152 terms

Genetics 2

Gregor Mendel
Before Gregor Mendel experimented with the inheritance of traits in garden peas, theories such as blending were put forward to explain how traits were passed from generation to generation

First, Mendel used experimental genetics to uncover the principles of genetics, that apply to pea plants as well as humans, and for ethical reasons human can not be used in experimental genetics.
Second, humans have very few offspring compared with pea plants, and it takes a long time for one generation (20 years in humans versus 100 days in peas)
Does each parent contributes equally to the traits of the offspring?
In plants and most animals, the females gametes are much larger than those of the male.
Pea plants
1. It should have a number of different traits that can be studied
2. The plant should be self-fertilizing and have a flower structure that minimized accidental pollination (contamination)
3. Offspring of self-fertilized plants should be fully fertile so that further crosses can be made
Mendel tested all available varieties of peas for 2 years to ensure TRUE-BREEDING, that is, that self-fertilization gave rise to the same traits in all the offspring, generation after generation
Mendel studied seven characters that affected the seeds, pods, flowers and stems of the plant.
Each character was represented by two different forms: tall and short, wrinkle and smooth, etc
seed shape
He took plants with smooth seeds and crossed them to plants with wrinkle seeds
In making that cross, flowers from one variety were fertilized using pollen from the other variety.

Mendel's crosses in the garden pea
Each trait involved one pair of alleles
Demonstrated that the phenotype associated with each trait is controlled by a pair of factors
parental generation (P1)
is the first generation of the controlled cross.
first filial generation (F1)
is the result of crossing the parental generation.
second filial generation (F2)
is produced from the crossing of the F1 progeny.
Mendel's Crosses
P1 generation are TRUE-BREEDING varieties
ALL F1 offspring have smooth seeds
Self-fertilization of F1 gives rise to F2 with ¾ smooth and ¼ wrinkled
Results of Mendel's Crosses
The F1 offspring showed only one of the two parental traits: SEPARATE UNITS
In all crosses, it did not matter which plant the pollen came from: EQUAL CONTRIBUTION
The trait not shown in the F1 offspring reappeared in about 25% of the F2 offspring
monohybrid crosses
Crosses that involve a single trait
Conclusion to crossing
Factors can be hidden (unexpressed)
Despite identical appearance, P1 and F1 plants must have different factors
F1 plants must carry hidden factors
F1 plants must carry two factors, one from each parent
the trait not expressed in the F1 but expressed in the F2 plants
The trait present in F1 plants
P1 and F1plants must have different factors.
Mendel realized that it was important to make a distinction between the appearance of an organism and its genetic contribution.
describe the appearance of an organism and the term
to describe the genetic makeup.
plants must carry hidden factors and plants must carry two factors, one from each parent.
are used to represent forms of a gene with a dominant pattern of inheritance are used to represent those with a recessive pattern of inheritance.
lowercase letters
are used to represent those with a recessive pattern of inheritance...s=wrinkled
Recessive Trait
Trait expressed in the F1 but repressed in some members of the F2 generation
Represented by a lowercase letter (rr)
Dominant Trait
Trait expressed in the F1 (heterozygous) condition
Mendel's first law: Principle of Segregation
Pairs of factors (genes) separate from each other during gamete formation and exhibit dominant/recessive relationships
Separation of a Gene Pair
each member of the F1 generation can make two kinds of gametes in equal proportions (S gametes and s gametes)
At Fertilization the random combination of these gametes produces the genotypic combination shown in the Punnett Square
The F2 has a genotypic ratio of 1SS:2Ss:1ss and the phenotypic ratio of 3 smooth and 1 wrinkled.
Analyzing genetic crosses
Punnett square is a method for analyzing genetic crosses devised by R.C. Punnett
The results from a cross between a true-breeding, white-flowered plant (pp) and a true breeding, purple-flowered plant (PP) can be visualized with a Punnett square
Dominant traits are capitalized while the recessive trait are lower-case letter
Self-Fertilization: The F2 Generation
Mendel reasoning allows us to predict the genotypes of the F2 generation
1/4 of theF2 plants should carry only genes for smooth seeds (SS), and when self-fertilized, all that offspring will have smooth seeds
Half (2/4) of the F2 plants should carry genes for both, smooth and wrinkled (Ss)
¼ of the F2 plants should carry only genes for wrinkled (ss) and have all wrinkled progeny in self-fertilized
Separation of Gametes
Mendel carried out these experiments before the discovery of mitosis and meiosis and before the discovery of chromosomes
His conclusions about how traits are inherited are, in fact, descriptions of the way chromosomes behave in meiosis.
One possible alternative form of a gene
Usually distinguished by its phenotypic effects
Having identical alleles
Individuals that carry identical alleles of a give trait (SS or ss) are homozygous for that gene
Having two different alleles
Individuals that carry different alleles of a give trait (SS or ss)
Independent Assortment in a Dihybrid Cross
The principle of independent assortment explains the inheritance of two traits
Before we discuss what it meant by independent assortment, let's see how the phenotypes and genotypes of the F1 and F2 were generated.
The F1 plants with smooth and yellow seeds were heterozygous for both seed shape and seed color
The genotype was SsYy, with S and Y alleles dominant to s and y
During meiosis in the F1 plants, the S and s alleles went into gametes independently of the Y and y alleles
Because each gene pair segregates independently, the F1 plants produces gametes with all combinations of those alleles in equal proportions: SY, Sy, sY and sy
Mendel's second law: Principle of Independent Assortment
The random distribution of alleles into gametes during meiosis
Leads to formation of all possible combinations of gametes with equal probability in a cross between two individuals
The scientific study of heredity

