Section 8.1Mutations: Types and Causes
The
development and function of an organism is in large part controlled by
genes.
Mutations can lead to changes in the structure of an
encoded protein or to a
decrease or complete loss in its expression. Because a
change in the DNA sequence
affects all copies of the encoded protein, mutations can
be particularly damaging to
a cell or organism. In contrast, any alterations in the
sequences of RNA or protein
molecules that occur during their synthesis are less
serious because many copies of
each RNA and protein are synthesized.
Geneticists often distinguish between the genotype and phenotype of an organism. Strictly speaking, the entire set of genes carried by an individual is its genotype, whereas the function and physical appearance of an individual is referred to as its phenotype. However, the two terms commonly are used in a more restricted sense: genotype usually denotes whether an individual carries mutations in a single gene (or a small number of genes), and phenotype denotes the physical and functional consequences of that genotype.
Many common human diseases, often
devastating in their effects, are due to mutations
in single genes. Genetic
diseases arise by spontaneous mutations in germ
cells (egg and sperm), which are
transmitted to future generations. For example, sickle-cell
anemia, which affects 1 in 500 individuals
of African descent, is
caused by a single missense mutation at codon 6 of
the β-globin gene;
as a result of this mutation, the glutamic acid at
position 6 in the normal
protein is changed to a valine in the mutant
protein. This alteration has a
profound effect on hemoglobin, the oxygen-carrier
protein of erythrocytes, which
consists of two α-globin and two β-globin subunits
(see Figure 3-11).
The deoxygenated form of the
mutant protein is insoluble in erythrocytes and
forms crystalline arrays. The
erythrocytes of affected individuals become rigid
and their transit through
capillaries is blocked, causing severe pain and
tissue damage. Because the
erythrocytes of heterozygous individuals are
resistant to the parasite causing
malaria, which is endemic in Africa, the mutant
allele has been maintained. It
is not that individuals of African descent are more
likely than others to
acquire a mutation causing the sickle-cell defect,
but rather the mutation has
been maintained in this population by interbreeding.
Spontaneous mutation in somatic cells (i.e., non-germline body cells) also is an important mechanism in certain human diseases, including retinoblastoma, which is associated with retinal tumors in children (see Figure 24-11). The hereditary form of retinoblastoma, for example, results from a germ-line mutation in one Rb allele and a second somatically occurring mutation in the other Rb allele (Figure 8-7a). When an Rb heterozygous retinal cell undergoes somatic mutation, it is left with no normal allele; as a result, the cell proliferates in an uncontrolled manner, giving rise to a retinal tumor. A second form of this disease, called sporadic retinoblastoma, results from two independent mutations disrupting both Rb alleles (Figure 8-7b). Since only one somatic mutation is required for tumor development in children with hereditary retinoblastoma, it occurs at a much higher frequency than the sporadic form, which requires acquisition of two independently occurring somatic mutations. The Rb protein has been shown to play a critical role in controlling cell division (Chapter 13).
In
a later section, we will see how normal copies of disease-related genes
can be
isolated and cloned.
Geneticists often distinguish between the genotype and phenotype of an organism. Strictly speaking, the entire set of genes carried by an individual is its genotype, whereas the function and physical appearance of an individual is referred to as its phenotype. However, the two terms commonly are used in a more restricted sense: genotype usually denotes whether an individual carries mutations in a single gene (or a small number of genes), and phenotype denotes the physical and functional consequences of that genotype.
A
fundamental genetic difference between organisms is whether their cells
carry a
single set of chromosomes or two copies of each
chromosome. The former are
referred to as haploid; the latter, as diploid. Many simple unicellular organisms are
haploid,
whereas complex multicellular organisms (e.g., fruit
flies, mice, humans) are
diploid.
Different forms of a gene (e.g., normal and mutant) are referred to as alleles. Since diploid organisms carry two copies of each gene, they may carry identical alleles, that is, be homozygous for a gene, or carry different alleles, that is, be heterozygous for a gene. A recessive mutation is one in which both alleles must be mutant in order for the mutant phenotype to be observed; that is, the individual must be homozygous for the mutant allele to show the mutant phenotype. In contrast, the phenotypic consequences of a dominant mutation are observed in a heterozygous individual carrying one mutant and one normal allele (Figure 8-1).
