Transcript Inheritance - askmrspierce

Unit 2: Inheritance
6 days
August 28:
Inheritance
• 4 main types of inheritance patterns:
– Recessive
– Dominant
– X-linked
– Mitochondrial
Inheritance
• Single genes traits caused by mutations
are often called Mendelian
• They occur in predictable proportions
• More than 3,917 diseases follow this
pattern
• 84% are know the be caused by mutations
is 1,990 different genes
Inheritance
• Different mutations in a single gene can
cause different diseases
• The remaining 16% are obviously
Mendelian in inheritance patterns – but the
mutant gene responsible is unknown
Inheritance
• Most of these disorders are pediatric in
onset
• About 10% manifest after puberty
• About 1% manifest after the reproductive
period
Inheritance
• In 1,000,000 live births the incidence of
single gene disorders is estimated to be
0.36%
• Of all hospitalized children it is estimated
that 6% to 8% have single gene disorders
Pedigrees
Inheritance
• Important things to consider with
mutations…
– Is the allele dominant?
– Is it located on an autosome?
Inheritance
• X-linked inheritance applies to all genes
on the X chromosome, that are unable to
recombine with genes on the Y
chromosome
• Those that can show autosomal patterns
of inheritance
Inheritance
• Autosomal disorders affect males and
female equally
• X-linked disorders tend to affect male at a
higher frequency because they are
hemizygous
• Typically female cells only express one of
the two X’s genes
Inheritance
• Recessive phenotypes are only expressed
in homozygous individuals or male
hemizygotes
• Most of these disorders are mutations that
cause the loss of function of an enzyme
• This is because if an individual has one
good copy, it can still make enough
enzyme for normal physiologic functioning
Inheritance
• Alternatively, dominant disorders are
expressed in any individual with the
mutation
• Pure dominant = both heterozygotes and
homozygotes are affected equally
– Rare in medical genetics
Inheritance
• Codominance = multiple alleles are
expressed at the same time
• Incomplete dominance = blending of the
two alleles, heterozygotes are ‘in the
middle’ pheontypically
– More common in medical diseases
– Homozygotes have worse effect
Inheritance
• More correctly, the inheritance of the
phenotype is ‘dominant’ or ‘recessive’ –
not the allele itself
Expression
• Some disorders can manifest themselves
differently based on age, other genetics,
environmental factors, etc.
• Sometimes it affects family members the
same
• At others it may have extremely varied
clinical severity
Expression
• Penetrance = the probability that a gene
will have phenotypic expression
• This means that if the penetrance is less
than 100%, some people may have the
genotype, and show no phenotypic
indications
• This is called reduced penetrance
Expression
• Expressivity = the severity of expression of
the phenotype among individuals with the
same genotype
• When the expression severity differs it is
called variable expressivity
Neurofibromatosis
• NF1 is a common disorder
• In 1 per 3,500 births
• Disorder of the nervous system, eye and
skin
Neurofibromatosis
• Characterized by growth of benign tumors,
skin pigmentation spots, or tumors in the
iris
• More rarely can include mental
retardation, CNS tumors, and cancer of
the nervous or muscular systems
Neurofibromatosis
• Adult heterozygotes almost always exhibit
some sign of the disease
– (penetrance =100%)
• Extremely variable expressivity
– Café au lait spots
– Benign tumors of the CNS
– Malignant sarcomas
Neurofibromatosis
• Even within a kindred some individuals are
affected severely and others are not
• Penetrance also appears to be age
dependent
Neurofibromatosis
• About half of the cases come from NEW
mutations, as opposed to inherited ones
• Potential to pass the disease on is 50%
• Can be detected presymptomatically or
even prenatally
Neurofibromatosis
Split-Hand Deformity
• Ectrodactyly
• Originates in the 6th or 7th week of
development
• Failure of penetrance can lead to ‘skipping’
of generations
• Makes genetic counseling difficult
• Approximately 70% penetrance
Split-Hand Deformity
Age at Onset
• Genetic Disorders:
– Can occur at any time
– Some may be lethal prenatally
– Some can be recognized prenatally
– Some only recognized at birth (congenitally)
– Sometimes an affected individual may not
appear to have relatives with the disorder,
because they died before expressing it, or are
not yet showing signs
August 29:
• One major job of medical genetics is to
identify which genotypes are responsible
for specific phenotypes
• Genetic heterogeneity = multiple
phenotypes that appear to be closely
related
• Can be caused by:
– Allelic heterogeneity = different mutations at
the same locus
– Locus heterogeneity = mutations at different
locus
Allelic Heterogeneity
• Many loci have several different mutations
that can occur
– i.e. a cystic fibrosis transmembrane
conductance regulator has more than 1,400
identified mutations
• Sometimes different mutations cannot be
identified by phenotype
• Other time different mutations means
different symptoms
• Homozygosity of a specific mutant allele is
typically uncommon
• Exceptions include:
– Consanguinity
– Specific ethnic groups in which the majority of
a disease is caused by the same mutant allele
– When there is only 1 mutant/disease causing
allele
Autosomal Patterns of Inheritance
• For recessive diseases there are 3 types
of mating that can result in affected
offspring:
– Rr x rr – carrier by affected
– Rr x Rr – carrier by carrier
– rr x rr – affected by affected
– Probabilities?
