Download EXTENSIONS AND DEVIATIONS OF MENDELIAN INHERITANCE

EXTENSIONS AND DEVIATIONS OF MENDELIAN
INHERITANCE
INTRODUCTION
„
„
In this lecture we will examine traits that deviate from the simple
dominant/recessive relationship
The inheritance patterns of these traits still obey Mendelian laws
„ However, they are more complex and interesting than Mendel
had realized
„
„
Mendelian inheritance describes inheritance patterns that obey
two laws
„ Law of segregation
„ Law of independent assortment
Simple Mendelian inheritance involves
„ A single gene with two different alleles
„ Alleles display a simple dominant/recessive relationship
Reminder
Mendel’s First Law: Law of Segregation
„
„
Each individual has a pair of factors (alleles) for each trait
The factors (alleles) segregate (separate) during gamete
(sperm & egg) formation
„
Each gamete contains only one factor (allele) from each pair
„
Fertilization gives the offspring two factors for each trait
Reminder
Mendel’s Second Law: Law of Independent Assortment
„
„
„
The pair of factors for one trait segregate
independently of the factors for other traits
All possible combinations of factors can occur in the
gametes
But not all traits follow simple Mendelian inheritance
Simple Mendelian: Alleles that obey Mendel’s laws, and follow a discrete
dominant/recessive relationship
X Linked: Inheritance of genes that are located on the X chromosome. In
mammals and fruit flies, males are hemizygous for x-linked genes, while
females have two copies
Lethal alleles: An allele that has the potential for causing the death of an
organism
Incomplete dominance: Inheritance where heterozygotes have
intermediate phenotypes e.g. production of pink flowers in crosses of
plants with red and white flowers
Codominance: Inheritance where heterozygotes express both alleles
e.g. inheritance of ABO blood group in humans
Overdominance: Inheritance where heterozygotes have traits that are
more beneficial than homozygotes.
e.g. sickle-cell trait
Incomplete penetrance: Inheritance where dominant phenotype is not
expressed even though an individual carries the dominant allele
e.g. individuals that carry polydactyly allele but have normal number of
fingers/toes
Sex-influenced inheritance: Some alleles are dominant in one sex and
recessive in the other
e.g. baldness in humans
Sex-limited inheritance: Traits that occur in only one of the sexes
e.g. breast development in mammals
„
„
Prevalent alleles in a population are termed wild-type alleles
„ These typically encode proteins that
„ Function normally
„ Are made in the right amounts
Reminder
Alleles that have been altered by mutation are termed mutant alleles
„ These tend to be rare in natural populations
„ They are likely to cause a reduction in the amount or function of
the encoded protein
„ Such mutant alleles are often inherited in a recessive fashion
„
„
Consider, for example, the traits that Mendel studied
Wild-type (dominant) allele
Mutant (recessive) allele
Purple flowers
White flowers
Axial flowers
Terminal flowers
Yellow seeds
Green seeds
Round seeds
Wrinkled seeds
Smooth pods
Constricted pods
Green pods
Yellow pods
Tall plants
plants
Another example is from Drosophila
Wild-type (dominant) allele
Mutant (recessive) allele
Red eyes
White eyes
Normal wings
Miniature wings
„
„
Genetic diseases are caused by mutant alleles
In many human genetic diseases , the recessive allele contains a
mutation
„ This prevents the allele from producing a fully functional protein
„ e.g. Niemann-Pick Type C (NPC1)
„
„
„
Neurodegenerative lysosomal storage disorder
Characterized by accumulation of cholesterol and other fatty acids in
endosomes and lysosomes
Defect in NPC1 gene
„
In a simple dominant/recessive relationship, the recessive allele does
not affect the phenotype of the heterozygote
„
„
So how can the wild-type phenotype of the heterozygote be
explained?
