable elements. The sequences of these repeats vary, but their length is constant for each type of transposable element. These repeats are not a part of the _____________ ___________ and do not travel with it. Rather, they are generated in the process of transposition at the point of insertion. The presence of flanking direct repeats indicates that staggered cuts are made in the target DNA when a transposable element inserts itself. The staggered cuts leave short-stranded pieces of DNA on either side of the transposable element. Replication of the single-stranded DNA then creates the flanking direct repeats.

flanking direct repeats; transposable element

Another way that mutations are classified is on the basis of their phenotypic effects. At the most general level, you can distinguish a mutation on the basis of its phenotype compared with the wild-type phenotype. A mutation that alters the wild-type allele is called a _______________ mutation, whereas a ________________ mutation (aka reversion) changes a mutant allele back into the wild-type allele.

forward; reverse

Historically, mutation have been partitioned into those that affect a single gene, called _________ mutations, and those that affect the number or structure of chromosomes, called _______________ mutations. This distinction arose because chromosome mutations could be observed directly, by looking at chromosomes with a microscope, while gene mutations could be detected only by observing their phenotypic effects. Now, with the creation of DNA sequencing, gene mutations and chromosome mutations are distinguished somewhat arbitrarily on the basis of the size of the DNA lesion. Nevertheless, it is practical to use chromosome mutation for a large-scale genetic alteration that affects chromosome structure or the number of chromosomes and to use gene mutation for a relatively small DNA lesion that affects a single gene.

gene; chromosome

Another genetic disease caused by faulty DNA repair is an inherited form of colon cancer called _______________ ________________ ____________ _____________ (HNPCC). It is one of the most common hereditary cancers, accounting for about 15% of colon cancers. Research findings indicate that HNPCC arises from mutations in the proteins that carry out mismatch repair.

hereditary nonpolyposis colon cancer

When a mispaired base has been incorporated into a newly synthesized nucleotide chain, an ________________ __________ is said to have occurred. Suppose that, in replication, thymine mispairs with guanine through wobble. In the next round of replication, the two mismatched bases separates, and each serves as a template for the synthesis of a new nucleotide strand. This time, thymine pairs with adenine, producing another copy of the original DNA sequence. On the other strand, however, the incorrectly incorporated guanine serves as the template and pairs with cytosine, producing a new DNA molecule that has an error: a C-G pair in place of the original T-A pair. The original incorporated error leads to a replicated error, which creates a permanent mutation because all the base pairings are correct and there is no mechanism for repair systems to detect the error.

incorporated error

Another class of gene mutations contains ______________ and _________________ (collectively called indels): the addition or removal of one or more nucleotide pairs Although base substitutions are often assumed to be the most common type of mutation, molecular analysis reveals that insertions and deletions are frequently more common. Insertions and deletions within sequences that encode proteins may lead to _______________ mutations: changes in the reading frame of the gene. These mutations often alter all amino acids encoded by the nucleotides following the mutation, so they generally have drastic effects on the phenotype. Some frameshifts also introduce premature stop codons, terminating protein synthesis early and resulting in a shortened (truncated) protein. Not all insertions and deletions lead to frameshifts, however; insertion and deletions consisting of any multiple of three nucleotides leave the reading frame intact, although the addition or removal of one or more amino acids may still affect the phenotype. Indels that do not affect the reading frame are called ____-__________ insertions and ____-__________ deletions

insertions; deletions; frameshift; in-frame; in-frame

Proflavin, acridine orange, ethidium bromide, and dioxin are ____________ ___________, which produce mutations by sandwiching themselves (intercalating) between adjacent bases in DNA, distorting the 3D structure of the helix and causing single-nucleotide insertions and deletions in replication. These insertions and deletions frequently produce frameshift mutations, so the mutagenic effects of the intercalating agents are often severe. Because intercalating agents generate both additions and deletions, they can ______________ the mutations they produce.

intercalating agents; reverse

An _________________ suppressor mutation occurs in a gene other than the one bearing the original mutation. These suppressors sometimes work by changing the way that the mRNA is translated.

intergenic

An ___________________ suppressor mutation occurs in the same gene that contains the mutation being suppressed. It may work in any of several ways. The suppressor may change a second nucleotide in the same codon altered by the original mutation, producing a codon that specifies the same amino acid that was specified by the original, nonmutated codon. It may also work by suppressing a frameshift mutation. If the original mutation, for example, is a one-base deletion, then the addition of a single base elsewhere in the gene will restore the former reading frame. Similarly, a mutation due to an insertion may be suppressed by a subsequent deletion in the same gene. Another way an intragenic suppressor mutation may work is by making compensatory changes in the protein. A first missense mutation can alter the folding of a polypeptide chain by changing the way in which amino acids in the protein interact with one another. A second missense mutation at a different site (the suppressor) can recreate the original folding pattern by restoring interactions between the amino acids.