Hemochromatosis
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More common in males
Autosomal recessive
0.5% of Northern Europeans
Disorder of iron metabolism
– Excessive body stores
– Can lead to iron overload
– Damages liver, heart, and pancreas
• Female incidence is a fifth to a tenth
– Low iron intake
– Less alcohol intake
– Loss of iron through menstruation
Hemochromatosis
Gene and Carrier Frequency
• Mutant alleles for recessive disorders are
generally rare
• Inherited through both parents
• Disease phenotype extremely rare
Cystic Fibrosis
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Most common in white children
Mutation of CFTR gene
Virtually absent in Asian populations
Relatively rare in African populations
• 1:2000 white children with disease
– (have two mutant copies)
• 1:29 are carriers
Cystic Fibrosis
• This means only 2% of the mutant alleles
are apparent
• 98% are hidden in carriers
Consanguinity
• A big problem for mutant recessive alleles
• Estimated that every person carries 8 to
10 mutant alleles
– About half lethal before birth when
homozygous
– Other half cause well-known disorders
Consanguinity
• Defined as the mating of two individuals
who are related to each other as close or
closer than the second cousin level
Consanguinity
• For matings between first cousins the
genetic risk to offspring is about double
that of non-related couples
– 3% to 5% as opposed to 2% to 3%
Consanguinity
• Relatively rare (1 to 10 per 1,000) in
Western societies
• Fairly common in parts of India, Asia, and
the Middle East (20% to 60% between first
cousins)
Consanguinity
• Some diseases are caused by alleles
which are so prevalent in the population
that consanguinity is rarely the cause
• In extremely rare disorders, however, often
the affected patients are consanguineous
Inbreeding
• Individuals from a small population tend to
pick mates from within their small
population
• Can be for cultural, geographical, or
religious reasons
September 3:
Incomplete Dominance
• Achondroplasia
– Homozygotes are more extreme in symptom
manifestation
– Often do not survive postnatal period
• Familial hypercholesterolemia
– Leads to premature coronary disorder
• Can be inherited from a parent or arise
due to spontaneous mutation
• New mutation’s survival in the population
depends on how they affect the patient’s
fitness
• One extreme have a fitness of zero –
referred to as genetically lethal
– Must be due to new mutations when dominant
• Other extreme are disorders that manifest
themselves later in life or have no major
affect on fitness
Sex-Limited Phenotype
• Extreme divergence of the 1:1 sex ratio
• Autosomally transmitted, but seen only in
one gender
– Male-limited precocious puberty
• Autosomal dominant
• Develop secondary sex characteristics at around 4
years old
• No effect in heterozygous females
• Not X linked (can pass from father to son)
• Normal fertility
X-linked Inheritance
• About 1,100 genes on the X chromosome
• ~40% know to be associated with various
diseases
• Only 2 possible genotypes in males, and 3
in females
• A male with a mutant allele at an X linked
locus is hemizygous
• Male:
– Hemizygous – affected
– Hemizygous – unaffected
• Female:
– Homozygous – unaffected
– Heterozygous – unaffected (usually)
– Homozygous – affected
X inactivation
• Process in which one X is mostly
inactivated
• This equalizes the expression of most X
linked genes in both sexes
• Different cells in a female’s body may have
different X’s active
• This leads to mosaicism
• This means that two different females with
the same disorder may have very different
clinical presentations
• Depends on which cells are affected
• X-linked ‘dominant’ versus ‘recessive’ are
determined in heterozygous females
• Not easily decoded due to random X
inactivation
• Some geneticists have proposed removing
these terms altogether for X linked
disorders
X-Linked Recessive
• Follows a wel defined pattern
• Expressed phenotypically in all male
carriers
• Only expressed in homozygous females
• Generally restricted to males – rare among
females
• Hemophilia A
– Known since ancient times
– Called ‘royal hemophilia’
– Descendants of Queen Victoria (carrier)
• When a father has Hemophilia A
– Daughters tend to be obligate carriers
– Sons are unaffected
• X-Linked color blindness
– Unusual in females
– More common when parents are
consanguineous
• When a heterozygous female does
express phenotypic traits of a recessive Xlinked trait she is called a Manifesting