Recessive
mutations inactivate the affected gene and lead to a loss of
function. For instance, recessive mutations
may remove part of or
all the gene from the chromosome, disrupt expression
of the gene, or alter the
structure of the encoded protein, thereby altering
its function. Conversely,
dominant mutations often lead to a gain of
function. For
example, dominant mutations may increase the
activity of a given gene product,
confer a new activity on the gene product, or lead
to its inappropriate spatial
and temporal expression. Dominant mutations,
however, may be associated with a
loss of function. In some cases, two copies of a
gene are required for normal
function, so that removing a single copy leads to
mutant phenotype. Such genes
are referred to as haplo-insufficient. In
other cases,
mutations in one allele may lead to a structural
change in the protein that
interferes with the function of the wild-type
protein encoded by the other
allele. These are referred to as dominant
negative
mutations.
Some alleles can be associated with both a recessive and a dominant phenotype. For instance, fruit flies heterozygous for the mutant Stubble (Sb) allele have short and stubby body hairs rather than the normal long, slender hairs; the mutant allele is dominant in this case. In contrast, flies homozygous for this allele die during development. Thus the recessive phenotype associated with this allele is lethal, whereas the dominant phenotype is not.
Different forms of a gene (e.g., normal and mutant) are referred to as alleles. Since diploid organisms carry two copies of each gene, they may carry identical alleles, that is, be homozygous for a gene, or carry different alleles, that is, be heterozygous for a gene. A recessive mutation is one in which both alleles must be mutant in order for the mutant phenotype to be observed; that is, the individual must be homozygous for the mutant allele to show the mutant phenotype. In contrast, the phenotypic consequences of a dominant mutation are observed in a heterozygous individual carrying one mutant and one normal allele (Figure 8-1).
Figure 8-1
For a recessive mutation to give
rise to a mutant phenotype in a
diploid organism, both alleles must
carry the mutation. However, one copy of a dominant mutant allele leads
to a mutant
phenotype. (more...)
Some alleles can be associated with both a recessive and a dominant phenotype. For instance, fruit flies heterozygous for the mutant Stubble (Sb) allele have short and stubby body hairs rather than the normal long, slender hairs; the mutant allele is dominant in this case. In contrast, flies homozygous for this allele die during development. Thus the recessive phenotype associated with this allele is lethal, whereas the dominant phenotype is not.
Recessive
and dominant mutations can be distinguished because they exhibit
different patterns of inheritance. To understand
why, we need to review the type
of cell division that gives rise to gametes (sperm and egg cells in higher plants and
animals). The body
(somatic) cells of most multicellular organisms
divide by mitosis (see Figure 1-10),
whereas the germ cells that give rise to gametes
undergo meiosis. Like body cells,
premeiotic germ cells are diploid, containing two of
each morphologic type of
chromosome. Because the two members of each such
pair of homologous chromosomes are descended
from different parents, their genes are similar but
not usually identical.
Single-celled organisms (e.g., the yeast S.
cerevisiae) that
are diploid at some phase of their life cycle also
undergo meiosis (see Figure 10-54).
Figure 8-2 depicts the major events in meiosis. One round of DNA replication, which makes the cell 4n, is followed by two separate cell divisions, yielding four haploid (1n) cells that contain only one chromosome of each homologous pair. The apportionment, or segregation, of homologous chromosomes to daughter cells during the first meiotic division is random; that is, the maternally and paternally derived members of each pair, called homologs, segregate independently, yielding germ cells with different mixes of paternal and maternal chromosomes. Thus parental characteristics are reassorted randomly into each new germ cell during meiosis. The number of possible varieties of meiotic segregants is 2n, where n is the haploid number of chromosomes. In the case of a single chromosome, as illustrated in Figure 8-2, meiosis gives rise to two types of gametes; one type carries the maternal homolog and the other carries the paternal homolog.
Now,
let’s see what phenotypes are generated by mating of wild-type
individuals with mutants carrying either a dominant
or a recessive mutation. As
shown in Figure 8-3a, half the gametes
from an individual heterozygous for a dominant
mutation in a particular gene
will have the wild-type allele, and half will have
the mutant allele. Since
fertilization of female gametes by male gametes
occurs randomly, half the first
filial (F1) progeny resulting from the
cross between a normal
wild-type individual and a mutant individual
carrying a single dominant allele
will exhibit the mu-tant phenotype. In contrast, all
the gametes produced by a
mutant homozygous for a recessive mutation will
carry the mutant allele. Thus,
in a cross between a normal individual and one who
is homozygous for a recessive
mutation, none of the F1 progeny will
exhibit the mutant phenotype
(Figure 8-3b). However, one-fourth
of the progeny from parents both heterozygous for a
recessive mutation will show
the mutant phenotype.