intragenic

In 1927, Hermann Muller demonstrated that mutations in fruit flies could be induced by X-rays. The results of subsequent studies showed that X-rays greatly increase mutation rates in all organisms. Because of their high energies, X-rays, gamma rays, and cosmic rays are all capable of penetrating tissues and damaging DNA. These forms of radiation, called ____________ ___________, dislodge electrons from the atoms that they encounter, changing stable molecules into free radicals and reactive ions, which then alter the structures of bases and break phosphodiester bonds in DNA. Ionizing radiation also frequently results in double-strand breaks in DNA. Attempts to repair these breaks can produce chromosome mutations.

ionizing radiation

The Ames test uses auxotrophic strains of bacterium Salmonella typhimurium that have defects in the _________________________ coat, which normally protects the bacteria from chemicals in the environment. Furthermore, the DNA-repair system in these strains has been __________________, enhancing their susceptibility to mutagens. Some compounds are not active carcinogens but can be converted into cancer-causing compounds in the body. To make the Ames test sensitive to such potential carcinogens, a compound to be tested is first incubated in mammalian liver extract that contains metabolic enzymes.

lipopolysaccharide; inactivated

One type of DNA repair is ___________ ___________, which corrects incorrectly inserted nucleotides that escape proofreading by DNA polymerase during replication. Distortions caused by incorrectly paired bases are detected by mismatch-repair enzymes. A complex of mismatch-repair enzymes then cuts out the distorted section of the newly synthesized strand, and DNA polymerase fills the gap with new nucleotides, using the original DNA strand as a template. The template strand is recognized by the presence of methyl groups on special sequences of that strand.

mismatch repair

A base substitution that results in a different amino acid in the protein is referred to as a ____________ mutation. A _____________ mutation changes a sense codon (one the specifies an amino acid) into a nonsense codon (one that terminates translation). If a nonsense mutation occurs early in the mRNA sequence, the protein will be truncated and often nonfunctional.

missense; nonsense

Although many mutations arise spontaneously, a number of environmental agents, including certain chemicals and radiation, are capable of damaging DNA. Any environmental agent that significantly increases the rate of mutation above the spontaneous rate is called a _____________.

mutagen

Because transposable elements can insert into genes and disrupt their function, transposition is generally ______________. In fact, more than half of all spontaneously occurring mutations in Drosophila result from the insertion of a transposable element in or near a functional gene.

mutagenic

Several human diseases are connected to defects in DNA repair. These diseases are often associated with high incidences of specific cancers because defects in DNA repair lead to increased rates of _____________.

mutation

The frequency with which a wild-type allele at a locus changes into a mutant allele is called the ________________ ____________. It is generally expressed as the number of mutations per biological unit, which may be mutations per cell division, per gamete, or per round of replication. For example, achondroplasia is a type of hereditary dwarfism in humans that results from a dominant mutation. On average, about four achondroplasia mutations arise in every 100,000 gametes, and so the mutation rate is about 4/100,000 or 0.00004, mutations per gamete. The mutation rate provides information about how often a mutation arises.

mutation rate

The differences in mutation rates among species may be due to differing abilities to repair _____________, unequal exposures to ______________, or biological differences in rates of spontaneously arising mutations. Even within a single species, spontaneous rates of mutation vary among genes. The reason for the variation is not entirely understood, but some regions of DNA are known hotspots for mutations.

mutations; mutagens

A ______________ mutation is a missense mutation that alters the amino acid sequence of a protein but does not significantly change its function. These mutations occur when one amino acid is replaced by another that is chemically similar or when the affected amino acid has little influence on protein function. For example, some of these mutations occur in the genes that encode hemoglobin; although these mutations alter the amino acid sequence of hemoglobin, they do not affect its ability to transport oxygen.

neutral

Recent research suggests that fewer mutations occur in DNA sequences that are associated with ________________. Reduced mutation rate may occur in these sequence because DNA associated with nucleosomes is less exposed to ______________, but they could also be explained by the effect of nucleosomes on DNA repair, recombination, or replication, all of which influence the rate of mutation.

nucleosomes; mutagens

Another repair pathway is _____________-____________ repair, which removes bulky DNNA lesions (such as pyrimidine dimers) that distort the double helix. In this repair, the two strands of DNA are separated and a section of the DNA containing the distortion is removed; the resulting gap is filled in by DNA polymerase, and DNA ligase seals the gap in the sugar-phosphate linkage. This type of repair can repair many different types of DNA damage. It is found in cells of all organisms from bacteria to humans annd is among the most important of all repair mechanisms.