There are two possible explanations
„
„
1. 50% of the normal protein is enough to accomplish the protein’s
cellular function
2. The heterozygote may actually produce more than 50% of the
functional protein
„ The normal gene is “up-regulated” to compensate for the lack
of function of the defective allele
1. Lethal Alleles
„
„
„
Essential genes are those that are absolutely required for
survival
„ The absence of their protein product leads to a lethal
phenotype
„ It is estimated that about 1/3 of all genes are essential
for survival
Nonessential genes are those not absolutely required for survival
A lethal allele is one that has the potential to cause the death of
an organism
„ These alleles are typically the result of mutations in essential
genes
„ They are usually inherited in a recessive manner
„
„
„
Many lethal alleles prevent cell division
„ These will kill an organism at an early age
Some lethal allele exert their effect later in life
„ Huntington disease
„ Characterized by progressive degeneration of the nervous
system, dementia and early death
„ The age of onset of the disease is usually between 30 to 50
Conditional lethal alleles may kill an organism only when certain
environmental conditions prevail
„ Temperature-sensitive (ts) lethals
„ A developing Drosophila larva may be killed at 30 C
„ But it will survive if grown at 22 C
„
„
„
Semilethal alleles
„ Kill some individuals in a population, not all of them
„ Environmental factors and other genes may help prevent the
detrimental effects of semilethal genes
A lethal allele may produce ratios that seemingly deviate from
Mendelian ratios
An example is the “creeper” allele in chicken
„ Creepers have shortened legs and must creep along
„ Such birds also have shortened wings
„
Creeper chicken are heterozygous
Creeper X Normal
Creeper X Creeper
1 creeper : 1 normal
1 normal : 2 creeper
Creeper is a dominant allele
Creeper is lethal in the
homozygous state
2. Incomplete Dominance
„
„
In incomplete dominance the heterozygote exhibits a phenotype
that is intermediate between the corresponding homozygotes
Example:
„ Flower color in the four o’clock plant
„ Two alleles
R
„ C = wild-type allele for red flower color
W = allele for white flower color
„ C
1:2:1 phenotypic
ratio NOT the 3:1
ratio observed in
simple Mendelian
inheritance
In this case, 50% of
the CR protein is not
sufficient to produce
the red phenotype
Incomplete Dominance
„
„
Whether a trait is dominant or incompletely dominant may depend
on how closely the trait is examined
Take, for example, the characteristic of pea shape
„ Mendel visually concluded that
„ RR and Rr genotypes produced round peas
„ rr genotypes produced wrinkled peas
„ However, a microscopic examination of round peas reveals that
not all round peas are “created equal”
3. Multiple Alleles and Codominance
„
„
Many genes have multiple alleles
„ Three or more different alleles
An interesting example is coat color in rabbits
„ Four different alleles
„ C (full coat color)
ch (chinchilla pattern of coat color)
„ c
„ Partial defect in pigmentation
h
„ c (himalayan pattern of coat color)
„ Pigmentation in only certain parts of the body
„ c (albino)
„ Lack of pigmentation
„ The dominance hierarchy is as follows:
ch > ch > c
„ C > c
„
„
„
The ABO blood group provides another example of multiple alleles
It is determined by the type of antigen present on the surface of
red blood cells
„ Antigens are substances that are recognized by antibodies
produced by the immune system
there are three different types of antigens found on red blood
A
„ Antigen A, which is controlled by allele I
B
„ Antigen B, which is controlled by allele I
„ Antigen O, which is controlled by allele i
„
„
Allele i is recessive to both IA and IB
Alleles IA and IB are codominant
„ They are both expressed in a heterozygous individual
N-acetylgalactosamine
B
„
„
„
The carbohydrate tree on the surface of RBCs is composed of three
sugars
A fourth can be added by the enzyme glycosyl transferase
„ The i allele encodes a defective enzyme
„ The carbohydrate tree is unchanged
A
„ I encodes a form of the enzyme that can add the sugar Nacetylgalactosamine to the carbohydrate tree
B
„ I encodes a form of the enzyme that can add the sugar galactose
to the carbohydrate tree
Thus, the A and B antigens are different enough to be recognized by
different antibodies
„
„
For safe blood transfusions to occur, the donor’s blood must be an
appropriate match with the recipient’s blood
For example, if a type O individual received blood from a type A, type
B or type AB blood
„ Antibodies in the recipient blood will react with antigens in the
donated blood cells
„ This causes the donated blood to agglutinate
„ A life-threatening situation may result because of clogging of
blood vessels
4. Overdominance
„
„
Overdominance is the phenomenon in which a heterozygote is more
vigorous than both of the corresponding homozygotes
„ It is also called heterozygote advantage
Example = Sickle-cell anemia
„ Autosomal recessive disorder
„ Affected individuals produce abnormal form of hemoglobin
„ Two alleles
A Æ Encodes the normal hemoglobin, hemoglobin A
„ Hb
S Æ Encodes the abnormal hemoglobin, hemoglobin S
„ Hb
„
HbSHbS individuals have red blood cells that deform into a sickle
shape under conditions of low oxygen tension
„ This has two major ramifications
„ 1. Sickling phenomenon greatly shortens the life span of the
red blood cells
„ Anemia results
„ 2. Odd-shaped cells clump
„ Partial or complete blocks in capillary circulation
„
Thus, affected individuals tend to have a shorter life span than
unaffected ones
„
„
„
The sickle cell allele has been found at a fairly high frequency in parts
of Africa where malaria is found
„ How come?
Malaria is caused by a protozoan, Plasmodium
„ This parasite undergoes its life cycle in two main parts
„ One inside the Anopheles mosquito
„ The other inside red blood cells
„ Red blood cells of heterozygotes, are likely to rupture when
infected by Pasmodium sp.