Mendel's principle of segregation and principle of independent assortment are the fundamental principles of genetics
Genes are located
The behavior of chromosomes in meiosis causes segregation and independent assortment of genes
Genes, Chromosomes, and Meiosis
Both chromosomes and genes occur in pairs
In meiosis members of a chromosome pair separate form each other and members of a gene pair separate from each other
Finally, the fusion of gametes during fertilization restores the diploid number of chromosomes and two copies of each gene to the zygote, producing the genotypes of the next generation
Each gene is located at a specific site on a chromosome, and each chromosome carries many genes.
Segregation and Independent Assortment in Meiosis
Mendel observations about segregation and independent assortment are explain by the behavior of chromosomes during meiosis
The arrangement of chromosomes at metaphase I is random.
As a result 4 combinations of the two genes are produced in the gametes
Mendelian Inheritance in Humans
Genes for human genetic traits exhibit segregation and independent assortment
Inheritance of certain human traits is predictable
Genes for human genetic traits exhibit segregation and independent assortment
So the inheritance of certain human traits is predictable
Segregation of Albinism
Homozygous (aa) cannot make a skin pigment called melanin. Melanin is the principal pigment in skin, hair and eyes. Albinos cannot make melanin and as a result have a very pale, white skin, white hair and colorless eyes
To apply Mendelian inheritance to humans, we will start with parents who are heterozygotes (Aa) with normal pigmentation.
During meiosis, the dominant and recessive allele separate from each other and end up in different gametes. Because each parent can produce two different gametes, A and a, there are four possible combinations of gametes at fertilization.
If they have enough children (20 or 30) we will see something close to the predicted phenotypic ratio of 3 pigmented:1 albino offspring and a genotypic ratio of 1AA:2Aa:1aa
Results are the same that Mendel's pea plant
This results does not mean that there will be one albino child and three normal pigmented children in every family with four children
It does mean that if the parents are hets, each children they have has 25% chance of being albino.
Independent Assortment of Two Traits
Let's examine a family in which each parent is heterozygous for albinism (Aa) and for another recessive trait: hereditary deafness (Dd)
Homozygous dominant (DD) or heterozygous (Dd) can hear , but homozygous recessive (dd) are deaf.
During meiosis, alleles for skin color and for hearing assort into gametes independently. As a result, each parent produces equal proportions of four different gametes: AD, Ad, aD, ad.
There are 16 possible combinations of gametes at fertilization, resulting in four different phenotypic classes.
Variations from Mendel
Alleles can interact in ways other than dominant/recessive
Incomplete dominance
Multiple alleles

Different genes can interact
Incomplete Dominance
The expression of a phenotype that is intermediate to those of the parents
R1R1 (red) x R2R2 (white) → R1R2 (pink)

Incomplete dominance has a distinctive phenotype in heterozygotes.
One case in which phenotypes do not follow the predicted ratios for a Mendelian trait is the inheritance of color in snapdragon.
Codominant alleles are fully expressed in heterozygotes
In some cases, both alleles in the heterozygote are fully expressed.
In humans the MN blood group is an example of this phenomenon
The MN blood group is controlled by one single gene, L, that direct the synthesis of glycoprotein, found on the surface of red blood cells. This gene has two alleles M and N. Each of them directs the synthesis of a different form of this glycoprotein.
Again in this case the expected Mendelian genotypic ratio is observed: ¼ MM: ½ MN: ¼ NN, showing that codominance does not violate the expectations of Mendel's laws.
Full phenotypic expression
of both members of a heterozygous gene pair
Multiple Alleles
Genes that have more than two alleles
For simplicity, we have been discussing only genes with two alleles. However, because alleles are different forms of a gene, there is no reason why a gene has to have only two alleles. Many genes have more than two.
Any individual can carry only two alleles of a gene, but a group of individuals can carry many different alleles of a gene.
In humans, the gene for ABO blood types is a gene with more than two alleles, three in this case. Your blood type is determined by genetically encodes molecules called antigens present on the surface of your red blood cells. These molecules are an identity tag recognized by the immune system.
There is one gene (I) for the ABO blood type and it has three alleles IA, IB, IO
If you are homozygous for the A allele (IAIA) you carry the A antigen on cells and have blood type A
If you are homozygous for the B allele (IBIB) you carry the B antigen on cells and have blood type B
The third allele O does not make any antigen, so individual homozygous for the O allele (IOIO) carry not encode antigen on their cells. The O allele is recessive to both A and B.
Because there are three alleles there are six possible genotypes
Multiple, Codominant Alleles
Each allele of codominant genes is fully expressed in the heterozygote. Type A blood has A antigen on the cell surface and type B has B antigens on the surface. In type AB, both A and B antigens are present on the surface. A and B are codominant.
In type O there is not antigen, this allele is recessive to both A and B.
A form of gene interaction in which one gene masks or prevents expression of another gene
Human Chromosome Set
Chromosome analysis is a powerful and useful technique in human genetics
Chromosome Number
The number of chromosomes in the nucleus of an organism is characteristic for a species
Chromosome Shape- Centromere
A region of a chromosome to which microtubule fibers attach during cell division
The location of a centromere gives a chromosome its characteristic shape
Each chromosome contains a specialized region known as the centromere, which divides the chromosome into two arms.
The location of the centromere is characteristic for each specific chromosome
In humans, the short arm of each chromosome is called the p arm, and the long arm is called the q arm
Human Chromosomes
The replicated chromosomes appear as double structures, consisting of sister chromatids joined by a single centromere
Chromosomes classification
-Metacentric: A chromosome that has a centrally placed centromere
-Submetacentric: A chromosome whose centromere is placed closer to one end than the other. The arms are unequal in length.
-Acrocentric: A chromosome whose centromere is placed very close to, but not at, one end
Human males and females have one pair of sex chromosomes that are not completely homologous.
Females have two homologous X chromosomes and males have a nonhomologous pair, consisting of one X chromosome and one Y chromosome. We have 1 pair.
Chromosomes other than sex chromosomes are called autosomes. We have 22 pairs.
Sex chromosomes
Human males and females have one pair of sex chromosomes that are not completely homologous.
Females have two homologous X chromosomes and males have a nonhomologous pair, consisting of one X chromosome and one Y chromosome. We have 1 pair.
Chromosomes other than sex chromosomes are called autosomes. We have 22 pairs.
Human Karyotype
A complete set of chromosomes from a cell that has been photographed during cell division and arranged in a standard sequence
System of Naming Chromosome Bands
For identification of the regions, the short arm of each chromosome is called the p arm, and the long arm is called the q arm. Each arm is subdivided into numbered regions beginning at the centromere. Within each region, the bands are identified by numbers. Thus any region in the human karyotype can be identified by a descriptive address

