Complex Traits - PowerPoint PPT Presentation

1 / 22
About This Presentation
Title:

Complex Traits

Description:

MZ twins have VG = 0. So, studies seeking to isolate genetic influences use ... However, MZ and DZ twins are often raised in very similar environments, ... – PowerPoint PPT presentation

Number of Views:73
Avg rating:3.0/5.0
Slides: 23
Provided by: t80
Learn more at: https://bios.niu.edu
Category:
Tags: complex | traits | twins

less

Transcript and Presenter's Notes

Title: Complex Traits


1
Complex Traits
2
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 dont easily fit the Mendelian patterns. We
    can call them multifactorial.
  • 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.

3
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
  • 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.

4
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

5
Runs in the Family
Recurrence Risk for Multiple Sclerosis
  • 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 ?. ?S
    for siblings ?R for relatives in general.
  • Recurrence risk depends on degree of
    relationship
  • 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.

6
Twin Studies
  • As pointed out by Darwins 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.
  • A further problem DZ twins of the same sex often
    look quite differentthey may not really get the
    same degree of similar treatment as MZ twins.
  • The relevant statistic concordance.
  • If twins both have the disease, they are
    concordant.
  • If one has it and the other doesnt, 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 Raynauds phenomenon
(fingertips lose circulation when exposed to cold
or strong emotion) MIG migraines CAD coronary
artery disease
7
Zygosity Diagnosis
  • Fetal membranes the chorion is the outer
    embryonic membrane it is derived from the
    fertilized egg.
  • 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 arent. 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.

8
Adoption Studies
  • Adopted children are good for separating genetic
    effects from environmental effects.
  • Two basic ideas
  • 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.

9
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 dont
    cover the true situation, you will get a wrong
    answer.

10
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.
  • 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.)
  • For example two heterozygotes for a recessive
    trait have 2 children Aa x Aa.
  • 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.

11
Linkage Analysis
  • Unfortunately, the standard lod score method
    doesnt 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. Doesnt
    rely on genetic model.
  • affected sib pair analysis
  • linkage disequilibrium

12
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.

13
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.

14
More Linkage Disequilibrium
  • A major complication turns out that whole blocks
    of chromosomes get inherited together over many
    generations. Crossing over isnt 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.

15
A Few Case Studies
  • Varying levels of success theres a long way to
    go on this problem
  • Breast Cancer
  • Alzheimer Disease
  • Type 1 (insulin-dependent) diabetes
  • Schizophrenia
  • Inflammatory Bowel Disease

16
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)

17
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
    dont involve either gene, and these genes dont
    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.

18
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.
  • mapped to 21q21
  • Further mapping showed 3 other major genes caused
    early onset familial Alzheimers
  • 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, beta-secretase 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
    gamma-secreatse cleavage and thus increase the
    production of a form of amyloid that gets
    deposited in Alzheimer's

19
More Alzheimer Disease
  • Families with multiple cases of late onset AD
    identified a locus at 19q13, later identified as
    APOE.
  • 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 dont do a good
    job of identifying risk.

20
Type 1 Diabetes
  • insulin-dependent diabetes mellitus (IDDM). An
    autoimmune disease in which the insulin-secreting
    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

21
More Diabetes
  • Family association ?s 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.
  • 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 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.
  • A small number of repeats (26-63) causes
    susceptibility to IDDM, while people with a large
    number of repeats (140-210) dont 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 doesnt occur.
  • The disease is genetically heterogeneous.

22
Schizophrenia
  • Schizophrenia is a psychiatric diagnosis with no
    obvious physical manifestations. It involves
    disorganized thinking, impairment of the persons
    perception of reality and ability to function
    socially. Sometimes hallucinations or delusions.
    It may be more than one disease.
  • A common misunderstanding is that schizophrenia
    involves split or multiple personalities. It
    doesnt thats a different disease. Schizo
    means divided from reality.
  • Schizophrenia typically appears in the late teens
    and early 20s. 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.
  • 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.
Write a Comment
User Comments (0)
About PowerShow.com