Genetics Chapter 16

What two things activate the nucleotide-excision repair way?

1. stalled replication forks 2. stalled transcription complexes

Patients with XP fall into 8 complementation groups, carrying mutations in one of ____ genes encoding proteins XPA through XPG.

8

Ionizing radiation results in the formation of ionized and excited molecules that can damage _________. Because of the _________ nature of biological systems, the molecules generated by the effects of ionizing radiation on water produce the ___________ (most or least?) damage. Many different types of reactive oxygen species are produced. The most damaging species lead to the formation of different adducts and degradation products.

DNA; aqueous; most

______________ mutations: The codon for one amino acid is changed into a translation-termination (stop) codon.

Nonsense

___________ mutation typically refers to the alteration of a single base air of DNA or of a small number of adjacent base pairs.

Point

Certain alkylating agents, such as ethylmethanesulfonate (EMS) and the widely used nitrosoguanidine (NG), operate by the specific mispairing pathway. Such agents add _________ groups (an ethyl group in EMS and a methyl group in NG) to many positions on all ____ bases. However, the formation of a mutation is best correlated with an addition to the oxygen at position 6 of guanine to create an O-6-alkylguanine. This addition leads to direct mispairing with __________, and would result in GC to A___ transitions at the next round of replication. Alkylating agents can also modify the bases in dNTPs (where N is any base), which are precursors in DNA synthesis.

alkyl; four; thymine; T

After DNA proofreading by DNA polymerase, _________-excision repair is the most important mechanism used to remove incorrect or damaged bases.

base-excision

A missense mutation may replace one amino acid with a chemically similar amino acid, called a _______________ substitution. In this case, the alteration is less likely to affect the protein's structure and function severely.

conservative

Two of the most frequent spontaneous lesions result from depurination and ______________.

deamination

For single-base substitutions, there are several outcomes for when a mutation arises in a polypeptide-coding part of a gene. All are direct consequences of two aspects of the genetic code: __________ of the code and the existence of ___________-termination codons.

degeneracy; translation

The resistant cells are selected by the __________ agent (in the past example, phage) rather than produced by it.

environmental

Trinucleotide-repeat diseases arise through the __________ of the number of copies of a _______-base-pair sequence normally present in several copies, often within the ____________ region of a gene.

expansion; three; coding

Spontaneous ___________, naturally occurring damage to the DNA, can generate mutations.

lesions

The production of mutations in the laboratory through exposure to mutagens is called ______________, and the organism is said to be mutagenized.

mutagenesis

The main target of base-excision repair is ____________ damage to bases.

nonbulky

A third enzyme, deoxyribophosphodiesterase, cleans up the backbone by removing a stretch of neighboring sugar-phosphate residues so that DNA ___________ can fill the gap with nucleotides complementary to the other strand. DNA __________ then seals the new nucleotide into the backbone.

polymerase; ligase

The mismatch errors due to ionization are frequently corrected by the __________ (editing) function of bacterial DNA polymerase III.

proofreading

When a large number of mutagens damage one or more bases, and so no specific base pairing is possible, the result is a __________ block because DNA synthesis will not proceed past a base that cannot specify its __________ partner by hydrogen bonding.

replication; complementary

The simplest of indel mutations is the addition or deletion of a __________ base pair.

single

The two main types of point mutation in DNA are base ____________ and base __________ or deletions.

substitutions; insertions

Huntington disease and Kennedy disease (also called X-linked spinal and bulbar muscular atrophy) result from the amplification of a ______-base-pair repeat, CAG. Unaffected persons have an average of 19 to 21 _______ repeats, whereas affected patients have an average of about 46. In Kennedy disease, which is characterized by progressive muscle weakness and atrophy, the expansion of the trinucleotide repeat is in the gene that encodes the __________ receptor.

three; CAG; androgen

___________-coupled nucleotide-excision repair (TC-NER) repairs transcribed regions of DNA.

transcription

Nonsense mutations will lead to the premature termination of ____________. Thus, they have a considerable effect on protein function. The closer a nonsense mutation is to the ___' end of the open reading frame (ORF), the more plausible it is that the resulting protein might possess some biological activity. However, many nonsense mutations produce completely inactive protein products.

translation; 3'

A _____________ is the opposite- the replacement of a base of one chemical category by a base of the other. Either a pyrimidine is replaced by a purine (from C to A, C to G, T to A, or T to G) or a purine is replaced by a pyrimidine (from A to C, A to T, G to C, or G to T).

transversion

___________ mutations arise through the action of certain agents called ________ that increase the rate at which mutations occur.