The area marked with the arrow is designated as 1q2.4 = chromosome 1, long arm q, region 2, band 4
Down syndrome
is caused by an extra copy of chromosome 21
Information From a Karyotype
Number of chromosomes
Sex chromosome content
Presence or absence of individual chromosomes
Nature and extent of large structural abnormalities
Four Chromosome Staining Procedures
There are four common staining procedures in chromosomal analysis. Most karyotypes are prepare by using the G-banding
Stains and dyes are used to produce a pattern of bands that is specific to each chromosome.
One of the most common methods is G-banding, in which the chromosomes first are treated with an enzyme (trypsin) that partially digest chromosomal proteins and then are stain with Giemsa. The resulting pattern of bands are used to identify individual chromosomes in cytogenetic analysis.
Chromosome Painting
Chromosome analysis is a painstaking procedure; to make it easier to spot abnormalities, cytogenetics now are using a technique called chromosome painting.
This method inviolves the use of DNA sequences attached to fluorecent dyes, painting the sequence a specific color.
Here we hava a karyotype of a nomal cell
What Cells can be used for Chromosome Studies?
Any cell with a nucleus can be used to make a karyotype: Lymphocytes, skin cells, cells from biopsies, tumor cells
Prenatal diagnosis
Sampling cells before birth
-Chorionic villus sampling (CVS)
A method of sampling the fluid surrounding the developing fetus by inserting a hollow needle and withdrawing suspended fetal cells and fluid
Used in diagnosing fetal genetic and developmental disorders
Usually performed in the sixteenth week of pregnancy
Chorionic Villus Sampling
A method of sampling fetal chorionic cells by inserting a catheter through the vagina or abdominal wall into the uterus
-Used in diagnosing biochemical and cytogenetic defects in the embryo
-Usually performed in the eighth or ninth week of pregnancy
CVS is used less often than amniocentesis
variation in chromosome number
Two major types of chromosomal changes
A change in chromosomal number
A change in chromosomal arrangement
Changes in Chromosome Number
A chromosomal number that is a multiple of the normal haploid chromosomal set

A chromosomal number that is not an exact multiple of the haploid set

Normal condition
Polyploidy and Aneuploidy effects
Polyploidy and aneuploidy are major causes of reproductive failure in humans

Polyploidy is seen only rarely in live births
The rate of aneuploidy in humans is much higher than in other primates and mammals; reasons for the difference are unknown
Polyploidy Changes the Number of Chromosome Sets
A chromosomal number that is three times the haploid number, having three copies of all autosomes and three sex chromosomes

A chromosomal number that is four times the haploid number, having four copies of all autosomes and four sex chromosomes
An increase in the number of chromosome sets in a cell is called POLYPLOIDY
Abnormalities in the number of chromosome sets can arise in several ways:
Errors in meiosis during gamete formation
Events at fertilization
Errors in mitosis after fertilization
Polyploidy can result from errors in mitosis and meiosis.
If homologous chromosomes fail to separate during meiosis I, meiosis II will produce diploid gametes. Fusion of this diploid gamete with a normal gamete will produce a triploid zygote.
A Triploid Karyotype
A chromosomal number that is three times the haploid number, having three copies of all autosomes and three sex chromosomes
A Tethraploid Karyotype
Polyploidy Changes the Number of Chromosome Sets
Polyploidy in humans can arise by at least two different mechanisms:
-errors in cell division
-errors at fertilization
In both cases is lethal
Polyploidy does not involve the mutation in any gene, only changes the number of gene copies.
Why this change in number is related to lethality, is unknown.
Aneuploidy Changes the Number of Individual Chromosomes
A condition in which one member of a chromosomal pair is missing; one less than the diploid number (2n - 1)