„ This prevents the propagation of the parasite
Therefore, HbAHbS individuals are “better” than
S
S
„ Hb Hb , because they do not suffer from sickle cell anemia
A
A
„ Hb Hb , because they are more resistant to malaria
„
„
„
At the molecular level, overdominance is due to two alleles that
produce slightly different proteins
But how can these two protein variants produce a favorable phenotype
in the heterozygote
Well, there are three possible explanations for overdominance at the
molecular/cellular level
„ 1. Disease resistance
„ 2. Homodimer formation
„ 3. Variation in functional activity
„
„
„
„
Overdominance is related to a common mating strategy used by
animal and plant breeders
Two different highly inbred strains are crossed
„ The hybrids may display traits superior to both parents
„ This phenomenon is termed hybrid vigor or heterosis
Heterosis is used to improve quantitative traits such as size,
weight and growth rate
Heterosis is different from overdominance, because it typically
involves many genes
„ Nevertheless, its beneficial effects may be attributed to
overdominance in one or more heterozygous genes
5. Incomplete Penetrance
„
„
In some instances, a dominant allele is not expressed in a
heterozygote individual
Example = Polydactyly
„ Autosomal dominant trait
„ Affected individuals have additional fingers and/or toes
„
„
A single copy of the polydactyly allele is usually sufficient to
cause this condition
In some cases, however, individuals carry the dominant allele but
do not exhibit the trait
Inherited the polydactyly allele from
his mother and passed it on to a
daughter and son
Does not exhibit the trait himself
even though he is a heterozygote
Incomplete Penetrance
„
„
„
The term indicates that a dominant allele does not always
“penetrate” into the phenotype of the individual
The measure of penetrance is described at the population level
„ If 60% of heterozygotes carrying a dominant allele exhibit the
trait allele, the trait is 60% penetrant
Note:
„ In any particular individual, the trait is either penetrant or not
Expressivity
„
„
Expressivity is the degree to which a trait is expressed
In the case of polydactyly, the number of digits can vary
„ A person with several extra digits has high expressivity of this
trait
„ A person with a single extra digit has low expressivity
„
„
The molecular explanation of expressivity and incomplete
penetrance may not always be understood
In most cases, the range of phenotypes is thought to be due to
influences of the
„ Environment
and/or
„ Other genes
Environment
„
„
Environmental conditions may
have a great impact on the
phenotype of the individual
Example 1
„ Snapdragon flower color vs.
Temperature and degree of
sunlight
Environment
„
Example 2 = Phenylketonuria
„ Autosomal recessive disorder in humans
„ Caused by a defect in the gene that encodes the enzyme
phenylalanine hydroxylase
„ Converts phenylalanine to tyrosine
„ Affected individuals cannot metabolize phenylalanine
„ Phenylalanine will thus accumulate
„ It ultimately causes a number of detrimental effects
„ Mental retardation, for example
Environment
„
Example 2 = Phenylketonuria
„
„
„
„
Newborns are now routinely screened for PKU
Individuals with the disease are put on a strict dietary regimen
„ Their diet is essentially phenylalanine-free
These individuals tend to develop normally
Thus the PKU test prevents a great deal of human suffering
„ Furthermore, it is cost-effective
Sex and Traits
„
„
The inheritance pattern of certain traits is governed by the sex of
the individual
These traits are of two main types
„ Sex-influenced
„ Sex-limited
7. Sex-influenced Traits
„
Traits where an allele is dominant in one sex but recessive in the
opposite sex
„ Thus, sex influence is a phenomenon of heterozygotes
Sex-influenced Traits
„
Example: Pattern baldness in humans
„
Caused by an autosomal gene
„ Allele B behaves as dominant in males, but recessive in
females
Genotype
Phenotype
in Females
Phenotype
in Males
BB
bald
bald
Bb
nonbald
bald
bb
nonbald
nonbald
Sex-influenced Traits
„
„
Pattern baldness appears to be related to the level of male sex
hormones
In females, a rare tumor of the adrenal gland can cause the
secretion of large amounts of male sex hormones
„ If this case a heterozygous Bb female will become bald
„ When the tumor is removed surgically, her hair returns to its
normal condition
„
The autosomal nature of pattern baldness has been revealed by
analysis of human pedigrees
Bald fathers can pass
the trait to their sons
8. Sex-limited Traits
„
„
Traits that occur in only one of the two sexes
For example in humans
„ Breast development is normally limited to females
„ Beard growth is normally limited to males
„
Another example: Feather plumage in chicken
„ Caused by an autosomal gene
„ Hen-feathering is controlled by a dominant allele expressed in
both sexes
„ Cock-feathering is controlled by a recessive allele only
expressed in males
Genotype
Phenotype
in Females
Phenotype
in Males
hh
hen-feathered
cock-feathered
Hh
hen-feathered
hen-feathered
HH
hen-feathered
hen-feathered
Sex-limited Traits
„
„
The pattern of hen-feathering depends on the production of sex
hormones
If the single ovary is surgically removed from a newly hatched hh
female
„ She will develop cock-feathering and look indistinguishable
from a male
GENE INTERACTIONS
„
„
Gene interactions occur when two or more different genes influence
the outcome of a single trait
Indeed, morphological traits such as height weight and pigmentation
are affected by many different genes in combination with
environmental factors