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Patterns of inheritance
Mendel’s rules apply to humans
What is the molecular basis for recessive mutant phenotypes?
Why are deleterious alleles maintained in populations?
What are haplotypes and how are they analyzed?
How are pedigrees used to distinguish modes of inheritance?
Mendel established that
some phenotypes were
dominant over others
What was the cause?
A molecular understanding
develops over 150 years
We now understand that genes encode
proteins which are responsible for
phenotypes
Plants with wrinkled seeds have a
disruption in a gene involved in starch
synthesis, so they are unable to absorb
normal amounts of water
Bhattachararyya, MK et al. (1990) Cell
60: 115.
Short plants have a missense (G to A)
mutation in gene for growth-stimulating
hormone (gibberellin oxidase)
Causes an alanine to threonine substitution
Lester et al. (1997) Plant Cell 9:1435
Normal peas turn yellow as chlorophyll breaks
down during ripening
The enzyme responsible for
this step in chlorophyll
breakdown is nonfunctional in
the staygreen mutant
Armstead et al. (2007) Science 315: 73.
seed coats are gray
seed coats are white
Transcription factor involved in turning on genes that synthesize
anthrocyanin (purple pigment)
Missense mutation changes G to A
Hellens et al. (2010) PLOS One
DOI: 10.1371
Humans have ~22,000 protein coding genes
Single gene mutations account for 1000-2000 diseases
Phenotype
Dominant
eye color
brown
hair color
brown
Recessive
Other
complex
red, blond
complex
Reynault’s
color blindness
Y (on X)
hemophilia
Y (on X)
autism
complex
Tay Sachs
Y
sickle cell anemia
Y
Huntington’s Dis.
Y
cancer disposition
Y
albino
Y
alopecia
rolling tongue
Y
Y
more than one gene causes it
rollers are dominant
Archibald Garrod
Realizes that inheritance of a
recessive human disease is consistent
with Mendel’s laws from following the
disease in families
English physician
1909 - publishes Inborn Errors of
Metabolism
Alkaptonuria has a dramatic phenotype!
Urine turns black when exposed to air
Caused by high levels of homogentisic
acid
Garrod realizes that patients lack an
enzyme that metabolizes “alkaptans”
(homogentisic acid)
Excess of homogentisic acid in connective tissues leads to arthritic
symptoms during the third or fourth decades of life
Symptoms are aggravated when kidneys malfunction
Garrod’s insight:
Alkaptonuria inheritance shows the pattern expected for a recessive
Mendelian trait
Observes:
Condition can be latent for several generations
Condition more common in first-cousin marriages
In families with 5 or more children, in which one child is affected,
the ratio of affected (19) to unaffected children (57) is ~3:1
What is the molecular basis for recessive mutant phenotypes?
Why are deleterious alleles maintained in populations?
What are haplotypes and how are they analyzed?
How are pedigrees used to distinguish modes of inheritance?
Alleles are alternative forms of a gene
New alleles arise by mutation
Passed down from the founder to subsequent generations
Hemoglobin is one of the best-studied molecules
Mutations in hemoglobin genes cause various anemias
Hemoglobin represents 98% of
the protein in red blood cells, the
major cell type in blood
The human β-globin gene has 444 nucleotides, encoding a
protein with 147 amino acids. How many DIFFERENT alleles
of β-globin are possible?
A.147
B.444
C.~1600
D.More than 1600
Hemoglobin
Hundreds of variants have been described
Common variants within a
population (generally little
effect on function) polymorphisms
Most severe effects
involve altered amino acids
on the surface or those
that affect iron binding
Sickle cell anemia: first “molecular disease”
Light microscope
Electron microscope
Hemoglobin fibers form under deoxygenated conditions in both
homozygotes (2 sec) and heterozygotes (70 sec)
A single nucleotide substitution
converts a codon for glutamic
acid to valine
GAG
GTG
Hydrophilic
Hydrophobic
Sickle cell anemia animation
Sickle cell allele is common in malaria-prone regions
Heterozygotes (carriers) are more resistant to malaria
Six different sickle cell
founder mutations have
been identified by 2005
The six founder mutations
occur in different
haplotypes - “chromosome
neighborhoods”
Balancing selection can increase the prevalence of deleterious mutations
Heterozygotes have a selective advantage under certain stresses
What is the molecular basis for recessive mutant phenotypes?
Why are deleterious alleles maintained in populations?
What are haplotypes and how are they analyzed?
How are pedigrees used to distinguish modes of inheritance?
Haplotypes arise from human variability
DNA sequences of 2 humans vary at each ~1200 bp
SNP: single nucleotide polymorphism
site where individuals differ by a single base pair
used as markers for human chromosomes
Sets of linked SNPs are used to identify particular haplotypes
Founder mutations from different parts of the world occur in
distinct haplotypes
A chromosome can be thought of as a group of physically- linked
haplotypes
Haplotype A
Haplotype B
Haplotype AA
Haplotype BB
Haplotype C
Haplotype D
Haplotype CC
Haplotype DD
Over time, crossovers will produce new haplotypes as well as new combinations
of haplotypes
Portion of the
founder’s haplotype
surrounding the
mutation gets smaller
in each generation due
to crossovers in
meiosis
Founder effects are common in small populations:
Particular allele becomes prevalent in a population
18,000 Amish in Pennsylvania are descended
from 200 individuals emigrating from
Switzerland in 1720
At least 80 genetic defects at high
frequency in population
Because portions of haplotypes are shared in inbred populations,
they are useful for identifying causes of inherited diseases
Gene (triangle) responsible for a trait is
linked to SNP markers on ancestral
chromosome (original haplotype)
Recombination over generations
produces new haplotypes in a population
Researchers look for haplotypes that
remain linked to the trait
What is the molecular basis for recessive mutant phenotypes?
