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Transcript
Complex Traits
Intro
•
•
Many traits (over 6000 in humans) are
inherited in a simple Mendelian fashion:
autosomal or sex-linked, dominant or
recessive. These patterns are fairly easy to
see when pedigrees are examined.
However, there are also a large number of
traits that don’t easily fit the Mendelian
patterns. We can call them “multifactorial”.
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•
•
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strong environmental effects affect expression
oligogenic: several genes interact to give the
mutant phenotype
polygenic: many genes, each with a small
effect
Some are for important physical diseases:
diabetes, multiple sclerosis, etc. Other
complex traits are more behavioral:
schizophrenia for example.
Some multifactorial traits are quantitative in
nature: height, for example.
Others have only two basic states, normal
and diseased, but there is an underlying
distribution of contributing factors: a
threshold trait.
More Intro
•
Locating genes responsible for these traits has been much less
successful than mapping Mendelian traits.
–
sometimes it is hard to get good diagnostic criteria for a diseases, especially
for psychological conditions. The Diagnostic and Statistical Manual of Mental
Disorders, version 4, issued in 1993 (DSM IV) is the standard list of
diagnostic criteria, but applying it to real cases is still a matter of subjective
judgment.
What we perceive as a single disease may have multiple genetic causes
Also: multiple alleles may cause identification problems.
–
–
•
General approach:
1.
2.
3.
4.
determine whether there is good evidence for a significant genetic component
to the trait, using recurrence risk, twin studies, and adoption studies.
attempt to find general features of the mode f inheritance and degree of
environmental effect by segregation analysis.
attempt to locate chromosome segments of interest by non-parametric linkage
analysis methods such as affected sib pairs and linkage disequilibrium.
Identify and clone the responsible genes.
Heritability
•
Complex traits usually have an environmental component as well as a
genetic component to their causes.
– Phenotype is due to a combination of genetics and environment.
•
•
•
•
To separate these components, we examine the variation in a trait, as
measured by the variance
– total variance = sum of variance due to genetics + variance due to environment +
covariance
– VT = VG + VE + 2Cov (G,E)
in a family, genetic variance is less because genes are shared. MZ twins
have VG = 0. So, studies seeking to isolate genetic influences use families
to isolate VG vs. VE.
H = VG / VT heritability of a trait. Unfortunately it doesn't account for
dominance or for co-variance. i.e. intelligent parents provide an enriched
environment for their children, which boosts IQ score
VG = VA + VD Dominance variance due to interactions between alleles, not
passed to any offspring. Additive variance is individual effect of alleles,
which is passed to offspring.
– h = VA / VT Narrow sense heritability. Used in breeding, smaller than H, more
realistic, but not used much in humans
Runs in the Family
•
•
•
The first question of importance:
how do we know a complex trait has
a genetic component?
Recurrence risk: the chance of a
person with an affected sibling (or
other relative) getting the disease as
compared to the chance for a
random person getting the disease.
Symbolized by λ. λS for siblings; λR
for relatives in general.
Recurrence risk depends on degree
of relationship:
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–
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•
1st degree: DZ twins, siblings,
parent/child. Share 50% of genes
2nd degree: uncle/nephew,
grandparent/grandchild: share 25%
of genes
3rd degree: first cousins: share
12.5% of genes
Recurrence risks are determined
strictly from observed data: they do
not involve any knowledge of the
underling genetics at all. Sometimes
called “empiric risk” for this reason.
Recurrence Risk for Multiple Sclerosis
Twin Studies
•
As pointed out by Darwin’s cousin Francis Galton,
monozygotic (MZ) twins are genetically identical,
while dizygotic (DZ) twins share half of their genes,
same as any other siblings. However, MZ and DZ
twins are often raised in very similar environments,
especially if of the same sex. Thus twins are
naturally occurring experiments in the relative
effects of genetics and environment.
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•
The relevant statistic: concordance.
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•
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A further problem: DZ twins of the same sex often look
quite different—they may not really get the same
degree of similar treatment as MZ twins.
If twins both have the disease, they are concordant.
If one has it and the other doesn’t, they are discordant.
Traits with a large genetic component will show a
higher concordance rate for MZ twins than for DZ
twins.