Figure 8-2 depicts the major events in meiosis. One round of DNA replication, which makes the cell 4n, is followed by two separate cell divisions, yielding four haploid (1n) cells that contain only one chromosome of each homologous pair. The apportionment, or segregation, of homologous chromosomes to daughter cells during the first meiotic division is random; that is, the maternally and paternally derived members of each pair, called homologs, segregate independently, yielding germ cells with different mixes of paternal and maternal chromosomes. Thus parental characteristics are reassorted randomly into each new germ cell during meiosis. The number of possible varieties of meiotic segregants is 2n, where n is the haploid number of chromosomes. In the case of a single chromosome, as illustrated in Figure 8-2, meiosis gives rise to two types of gametes; one type carries the maternal homolog and the other carries the paternal homolog.
Figure 8-2
Meiosis. A premeiotic germ cell
has two copies of each chromosome
(2n), one maternal and one
paternal.
Chromosomes are replicated during the S
phase, giving a
(more...)
Figure 8-3
Segregation patterns of dominant
and recessive mutations. Crosses between genotypically normal
individuals (blue) and mutants
(yellow) that are heterozygous for a
dominant mutation (a) or
(more...)
A
mutation involving a change in a single base pair, often called a point mutation, or a deletion of a
few base pairs generally affects the function of a
single gene (Figure 8-4a). Changes in a single base
pair may produce one of three types of mutation:
The second major type of mutation involves large-scale changes in chromosome structure and can affect the functioning of numerous genes, resulting in major phenotypic consequences. Such chromosomal mutations (or abnormalities) can involve deletion or insertion of several contiguous genes, inversion of genes on a chromosome, or the exchange of large segments of DNA between nonhomologous chromosomes (Figure 8-4b).
Figure 8-4
Different types of mutations.
(a) Point mutations, which involve alteration in a single base pair, and
small deletions generally directly affect
the function of only one gene.
A wild-type peptide (more...)
- Missense mutation, which results in a protein in which one amino acid is substituted for another
- Nonsense mutation, in which a stop codon replaces an amino acid codon, leading to premature termination of translation
- Frameshift mutation, which causes a change in the reading frame, leading to introduction of unrelated amino acids into the protein, generally followed by a stop codon
The second major type of mutation involves large-scale changes in chromosome structure and can affect the functioning of numerous genes, resulting in major phenotypic consequences. Such chromosomal mutations (or abnormalities) can involve deletion or insertion of several contiguous genes, inversion of genes on a chromosome, or the exchange of large segments of DNA between nonhomologous chromosomes (Figure 8-4b).
Mutations
arise spontaneously at low frequency owing to the chemical instability
of purine and pyrimidine bases and to errors during
DNA replication. Natural
exposure of an organism to certain environmental
factors, such as ultraviolet
light and chemical carcinogens (e.g., aflatoxin B1),
also can cause
mutations.
A common cause of spontaneous point mutations is the deamination of cytosine to uracil in the DNA double helix. Subsequent replication leads to a mutant daughter cell in which a T·A base pair replaces the wild-type C·G base pair. Another cause of spontaneous mutations is copying errors during DNA replication. Although replication generally is carried out with high fidelity, errors occasionally occur. Figure 8-5 illustrates how one type of copying error can produce a mutation. In the example shown, the mutant DNA contains nine additional base pairs.
In
order to increase the frequency of mutation in experimental organisms,
researchers often treat them with high doses of
chemical mutagens or expose them
to ionizing radiation. Mutations arising in response
to such treatments are
referred to as induced mutations. Generally,
chemical mutagens
induce point mutations, whereas ionizing radiation
gives rise to large
chromosomal abnormalities.
Ethylmethane sulfonate (EMS), a commonly used mutagen, alkylates guanine in DNA, forming O6-ethylguanine (Figure 8-6a). During subsequent DNA replication, O6-ethylguanine directs incorporation of deoxythymidylate, not deoxycytidylate, resulting in formation of mutant cells in which a G·C base pair is replaced with an A·T base pair (Figure 8-6b). The causes of mutations and the mechanisms cells have for repairing alterations in DNA are discussed further in Chapter 12.
