Download Lectures 15-17: Patterns of Inheritance Genotype Vs. Phenotype

Lectures 15-17: Patterns of Inheritance
I.
II.
III.
IV.
Genotype Vs. Phenotype
a. Genotype: a person’s genetic constitution
b. Phenotype: observable expression of a genotype
Pedigrees
a. Family tree is a shorthand system for recording pertinent family information
b. Person of interest is referred to as the index case, proband, or prospositus or if female
called proposita
c. Position of the proband is indicated by an arrow
Patterns of Single Gene Inheritance (Mendelian traits)
a. Dominant: trait is expressed whenever the gene is present, whether as heterozygote or
homozygote
b. Recessive: Trait is only expressed in the homozygote (need two copies of the gene)
c. Co-dominant: effects of both alleles may be seen in the heterozygote
d. You must think about whether gene is located on autosome or sex chromosome
What accounts for genetic variation?
a. Mendel’s Law of Segregation – “The First Law”
i. The Law of Segregation states that every individual possesses a pair of genes for any
particular trait and that each parent passes a randomly selected copy of only one of
these to its offspring. The offspring then receives its own pair of genes for that trait.
Whichever of the two genes in the offspring is dominant determines how the
offspring expresses that trait (e.g. the color of a plant, the color of an animal's fur,
the color of a person's eyes).
b. Law of Independent Assortment – “Second Law”
i. The Law of Independent Assortment, also known as "Inheritance Law" states that
separate genes for separate traits are passed independently of one another from
parents to offspring. That is, the bioIndependent assortment occurs during meiosis I
in eukaryotic organisms, specifically metaphase I of meiosis, to produce a gamete
with a mixture of the organism's maternal and paternal chromosomes. Along with
chromosomal crossover, this process aids in increasing genetic diversity by
producing novel genetic combinations. Logical selection of a particular gene in the
gene pair for one trait to be passed to the offspring has nothing to do with the
selection of the gene for any other trait. More precisely the law states that alleles of
different genes assort independently of one another during gamete formation
c. After meiosis I, each cell only retains ONE of the homologous pairs
i. A choice is made separately for each chromosome
d. We are UNIQUE because of three processes
i. Independent Assortment (Humans have 2^23 possible combinations of
chromosomes)
ii. Recombination events
iii. New Mutations
1. Mutation is the ultimate source of genetic information
a. Some mutations repaired, not all are
V.
VI.
VII.
2. Ex of natural selection: the frequency of the sickle cell allele and the
distribution of Plasmodium falciparum (malaria parasite) correspond
(selective advantage to the heterozygote)
Natural polymorphisms and Linkage
a. Everyone is slightly different due to their genetic code, due to unrepaired mutations in
(usually) non-coding regions
b. Humans are 99.9% identical
c. Human genome project identified 1.45 million known SNPs (single nucleotide
polymorphisms) and the differences were evaluated for its association with a disease
d. SNPs used to locate disease genes through linkage
i. Mendel’s principle of independent assortment does NOT apply for 2 loci which are
“linked” (close together on the chromosome)
ii. Crossover between two loci which are FAR APART from each other will disrupt their
positions relative to each other, separating them onto two different chromosomes
during meisosi (NOT linked)
iii. When crossover occurs between two loci positioned CLOSE to each other on the
same chromosome, the two markers will stay together on the same chromosome
during meiosis because they are LINKED
iv. LOD score (logarithm of the odds)
1. Ex: LOD=+3.0 : odds are 1000 to 1 FOR linkage (if negative it would be
against)
2. Numbers derived from studies of large families
Probability
a. Events during meiosis are independent, so the probability is ½ for one of the two alleles the
next time a chromosome pair is transmitted to an egg or sperm
b. Multiplication rule (AND)
i. If two trials are independent, you can multiply to figure out the probability of the
outcome
c. Addition Rule (OR)
i. If the outcome is dependent on the other, add the probabilities together
ii. OR, when the two events are LINKED (think LOD score)
d. Review punnett squares
Autosomal Dominant Inheritance
a. Most mutations that cause disease are rare in population
b. This is more common than autosomal recessive
c. Autosomal dominant traits manifest in a heterozygous state
d. General Characteristics of Autosomal Dominant Disorders
i. Child born to a parent with an autosomal dominant trait has a 50% chance of
inheriting it and being similarly affected
ii. Lack of skipped generations
iii. Roughly equal numbers of affected males and females
iv. Phenotypically normal parents do NOT transmit the trait (unless phenotype appears
later in life)
v. Father-son transmission may be observed.
e. PLEIOTROPY
i.
ii.
iii.
iv.