Induced; mutagens

_______________ agents: These agents form another important class of DNA modifiers. This group of compounds includes proflavin, acridine orange, and a class of chemicals termed ICR compounds. These agents are planar molecules that mimic _______ pairs and are able to slip themselves in (intercalate) between the stacked _____________ bases at the core of the DNA double helix. In this intercalated position, such an agent can cause on insertion or __________ of a single nucleotide pair.

Intercalating; base; nitrogen; deletion

_____________ mutations can be generated by different processes. Replication errors and spontaneous _____________ generate most spontaneous base substitutions. Replication errors can also cause deletions that lead to __________ mutations.

Spontaneous; lesions; frameshift

____________ substitutions never alter the amino acid sequence of the polypeptide chain.

Synonymous

_____________ mutations: The mutation changes one codon for an amino acid into another codon for that same amino acid. These mutations in exons are also referred to as silent mutations.

Synonymous

Patients afflicted with Cockayne syndrome have a variety of ___________ disorders including dwarfism, deafness, and retardation.

developmental

Mutagens induce ___________ by a variety of mechanisms. Some mutagens __________ normal bases and are incorporated into DNA where they can __________. Others damage bases and either cause _________ mispairing or _________ pairing by causing nonrecognition bases.

mutations; mimic; mispair; specific; destroy

In the 1970s, Bruce Ames recognized that there is a strong correlation between the ability of compounds to cause cancer and their ability to cause ___________. He surmised that measurement of mutation rates in bacterial systems would be an effective model for evaluating the mutagenicity of compounds as a first level of detection of potential carcinogens. However, it became clear that not all carcinogens were themselves mutagenic; rather, come carcinogens' metabolites produced in the body are actually the _________ agents.. Typically, these metabolites are produced in the __________, and the enzymatic reactions that convert the carcinogens into the bioactive metabolites did not take place in bacteria.

mutations; mutagenic; liver

Can the existence of mutants in a population before selection be demonstrated directly? This demonstration was made possible by the use of a technique called replica ________, developed largely by Esther Lederberg in 1952. A population of bacteria was plated on nonselective medium - that is, medium containing no phage - and from each cell a colony grew. This plate was called the __________ plate. A sterile piece of velvet ws pressed down lightly on the surface of the master plate, and the velvet picked up cells wherever there was a colony. In this way, the velvet picked up a colony "imprint" from the whole plate. The velvet was then touched to replica plates containing selective medium (that is, containing T1 phage). On touching velvet to plates, cells clinging to the velvet are inoculated on to the replica plates in the same relative positions as those of the colonies in the original _________ plate. As expected, rare resistant mutant colonies were found on the replica plates, but the multiple replica plates showed identical patterns of _________ colonies. If the mutations had occurred __________ (before or after?) exposure to the selective agents, the patterns for each plate would have been as random as the mutations themselves. The mutation events must have occurred before exposure to the selective agent. Again, these results confirm that mutation is occurring ____________ all the time, rather than in response to a selective agent.

plating; master; resistant; after; randomly

Like nonsense mutations, indel mutations may have consequences on _____________ sequence that extend far beyond the site of the mutation itself. Recall that the sequence of _________ (type of RNA) is "read" by the translational apparatus in register ("in frame"), three bases (one codon) at a time. The addition or deletion of a single base pair of DNA changes the reading frame for the remainder of the translation process, from the site of the base-pair mutation to the next _________ codon in the new reading frame. Hence, these lesions are called __________ mutations.

polypeptide; mRNA; stop; frameshift

Huntington disease has been associated with the expansion of _____________ repeats in a gene or its regulatory regions.

trinucleotide

_____________, the more common of the two, is the loss of a purine base. It consists of the interruption of the glycosidic bond between the base and deoxyribose and the subsequent loss of a guanine or an adenine residue from the DNA. The DNA backbone remains ___________.

Depurination; intact

The parts of a gene that do not directly encode a protein contain many crucial DNA binding sites for proteins interspersed among sequences that are nonessential to gene expression or gene activity. At the DNA level, the binding sites include the sites to which __________ polymerase and its associated factors bind, as well as sites to which specific ___________-regulating proteins bind.