nucleotide-excision

Deamination can alter the _____________ properties of a base; the deamination of cytosine, for example, produces uracil, which pairs with adenine in replication. After another round of replication, the adenine will pair with thymine, creating a T-A pair in place of the original C-G pair; this chemical change is a ______________ mutation. This type of mutation is often prevented by enzymes that remove __________ whenever it is found in DNA. Their ability to recognize the product of cytosine deamination may explain why thymine, not uracil, is found in DNA. In mammals, including humans, some cytosine bases in DNA are naturally methylated and exist in the form of 5-methyl-cytosine (5mC). When deaminated, 5mC becomes thymine. Because thymine pairs with adenine in replication, the deamination of 5-methyl-ctyosine changes an original C-G pair to T-A. Consequently, C-G to T-A transitions are frequent in mammalian cells, and 5mC sites are mutation hotspots in humans.

pairing; transition; uracil

The integrity of DNA is under constant assault from radiation, chemical mutagens, and spontaneously arising changes. In spite of these damaging agents, the rate of mutation remains remarkably low, thanks to the efficiency with which DNA is ________________.

repaired

A possible source of nucleotide repeat expansion is the formation of hairpins and other special DNA structures, which can cause nucleotides in the template strand to be _______________ twice, thus increasing the number of repeats on the newly synthesized strand.

replicated

Among DNA transposons, transposition may be replicative or nonreplicative. In _______________ transposition, a new copy of the transposable element is introduced at a new site while the old copy remains behind at the original site, so the number of copies of the transposable element increases as a result of transposition. In __________________ transposition, the transposable element excises from the old site and inserts at a new site without any increase in the number of its copies. Nonreplicative transposition requires the replication of only the few nucleotides that constitute the flanking direct repeats. Retrotransposons use replicate transposition only.

replicative; nonreplicative

A dramatic example of the mutagenic effect of transposable elements is seen in the color of grapes, which come in black, red, and white varieties. Black and red grapes result from the production of red pigments, called antyocyanins, in the skin, which are lacking in white grapes. A mutation in black grapes that turned off the production of anthocyanins produced white grapes. This mutation consisted of the insertion of a 10,422 bp _____________________ called Gret1 near a gene that promotes the production of anthocyanins. The Gret1 retrotransposon apparently disrupted sequences that regulate the gene, effectively shutting down anthocyanin production and producing a white grape with no anthocyanins. Interestingly, red grapes resulted from a second mutation that occurred in white grapes. This mutation (probably due to faulty recombination) removed most, but not all, of the retrotransposon, switching anthocyanin production back on, though not as intensely as in the original black grapes. Because transposition entails the exchange of DNA sequences and recombination, it often leads to DNA rearrangements. Homologous recombination between multiple copies of transposons also leads to _________________, ________________, and _______________.

retrotransposon; duplications; deletions; inversions

Transposable elements have clearly played an important role in shaping the genomes of many organisms. The large size of many eukaryotic genomes is due primarily to the abundance of transposable elements, particularly ______________________. Homologous recombination between copies of transposable elements has been an important force in producing gene duplications and other DNA rearrangements. Furthermore, some transposable elements may carry extra DNA with them when they transpose to a new site, providing the potential to move DNA sequences that regulate genes to new sites, where they may later the expression of genes.

retrotransposons

Because of the redundancy of the genetic code, some different codons specify the same amino acid. A _____________ mutation changes a codon to a synonymous codon that specifies the same amino acid, altering the DNA sequence without changing the amino acid sequence of the protein. Not all silent mutations, however, are truly silent: some do have phenotypic effects. Isoaccepting tRNAs are used for different synonymous codons. Because some isoaccepting tRNAs are more abundant than others, which synonymous codon is used may affect the rate of protein synthesis. The rate of protein synthesis can influence the phenotype by affecting the amount of protein present in the cell and, in a few cases, the folding of the protein. Other silent mutations can alter sequences near the exon-intron junctions that affect ______________. Additional silent mutations can influence the binding of miRNAs to complementary sequences in the mRNA, which determines whether the mRNA is translated.

silent; splicing

In multicellular organisms, mutations can be broadly sorted between two categories: ______________ mutations and __________-________ mutation.

somatic; germ-line

Because of the huge number of cells present in a typical eukaryotic organism, _____________ mutations are numerous. Many of these mutations have no obvious effect on the phenotype of the organism because the function of the mutant cell is replaced by that of normal cells, or the mutant cell dies and is replaced by normal cells. However, cells with a ______________ mutation that stimulates cell division can increase in number and spread; this type of mutation can give rise to cells with a selective advantage and is the basis for many cancers.

somatic; somatic

Mutations result from both internal and external factors. Those that occur under normal conditions are termed ___________________ mutations, whereas those that result from changes caused by environmental chemicals or radiation are _______________ mutations.