Why are deleterious alleles maintained in populations?
What are haplotypes and how are they analyzed?
How are pedigrees used to distinguish modes of inheritance?
Inheritance of autosomal recessive traits
Males and females can show the trait
Males and females can pass on the trait
Trait can skip generations
Parents of an affected individual may or may
not show the trait
Heterozygotes “carry” the trait - aka “carriers”
Carriers must be inferred if only symptoms are used, but can be
identified with molecular analyses such as DNA
Newborns are commonly tested for some recessive metabolic diseases
parents are frequently not aware that they carry a disease allele
States have various
regulations for testing
Phenylketonuria
Congenital hypothroidism
Biotinidase deficiency
Maple syrup urine disease
Galactosemia
Homocystinuria
Sickle cell anemia
Medium chain acyl-CoA dehydrogenase
deficiency (MCAD)
Early detection of a metabolic disease can prevent some
complications
Phenylketonuria is a a recessive condition caused by a deficiency
of phenylalanine hydroxylase
Excess phenylalanine is converted
to metabolites that interfere with
myelin formation, leading to mental
retardation
2 sisters with phenylketonuria
Low phenylalanine diet can prevent many of the symptoms
Most genetic diseases in humans are caused by recessive alleles.
Some are fairly prominent in the population.
Cystic fibrosis
5% US Population carries the gene affects ~1/2500 births
Most prominent
symptom is mucus
accumulation in the lungs
Also have salty sweat
Other organs also affected
Cystic fibrosis gene encodes an ion
transporter in cell membranes
Most common mutation is a 3-nucleotide
deletion of a phenylalanine codon
Some irony!
The transporter actually
works, but cells find it
abnormal and degrade it
What are the odds that two individuals carrying a
cystic fibrosis allele will have a child with cystic
fibrosis?
A. 1/4
B. 1/2
C. 2/3
D. 3/4
What are the odds that two individuals carrying a
cystic fibrosis allele will have a child who carries
the cystic fibrosis allele?
A. 1/4
B. 1/2
C. 2/3
D. 3/4
Tay-Sachs Disease
Bernard Sachs noted high frequency of
disease in Ashkenazi Jews
1/250 US citizens carries a mutant allele
1/27 in Ashkenazi Jewish and Cajun
populations (different alleles)
British ophthalmologist
Warren Tay described
cherry-red spot on
retina of affected
children (1881)
Loss of a metabolic
enzyme causes toxic
build-up of lipids
A healthy child is born to two parents, each of whom
carries the Tays Sach allele. What is the
probability that the child carries the Tay Sachs
allele?
A. 1/4
B. 1/2
C. 2/3
D. 3/4
Consanguineous matings increase the
odds of recessive alleles appearing in
the phenotype (recessive homozygotes)
Another royal pedigree shows
considerable inbreeding
From a genetic standpoint, this
is not good!
Autosomal dominant traits are detected in the
phenotype
Males and females can show the trait
Males and females pass on the trait
with equal frequencies
Trait appears in every generation
Far fewer autosomal dominant than autosomal recessive medical conditions
have been described
Effects are serious in heterozygotes, may be fatal in homozygotes
Proteins produced from the genes don’t work well with other
proteins in the cell
Achondroplasia
Affects 1/15-40,000
Defect of a growth factor receptor
Huntington’s Disease
Neurodegenerative disease
characterized by loss of motor
control and dementia
Caused by a dominant gene whose symptoms appear
in adults and increase with age
Disease shows anticipation: symptoms occur earlier
in each generation
Woody Guthrie
Gene was identified using a large pedigree
of a population near Lake Maracaibo,
Venezuela by haplotype analysis
Inheritance traced to a single ancestor –
Founder mutation helped to identify the
gene
Co-dominance: Both alleles can be apparent in the phenotype
RBCs carry antigens on their surfaces immune cells recognize and destroy cells
with foreign antigens
ABO antigens are produced by 3 different
alleles of one gene
Karl
Landsteiner
1930 - Nobel Prize in Physiology or Medicine
“for his discovery of human blood groups”
Transfusion with the wrong blood type can be fatal
Compatibility can be tested by mixing blood (clumps are BAD!!)
A
B
potential
transfusion type
AB
O
AB
B
A
patient blood type
O
O allele is recessive to
both A and B alleles
A and B alleles are
codominant
A woman with B type blood marries and man with A
type blood. Which of the following blood types
could they expect in their children?
A. Type A
B. Type B
C. Type AB
D. Type O
E. All types are possible
Carriers are identified by hatch marks
Affected individuals are shown by filled symbols
The pedigree above is consistent with:
A. Autosomal dominant inheritance
B. Autosomal recessive inheritance
C. Sex-linked inheritance
D. None of the above
Affected individuals are shown by filled symbols
The pedigree above is consistent with:
A. Autosomal dominant inheritance
B. Autosomal recessive inheritance
C. Sex-linked inheritance
D. None of the above
Pedigrees for sex-linked traits show different patterns of
transmission in males and females
Traits on the X chromosome that are recessive in females
are dominant in males
X-linked recessive traits are:
• expressed in males
• observed more frequently in
males
• expressed in female homozygotes
with affected fathers
• passed from mothers to sons
can infer this female is
heterozygous
Because males have a single X chromosome, diseases associated
with recessive mutations are apparent in the phenotype
Consequently, more traits have been mapped to the X than to any
other chromosome
red-green colorblindness
hemophilia - factor VIII
muscular dystrophy - dystrophin
Hemophilia allele originated with Queen
Victoria and spread through royal houses