RNA; transcription

Some chemical compounds are sufficiently similar to the normal nitrogen bases of DNA that they occasionally are incorporated into DNA in place of normal bases; such compounds are called base _______________.

analogs

Important repair systems exploit the properties of _____-__________ complementarity to restore damaged DNA segments to their initial, undamaged state. In these systems, a base or a longer segment of a DNA chain is ___________ and replaced with a newly synthesized nucleotide segment complementary to the opposite template strand. These pathways include the removal and ____________ of one or more bases.

antiparallel; removed

A mammalian cell spontaneously loses about 10,000 purines from its DNA in a 20-hour cell-cycle period at 37 degrees Celsius. If these lesions were to persist, they would result in a significant genetic damage because, in replication, the resulting ___________ sites cannot specify a base complementary to the original purine. However, efficient repair systems remove apurinic sites. Under certain conditions, a base can be inserted across from an apurinic site; this insertion will frequently result in a mutation. Unrepaired uracil residues will pair with _________ (A) in replication, resulting in the conversion of a GC pair into an AT pair (a GC to AT transition).

apurinic

The four phases of nucleotide-excision repair process: 1. Recognition of damaged _______(s) 2. Assembly of a ____________ complex at the site 3. Cutting of the damaged strand several nucleotides ____________ and downstream of the damage site and removal of nucleotides (30) between the cuts 4. Use of the undamaged strand as a ____________ for DNA polymerase followed by strand ligation.

base; multiprotein; upstream; template

Many point mutations within noncoding sequences elicit little or no phenotypic change; these mutations are located between DNA ______ sites for regulatory proteins. Such sites may be functionally irrelevant, or other sites within the gene may duplicate their function.

binding

Alternatively, some binding-site mutations might completely obliterate a required step in normal gene expression (such as the binding of RNA polymerase or splicing factors) and hence totally inactivate the gene product or totally __________ its formation.

block

Ionizing radiation can also damage DNA ___________ (directly or indirectly?) rather than through reactive oxygen species. Such radiation may cause breakage of the N-glycosydic bond, leading to the formation of apurinic or apyrimidinic sites, and can cause strand ___________. In fact. strand breaks are responsible for most of the lethal effects of ionizing radiation.

breaks

XP pateitns get early ___________, whereas Cockayne syndrome patients age _________.

cancers; prematurely

The extraordinarily high frequency of a mutation at the trinucleotide repeats in fragile X syndrome suggests that in human cells, after a threshold level of about 50 repeats, the replication machinery cannot faithfully replicate the ____________ (correct or incorrect?) sequence and large variations in repeat numbers result.

correct

Alkyltransferases are enzymes that also __________ reverse lesions. They remove certain _________ groups that have been added to position O-6 of guanine by such mutagens as nitrosoguanidine and ethylmethanesulfonate. The methyltransferase from E. coli transfers the methyl group from O-6-methylguanine to a cysteine residue in the enzyme's active site. However, the transfer ____________ (activates or inactivates?) the enzyme, and so this repair system can be saturated if the level of alkylation is high enough.

directly; alkyl; inactivates

The ramifications of mutations in parts of a gene other than the polypeptide-coding segments are harder to predict than are those of mutations in coding segments. In general, the functional consequences of any point mutation in a such a region depend on whether the mutation _________ (or creates) a __________ site. Mutations that disrupt these sites have the potential to change the expression pattern of a gene by altering the response to certain ______________ cues. Such regulatory mutations will alter the amount of the _________ product produced but not the ____________ of the protein.

disrupts; binding; environmental; protein; structure

Replication error s can also lead to ___________ mutations. Such mutations result in greatly altered __________. Certain kinds of replication errors can lead to _________ mutations-that is, insertion or deletions of one or more base pairs. These insertions or deletions produce frameshift mutations when they add or subtract a number of bases not divisible by _______(the size of a codon) in the protein-coding regions. Indels arise when loops in the single-stranded regions are stabilized by the "__________ mispairing" of repeated sequences in the course of replication. This mechanism is sometimes called replication ___________.