A condition in which one chromosome is present in three copies, and all others are diploid; one more than the diploid number (2n + 1)

Aneuploidy is the addition or deletion of individual chromosomes from the normal diploid set of 46
Nondisjunction in Meiosis I
The most common cause of aneuploidy is called Nondisjunction
The failure of homologous chromosomes to separate properly during anaphase
Here you can see nondisjunction in meiosis I with two pairs of homologous chromosomes. One pair fails to separate properly at anaphase I of meiosis.
Two gametes carry both members of a chromosome pair (n+1) and two are missing a chromosome (n-1)
Gametes missing a copy of a specific chromosome will produce a monosomic zygote. Those with an extra copy of a chromosome will produce a trisomic zygote.
Effects of Monosomy and Trisomy
Autosomal monosomy is a lethal condition
Eliminated early in development (spontaneous abortion)

Autosomal trisomy is relatively common
Most result in spontaneous abortion
Three types can result in live births (13, 18, 21)
Trisomy 8 mosaicism
Complete trisomy 8 causes severe effects on the developing fetus and can be a cause of miscarriage.
Complete trisomy 8 is usually an early lethal condition, whereas trisomy 8 mosaicism is less severe and individuals with a low proportion of affected cells may exhibit a comparatively mild range of physical abnormalities and developmental delay.
Individuals with trisomy 8 mosaicism are more likely to survive into childhood and adulthood, and exhibit a characteristic and recognizable pattern of developmental abnormalities. Common findings include retarded psychomotor development, moderate to severe mental retardation, variable growth patterns which can result in either abnormally short or tall stature, an expressionless face, and many musculoskeletal, visceral, and eye abnormalities, as well as other anomalies.
In genetics a mosaic or mosaicism denotes the presence of two or more populations of cells with different genotypes in one individual who has developed from a single fertilized egg.]
Trisomy 13: Patau Syndrome (47,+13)
The karyotype revealed 47 chromosomes, and the extra chromosome was identify as chromosome 13. We represented like 47,+13
Half of all affected individual die the first month, and the mean survival time is 6 months.
The phenotype involves facial malformations, eye defects, extra finger-toes,. Internally there are usually severe malformations of the brain and nervous system as well as heart defects.
The involvement of so many organs system indicated that abnormalities form early in embryonic development.
Parental age is the only factor known to be related.
Trisomy 18: Edwards Syndrome (47,+18)
Infants with Edwards syndrome are small at birth, grow very slowly and are mentally retarded.
For reason still unknown, 80% of all trisomy 18 births are females
Heart malformations are always present and heart failure or pneumonia usually causes death.
The average survival is 2 to 4 months.
Advance maternal age is a factor.
Trisomy 21: Down Syndrome
Trisomy 21
Aneuploidy involving the presence of an extra copy of chromosome 21, resulting in Down syndrome

Trisomy 21 is the only autosomal trisomy that allows survival into adulthood
Trisomy 21: Down Syndrome (47,+21)
Down syndrome occurs in about 0.5% of all conceptions and in 1 in 800 live births.
It is a leading cause of childhood mental retardation and heart defects in the United States.
Improvement in medical care have increased survival rates dramatically, so that many people with Down syndrome survive into adulthood, although few reach the age of 50 years.
keep in mind
Monosomy and trisomy involve the loss and gain of a single chromosome to a diploid genome

Polyploidy results when there are more than two complete sets of chromosomes
What Are the Risks for Autosomal Trisomy?
Autosomal trisomy is selected against less stringently than autosomal monosomy
Cases of partial development and live births of trisomic individuals occur
Only individuals with trisomy 21 survive into adulthood
Why is Maternal Age a Risk Factor?
Meiosis is not completed until ovulation
Intracellular events may increase risk of nondisjunction, resulting in aneuploidy

Maternal selection
Embryo-uterine interactions that normally abort abnormal embryos become less effective
Aneuploidy of the Sex Chromosomes
Aneuploidy of sex chromosomes involves both X and Y chromosomes

A balance is needed for normal development
At least one copy of the X chromosome is required for development
Increasing numbers of X or Y chromosomes causes progressively greater disturbances in phenotype and behavior
Turner Syndrome
Monosomy of the X chromosome (45,X) that results in female sterility

One MZ twin with Turner syndrome

Females with Turner syndrome are short and wide-chested with rudimentary ovaries.
Many Turner patients have a narrow constriction of the aorta.
There is no mental retardation associated with this syndrome.
Two X chromosomes are needed for normal female development.
Complete absence of an X chromosome in the absence or presence of a Y chromosome is lethal, emphasizing that the X chromosome is an essential component of the karyotype.
Klinefelter Syndrome (47,XXY)
Aneuploidy of the sex chromosomes involving an XXY chromosomal constitution.
The features of this syndrome do not develop until puberty. Affected individual are male but have very low fertility, some have learning disabilities or subnormal intelligence.
A significant number are mosaics, with some cells having an XY chromosome combination and other having a XXY set of chromosomes.
Additional X chromosomes in these karyotypes increase the severity of the phenotypic symptoms
XYY Syndrome (47,XYY)
These individual are above average in height and personality disorders, some subnormal intelligence.
The frequency of XYY individuals in penal and mental institutions is significantly higher that it is in the population.
It has been associated the tendency to violent criminal behavior with the presence of an extra Y chromosome
This karyotype has been used on several occasions as a legal defense (unsuccessfully, so far) in criminal trials.
There is not strong evidence to support a direct link, in fact vast majority of XYY males lead socially normal lives.
Aneuploidy of the Sex Chromosomes
Aneuploidy of sex chromosomes have less impact that aneuploidy in autosomes