For 100% genetic trait, should be 1.0 in MZ twins
and 0.5 for DZ of same sex. Concordance ratio:
MZ/ DZ. the higher it is, the more genetic a trait is.
HPT: hypertension; RP: Raynaud’s phenomenon (fingertips
lose circulation when exposed to cold or strong emotion);
MIG: migraines; CAD: coronary artery disease
Zygosity Diagnosis
•
Fetal membranes: the chorion is the outer
embryonic membrane; it is derived from the
fertilized egg.
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•
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All DZ twins have separate chorions, but ¾ of
MZ twins have a single chorion.
Some MZ twins are within the same amnion
(inner membrane) while others aren’t. Some
DZ twins share a placenta.
Anthropometric traits (i.e. body
measurements): fingerprints (but they are
not necessarily identical), eye and hair color,
facial structure. An experienced observer
can diagnose zygosity very accurately.
Genotype: blood groups, DNA markers.
Should be identical in MZ. Many DNA tests
available for parents nowadays.
Complications: MZ twins will have different
patterns of X chromosome inactivation (if
female), different sets of immunoglobublin
genes, and they will have been exposed to
slightly different environments since the
moment the initial embryo split. They are not
100% identical, and in practice MZ twins are
not 100% concordant for complex traits.
Adoption Studies
•
Adopted children are good for
separating genetic effects from
environmental effects.
Two basic ideas:
•
1.
2.
–
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if you look at adopted people with a
genetic disease, does that disease
run in their biological family or in
their adopted family?
If the biological parents of an
adopted child have a genetic
disease, does the child get the
disease despite being raised in a
different family?
Problem: adoption is not a random
process: a lot of effort often goes
into matching characteristics
between birth family and adoptive
family.
Also, studying the genetics of the
birth family can be difficult due to
privacy issues.
Segregation Analysis
• A method of pedigree analysis that can estimate the
number and mode of inheritance of major genes
contributing to a disease as well as their mode of
inheritance as well as incomplete penetrance and
environmental components.
• A maximum likelihood method similar to lod scores: vary
a large number of parameters systematically and find the
combination that best fits the data.
• But: more parameters = more degrees of freedom = a
need for larger amounts of data.
• And, a truism from the world of computers: garbage in,
garbage out. If the options and parameters you use in
segregation analysis don’t cover the true situation, you
will get a wrong answer.
Ascertainment Bias
•
Segregation analysis requires a lot of data from affected families. Problem is, a
family with no affected members will probably not be counted even if their children
are at risk. This is called “complete truncate ascertainment”: you see all families with
at least one affected child.
–
•
For example: two heterozygotes for a recessive trait have 2 children: Aa x Aa.
–
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–
–
•
another model of ascertainment bias (“single selection”) starts from the premise that the
chance of seeing an affected family is proportional to the number of affected children.
(Recalling a bit of military dogma: something happening once is happenstance, twice is
coincidence, three times is enemy action.)
There is a 1/4 chance of an affected child; thus there is 1/16 chance that both children are
affected, 6/16 chance that one child is affected, and 9/16 chance that neither is affected.
In 16 possible families (2 children each), there will be 32 children of which 8 are affected (=
1/4).
However, the families with no affected children will never be seen, so if you just look at
families with at least one affected, there are 7 families, 14 children, and 8 children are
affected (= 4/7).
This fraction is very different from 1/4, and might lead you to suspect a dominant rather than
a recessive, or some other theory.
Mathematical methods exist to correct this bias.
Another approach: select families at random, as visitors to a health clinic for example.
Linkage Analysis
• Unfortunately, the standard lod score method
doesn’t work well for complex traits, because it
requires a definite model of how the trait is
inherited: the first step in lod score mapping is to
determine the expected frequency of offspring
phenotypes as a function of the recombination
fraction.
• Non-parametric methods: look for chromosome
segments shared by affected individuals.
Doesn’t rely on genetic model.
– affected sib pair analysis
– linkage disequilibrium
Affected Sib Pair Analysis
•
If two siblings both are affected by a
genetic disease, they will (in most
cases) share a region of chromosome
surrounding the disease gene. This
segment is “identical by descent”
(IBD): it was derived from a common
ancestor, their parent.