frameshift; proteins; indel; three; slipped; slippage

An example of a trinucleotide-repeat disease is the human disease called fragile X syndrome. This disease is the most common form of inherited ____________ impairment, occurring in close to 1 of 1500 males and 1 of 2500 females. It is manifested cytologically by a fragile site in the X chromosome that results in breaks in __________ (but this does not lead to the disease phenotype). Fragile X syndrome results from changes in the number of a (CGG)n repeat in a region of the FMR-1 gene that is transcribed but not ____________.

mental; vitro; translated

What is the consequence of the frequent mutation of 5-methylcysotine to thymine?

methylated regions of the genome (which are usually transcriptionally inactive) are converted, over evolutionary time, to AT-rich regions

IN base-excision repair, ____________ damage to the DNA is recognized by one of several enzymes called DNA ___________ that cleave the base-sugar bonds, releasing the incorrect ________. Repair consists of the removal of the site that now lacks a base and the __________ of the correct base as guided by the complementary base in the undamaged strand.

nonbulky; glycosylases; base; insertion

One amino acid may be replaced by a chemically different amino acid in a ______________ substitution. This type of alteration is more likely to produce a severe change in protein structure and function.

nonconservative

Two autosomal recessive diseases in humans, xeroderma pigmentosum (XP) and Cockayne syndrome, are caused by defects in __________-__________ repair.

nucleotide-excision

After they are in place, analogs have pairing properties unlike those of the normal bases; thus, they can produce mutations by causing incorrect __________________ to be inserted opposite them in replication.

nucleotides

Mutation is a __________ process. Any allele in any cell may mutate at any __________.

random; time

The results of Luria and Delbrucks's "fluctuation test" showed that mutation was occurring _________ in time: the early mutations gave the higher members of resistant cells because the mutant cells had time to produce many resistant descendants. The later mutations produced fewer resistant cells. This result led to the reigning "paradigm" of mutation; that is, whether in viruses, bacteria, or eukaryotes, mutations can occur in any cell at any __________ and their occurrence is ________. For this and other work, Luria and Delbruck were awarded the Nobel Price in Physiology or Medicine in 1969.

randomly; time; random

Spontaneous mutations arise from a variety of sources. One source is the DNA _________ process, Although DNA replication is a remarkably accurate process, mistakes are made in the copying of the millions, even billions of base pairs in a genome. Spontaneous mutations also arise in part because DNA is a very labile molecule and the cellular environment itself can damage it.

replication

Errors in DNA __________: An error in DNA replication can result when an illegitimate nucleotide pair (say, A-C) forms in DNA synthesis, leading to a base substitution that may be either a transition or a ____________. Other errors may add or subtract __________ pairs such that a __________ mutation is created.

replication; transversion; base; frameshift

Direct reversal of damaged DNA: The most straightforward way to repair a lesion is to _________ it directly, thereby regenerating the normal base.

reverse

At the RNA level, additional important binding sites include the _________-binding sites of bacterial mRNAs, the 5' and 3' ________ sites for exon joining in eukaryotic mRNAs, and sites that regulate translation and localize the mRNA to particular areas and compartments within the cell.

ribosome; splice

The original base analog exists in only a ____________ (single or double?) strand, but it can cause a nucleotide-pair substitution that is replicated in all DNA copies descended from the original strand.

single

Luria reasoned that, if mutations occurred __________, then the mutations might be expected to occur at different _________ in different cultures. In this case, the numbers of resistant colonies per culture should show high ________ (or "fluctuation" in his word). He later claimed that the idea came to him as he watched the fluctuating returns obtained by colleagues gambling on a slot machine at a faculty dance in a local country club; hence the origin of the term "jackpot" mutation.

spontaneously; times; variation

Patients with Cockayne syndrome have a mutation in one of two proteins called CSA and CSB, which are thought to recognize stalled _________ complexes.

stalled

GG-NER is initiated when a protein complex of XPC and RAD23B recognizes a distorted double helix caused by a damaged base and binds to the opposite ___________.

strand

Base _____________ are mutations in which one base pair is replaced by another.

substitutions

Numerous DNA glycosylases exist. One, uracil-DNA glycoslyase, removes __________ from DNA. Uracil residues, which result from the spontaneous deamination of cytosine, can lead to a C-to-T _________ if unrepaired. One advantage of having thymine (5-methyluracil) rather than uracil as the natural pairing partner of adenine in DNA is that spontaneous cytosine deamination events can be recognized as abnormal and then excised and repaired. If uracil were a normal constituent of DNA, such repair would not be possible.