Heterozygote
X-Linked Dominant
• Considered dominant if it is regularly
expressed in heterozygotes
• Lack of male-to-male transmission
• In affected males:
– ALL daughters will be affected, but NO sons
will be affected
• In affected females:
– Pattern is the same as autosomal dominant
inheritance
Male Lethality
• Some X-linked disorders are lethal in
males
• Transmission by affected females who
produce affected females, normal females,
and normal males in equal proportions
(1:1:1)
Rett Syndrome
• Seen almost exclusively in females
• Meets criteria for X-linked dominant with
male lethality
• Rapid onset of neurological symptoms
between 6 and 18 months
• Become spastic, develop autustic
features, irritable behavior, outbursts of
crying, flapping movements of arms and
hands
Rett Syndrome
• Some instances of phenotypically normal
women having multiple daughters with
Rett
– Skewed mosaicism
– Germline mosaicism
Pseudoautosomal Inheritance
• Genes in the pseudoautosomal regions of
the X and Y
• Can change between the two sex
chromosomes
• Follow patterns of X linked disease, with
the occasional father to son transmission
Mosaicism
• Presence of two cell lines that originated
from the same zygote
– Can result from X inactivation
– Can result from mutations in somatic cells
during lifetime
• Can be:
– Pure somatic mosaicism
– Pure germline mosaicism
– Can affect partial germlines
• About 30 mitotic divisions in female’s germ
cells before meiosis
• Several hundred in males
Osteogenesis Imperfecta
• Germline mosaicism documented in
around 6%
• Abnormal collagen, brittle bones, frequent
fractures
Mutations in the Mitochondrial
Genome
• Some disorders are now known to stem
from mutations in the mitochondrial DNA
• Maternal inheritance
September 9:
Common Disorders,
with Complex Inheritance
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Congenital birth defects
Myocardial infarction
Cancer
Mental illness
Diabetes
Alzheimer Disease
• Morbidity or mortality of 2/3’s of population
• Does not follow mendelian patterns of
inheritance
• Not single gene disorders
• Rather, complex interaction of several
genetic and environmental factors
• Called Multifactorial (or Complex)
inheritance pattern
• Gene-gene interactions
• Gene-environment interactions
– Both run in families
• We do not completely understand all of the
components involved in the transmission
and manifestation of these disorders
• Physicians rely on empirically derived risk
figures
Qualitative vs. Quantitative
• Qualitative = you have it or you don’t
• Quantitative = depends on you specific
numbers/measurements
Familial Aggregation
• Can be genetic
• Confounding factors
• When two family members both have a
disease they are considered concordant
• When one member has a disease that
another does not they are considered
discordant
Relative Risk
• Relative risk ratio = λr
• Prevalence of the disease in the relatives
of the affected person / Prevalence of the
disease in the general population
λr Values
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Schizophrenia
Autism
Bipolar Disorder
Type 1 Diabetes
Crohn’s Disease
Multiple Sclerosis
12
150
7
35
25
24
Case-Control Studies
• Compare two individuals, one affected and
one not affected
• Goal is to have all environmental
conditions the same
• Can have confounding variables
– i.e. ethnicity and diet
Twin Studies
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Monozygotic (MZ) twins
Dizygotic (DZ) twins
Siblings
Parents
Controls (unrelated individuals)
Twin Studies
• Concordance in MZ twins
• Discordance in MZ twins
• Twins reared apart
Issues to Consider
• Limitations on studies of twins once
adulthood is reached
– Often environments differ more dramatically
as adults
• Female MZ twin X-inactivation
• Can only be an average if genes are just
predisposing for disease
Quantitative Traits
• Involve measurable physiologic quanities:
– Blood pressure
– Serum cholesterol concentration
– Body mass index
• Both genetic and environmental factors
Normal Distribution
• Most of these quantitative factors follow a
normal bell (gaussian) distribution
• Must consider the mean (peak) and the
variance (standard deviation)
Normal Range
• Within 2 standard deviations from the
mean for a given trait
• Only 5% will fall outside this range
Statistical Analysis
• Geneticists measure correlation of
different factors
– Positive correlation
– Negative correlation
• i.e. parent height vs. child height
Heritability
• The fraction of the total phenotypic