–
•
•
•
if it is uncertain that the siblings
inherited the disease gene from the
same parent, they fall into a less-useful
category of “identical by state” (IBS).
use many co-dominant markers to find
IBD regions among many affected sib
pairs.
Usually results in a large region, a
significant fraction of an entire
chromosome: too big for positional
cloning.
Also: if more than one gene causes
the trait, the necessary large amount
of data will never converge to a single
chromosome region.
Linkage Disequilibrium
•
•
•
Gene mapping using recombination
methods (such as affected sib pair
analysis) suffers from not having enough
crossovers in one generation to localize a
gene very well.
Linkage disequilibrium uses crossovers
that have occurred over several
generation.
The idea is that if you start with a single
mutation, over many generations
crossing over will separate the region
around the mutation from most of the rest
of the genome.
–
–
–
–
Regions of chromosome distant from the
disease mutation will become randomized.
However, right near the mutation random
crossovers will not have separated the
disease locus from its surrounding
haplotype: a particular DNA haplotype will
be in disequilibrium with the disease trait.
The trick is to find that haplotype.
The further back in time since the mutation
occurred, the smaller the region of
disequilibrium.
More Linkage Disequilibrium
• A major complication: turns out
that whole blocks of
chromosomes get inherited
together over many
generations. Crossing over
isn’t completely random.
Means that genes occur in LD
blocks separated by
recombination hotspots.
• Another problem: LD methods
depend on there being only a
single original disease
mutation that occurred in a
particular haplotype. Multiple
mutations will each have their
own LD haplotype.
A Few Case Studies
• Varying levels of success: there’s a long
way to go on this problem
•
•
•
•
•
Breast Cancer
Alzheimer Disease
Type 1 (insulin-dependent) diabetes
Schizophrenia
Inflammatory Bowel Disease
Breast Cancer
•
Most cancer is spontaneous, but certain types run in specific families.
– Often associated with early onset of the disease
•
•
For breast cancer, the lifetime risk for a woman is about 1 in 12. (For men,
the risk is about 1 in 1000).
However, roughly 5% of cases are from families with near-Mendelian
inheritance.
– Recurrence risk is about 47-fold for sisters of breast cancer patients whose
mothers also had it, as opposed to random members of the population.
– These families also have early onset (age 45 or less), bilateral involvement, and
associated ovarian cancer in many cases. Also, some males in these families
get it.
•
•
Complex segregation analysis concluded that transmission was most
compatible with an autosomal dominant gene.
Large segregation analysis found a gene at 17q21. Used 23 extended
families of European origin with 146 cases of breast cancer. Lod score of
5.98 for early onset cases, but no linkage for late onset. A later study
almost as large failed to find this linkage, but it was confirmed by other
studies.
– Lifetime penetrance of 80-90% for breast cancer and 40-50% for ovarian (since
revised downward to 60-80% for breast cancer)
More Breast Cancer
•
•
•
•
Positional cloning (with accompanying
agony) of the gene, called BRCA1.
Lots of different mutations seen, in
many ethnic groups.
Another major gene, BRCA2, mapped
to 13q12 and cloned.
Both genes are involved in DNA repair
as part of a larger complex. Other
cancers sometimes include BRCA1
and BRCA2 mutations. DNA repair
failure may be the actual effect of
these genes on cancer.
However, many spontaneous cases of
breast cancer don’t involve either
gene, and these genes don’t cover all
of cancer family cases either. There
are several other genes known to
increase susceptibility, and there is
also a background level of polygenic
risk. A case of the phenotype being
distant enough from the genes to
make an exact causation pathway
difficult.
Alzheimer Disease
•
•
•
•
disease first described by Alois Alzheimer in Germany in
the late 1800's. His boss named the disease after him.
amyloid plaques are found in the brains of people with
Alzheimer's, and also in people with trisomy-21, Down
syndrome. Plaque formation seems to be an early and
inevitable part of the disease.
--the amyloid consists of aggregates of a 42 amino acid
polypeptide, which comes from exons 16 and 17 of a
protein called "amyloid beta A4 precursor protein" or APP.
Some families show an early onset type (before age 65)
that inherits in near Mendelian fashion as an autosomal
dominant.
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•
•
mapped to 21q21
Further mapping showed 3 other major genes caused
early onset familial Alzheimer’s:
Other early onset families led to locating presenillin 1 and
presenillin2. These proteins are part of a transmembrane
protein complex called “gamma-secretase”.