uracil

Each of the bases in DNA can appear in one of several tautomeric forms that can pair to the ________ base. Mismatches can also result when one of the bases becomes ___________. This type of mismatch may occur ___________ (more or less?) frequently than mismatches due to tautomerization.

wrong; ionized; more

Ultraviolet light usually causes damage to nucleotide bases in most organisms, because it generates a number of distinct types of alterations in _________, called photoproducts. The most likely of these products to lead to mutations are two different lesions that unite adjacent ____________(purine or pyrimidine?) residues in the same strand. These lesions are the cyclobutane pyrimidine photodimer and the 6-4 photoproduct.

DNA; pyrimidine

In Huntington disease, the wild-type _______ gene includes a repeated sequence. often within the ____________-coding region, and mutation correlates with a considerable expansion of this repeat region. The severity of the disease correlates with the number of repeat __________.

HD; protein

________________-excision repair (NER) is an extremely versatile pathway that is able to relieve replication and transcription blocks and repair the damage.

Nucleotide

During base-excision repair, an enzyme called AP endonuclease nicks the damaged strand upstream of the _____ site. (site was talked about on last notecard).

AP

Base-excision repair is carried out by ___ (DNA or RNA?) glycosylases that cleave base-sugar bonds, thereby liberating teh altered bases and generating apurinic or apyrimidinic (AP) sites.

DNA

Nonbulky damage can result from methylation, deamination, oxidation, or the spontaneous loss of a ________ (DNA or RNA?) base.

DNA

Xeroderma pigmentosum is characterized by the early development of ___________, especially skin cancer, and in some cases, neurological defects.

cancers

Frameshift mutations cause the entire amino acid sequence translationally downstream of the mutant site to bear no relation to the ____________ amino acid sequence.

original

The treated bacteria for each of these strains were exposed to the test compound, then grown on petri plats containing medium lacking histidine. The absence of this nutrient ensured that only revertant individuals containing the appropriate base ________ or __________ mutation would grow. The number of colonies on each plate and the total number of bacteria tested were determined, allowing Ames to measure the frequency of ___________. Compounds that yielded metabolites inducing elevated levels of reversion relative to untreated control liver extracts would then clearly be __________ and would be possible carcinogens. The Ames test thus provided an important way of screening thousands of compounds and evaluating one aspect of their risk to health and the environment.

substitution; frameshift; reversion; mutagenic

A common mechanism responsible for a number of genetic disorders is the expansion of a ______-base-pair repeat. For this reason, they are termed _____________-repeat diseases.

three; trinucleotide

A ______________ is the replacement of a base by the other base of the same chemical category. Either a purine is replaced by a purine (from A to G or from G to A) or a pyrimidine is replaced by a pyrimidine (from C to T or from T to C).

transition

Base substitutions can be divided into two subtypes: ____________ and transversions.

transitions

In fragile X syndrome, the trinucleotide expansion is near the _____' end of the FMR-1 mRNA, _________ (before or after?) the translation start site. We cannot ascribe the phenotypic abnormalities of the FMR-1 mutations to an effect on protein structure. The mutant FMR-1 genes are hypermethylated, a feature associated with transcriptionally silenced genes. Repeat expansion is hypothesized to lead to changes in chromatin structure that silence the __________ of the mutant gene. The FMR-1 gene is deleted in some patients with fragile X syndrome. These observations support a loss-of-function mutation.

5'; before; transcription

Coding and regulatory regions, which are less methylated, remain ___-rich regions.

GC

______________ mutations: The codon for one amino acid is changed into a codon for another amino acid. These mutations are sometimes called nonsynonymous mutations.