A common cause of spontaneous point mutations is the deamination of cytosine to uracil in the DNA double helix. Subsequent replication leads to a mutant daughter cell in which a T·A base pair replaces the wild-type C·G base pair. Another cause of spontaneous mutations is copying errors during DNA replication. Although replication generally is carried out with high fidelity, errors occasionally occur. Figure 8-5 illustrates how one type of copying error can produce a mutation. In the example shown, the mutant DNA contains nine additional base pairs.
Figure 8-5
One mechanism by which errors in
DNA replication produce
spontaneous mutations. The replication
of only one strand is shown; the other strand is
replicated normally, as shown at the
top. (more...)
Ethylmethane sulfonate (EMS), a commonly used mutagen, alkylates guanine in DNA, forming O6-ethylguanine (Figure 8-6a). During subsequent DNA replication, O6-ethylguanine directs incorporation of deoxythymidylate, not deoxycytidylate, resulting in formation of mutant cells in which a G·C base pair is replaced with an A·T base pair (Figure 8-6b). The causes of mutations and the mechanisms cells have for repairing alterations in DNA are discussed further in Chapter 12.
Figure 8-6
Induction of point mutations by
ethylmethane sulfonate (EMS), a
commonly used mutagen. (a) EMS alkylates
guanine at the oxygen on position 6 of the purine
ring, forming O6-ethylguanine
(Et-G),
(more...)
Many common human diseases, often
devastating in their effects, are due to mutations
in single genes. Genetic
diseases arise by spontaneous mutations in germ
cells (egg and sperm), which are
transmitted to future generations. For example, sickle-cell
anemia, which affects 1 in 500 individuals
of African descent, is
caused by a single missense mutation at codon 6 of
the β-globin gene;
as a result of this mutation, the glutamic acid at
position 6 in the normal
protein is changed to a valine in the mutant
protein. This alteration has a
profound effect on hemoglobin, the oxygen-carrier
protein of erythrocytes, which
consists of two α-globin and two β-globin subunits
(see Figure 3-11).
The deoxygenated form of the
mutant protein is insoluble in erythrocytes and
forms crystalline arrays. The
erythrocytes of affected individuals become rigid
and their transit through
capillaries is blocked, causing severe pain and
tissue damage. Because the
erythrocytes of heterozygous individuals are
resistant to the parasite causing
malaria, which is endemic in Africa, the mutant
allele has been maintained. It
is not that individuals of African descent are more
likely than others to
acquire a mutation causing the sickle-cell defect,
but rather the mutation has
been maintained in this population by interbreeding.Spontaneous mutation in somatic cells (i.e., non-germline body cells) also is an important mechanism in certain human diseases, including retinoblastoma, which is associated with retinal tumors in children (see Figure 24-11). The hereditary form of retinoblastoma, for example, results from a germ-line mutation in one Rb allele and a second somatically occurring mutation in the other Rb allele (Figure 8-7a). When an Rb heterozygous retinal cell undergoes somatic mutation, it is left with no normal allele; as a result, the cell proliferates in an uncontrolled manner, giving rise to a retinal tumor. A second form of this disease, called sporadic retinoblastoma, results from two independent mutations disrupting both Rb alleles (Figure 8-7b). Since only one somatic mutation is required for tumor development in children with hereditary retinoblastoma, it occurs at a much higher frequency than the sporadic form, which requires acquisition of two independently occurring somatic mutations. The Rb protein has been shown to play a critical role in controlling cell division (Chapter 13).
Figure 8-7
Role of spontaneous somatic
mutation in retinoblastoma, a
childhood disease marked by retinal
tumors. Tumors arise from retinal cells that carry two mutant
Rb− alleles. (a)
In
(more...)
- Diploid organisms carry two copies (alleles) of each gene, whereas haploid organisms carry only one copy.
- Mutations are alterations in DNA sequences that result in changes in the structure of a gene. Both small and large DNA alterations can occur spontaneously. Treatment with ionizing radiation or various chemical agents increases the frequency of mutations.
- Recessive mutations lead to a loss of function, which is masked if a normal copy of the gene is present. For the mutant phenotype to occur, both alleles must carry the mutation.
- Dominant mutations lead to a mutant phenotype in the presence of a normal copy of the gene. The phenotypes associated with dominant mutations may represent either a loss or a gain of function.
- In meiosis, a diploid cell undergoes one DNA replication and two cell divisions, yielding four haploid cells (Figure 8-2). The members of each pair of homologous chromosomes segregate independently during meiosis, leading to the random reassortment of maternal and paternal alleles in the gametes.
- Dominant and recessive mutations exhibit characteristic segregation patterns in genetic crosses (see Figure 8-3).