–
–
amyloid is generated from APP by 2 cleavages. First, betasecretase cuts of mot of the extracellular portion of APP.
Then, gamma secretase cuts the remaining portion of APP
within the membrane. This generates the 42 amino acid
amyloid protein that aggregates and causes the disease.
Mutant forms of PS1 or PS2 increase the rate of gammasecreatse cleavage and thus increase the production of a
form of amyloid that gets deposited in Alzheimer's
More Alzheimer Disease
•
Families with multiple cases of late
onset AD identified a locus at 19q13,
later identified as APOE.
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APOE is apolipoprotein E, with 30 or so
known alleles, several of which lead to
elevated cholesterol and triglycerides in
the plasma, along with increased risk of
atherosclerosis. The protein is the
main component of chylomicrons (lipid
digestion). The variant forms (called
E2) don't bind well to the receptor on
liver cells. Also binds to amyloid
protein.
Alzheimer's is associated with the E4
form, whose allele frequency is about
15% in European origin people.
Homozygosity almost inevitably leads
to Alzheimer's by age 80, with
heterozygosity increasing the risk.
But, many Alzheimer's cases don't
seem to involve this gene, so gene
tests for it don’t do a good job of
identifying risk.
Type 1 Diabetes
• insulin-dependent diabetes
mellitus (IDDM). An autoimmune
disease in which the insulinsecreting beta cells of the
pancreas are destroyed. usually
occurs at a young age, and brings
a lifelong dependence on insulin.
• Insulin causes sugar to move from
the blood into the cells. In the
absence of insulin, blood sugar
builds up while the cells starve.
• Insulin is a peptide hormone that
binds to a surface receptor and
initiates a signaling cascade that
results in the activation of glucose
transporters
More Diabetes
•
•
Family association: λs = 15, and MZ concordance is 30%.
Linkage to MHC, the class 2 gene DQ beta. Low risk is associated with an aspartic
acid at residue 57; other amino acids there confer a high risk.
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A second important locus for IDDM is INS, the insulin gene itself. Specifically, a
region at the 5’ end of the gene, a 14 bp minisatellite.
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in one study, 96% of diabetics were homozygous for an amino acid there than aspartate at
this position, while only 20% of controls were homozygous for non-Asp.
This difference accounts for a 30 fold difference in the rate of IDDM when comparing
Chinese and European-Americans.
A small number of repeats (26-63) causes susceptibility to IDDM, while people with a large
number of repeats (140-210) don’t get diabetes.
More repeats means a 2-3 fold increased rate of insulin transcription.
The argument is that more insulin means that during maturation of T cells in the thymus
around the time of birth, any that react to insulin are more likely to be deleted if the beta cells
are producing more insulin.
At least 15 other loci have been identified that increase susceptibility to IDDM. All
seem to have small effects, and replication of results in different studies often doesn’t
occur.
The disease is genetically heterogeneous.
Schizophrenia
•
Schizophrenia is a psychiatric diagnosis with no obvious
physical manifestations. It involves disorganized thinking,
impairment of the person’s perception of reality and ability to
function socially. Sometimes hallucinations or delusions. It
may be more than one disease.
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•
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Schizophrenia typically appears in the late teens and early
20’s. Incidence in the general population is about 1%
It can be triggered by stressful events or drug use, or have no
obvious triggering event.
There is a strong genetic component.
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•
A common misunderstanding is that schizophrenia involves split or
multiple personalities. It doesn’t: that’s a different disease.
“Schizo” means “divided from reality”.
Concordance rate for MZ twins is 46%, even when reared in
separate families, and 14% for DZ twins of the same sex.
Recurrence risk is 14 for first degree relatives, 4.25 for second
degree and 2 for third degree.
Adoption studies show that the risk is associated with the biological
family and not the adopted family.
Numerous mapping studies using many methodologies over
the past 30 years have identified 20 or more chromosomal
regions that seem to be associated with schizophrenia in some
pedigrees. Some show up repeatedly, but often they are not
reproduced in further studies.
Schizophrenia
•
•
About 1% of the US population has some form of schizophrenia. Most
develop it between ages 16 and 30, and only rarely after age 45. It can
be hard to recognize in younger people.