spontaneous; induced

Transposition is the movement of a transposable element from one location to another. Several different mechanisms are sued for transposition in both prokarytoic and eukaryotic cells. Nevertheless, all types of transposition have several features in common: _____________ breaks are made in the target DNA; the ______________ ___________ is joined to single-stranded ends of the target DNA; and DNA is replicated at the single-stranded _________.

staggered; transposable element; gaps

A _______________ mutation is a genetic change that hides or suppresses the effect of another mutation. This type of mutation is different from a _______________ mutation, in which the mutated site changes back into the original wild-type sequence. A suppressor mutation occurs at a site that is distinct from the site of the original mutation; thus, an individual with a ______________ mutation is a double mutant, possessing both the original mutation and the suppressor mutation but exhibiting the phenotype of a nonmutated wild type. Geneticist distinguish between two classes of suppressor mutations: ________________ and ___________________

suppressor; reverse; suppressor; intragenic; intergenic

The primary cause of spontaneous replication errors was formerly thought to be ____________ ____________, in which the positions of protons in the DNA bases change. Each of the four bases exist in different chemical forms called tautomers. The two tautomeric forms of each base are in dynamic equilibrium, although one form is much more common than the other. The standard Watson-and-Crick base pairings - adenine with thymine, and cytosine with guanine - occur between the common forms of the bases, but if the bases are in their rare tautomeric forms, other base pairings are possible. For example, the common form of cytosine pairs with guanine, but the rare tautomer of cytosine pairs with adenine. Watson and Crick proposed that tautomeric shifts might produce mutations, and for many years their proposal was the accepted model for spontaneous replication errors. However, there has never been convincing evidence that the rare tautomers are the cause of spontaneous mutations. Furthermore, research now show little evidence of tautomers in DNA.

tautomeric shifts

At the ends of many, but not all, transposable elements are ___________ ___________ ____________, which are sequences from 9 to 40 bp in length that are inverted complements of one another. The sequence from left to right in the top strand is the same as the sequence from right to left in the bottom strand. These are recognized by enzymes that catalyze trasposition and are required for transposition to occur.

terminal inverted repeats

The simplest type of gene mutation is a _________ mutation, the alteration of a single nucleotide in the DNA. There are also two types of base substitutions. In a ____________, a purine is replaced by a different purine, or a pyrimidine is replaced by a different pyrimidine. In a _________________, a purine is replaced by a pyrimidine, or a pyrimidine is replaced by a purine. The number of possible transversions is twice the number of possible transitions, but transitions arise more frequently because transforming a purine into a different purine or a pyrimidine into a different pyrimidine is easier than transforming a purine into a pyrimidine or vice versa.

transition; transversion

There are many different types of transposable elements: some have simple structures, encompassing only those sequences necessary for their own _________________ (movement), whereas others have complex structures and encode a number of functions not directly related to _________________. Despite this variation, many transposable elements have certain features in common.

transposition; transposition

There are a number of complex pathways for repairing DNA, but several general statements can be made about DNA repair. First, most DNA-repair mechanisms require _________ nucleotide strand(s) of DNA because most replace whole nucleotides, and a template strand is needed to specify the base sequence. A second general feature of DNA repair is ____________________, meaning that many types of DNA damage can be corrected by more than one pathway of repair. This redundancy illustrates the extreme importance of DNA repair to the survival of the cell: if a mistake escapes one repair system, it's likely to be repaired by another system, ensuring that almost all mistakes are corrected.

two; redundancy

Another process that produces insertions and deletions is unequal crossing over. In normal crossing over, the homologous sequences of the two DNA molecules align, and crossing over produces no net change in the number of nucleotides in either molecule. Misaligned pairing can cause __________ ____________ ___________, which results in one DNA molecule with an insertion and the other with a deletion.

unequal crossing over

Mutation is both good and bad. Mutation is the source of all genetic _______________, the raw material of evolution. On the other hand, many mutations have detrimental effects, and mutation is the source of many diseases and disorders.

variation

A number of cases of human genetic disease have been traced to the insertion of a transposable element into a ______ gene. For example, insertion of the L1 transposable element into the gene for blood clotting factor VIII has caused hemophilia. Although most mutations resulting from transposition are detrimental, transposition can occasionally activate a gene or change the phenotype of the cell in a ______________ way. For instance, bacterial transposable elements sometimes carry genes that encode antibiotic resistance, and several transposable elements have created mutations that confer insecticide resistance in insects.

vital; beneficial

Mispairings often arise through ____________, in which normal, protonated, and other forms of the bases are able to pair because of flexibility in the DNA helical structure. These structures have been detected in DNA molecules and are now thought to be responsible for many of the mispairings in replication.

wobble