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and Causes
The
development and function of an organism is in large part controlled by
genes.
Mutations can lead to changes in the structure of an
encoded protein or to a
decrease or complete loss in its expression. Because a
change in the DNA sequence
affects all copies of the encoded protein, mutations can
be particularly damaging to
a cell or organism. In contrast, any alterations in the
sequences of RNA or protein
molecules that occur during their synthesis are less
serious because many copies of
each RNA and protein are synthesized.
Geneticists often distinguish between the genotype and phenotype of an organism. Strictly speaking, the entire set of genes carried by an individual is its genotype, whereas the function and physical appearance of an individual is referred to as its phenotype. However, the two terms commonly are used in a more restricted sense: genotype usually denotes whether an individual carries mutations in a single gene (or a small number of genes), and phenotype denotes the physical and functional consequences of that genotype.
Many common human diseases, often
devastating in their effects, are due to mutations
in single genes. Genetic
diseases arise by spontaneous mutations in germ
cells (egg and sperm), which are
transmitted to future generations. For example, sickle-cell
anemia, which affects 1 in 500 individuals
of African descent, is
caused by a single missense mutation at codon 6 of
the β-globin gene;
as a result of this mutation, the glutamic acid at
position 6 in the normal
protein is changed to a valine in the mutant
protein. This alteration has a
profound effect on hemoglobin, the oxygen-carrier
protein of erythrocytes, which
consists of two α-globin and two β-globin subunits
(see Figure 3-11).
The deoxygenated form of the
mutant protein is insoluble in erythrocytes and
forms crystalline arrays. The
erythrocytes of affected individuals become rigid
and their transit through
capillaries is blocked, causing severe pain and
tissue damage. Because the
erythrocytes of heterozygous individuals are
resistant to the parasite causing
malaria, which is endemic in Africa, the mutant
allele has been maintained. It
is not that individuals of African descent are more
likely than others to
acquire a mutation causing the sickle-cell defect,
but rather the mutation has
been maintained in this population by interbreeding.
Spontaneous mutation in somatic cells (i.e., non-germline body cells) also is an important mechanism in certain human diseases, including retinoblastoma, which is associated with retinal tumors in children (see Figure 24-11). The hereditary form of retinoblastoma, for example, results from a germ-line mutation in one Rb allele and a second somatically occurring mutation in the other Rb allele (Figure 8-7a). When an Rb heterozygous retinal cell undergoes somatic mutation, it is left with no normal allele; as a result, the cell proliferates in an uncontrolled manner, giving rise to a retinal tumor. A second form of this disease, called sporadic retinoblastoma, results from two independent mutations disrupting both Rb alleles (Figure 8-7b). Since only one somatic mutation is required for tumor development in children with hereditary retinoblastoma, it occurs at a much higher frequency than the sporadic form, which requires acquisition of two independently occurring somatic mutations. The Rb protein has been shown to play a critical role in controlling cell division (Chapter 13).
In
a later section, we will see how normal copies of disease-related genes
can be
isolated and cloned.
Geneticists often distinguish between the genotype and phenotype of an organism. Strictly speaking, the entire set of genes carried by an individual is its genotype, whereas the function and physical appearance of an individual is referred to as its phenotype. However, the two terms commonly are used in a more restricted sense: genotype usually denotes whether an individual carries mutations in a single gene (or a small number of genes), and phenotype denotes the physical and functional consequences of that genotype.
A
fundamental genetic difference between organisms is whether their cells
carry a
single set of chromosomes or two copies of each
chromosome. The former are
referred to as haploid; the latter, as diploid. Many simple unicellular organisms are
haploid,
whereas complex multicellular organisms (e.g., fruit
flies, mice, humans) are
diploid.
Different forms of a gene (e.g., normal and mutant) are referred to as alleles. Since diploid organisms carry two copies of each gene, they may carry identical alleles, that is, be homozygous for a gene, or carry different alleles, that is, be heterozygous for a gene. A recessive mutation is one in which both alleles must be mutant in order for the mutant phenotype to be observed; that is, the individual must be homozygous for the mutant allele to show the mutant phenotype. In contrast, the phenotypic consequences of a dominant mutation are observed in a heterozygous individual carrying one mutant and one normal allele (Figure 8-1).