VIII.
Autosomal trait may involve a single gene or organ system
Dominant traits often manifest their effects in various ways
Pleiotropy: a single gene can give rise to two apparently unrelated effects
Ex: tuberous sclerosis (mutations in TSC1 and TSC2 genes): wide range of
pathologies including learning difficulties, epilepsy, facial rash called adenoma
sebaceum or subungal fibromas
1. CNS tumors are the leading cause of mortality in TSC
f. Variable expression
i. This refers to the way that dominant traits present with striking variation from
person to person
ii. Ex: polycystic kidney disease: some affected individuals develop renal failure in early
adulthood and others present with just a few renal cysts and no major effects on
renal function
g. Penetrance of Genes
i. An individual heterozygous for certain dominant gene mutations may have no
obvious abnormal clinical features
1. This is referred to as reduced penetrance or “skipping a generation”
ii. Reduced penetrance is attributed to the effects of modifying genes
iii. Ex: Reduced penetrance in familiar cancer syndromes. See this in BRCA1 andBRCA2
mutations in breast cancer. Some people with these mutations will develop breast
cancer, some will not.
iv. Reduced penetrance probably results from a combo of genetic, environmental, and
lifestyle factors, many of which are unknown
h. Familial Hypercholesterolemia
i. Results from defects in gene encoding LDL receptor (two mutant classes)
ii. Phenotype: elevated plasma cholesterol with strong risk for coronary
atherosclerosis
i. Huntington Disease
i. Caused by expansion of a trinucleotide repeat (CAG)
Autosomal Recessive Inheritance
a. Rarer in the population since only the homozygote expresses the phenotype
b. General Characteristics
i. After the birth of an affected child, each subsequent child born to this couple has a
25% chance of being affected
ii. Phenotype often only among siblings, not parents or offspring
iii. Usually males and females equally likely to be affected
iv. Increased incidence from parents who are consanguineous (related by blood)
c. Sickle Cell Anemia
i. Homozygous: SCD-sickle cell disease
ii. Heterozygous: sickle cell trait
iii. Mutant form of Hb known as HbS
iv. HbS is less soluble than normal HbA and under oxygen stress can polymerize causing
deformation or sickling of RBCs
v. Results from the substitution of valine for glutamic acid at the sixth position in the
beta-globin chain
IX.
d. Hereditary Hemochromatosis
i. Most common form of iron overload disease
ii. Inherited disorder that causes the body to absorb and store too much iron
iii. HFE, which helps regulate the amt of iron absorbed from food
iv. Most common in US Northern European/Caucausian population
e. Degrading Enzymes
i. Mucopolysaccharidoses
1. Defect in polysaccharide breakdown in lysosomes
2. Hunter syndrome (x-linked)
3. Hurler Syndrome (AR)
ii. Sphingolipidoses
1. Defect in sphingolipid breakdown in lysosomes
2. Fabry disease (x-linked)
3. Tay-Sachs, Gaucher, Farber (AR)
Sex-chromosome-Related Issues
a. X-Linked Inheritance
i. Ex: red-green color blindness, hemophilia A, Duchennes Muscular dystrophy
ii. Because females have 2 copies of X chromosomes and males only have one
(hemizygosity), X-linked recessive diseases are much more common among males
than females
iii. An affected male having children with a normal female will have female offspring
that are all obligate carriers, but none of the sons affected
iv. A male cannot transmit an x-linked trait to his son (rare exceptions include
uniparental disomy)
v. For a carrier female of an X-linked disorder, each of her sons has a 50% chance of
being affected and each daughter has a 50% chance of being an obligate carrier
vi. X-linked RECESSIVE INHERITANCE
1. General Characteristics
a. Recurrence risk for heterozygous female/normal male is 50% of
sons affected and 50% of daughers heterozygous carriers
b. Recurrence risk for affected male/normal female: no sons affected
and all daughters heterozygous carriers
c. Skipped generations
d. Much greater prevalence of affected males; affected homozygous
fmales rare; occasionally heterozygous females may manifest traits
e. NO male to male transmission
2. Duchenne muscular dystrophy
a. Produces a progressive proximal muscle weakness with massive
elevations of muscle enzymes in the serum including creatine kinase
b. Patients do not survive to reproductive age, therefore disorders are
transmitted through mother and not affected males.