“lose touch with reality”:
– hallucinations (seeing or hearing things that aren’t there). Voices telling you
what to do, invisible fingers touching you, smelling odors no one else can
detect. Hearing voices is the most common symptom.
– Delusions: false beliefs that cannot be changed by facts (especially if they
are not common in your culture). People of television are speaking directly
to you, radio waves are controlling your behavior, belief that you are a
famous historical figure (like Napoleon), belief that others are plotting
against you or trying to harm you.
– Movement disorders: agitated body movements, repeating the same
motions over and over, walking oddly.
– “flat affect”: your face shows no emotion and you talk in a dull monotone
– Inability to plan, or sustain planned activities, or make decisions.
– inability to interact with others properly: speech is disconnected and makes
no sense to others.
What Causes Schizophrenia?
• The actual cause isn’t clear, but both genetics and the
environment play a role.
– Genetics: it “runs in families”. The risk in the general population is 1%, but
it’s 10% if a sibling or parent has it, and 50% if an identical twin has it.
However, no specific gene is known to cause schizophrenia, despite serious
efforts to find one. It is a “complex genetic trait”: probably many genes
contribute small amounts to your risk.
– Environment: possibly virus exposure or malnutrition before birth play a role
(but no specific viruses have been identified). Trauma: child abuse and
neglect seems to play a significant role in the development of some
schizophrenia. Post-traumatic stress disorder and other adult traumas may
also play a role. Hallucinogenic drugs such as LSD can trigger
schizophrenia in people who are pre-disposed to get it.
– Marijuana use is high among schizophrenics, and tobacco use is also far
above the general population, but this may be the result of self-medication
and not causation. But, marijuana may increase the risk.
• No obvious differences in brain structure associated with
schizophrenia. It is strictly a mental illness.
Treatment
•
•
•
•
Old days: jail, insane asylum, being treated as a witch or possessed by
demons. Or, occasionally treated as a saint communicating with God.
Pyschosurgery. The lobotomy involved destroying part of the frontal
lobes of the brain. It became very popular in the 1940’s, but in the 1950’s,
psychoactive drugs were shown to be more effective and less damaging.
Electroconvulsive therapy. Mostly used for chronic depression today.
Drug treatment. First generation drugs included reserpine and thorazine.
Newer drugs target the dopamine system in the brain.
– They have some side effects like drowsiness and dizziness. Also, major weight
gain and an increased risk of diabetes.
– Long term use can result in “tardive dyskinesia”, which is uncontrollable muscle
movements.
– If you stop taking the medication abruptly, relapse can occur. Many people
stop taking them because they feel better and the side effects get intolerable.
Drug treatment may need to be lifelong.
– Different people respond to different drugs in different ways: it is necessary to
try several out to find the best one.
•
Behavioral treatment: it is possible to develop mental skills to manage the
disease: to ignore the voices in your head, to act normal even if you don’t
feel normal, to rest the reality of your thoughts. Self-help groups and
family education help a lot.
Saints, Demonic Possession, Insane Asylums
• z
Psychosurgery
•
•
The lobotomy (also called leucotomy) was invented by Portuguese
doctor Egas Moniz, who won a Nobel Prize for it in 1949.
The idea was to destroy the prefrontal cortex, or sever their connection
to the rest of the brain. It was meant to help cases of severe mental
illness, at a time when there was no effective treatment. Psychotic
people were simply confined to insane asylums before this.
–
•
•
The prefrontal cortex the part of the brain immediately behind the eyes,
which is involved with the executive function of the brain: predicting
outcomes, differentiating between conflicting ideas, personality expression,
decision making and social behavior.
Walter Freeman, an American psychiatrist, simplified the procedure so
it could be done in cheaply in a mental hospital. A thin instrument was
placed under the eyelid and against the top of the eye socket. Then it
was pounded through the thin bone into the brain with a mallet. The
instrument was swept from side to side, severing the connections.
Repeated on the other side.
Approximately 40,000 lobotomies in the US in the 1940’s and early
1950’s. Freeman drove around in a “lobotomobile”, performing the
surgery at mental hospitals. Stopped with the advent of drug therapy.
Freeman lost his medical license after killing a patient.