Recessive
mutations inactivate the affected gene and lead to a loss of
function. For instance, recessive mutations
may remove part of or
all the gene from the chromosome, disrupt expression
of the gene, or alter the
structure of the encoded protein, thereby altering
its function. Conversely,
dominant mutations often lead to a gain of
function. For
example, dominant mutations may increase the
activity of a given gene product,
confer a new activity on the gene product, or lead
to its inappropriate spatial
and temporal expression. Dominant mutations,
however, may be associated with a
loss of function. In some cases, two copies of a
gene are required for normal
function, so that removing a single copy leads to
mutant phenotype. Such genes
are referred to as haplo-insufficient. In
other cases,
mutations in one allele may lead to a structural
change in the protein that
interferes with the function of the wild-type
protein encoded by the other
allele. These are referred to as dominant
negative
mutations.
Some alleles can be associated with both a recessive and a dominant phenotype. For instance, fruit flies heterozygous for the mutant Stubble (Sb) allele have short and stubby body hairs rather than the normal long, slender hairs; the mutant allele is dominant in this case. In contrast, flies homozygous for this allele die during development. Thus the recessive phenotype associated with this allele is lethal, whereas the dominant phenotype is not.
Different forms of a gene (e.g., normal and mutant) are referred to as alleles. Since diploid organisms carry two copies of each gene, they may carry identical alleles, that is, be homozygous for a gene, or carry different alleles, that is, be heterozygous for a gene. A recessive mutation is one in which both alleles must be mutant in order for the mutant phenotype to be observed; that is, the individual must be homozygous for the mutant allele to show the mutant phenotype. In contrast, the phenotypic consequences of a dominant mutation are observed in a heterozygous individual carrying one mutant and one normal allele (Figure 8-1).
Figure 8-1
For a recessive mutation to give
rise to a mutant phenotype in a
diploid organism, both alleles must
carry the mutation. However, one copy of a dominant mutant allele leads
to a mutant
phenotype. (more...)
Some alleles can be associated with both a recessive and a dominant phenotype. For instance, fruit flies heterozygous for the mutant Stubble (Sb) allele have short and stubby body hairs rather than the normal long, slender hairs; the mutant allele is dominant in this case. In contrast, flies homozygous for this allele die during development. Thus the recessive phenotype associated with this allele is lethal, whereas the dominant phenotype is not.
Recessive
and dominant mutations can be distinguished because they exhibit
different patterns of inheritance. To understand
why, we need to review the type
of cell division that gives rise to gametes (sperm and egg cells in higher plants and
animals). The body
(somatic) cells of most multicellular organisms
divide by mitosis (see Figure 1-10),
whereas the germ cells that give rise to gametes
undergo meiosis. Like body cells,
premeiotic germ cells are diploid, containing two of
each morphologic type of
chromosome. Because the two members of each such
pair of homologous chromosomes are descended
from different parents, their genes are similar but
not usually identical.
Single-celled organisms (e.g., the yeast S.
cerevisiae) that
are diploid at some phase of their life cycle also
undergo meiosis (see Figure 10-54).
Figure 8-2 depicts the major events in meiosis. One round of DNA replication, which makes the cell 4n, is followed by two separate cell divisions, yielding four haploid (1n) cells that contain only one chromosome of each homologous pair. The apportionment, or segregation, of homologous chromosomes to daughter cells during the first meiotic division is random; that is, the maternally and paternally derived members of each pair, called homologs, segregate independently, yielding germ cells with different mixes of paternal and maternal chromosomes. Thus parental characteristics are reassorted randomly into each new germ cell during meiosis. The number of possible varieties of meiotic segregants is 2n, where n is the haploid number of chromosomes. In the case of a single chromosome, as illustrated in Figure 8-2, meiosis gives rise to two types of gametes; one type carries the maternal homolog and the other carries the paternal homolog.
Now,
let’s see what phenotypes are generated by mating of wild-type
individuals with mutants carrying either a dominant
or a recessive mutation. As
shown in Figure 8-3a, half the gametes
from an individual heterozygous for a dominant
mutation in a particular gene
will have the wild-type allele, and half will have
the mutant allele. Since
fertilization of female gametes by male gametes
occurs randomly, half the first
filial (F1) progeny resulting from the
cross between a normal
wild-type individual and a mutant individual
carrying a single dominant allele
will exhibit the mu-tant phenotype. In contrast, all
the gametes produced by a
mutant homozygous for a recessive mutation will
carry the mutant allele. Thus,
in a cross between a normal individual and one who
is homozygous for a recessive
mutation, none of the F1 progeny will
exhibit the mutant phenotype
(Figure 8-3b). However, one-fourth
of the progeny from parents both heterozygous for a
recessive mutation will show
the mutant phenotype.