3. Hemophilia
vii. X-linked dominant (he said not to worry about any of these!)
b. X chromosome inactivation (Lyon Hypothesis) (don’t worry about this either)
i. Male’s X chromosome is inherited from MOM
X.
XI.
XII.
ii. Female inherits two x chromosomes, one from each parent.
iii. Mosaicism – x Chromosome inactivation
1. Skin pigmentation (x linked dominant)
Co-Dominant Inheritance
a. Ex: ABO blood groups (multiple alleles equally expressed)
b. He said don’t worry about Rh stuff
Mitochondrial Inheritance
a. A few pedigress of inherited diseases cannot be explained by typical Mendelian Inheritance
of nuclear genes
b. Remember: mitochondria responsible for energy production’
c. These diseases mainly affect muscle and nerve (especially of the eye)
d. Ex of disease: Leber’s hereditary Optic Neuropathy
e. Inheritance of mitochondrial disorders strictly maternal. Females transmit these traits to
offspring.
f. More mitochondrial diseases
i. Kearns-Sayre syndrome: early onset opthalmopolagia with heart block, retinal
pigmentation
ii. MERFF (Myoclonic epilepsy ragged red fibers in muscle, ataxia, sensorineural
deafness)
iii. MELAS (mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes)
iv. LHON (Leber’s Hereditary optic neuropathy)
v. Retinitis Pigmentosa
g. Cells can contain some mitochondria with mutant DNA and some with normal DNA. These
cells often give rise to daughter cells with a varying number of mutant and normal
mitochondria. This also occurs in the eggs of successive generations, causing some offspring
to have more mutant DNA and worse symptoms than mother had.
h. Threshold: above a certain percent of mutated mitochondria per cell, a person exhibits a
disease phenotype
i. Mammalian mitochondrial DNA (mtDNA) encodes 13 polypeptides, all of which are integral
members of the mitochondrial respiratory chain, 22 distinct tRNAs, and 2 rRNAs that are
used for mitochondrial protein synthesis.
j. Most of the copies of mtDNA are identical at birth (homoplasmy). Occasionally, a
subpopulation of mtDNA molecules carry a pathogenic mutation. Cells with a
heterogeneous population of such mtDNA molecules (heteroplasmy) can lead to a variety of
clinical symptoms predominantly affecting muscle and nerve
Why do many diseases exhibit differences in expression?
a. Penetrance : all or nothing concept
i. When some people who have the appropriate genotype fail to express the gene, the
disease has reduced penetrance
b. Expressivity: severity of expression
c. Pleiotropic: diverse but seemingly unrelated phenotypic effects
Moving on to lecture 17 – Polygenic and Multifactorial Inheritance
I.
II.
III.
Multifactorial Inheritance
a. Many diseases demonstrate familial clustering yet do not conform to any recognizable
pattern of Mendelian or single-gene inheritance
b. Both genetic and environmental factors are most likely involved in causing these disorders
c. Ex: height/stature
i. Get bell shaped
curve if you plot for
population, giving
you Gaussian
distribution
d. Bell curve works for
QUANTITATIVE TRAITS
Polygenic Inheritance and
Continuous Variation
a. Distribution of genotypes for
characteristics of height and weight with
one, two, and three loci each with two
alleles of equal frequency
b. The values for each genotype can be
obtained from the binomial expansion (p
+ q)(2n), where p = q = ½ and n is the
number of loci
c. If height were determined by two
equally frequent alleles, a (tall) and b
(short), at a single locus this would give a
discontinuous phenotype of three
groups in a ratio of 1 (tall – aa): 2
(average –ab/ba): 1(short – bb).
d. If height were determined by two alleles
at each of two loci interacting in an additive fashion, this would give a phenotypic
distribution of five groups in a ration of 1 (4 tall genes): 4 (3 tall + 1 short): 6 (2 tall + 2
short): 4 (1 tall + 3 short): 1 (4 short).
e. For a system with three alleles the phenotypic ration would be 1: 6: 15: 20: 15: 6: 1.
f. As the number of loci increases, the distribution increasingly comes to resemble a normal
(bell shaped) curve.
g. This observation supports the idea that characteristics such as height are determined by
additive effect of many genes at different loci.