variance of a quantitative trait that is
caused by genes
• A measure of the extent to which different
alleles at various loci are responsible for
the variability in a given quantitative trait
seen across the population
Examples of Diseases
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Venous Thrombosis
Hirschprung Disease
Type 1 Diabetes
Alzheimer
Anencephaly
Spina Bifida
Cleft Lip and Palate
Congenital Heart Defects
Schizophrenia
Bipolar Disorder
Coronary Artery Disease
September 12:
• Any change in the nucleotide sequence or
arrangement of DNA
• 3 main categories:
– Chromosome number (genome mutations)
– Chromosome structure alterations
(chromosome mutations)
– Individual gene alterations (gene mutations)
Genome Mutations
• Alterations in the number of intact
chromosomes arising from errors in
chromosome segregation during meiosis
or mitosis
• Called aneuploidy
Origin
• Missegregation responsible for aneuploidy
• Most common type of mutations in
humans
• One event per 25 to 50 meiotic cell
divisions
• Probably a low estimate since many are
spontaneously aborted before detection
• Frequently seen in cancer cells
Chromosome Mutations
• Changes involving only a part of a
chromosome
• Partial duplications or triplications
• Deletions
• Inversions
• Translocations
• Can be spontaneuos
Origin
• Approximately one rearrangement per
1,700 cell divisions
• Less frequent than genome mutations
• Rarely passed on to subsequent
generations
• Rarely viable
• Frequently seen on cancer cells
Gene Mutations
• Changes in DNA sequence of the nuclear
or mitochondrial genome
• A single nucleotide to several million base
pairs
Origin
• Either error during process of replication or
failure to repair DNA post-damage
• Some are spontaneous
• Some caused by mutagens
• Not all mutations have clinical
consequences
• May not alter the amino acid sequence
• May not alter the functioning of a protein
• May be in nonsense regions
• The majority of replication errors are
rapidly removed from the DNA and
corrected by a series of repair enzymes
• First identify the errors, then replaces
them with correct base
• Called proof reading
• And incorrect nucleotide is introduced only
once every 10 million base pairs
• Replication error checking corrects more
than 99.9% of errors
• Totals to less than 1 new base pair
mutation per cell division
Consequences of Different
Mutations
• Types:
– Nucleotide substitutions
– Deletions and insertions
– Dynamic mutations
Nucleotide Substitutions
• Missense or Point Mutations
– Alter the sense of the code by altering an
amino acid in the protein
Nucleotide Substitutions
• Chain termination mutations:
– Cause the replacement of an amino acid in a
protein chain with a STOP codon
– Called nonsense mutations
– Often the truncated mRNA is unstable and is
not translated
– Does not make a functional protein
Nucleotide Substitutions
• RNA processing mutations:
– Problems with splicing out introns
– Problems with capping
– Problems with poly-A tail
Nucleotide Substitutions
• Hotspots of mutation:
– Mutations that are caused by one purine
being substituted for the other or one
pyrimidine being substituted by the other are
called transitions
– The replacement of a purine with a pyrimidine
or vice versa is called a transversion
– Most commonly occur at CG doublet (more
than 30% of single nucleotide substitutions)
Deletions and Insertions
• Small deletions and insertions:
– When the error is not a multiple of three it
causes a change in the amino acids of that
coding section
• Called a frameshift mutation
– If the error is a multiple of three no framshift
occurs
Deletions and Insertions
• Large deletions and insertions:
– Relatively uncommon
– Often a result of reverse transcription, and
incorporates segments of processed mRNA
being returned to the genome as DNA
Deletions and Insertions
• Effects of recombination:
– Can occur between two chromatids during
meiosis or mitosis, and typically the result of
similar genes lined up being mispaired
– Called unequal crossing over
– Leads to gene duplication or deletion
– An example of this is in hemophilia A where
several exons are inverted and gene structure
is disrupted
Dynamic Mutations
• A repeat in the coding region of a gene,
which is expanded during gametogenesis
• Generates abnormal protein product
• It is thought that during replication the
growing strand ‘slips’ and loses its place
• It then start over in the wrong location
Mutation Rates by Sex
• Nondisjunction more typical in females