Figure 8-2 depicts the major events in meiosis. One round of DNA replication, which makes the cell 4n, is followed by two separate cell divisions, yielding four haploid (1n) cells that contain only one chromosome of each homologous pair. The apportionment, or segregation, of homologous chromosomes to daughter cells during the first meiotic division is random; that is, the maternally and paternally derived members of each pair, called homologs, segregate independently, yielding germ cells with different mixes of paternal and maternal chromosomes. Thus parental characteristics are reassorted randomly into each new germ cell during meiosis. The number of possible varieties of meiotic segregants is 2n, where n is the haploid number of chromosomes. In the case of a single chromosome, as illustrated in Figure 8-2, meiosis gives rise to two types of gametes; one type carries the maternal homolog and the other carries the paternal homolog.
Figure 8-2
Meiosis. A premeiotic germ cell
has two copies of each chromosome
(2n), one maternal and one
paternal.
Chromosomes are replicated during the S
phase, giving a
(more...)
Figure 8-3
Segregation patterns of dominant
and recessive mutations. Crosses between genotypically normal
individuals (blue) and mutants
(yellow) that are heterozygous for a
dominant mutation (a) or
(more...)
A
mutation involving a change in a single base pair, often called a point mutation, or a deletion of a
few base pairs generally affects the function of a
single gene (Figure 8-4a). Changes in a single base
pair may produce one of three types of mutation:
The second major type of mutation involves large-scale changes in chromosome structure and can affect the functioning of numerous genes, resulting in major phenotypic consequences. Such chromosomal mutations (or abnormalities) can involve deletion or insertion of several contiguous genes, inversion of genes on a chromosome, or the exchange of large segments of DNA between nonhomologous chromosomes (Figure 8-4b).
Figure 8-4
Different types of mutations.
(a) Point mutations, which involve alteration in a single base pair, and
small deletions generally directly affect
the function of only one gene.
A wild-type peptide (more...)
- Missense mutation, which results in a protein in which one amino acid is substituted for another
- Nonsense mutation, in which a stop codon replaces an amino acid codon, leading to premature termination of translation
- Frameshift mutation, which causes a change in the reading frame, leading to introduction of unrelated amino acids into the protein, generally followed by a stop codon
The second major type of mutation involves large-scale changes in chromosome structure and can affect the functioning of numerous genes, resulting in major phenotypic consequences. Such chromosomal mutations (or abnormalities) can involve deletion or insertion of several contiguous genes, inversion of genes on a chromosome, or the exchange of large segments of DNA between nonhomologous chromosomes (Figure 8-4b).
Mutations
arise spontaneously at low frequency owing to the chemical instability
of purine and pyrimidine bases and to errors during
DNA replication. Natural
exposure of an organism to certain environmental
factors, such as ultraviolet
light and chemical carcinogens (e.g., aflatoxin B1),
also can cause
mutations.
A common cause of spontaneous point mutations is the deamination of cytosine to uracil in the DNA double helix. Subsequent replication leads to a mutant daughter cell in which a T·A base pair replaces the wild-type C·G base pair. Another cause of spontaneous mutations is copying errors during DNA replication. Although replication generally is carried out with high fidelity, errors occasionally occur. Figure 8-5 illustrates how one type of copying error can produce a mutation. In the example shown, the mutant DNA contains nine additional base pairs.
In
order to increase the frequency of mutation in experimental organisms,
researchers often treat them with high doses of
chemical mutagens or expose them
to ionizing radiation. Mutations arising in response
to such treatments are
referred to as induced mutations. Generally,
chemical mutagens
induce point mutations, whereas ionizing radiation
gives rise to large
chromosomal abnormalities.
Ethylmethane sulfonate (EMS), a commonly used mutagen, alkylates guanine in DNA, forming O6-ethylguanine (Figure 8-6a). During subsequent DNA replication, O6-ethylguanine directs incorporation of deoxythymidylate, not deoxycytidylate, resulting in formation of mutant cells in which a G·C base pair is replaced with an A·T base pair (Figure 8-6b). The causes of mutations and the mechanisms cells have for repairing alterations in DNA are discussed further in Chapter 12.