A balance is needed for normal development
At least one copy of the X chromosome is required for development
Increasing numbers of X or Y chromosomes causes progressively greater disturbances in phenotype and behavior

Aneuploidy of the X and Y chromosomes is more common than autosomal aneuploidy.
Changes in the number of sex chromosomes have less impact than changes in autosomes
What Are Some Consequences of Aneuploidy?
Aneuploidy is the leading cause of reproductive failure in humans
Results in spontaneous abortions and birth defects

Aneuploidy also is associated with most cancers
Other Forms of Chromosome Abnormalities
Uniparental disomy
A condition in which both copies of a chromosome are inherited from a single parent

Fragile sites
Appear as gaps or breaks in chromosome-specific locations
Two Mechanisms of Uniparental Disomy
Normally meiosis ensures that one member of each chromosomal pair is derived from the mother and one from the father.
On rare occasions, however, a child gets both copies from one parent

UPD is associated with several genetic diseases
X-linked disorders
Autosomal recessive disorders (Prader-Willi syndrome, Angelman syndrome)
Fragile Sites on the X Chromosome
Fragile sites appear as gaps or breaks at specific sites on a chromosome when cells are grown in the laboratory.
Fragile traits are inherited as codominat traits. Over 100 fragile sites have been identified in the human genome.
The molecular nature of these fragile sites is unknown
Several fragile sites are located in the X chromosome. FRAX A and E are associated with genetic disorders. FRAX F is associated with a common form of mental retardation in males
Structural Alterations Within Chromosomes
Changes in the arrangement of chromosomes
loss of chromosome segment

Deletions involve loss of chromosomal material

Deletions of chromosomal segments are associated with several genetic disorders
Cri du chat syndrome
Prader-Willi syndrome
movement of the segment from one form to another

Translocation involves exchange of chromosome parts
Often produces no overt phenotypic effects
Can result in genetically imbalanced and aneuploid gametes

Translocations move a chromosome segment to a nonhomologous chromosome.
There are two major types of translocations: reciprocal and Robertsonian translocations.
extra copies of a chromosome segment
the order of part of the chromosome is reversed
Cri du Chat
Cri du chat syndrome
A deletion of the short arm of chromosome 5
Associated with an array of congenital malformations
Reciprocal Translocation
In a reciprocal translocation, to nonhomologous chromosomes exchange parts.
No genetic information is gained or lost in the exchange, but genes are move to new chromosomal locations.
In some cases there are no phenotypic effects, and the translocation is pass through a family for generations
Robertsonian Translocation
A translocation resulting in Down syndrome
Robertsonian translocation makes Down syndrome a heritable genetic disease
Potentially present in one in three offspring
Robertsonian Translocation
In balanced form, a Robertsonian translocation takes the place of two acrocentric chromosomes and results in no problems for the person carrying it.
But in unbalanced form, Robertsonian translocations produce chromosome imbalance and cause syndrome of multiple malformations and mental retardation.
Robertsonian translocations between chromosomes 13 and 14 (when transmitted in unbalanced for may lead to Trisomy 13) lead to the trisomy 13 (Patau) syndrome.
And the Robertsonian translocations between 14 and 21 and between 21 and 22 (may result in Trisomy 21) (Down) syndrome.
Mutations Are Heritable Changes
Without the phenotypic variations produced by mutations, it would be difficult to determine whether a trait is under genetic control and impossible to determine its mode of inheritance
Mutation can occur spontaneously as a result of errors in DNA replication or be induced by exposure to radiation or chemicals
Without the variation that arises from changes in DNA sequences, there would be no phenotypic variation, no adaptation to environmental changes and no evolution.
Mutation is the source of genetic variation among species.
On the downside, they are also the source of genetic changes that can lead to cell death, genetic diseases and cancer.
Mutations also provide the basis for genetic analysis. They act as "markers" for genes so that they can be followed during their transmission from parents to offspring.
How Mutations Can Be Detected?
Mutations can be classified in a variety of ways by using criteria such as pattern of inheritance, phenotype, biochemistry, and degrees of lethality
The Role of Mutations
Accidental changes in genes are called mutations
Mutation might occur within regions of a gene that code a protein
Mutations occur only rarely and almost always result in recessive alleles
in some cases, particular mutant alleles have become more common in human populations and produce harmful effects called genetic disorders
Dominant Mutations
Dominant mutations are easiest to detect; they are expressed in the heterozygous condition (Aa)
Sudden appearance of a dominant mutation in a family can be observed in a single generation
Accurate pedigree information can be used to identify the individual in whom a mutation arose
Pedigree: A Dominant Trait
A dominant trait appeared (II-5) in a family that has not previous history of this condition.
The trait is now transmitted through next generations in an autosomal dominant fashion
Recessive Mutations
If the mutation is autosomal recessive, it is almost impossible to identify the original mutant individual
It is more difficult to determine the origin of a sex-linked recessive mutation
May be detected by examining males in a family line
Pedigree: Autosomal Recessive Trait
If the mutation is autosomal recessive, it is almost impossible to identify the original mutant individual
Pedigree: An X-Linked Recessive Trait
It is more difficult to determine the origin of a sex-linked recessive mutation
May be detected by examining males in a family line. Why is that?
The sex-linked X chromosome disorder manifests almost entirely in males, although the gene for the disorder is located on the X chromosome and may be inherited from either mother or father. Expression of the disorder is much more common in males than in females. This is because, although the trait is recessive, males only inherit one X chromosome, from their mothers. Thus if the hemophilia gene is transmitted on it, there is no possibility for the male to inherit a hemophilia-free gene from his father to mask or dilute the symptoms. By contrast, a female who inherits a gene for hemophilia on one of her X chromosomes will also have inherited a second X chromosome from the other parent which is likely to carry a hemophilia-free gene that would prevent full expression of symptoms.
It will be difficult to determine if the heterozygous female who transmit the trait to her son is the source of the mutation or is only passing on a mutation that arose in an ancestor
Spontaneous Mutation Rates
Mutations can be classified as either spontaneous or induced, although these two categories overlap to some degree
Spontaneous mutations are changes in the nucleotide sequence of genes that appear to have no known cause. No specific agents are associated with their occurrence, and they are generally assumed to be accidental
Studies of mutation rates in a variety of dominant and sex-linked recessive traits indicate that mutations in the human genome are rare events; about 1 in 1 million copies of a gene
Mutation rate: The number of events that produce mutated alleles per locus (or gene) per generation
Spontaneous Mutation Rates 2
Studies of mutation rates indicate that mutations in the human genome are rare about 1 in 1 million copies of a gene