Polygenic Inheritance and the Normal Distribution
a. Support for the idea that complex traits such as height, intelligence, etc. are due to the
additive effects of many genes at different loci comes from studies on familial correlations
for these traits.
b. Correlation is a statistical measure of the degree of association of variable phenomena, or,
in more simple terms, a measure of the degree of resemblance or relationship between two
parameters
IV.
V.
VI.
c. First-degree relatives share approximately 50% of their genes; therefore, one could predict
that with a trait such a height (if polygenic) the correlation between first-degree relatives
such as siblings would be 0.5.
d. However, human characteristics such as height and intelligence are also influenced by
environment as well as other genes that are not additive
e. These factors could account for the observed tendency of offspring to show what is known
as regression of the mean, i.e., tall or intelligent parents have children whose average height
or intelligence is slightly lower than the average or mid-parental value
f. Parents who are very short or of low intelligence tend to have children whose average
height or intelligence is lower than the general population average, but higher than the
average value of the parents.
Multifactorial Inheritance – the Liability/Threshold Model
a. According to this model, all of the factors that influence the development of a multifactorial
disorder – genetic or environmental – can be lumped together as a single phenomenon
known as liability
b. Liabilities of all population members
form a continuous variable. This is a
normal distribution in both the
general population and relative in the
affected population.
c. The curve is shifted to the right for
relatives and the extent of the shift
depends on relatedness.
d. It is proposes that a threshold exists
above which the abnormal phenotype
is expressed.
e. This is known as the population
incidence (for a general population) or
among relatives, a familial incidence.
Threshold inheritance examples
a. Cleft lip/palate
b. Club foot
c. Congenital heart defects
d. Hydrocephaly
e. Neural tube defects
f. Pyloric stenosis
g. Folic acid important – needed to produce nucleotides (found in green veggies, liver, grains)
h. Folic supplementation started one month before conception and continued two months
after conception is a principle preventative factor
Qualitative and Quantitative Traits (two categories of multifactorial disorders
a. Qualitative Traits – a genetic disease that is either present or absent (also referred to as
discrete traits).
i. Familial aggregation of disease
1. Diseases with complex inheritance may cluster in families
ii.
iii.
iv.
v.
vi.
vii.
2. Familial aggregation, however, does not infer that a disease must have a
genetic contribution
3. Gene mapping studies have been used to determine clear genetic
contributions
Concordance and Discordance
1. Concordance: when two related individuals in family have same disease
2. Discordance: when only one member of the pair of relatives is affected
3. Discordance can be explained by the unaffected individual not experiencing
the same environmental stimulus required to manifest the disease
4. Concordance for a phenotype can occur even when the two affected
relatives have different predisposing genotyepes – the disease in one
relative may be a “phenocopy” or “genocopy” of the disease
To measure familial aggregation in qualitative traits use lambda*r=prevalence of
disease in the relative of an affected person/prevalence of the disease in the
general population (relatives includes sibs and parents)
1. Larger lambda*r = greater familial aggregation
2. If it equals 1: that indicates that a relative is no more likely to develop the
disease than is any individual in the population
The more closely related two individuals are in a family, the more alleles they have
in common, inherited from a common ancestor
Concordance increases as relatedness increases when genes are important
contributors to disease
Twins
1. Monozygotic (identical) twins have crazy high levels of concordance
a. Arose from cleavage of single fertilized zygote
b. With sickle cell, both have it
c. With type I diabetes mellitus, only about 40% of other twins have
same disease
i. Indicates that nongenetic factors have a role in disease
2. Dizygotic twins and other first degree relatives such as parent and child or a
pair of sibs represent the next degree of relatedness
a. Arose from simultaneous fertilization of two eggs by two sperm
b. On average they share 50% of the alleles as all loci (just like normal
sibs)
3. Comparison of MZ and same sex DZ twins shows the frequency of disease
occurrence between relatives who experience the same prenatal and
possibly same postnatal environment
4. If twins separated at birth, you can observe disease concordance in
individuals raised in different environment (with identical genotypes for MZ
twins)
a. Useful for psychiatric disroders, substance abuse, eating disorders
i. Alcoholism: high concordance
Parent-Child Allele sharing
1. In a parent-child pair, the child has one allele in common with each parent
at every locus or the allele the child inherited from that parent
viii. Siblings
1. Sibs inherit the same two alleles 25% of the time, and one allele in common
50% of the time
ix. Use unrelated family member controls to separate environmental and genetic
influences
b. Quantitative traits: traits that are measurable physiological or biochemical quantities such
as height, blood pressure, serum, cholesterol, BMI.