A common cause of spontaneous point mutations is the deamination of cytosine to uracil in the DNA double helix. Subsequent replication leads to a mutant daughter cell in which a T·A base pair replaces the wild-type C·G base pair. Another cause of spontaneous mutations is copying errors during DNA replication. Although replication generally is carried out with high fidelity, errors occasionally occur. Figure 8-5 illustrates how one type of copying error can produce a mutation. In the example shown, the mutant DNA contains nine additional base pairs.
Figure 8-5
One mechanism by which errors in
DNA replication produce
spontaneous mutations. The replication
of only one strand is shown; the other strand is
replicated normally, as shown at the
top. (more...)
Ethylmethane sulfonate (EMS), a commonly used mutagen, alkylates guanine in DNA, forming O6-ethylguanine (Figure 8-6a). During subsequent DNA replication, O6-ethylguanine directs incorporation of deoxythymidylate, not deoxycytidylate, resulting in formation of mutant cells in which a G·C base pair is replaced with an A·T base pair (Figure 8-6b). The causes of mutations and the mechanisms cells have for repairing alterations in DNA are discussed further in Chapter 12.
Figure 8-6
Induction of point mutations by
ethylmethane sulfonate (EMS), a
commonly used mutagen. (a) EMS alkylates
guanine at the oxygen on position 6 of the purine
ring, forming O6-ethylguanine
(Et-G),
(more...)
Many common human diseases, often
devastating in their effects, are due to mutations
in single genes. Genetic
diseases arise by spontaneous mutations in germ
cells (egg and sperm), which are
transmitted to future generations. For example, sickle-cell
anemia, which affects 1 in 500 individuals
of African descent, is
caused by a single missense mutation at codon 6 of
the β-globin gene;
as a result of this mutation, the glutamic acid at
position 6 in the normal
protein is changed to a valine in the mutant
protein. This alteration has a
profound effect on hemoglobin, the oxygen-carrier
protein of erythrocytes, which
consists of two α-globin and two β-globin subunits
(see Figure 3-11).
The deoxygenated form of the
mutant protein is insoluble in erythrocytes and
forms crystalline arrays. The
erythrocytes of affected individuals become rigid
and their transit through
capillaries is blocked, causing severe pain and
tissue damage. Because the
erythrocytes of heterozygous individuals are
resistant to the parasite causing
malaria, which is endemic in Africa, the mutant
allele has been maintained. It
is not that individuals of African descent are more
likely than others to
acquire a mutation causing the sickle-cell defect,
but rather the mutation has
been maintained in this population by interbreeding.Spontaneous mutation in somatic cells (i.e., non-germline body cells) also is an important mechanism in certain human diseases, including retinoblastoma, which is associated with retinal tumors in children (see Figure 24-11). The hereditary form of retinoblastoma, for example, results from a germ-line mutation in one Rb allele and a second somatically occurring mutation in the other Rb allele (Figure 8-7a). When an Rb heterozygous retinal cell undergoes somatic mutation, it is left with no normal allele; as a result, the cell proliferates in an uncontrolled manner, giving rise to a retinal tumor. A second form of this disease, called sporadic retinoblastoma, results from two independent mutations disrupting both Rb alleles (Figure 8-7b). Since only one somatic mutation is required for tumor development in children with hereditary retinoblastoma, it occurs at a much higher frequency than the sporadic form, which requires acquisition of two independently occurring somatic mutations. The Rb protein has been shown to play a critical role in controlling cell division (Chapter 13).
Figure 8-7
Role of spontaneous somatic
mutation in retinoblastoma, a
childhood disease marked by retinal
tumors. Tumors arise from retinal cells that carry two mutant
Rb− alleles. (a)
In
(more...)
- Diploid organisms carry two copies (alleles) of each gene, whereas haploid organisms carry only one copy.
- Mutations are alterations in DNA sequences that result in changes in the structure of a gene. Both small and large DNA alterations can occur spontaneously. Treatment with ionizing radiation or various chemical agents increases the frequency of mutations.
- Recessive mutations lead to a loss of function, which is masked if a normal copy of the gene is present. For the mutant phenotype to occur, both alleles must carry the mutation.
- Dominant mutations lead to a mutant phenotype in the presence of a normal copy of the gene. The phenotypes associated with dominant mutations may represent either a loss or a gain of function.
- In meiosis, a diploid cell undergoes one DNA replication and two cell divisions, yielding four haploid cells (Figure 8-2). The members of each pair of homologous chromosomes segregate independently during meiosis, leading to the random reassortment of maternal and paternal alleles in the gametes.
- Dominant and recessive mutations exhibit characteristic segregation patterns in genetic crosses (see Figure 8-3).
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