– 80% to 100% of trisomy 13, 18, 21, and X are
from the maternal line
– Due to the oocytes staying suspended in
meiosis I for years or even decades
• Depending on male’s age 1 in 10 to 1 in 3
sperm have a new deleterious mutation
somewhere
September 16:
Genetic Variation in Populations
• Population genetics is the quantitative
study of the distribution of genetic variation
and of how the frequencies of genes and
genotypes are maintained or change
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Mutation
Reproduction
Selection
Migration
• Frequency of alleles and genotypes in
families and communities
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Anthropology
Evolutionary biology
Human genetics
Medicine
CCR5
• Encodes for a cell surface cytokine
receptor
• Entry point for HIV
• A 32 base pair deletion causes this
receptor to not be expressed
• No entry point for virus
• Resistant to HIV
CCR5
• Benign trait
• Only know consequence is resistance to
HIV
• Easily observable with PCR
CCR5
• In a sample of 788 individuals from Europe we
can look at a gene pool
– Each homozygote has 2 copies of the allele, and
each heterozygote has 1 copy
Normal CCR5 allele:
((2x647) + (1x134)) / (788x2) = 0.906
Mutant ΔCCR5 allele:
((2x7) + (1x134)) / (788x2) = 0.094
The Hardy-Weinberg Law
• Required Assumptions:
– The population is large and matings are
random
– Allele frequencies remain constant over time
because
• There is no appreciable rate of mutation
• All genotypes are equally capable of mating and
passing on their genes
• There has been no significant immigration from
populations with allele frequencies dramatically
different from the endogenous population
The Hardy-Weinberg Law
• Simple mathematical relationship for
calculating genotype frequencies from
allele frequencies
• Named for Geoffrey Hardy
– English mathematician
• Wilhelm Weinberg
– German physician
• Independently formulated it in 1908
The Hardy-Weinberg Law
• First critical component:
– Under certain ideal conditions a simple
relationship exists between allele frequencies
and genotype frequencies in a population
• p is the frequency of allele A
• q is the frequency of allele a
The Hardy-Weinberg Law
• The chance of AA is p2
• The chance of aa is q2
• The chance of Aa is 2pq
• The frequency of all three genotypes is
expressed by:
(p+q)2 = p2 + 2pq + q2
The Hardy-Weinberg Law
• The second component of the HardyWeinberg Law is:
– If allele frequencies do not change from
generation to generation then genotype
frequencies will not change either
– This means the system will reach and
equilibrium
The Hardy-Weinberg Law
• Simple binomial distribution
• p+q=1
• Good for genetic counseling for autosomal
recessive disorders
The Hardy-Weinberg Law
• Stratification
– A population in which a number of subgroups
have remained relatively genetically
separated during modern times
– U.S. subgroups include white, black,
Hispanic, and native American
• i.e. sickle cell disease
The Hardy-Weinberg Law
• Assortative mating
– Choice of mate based on a particular trait
– People tend to chose mates who resemble
themselves
• Native language, intelligence, stature, skin color,
musical talent, athletic ability
– Extends to medical issues
The Hardy-Weinberg Law
• Consanguinity and inbreeding
– Applies to rare disorders
– Genetic isolates
– Ashkenazi Jews in North America
• Mutant allele for Tay-Sachs Disease
• 100 times higher than in other populations
Exceptions to Constant Allele
Frequency
• Genetic Drift in small populations
– Random
– Survival of a carrier
• Mutation and Selection
– Dominant and X-linked
– Fitness of allele
– Miscarriages
Exceptions to Constant Allele
Frequency
• Migration and gene Flow
– Slow diffusion of genes across a barrier
– Migrant population are gradually assimilated
– i.e. CCR5 gene is ~10% in white European, a
few % in the Middles East and India, and
virtually 0% in Africa and the Far East
• Originated in white Europeans, and slowly is
spreading
Founder Effect
• When a small subpopulation breaks off from a
larger population the gene frequencies of the
small population may be different due to random
sampling
– Lake Maracaibo Venezuela – Huntington disease
– Old Order Amish – short-limbed dwarfish, polydactyly,
abnormal nails and teeth, congenital heart defects
– Lac Saint Jean Quebec – hepatic failure and renal
tubular dysfunction
– Finland – choroideremia and gyrate atrophy
(degenerative eye issues)
Heterozygote Advantage
• Malaria and sickle cell disease