Mutation rate
The number of events that produce mutated alleles per locus (or gene) per generation
Mutation rate: Example
4 of 100 births show a mutation from a recessive to a dominant allele. Because each of these 100 individuals carries two copies of the gene, we have sample 200. The four births represent four mutated genes (assuming they are heterozygous and carry only one mutant allele).
The mutation rate is 4/200=0.02 per allele per generation
Mutation Rates for Specific Genes Can Sometimes be Measured
Mutation rates can be measured only for dominant alleles under certain conditions:
1. Phenotype must never be produced by recessive alleles
2. Phenotype must always be fully expressed and completely penetrant
3. Paternity must be clearly established
4. Phenotype must never be produced by nongenetic agents
Mutation Rates and Dominant Mutations
One dominant inherited trait, achondroplasia, is a form of dwarfism that produces short arms, short legs, and an enlarged skull.
A survey found 7 achondroplastic children of unaffected parents in a total of 242257 births. For those data, the mutation rate has been calculated at 1.4x10-5, or about one mutation in every 100000 copies of the gene.
Although the mutation rate for achondroplasia can be measured directly, it is not clear whether this gene's mutation rate is typical of all human genes
Mutation Rates for Selected Genes
To get an accurate picture of the mutation rate in humans, it is important to measure the mutation rate in a number of different genes before making any general statement.
Two other dominant mutations have widely different rates
Neurofibromatosis has a high mutation rate: 1x10-4, one of the highest rates found in humans.
The other is Huntington disease: 1x10-6, the lowest
Measurement of some genes are listed in this table. The average rate is 1x10-5
All these genes are inherited in an autosomal or X-linked way. It is almost impossible to do it when they are recessive.
Why Do Genes Have Different Mutation Rates?
Several factors influence the mutation rate and contribute to the wide range of values we observed.
Size of the gene: Larger genes have higher mutation rates.
-Neurofibromatosis is an extremely large gene, over 300000 base pairs long.
-The gene for Duchenne and Becker muscular dystrophy (DMD), the largest gene identified to date in humans, contains more that 2 millions base pairs.
Nucleotide sequence: Presence of nucleotide repeats are associated with higher mutation rates.
For example in the gene for Fragile-X -Syndrome, the sequence CGG is repeat 6 to 50 times in normal individuals, but more that 250 showed symptoms.
Spontaneous chemical changes: C/G base pairs are more likely to mutate than A/T pairs.
Cytosine is especially susceptible to chemicals that can change the nucleotide sequence in DNA
Environmental Factors Influence Mutation Rates
Environmental agents, including radiation and chemicals, can cause mutations
The process by which electromagnetic energy travels through space or a medium such as air

Radiation causes biological damage
Ions and charged atoms are highly reactive and can cause mutation in DNA
Because cells are 80% water, radiation generated Free radicals by splitting water molecules into hydrogen ions (H+) and hydroxyl radicals (OH-) and can cause mutations in DNA
Often, the cell can repair these mutations. However, if too many mutations accumulate in the cell, the repair system can be overwhelmed, If mutation are nor repaired, cell death or cancer can result. In germ cells, mutations that are not repaired are transmitted from generation to generation as newly mutated alleles.
types of radiation
Ionizing radiation: Radiation that produces ions during interaction with other matter, including molecules in cells
However some forms of radiation can cause mutations without producing ions. For example, UV light cause mutations in DNA without producing ions, the energy is absorbed directly by DNA and results in mutations.
Remember the exposure to radiation is unavoidable. Everything in the physical world contain sources of radiation. This include our bodies, the air we breathe, the food we eat, and the bricks in our houses. Some of this radiation is left over from the birth of the Universe., and some have been created by the interaction of atoms on Earth with cosmic radiation. These natural sources are called Background radiation.
We also are exposed to medical testing, nuclear testing, nuclear power, etc.
How Much Radiation Are We Exposed To?
Unit of radiation exposure used to measure radiation damage in humans
The amount of ionizing radiation that has the same effect as a standard amount of x-rays