Missense

___________ mutations are naturally occurring mutations and arise in all cells.

Spontaneous

One base analog widely used in research is 2-aminopurine (2-AP). This analog of adenine can pair with thymine but can also mispair with ___________ when protonated. Therefore, when 2-AP is incorporated into DNA by pairing with thymine, it can generate AT to G__ transitions by mispairing with ___________ in subsequent replications. Or, if 2-AP is incorporated by mispairing with cytosine, then GC to ___ ___ transitions will result when it pairs with ___________. Genetic studies have shown that 2-AP causes ________ (transitions or transversions?) almost exclusively.

cytosine; C; cytosine; AT; thymine; transitions

Insertion or deletion mutations are actually insertions or deletions of ___________ pairs; nevertheless, the convention is to call them ________-pair insertions or deletions. Collectively, they are termed _______ mutations (for insertion-deletion).

nucleotide; base; indel

_______________ genomic nucleotide-excision repair (GG-NER) corrects lesions anywhere in the genome and is activated by stalled replication forks.

global

There are two types of nucleotide-excision repair that differ in damage recognition: __________ genomic nucleotide-excision repair (GG-NER) and ____________-coupled nucleotide-excision repair (TC-NER).

global; transcription

One experiment by Salvador Luria and Max Delbruck in 1943 was particularly influential in shaping our understanding of the nature of mutation, not only in bacteria, but in organisms generally. It was known at the time that, if E. coli bacteria are spread on a plate of nutrient medium in the presence of phage T1, the phages coon infect and _________ the bacteria. Rarely, but regularly, colonies were seen that were resistant to phage attack; these colonies were stable and so appeared to be genuine mutants. However, whether these mutants were produced spontaneously but randomly in time or the presence of the phage induced a physiological change that caused resistance was not known.

kill

Ames realized that he could overcome this problem by treating special strains of the bacterium Salmonella typhimurium with extracts of rat ________(organ) containing metabolic enzymes. The special strain of S. typhimurium had one of several mutant alleles of a gene responsible for __________ synthesis that were known to "revert" (that is, return to wild-type phenotype) only by certain kinds of additional mutational events.

livers; histidine

Active oxygen species, such as superoxide, radicals, hydrogen peroxide, and hydroxyl radicals are produced as by-products of normal aerobic metabolism. They can cause __________ damage to DNA, as well as to precursors of DNA (such as GTP), resulting in ___________. Mutations from oxidative damage have been implicated in a number of human diseases. The thymidine glycol product blocks DNA replication if unrepaired.

oxidative; mutation

Properties common to some trinucleotide-repeat diseases suggest a common mechanism by which the abnormal ___________ (genotypes or phenotypes?) are produced. First, many of these disease seem to include neurodegeneration - that is, cell _________ within the nervous system. Second, in such diseases, the trinucleotide repeats fall within the open reading frames of the transcripts of the mutated gene, leading to expansions or contractions of the number of repeats of a single ________ acid sequence in the polypeptide (for example, CAG repeats encode a polyglutamine repeat)

phenotypes; death; amino

Frameshift mutations typically result in complete loss of normal ________ structure and function.

protein

Mutagens induce mutations by at least three different mechanisms. They can ______________ a base in the DNA, ____________ a base so that it specifically mispairs with another base, or _______________ a base so that it can no longer pair with any base under normal conditions.

replace; alter; damage

Some mutagens are not incorporated into the DNA but instead alter a base in such a way that it will form a ___________ mispair.

specific

Single-base-pair changes that inactivate proteins are often due to ______ site mutations. Such changes can dramatically change the ___________ (type of RNA) transcript by leading to large insertions or deletions that may or may not be in frame.

splice; mRNA

An example of a lesion being repaired by direct reversal is the case of a mutagenic photodimer caused by UV light. The cyclobutane pyrimidine dimer (CPD) can be repaired by an enzyme called CPD photolyase.The enzyme binds to the photodimer and _________ it to regenerate the original bases. This repair mechanism is called photoreactivation because the enzyme requires light to function. Other repair pathways are required to remove UV damage in the absence of light of the appropriate wavelength (>300nm).

splits

Oxidatively damaged bases represent a third type of ______________ lesion that generates mutations.

spontaneous

If proofreading does not occur, all the mismatches described so far lead to ______________ mutations in which a purine substitutes for a purine or a pyrimidine for a pyrimidine. Other repair systems correct many of the mismatched bases that escape correction by the polymerase editing function.

transition

In ____________ mutations, a pyrimidine substitutes for a purine, or vice versa. The creation of a transversion by a replication error would require, at some point in the course of replication, the mispairing of a purine with a __________ or a pyrimidine with a ____________. Although the dimensions of the DNA double-helix render such mismatches energetically unfavorable, we now know that from X-ray diffraction studies that G-A pairs, as well as other purine-purine pairs, can form.

transversion; purine; pyrimidine