i. See normal (Gaussian) distribution
ii. Statistical theory says only 5% of the population will have measurements more than
2 standards above or below the population mean
iii. Familial aggregation
1. Quantitative traits aren’t just present or absent like qualitative
2. Geneticists measure the correlation of a particular physiological quantity
among relatives – the tendency for the actual values of a physiological
measurement to be more similar among the relatives than the general
population
3. A positive correlation exists between the blood pressure measurements in a
group of patients and the blood pressure measurements in a group of
patients and blood pressure measurements of their relatives if it is found
that the higher a patient’s blood pressure, the higher are blood pressures of
the patients relatives.
4. A negative correlation exists when the greater the increase in the patient’s
measurements, the lower the measurement is in the patients relatives.
5. Heritability
a. Symbolized as h2
b. Developed to quantify the role of genetic differences in determining
variability of quantitative traits.
c. Defined as the fraction of the total phenotypic variance of a
quantitative trait that is caused by genes and is therefore a measure
of the extent to which different alleles at various loci are
responsible for the variability in a given quantitative trait seen
across a population
d. The higher the heritability, the greater is the contribution of genetic
differences among people in causing variability of the trait
e. The value of h2 varies from 0, if the genes contribute nothing to
total phenotypic variance, to 1, if genes are totally responsible for
the phenotypic variance.
6. Estimating Heritability from twin studies
a. The variance in the values of a physiological measurement made in
a set of twins (who share 100% of their genes) is compared with the
variance in the values of that measurment made in a set of DZ twins
(who share 50% of their genes).
b. The formula of calculating h2 is
h2 = Variance in DZ pairs – Variance in MZ pairs/Variance in DZ pairs.
VII.
c. If the variability of the trait is determined chiefly by environment,
the variance within pairs of DZ twins will be similar to that seen
within pairs of MZ twins and the numerator and h2 will approach 0.
d. If variability is determined exclusively by genetic makeup, the
variance of the MZ pairs is 0 and h2 is 1.
Specific examples of congenital malformations and complex diseases
a. Alzheimer’s Disease
i. Age, gender, and family history are most significant risk factors
ii. Once a person reaches 65 years of age, the risk for any dementia and AD
specificially, increases substantially with age and female sex
iii. Molecular testing for ApoE genptypes
1. Apolipoproteins distribute fats and cholesterol
2. ApoE is the primary type of apolipoprotein made in the brain
3. The risk of AD increases with apoE4 (one or two copies with LOAD)
a. Association is greatest when there is a positive family history of
dementia
b. 42% of individuals with this gene have no APO e4 allele
iv. In addition to three rare autosomal dominant forms of the disease where onset is in
the 3rd to 4th decade, there is a late onset form after the age of 60
v. This has no obvious mendelian inheritance pattern but does show familial
aggregation
vi. Genome-Wide Association Studies (GWAS) are used for complex disorders
1. Allows assessment of thousands of genetic variants without any prior
assumption on biological pathways
2. Have identified CLU or clusterin(aka apolipoprotein gene) as the first
consistent AD risk gene since APOE e4 allele
3. A study has identified SNPs in the GRB-Associated binding protein (GAB2
gene) as an independent risk factor modifying the APOE e4 allele risk in
LOAD.(
b. Type I Diabetes
i. MHC haplotype accounts for some of the genetic contribution
ii. Other genes predispose to development of disease
c. Multifactorial Congenital Malformations (Neural Tube defects)
i. Anencephaly and spina bifida are neural tube defects that frequently occur together
in families are considered to have a common pathogenesis
ii. Anencephaly: the forebrain, overlying meninges, vault of the skull and skin are
absent
iii. In spina bifida, there is a failure of fusion of the arches of the vertebrae
iv. The exact causes of these malformations are unknown, but there is a famililal
aggregation suggesting polygenic inheritance