A rem is equal to 1,000 millirems
doses of radiation
100 rem=100000 mrem cells begin to die
400 rem=400000 mrem 50% people will die within 60 days of they are not treated
Chemicals Can Cause Mutations
Some chemicals cause nucleotide substitutions or change the number of nucleotides in DNA

Other chemicals structurally change the bases in DNA, causing a base pair change after replication
Base Analogs: Thymine and 5′- Bromouracil
One of these chemical are called
Base analogs: Mutagenic chemicals (purine or pyrimidine) that structurally resemble nucleotides and are incorporated into DNA or RNA during synthesis

Example: 5′-bromouracil has a structure similar to thymine.
Results in a A/T → G/C mutation
Conversion of Cytosine to Uracil
Chemical Modifications of Bases
Some chemical mutagens directly modify the bases in DNA, changing one base to another
Example: Nitrous acid changes cytosine into uracil, resulting in a G/C → A/T mutation
Chemicals That Bind to DNA: Acridine Orange
Chemicals That Bind to DNA
Chemicals that bind directly to DNA (intercalating agents) generally produce frameshift mutations by distorting the double helix, resulting in addition or deletion of a base pair during DNA replication
Example: Acridine orange replaces a base pair
It is about the same size as a purine/pyrimidine base pair and wedges itself into DNA distorting the shape of the double helix
Mutations at the Molecular Level: DNA as a Target
Molecular analysis of mutations shows a direct link between gene, protein, and phenotype
Mutations arise spontaneously as the result of errors in DNA replication or as the result of structural shifts in nucleotide bases
To understand the consequence of DNA mutation one has to consider two major factors: WHAT kind of mutation has occurred and WHERE it has occurred.
If the mutation occurs in the junk DNA then it may have no consequence.
If it occurs in the promotor region of a gene it may alter the regulation of the expression of that gene.
If it occurs in the coding region of a gene it may affect the protein sequence.
The main type of mutations are deletions, insertions (these can be due to translocation of one segment of DNA from one location to another) and point mutations (i.e. substitutions of one nucleotide for another)
Two Types of Mutations
Point mutations
1. Nucleotide substitutions
Mutations that replace one or more nucleotides in a DNA molecule with other nucleotides but do not alter the number of nucleotides in a gene
Insertion and deletions (Indels)
1. In frame mutations
2. Out of frame or frameshift mutations
Mutational events in which a number of bases (other than multiples of three) are added to or removed from DNA, causing a shift in the codon reading frame, often producing dramatic alterations in structure and function of proteins
Point Mutations
Missense mutations
Silent mutation
Sense mutations
Nonsense mutations
Splice-site mutations
Silent Mutations
have no effect on the amino
acid produced by a codon because of redundancy in the genetic code

Example: The UCA codon in can mutate to UCC, UCA, or UCG and still code Serine
Missense Mutations
Mutations that cause the substitution of one amino acid for another in a protein

Example: The GAG codon in hemoglobin can mutate to GUG, AAG, or GCG
Hemoglobin Variants: Single Nucleotide Substitutions
EXAMPLE: sickle-cell disease. The replacement of A by T at the 17th nucleotide of the gene for the beta chain of hemoglobin changes the codon GAG (for glutamic acid) to GTG (which encodes valine). Thus the 6th amino acid in the chain becomes valine instead of glutamic acid.
Hemoglobin variants provide many examples of how a change in one nucleotide in a gene can affect protein structure and function
Sense mutations
Mutations in a single nucleotide can change a termination codon into one that codes for an amino acid, producing elongated proteins

Example: Stop codon UAA in alpha globin can mutate to CAA
Alpha Globins with Extended Chains
Several hemoglobin variants with longer than normal globin molecules are shown in this table.
In each case, the extended polypeptide chain van be explained by a single nucleotide in the normal termination codon. In hemoglobin Constant Springs-1, the mRNA codon 142 is changed from UAA to CAA, replacing the stop codon with a glycin. In this case 30 more aminoacids are inserted into the alpha globin molecule before other stop is reached.
Nonsense mutations
Mutations that change an amino acid specifying a codon to one of three termination codons

Example: A UAU codon in beta globin can mutate to a stop codon UAA
Splice-site mutations
The removal of intron sequences, as pre-mRNA is being processed to form mRNA, must be done with great precision.
Nucleotide signals at the splice sites guide the enzymatic machinery.
If a mutation alters one of these signals, then the intron is not removed and remains as part of the final RNA molecule.
The translation of its sequence alters the sequence of the protein product.
Insertions and Deletions (Indels)
Normal code


Insertions change the reading frame, changing the amino acids in the protein and result in a nonfunctional gene product

Extra base pairs may be added (insertions) or removed (deletions) from the DNA of a gene. The number can range from one to thousands. Collectively, these mutations are called indels.
Indels involving one or two base pairs (or multiples of two) can have devastating consequences to the gene because translation of the gene is "frameshifted". This figure shows how by shifting the reading frame one nucleotide to the right, the same sequence of nucleotides encodes a different sequence of amino acids. The mRNA is translated in new groups of three nucleotides and the protein specified by these new codons will be worthless. Scroll up to see two other examples (Patients C and D).
Frameshifts often create new STOP codons and thus generate nonsense mutations. Perhaps that is just as well as the protein would probably be too garbled anyway to be useful to the cell.
Indels of three nucleotides or multiples of three may be less serious because they preserve the reading frame (see Patient E above).
However, a number of inherited human disorders are caused by the insertion of many copies of the same triplet of nucleotides. Huntington's disease and the fragile X syndrome are examples of such trinucleotide repeat diseases.
Trinucleotide Repeats and Gene Expansions
Trinucleotide repeats are a class of mutations associated with a number of genetic disorders.
This type of mutation is a sequence of three nucleotides repeated several times in consecutive order within or adjacent to a gene
This expansion involves only one of the two alleles, and the phenomenon is called Allelic expansion
The potential for expansion is a characteristic of a specific allele and occurs only within that allele
Fragile-X Syndrome
Heterozygous mothers are phenotypically normal
Fragile-X phenotype includes mental retardation

20% to 50% of hemizygous males are phenotypically normal (transmitter males)
Males in which the mutation has low penetrance

Daughters of transmitter males have a high risk of bearing affected children
Pedigree: Fragile X Syndrome
Several disorders in humans are caused by the inheritance of genes that have undergone insertions of a string of 3 or 4 nucleotides repeated over and over.
A locus on the human X chromosome contains such a stretch of nucleotides in which the triplet CGG is repeated (CGGCGGCGGCGG, etc.).
The number of CGGs may be as few as 5 or as many as 50 without causing a harmful phenotype (these repeated nucleotides are in a noncoding region of the gene).
Even 100 repeats usually cause no harm.
However, these longer repeats have a tendency to grow longer still from one generation to the next (to as many as 4000 repeats).
This causes a constriction in the X chromosome, which makes it quite fragile.
Males who inherit such a chromosome (only from their mothers, of course) show a number of harmful phenotypic effects including mental retardation.
Females who inherit a fragile X (also from their mothers; males with the syndrome seldom become fathers) are only mildly affected.
Gene Expansion is Related to Anticipation
Anticipation: Is a phenomenon in which genetic disorder at earlier ages becomes more severe in successive generations

Certain regions of the genome are unstable and undergo dynamic change (allelic expansion)
Explains genetic disorders that do not show simple Mendelian inheritance (for example, those showing incomplete penetrance or variable expression)
Mutations and DNA Damage Can Be Repaired
Not all mutations cause genetic damage
Cells have enzyme systems that repair DNA
Correct errors in replication
Repair damage caused by environmental agents such as ultraviolet light, radiation, and chemicals
DNA polymerase
corrects mistakes in DNA replication (proofreading function)
DNA Damage From UV Light
Thymine dimer
Chemical bonds formed between a pair of adjacent thymine bases in a the same DNA strand affecting a normal replication
Genetic Disorders Can Affect DNA Repair Systems
Xeroderma pigmentosum,
are caused by mutations in genes that repair DNA
Mutations, Genotypes, and Phenotypes
Mutations in the Cystic Fibrosis Gene
In most genes associated with a genetic disorder, many different types of mutations can cause a mutant phenotype
In the cystic fibrosis gene, many different mutations have been identified, including deletions, nucleotide substitutions, and frameshift mutations
Genomic imprinting
When expression of a gene depends on whether it is inherited from the mother or the father
Also known as genetic or parental imprinting
Evidence For Imprinting in Mammals
In mice and other mammals, including humans, embryonic development proceeds normally when fertilized eggs contain a maternal and paternal genome.
Experimental embryos with only a male genome develop abnormal embryonic structures but have normal placentas. Embryos with only a female genome develop normal embryonic structures but have abnormal placentas. Both conditions are lethal, and we can conclude that both maternal and paternal genomes are required for normal development
Genomic Imprinting and Genetic Disorders
Only segments of chromosomes 4, 8, 15, 17, 18, and 22 are imprinted

Disorders of chromosome 15 (80% of cases)
Prader-Willi syndrome (PWS): deletion on the paternal copy
Angelman syndrome (AS): deletion on the maternal copy
Genomic Imprinting is Not Permanent
What Is Imprinting?
For most genes, we inherit two working copies -- one from mom and one from dad. But with imprinted genes, we inherit only one working copy. Depending on the gene, either the copy from mom or the copy from dad is epigenetically silenced. Silencing usually happens through the addition of methyl groups during egg or sperm formation. The epigenetic tags on imprinted genes usually stay put for the life of the organism. But they are reset during egg and sperm formation. Regardless of whether they came from mom or dad, certain genes are always silenced in the egg, and others are always silenced in the sperm.

-In each generation, the previous imprinting is erased and the gene is reimprinted: During gamete formation or early development
-Imprinting is an epigenetic change: Involving reversible changes by chemical modifications to DNA and gene function without affecting the nucleotide sequence