MULTIFACTORIAL TRAITS

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MULTIFACTORIAL TRAITS

• Body mass
• Lipid metabolism
• Blood pressure
• Height

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MULTIFACTORIAL TRAITS

• Traits can be either Mendelian or polygenic
• Polygenic traits are regulated by more than one
  gene
• Traits can also be multifactorial, meaning they
  have an environmental component
• Traits like height, blood pressure and behavior
  are all multifactorial traits

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POLYGENIC TRAITS

• Polygenic trait the combined action of many genes
  produces a continuously varying trait
• Multiple genes that regulate height and blood
  pressure result in continuously varying traits
  that exhibit a range of possible phenotypes

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2 loci
1 locus
aa Aa AA
aaBB aaBb AaBb
AaBB aabb Aabb AAbb AABb AABB
Many loci
3 loci
AABbcc AAbbcc AAbbCc AABbcc AaBbcc AaBbCc
AABbCc AaBbCc AabbCC AAbbCC Aabbcc aaBbCc AaBBcc
AaBBCc AABBCc aabBcc aabbCC aaBBCc AaBbCC
AABbCC Aabbcc aabbCc aaBBcc aaBbCC aaBBCC
AaBBCC AABBCC
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MULTIFACTORIAL INHERITANCE

• Multifactorial inheritance underlies some of the
  more clinically important human traits including
• Heart disease
• Stroke
• Diabetes
• Schiozphrenia

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HERITABILITY

• How can we sort out the relative contributions of
  genetics and environment for a polygenic trait?
• Use a measurement called heritability (H)
• H estimates the of the phenotypic variation for
  a trait that is due to genes
• Measurements of heritability rely on twin studies

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HERITABILITY

• Heritability 1 for a trait that is fully
  genetic like Down syndrome
• Heritability 0 for a trait that is fully
  environmental
• Most traits lie in between
• A measurement of H is useful only for a given
  population at a given time
• H values may not be compared between populations

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HERITABILITY

• One way to estimate heritability is to compare
  pairs of related individuals
• We expect related individuals to share a certain
  proportion of their genes
• The correlation coefficient is the proportion of
  genes that 2 people related in a certain way
  share.
• Correlation coefficient is also called the
  coefficient of relatedness.
• A parent and child share ? of their genes
• Siblings share ? of their genes

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Multifactorial Inheritance

• Breeders want to know about the heritability of
  traits
• They care if milk yield, lean meat content,
  cotton fiber density are genetic or due to
  environment
• Breeders can regulate the environment
• And then influence inheritance by breeding
  certain individuals with desirable traits
• Studying multifactorial traits in humans is more
  difficult
• The best way to tease apart the genetic and
  environmental components of multifactorial traits
  in humans is to look at
• TWINS
• ADOPTED INDIVIDUALS

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Adopted Individuals

• Adopted children share the same environmental
  influences but not the same genes
• Biologists have assumed that similarities between
  children and their adoptive parents were due to
  environmental factors
• Conversely similarities between adopted children
  and their biological parents reflected a genetic
  component

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TWIN STUDIES

• Examination of twins can often provide more
  information about the heritability of a trait
  than looking at adopted individuals
• The assumption is that differences in a given
  trait between monozygotic twins is due to
  environmental factors
• Differences between dizygotic twins reflects both
  genetic and environmental differences
• Best approach is to compare identical twins and
  fraternal twins

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TWIN STUDIES

• A trait that occurs more frequently in
  monozygotic twin pairs than in dizygotic twin
  pairs has a genetic component
• Geneticists calculate the concordance of a trait
  as the of pairs in which both twins express the
  trait

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CONCORDANCE STUDIES

• Concordance looks at the of pairs in which both
  twins express the trait
• Diseases caused by single genes are 100
  concordant in monozygotic twins
• If one monozygotic twin has the disease so does
  the other.
• In dizygotic twins the concordance is generally
  50 for a dominant trait and 25 for a recessive
  trait
• A trait heavily influenced by environmental
  factors would have similar concordance values for
  both types of twins

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LIPID METABOLISM

• Lipids are essential for building cell membranes
• Genes control how well the body handles levels of
  lipids in the blood
• These genes code for
• enzymes that break down fats
• Proteins that transport cholesterol in the blood
  and across cell membranes
• Mutations in these genes can have a big impact on
  cardiovascular health and the build up of lipids
  in the blood

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Heart Health

• Genes control how the body handles fats
• Fats travel in the circulation bound to proteins
  to form lipoproteins
• Cells require sufficient lipid levels inside but
  cannot allow accumulation on the outside
• Several genes control lipid levels in the blood
  by regulating enzymes that process lipids and the
  proteins that transport them as well as the
  receptor proteins that carry them into cells
• Enzyme lipoprotein lipase breaks down fat (low
  density lipoproteins LDLs). This enzyme is
  activated by high density lipoproteins (HDLs)
• High HDLs and low LDLs make for a healthy
  cardiovascular system

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BODY WEIGHT

• 35 of adults in US are overweight
• Another 30 are obese
• This increases their risk of developing
• Hypertension
• Diabetes
• Stroke
• Gallstones
• Sleep apnea
• Scientific studies use a body mass index (BMI)
  which is weight/height2

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BODY WEIGHT

• Heritability for body mass index .55
• At least 17 genes interact to control body weight
• Genes that affect how much we eat, metabolic rate
  and fat distribution
• One of these genes encodes a protein hormone
  called leptin
• Eating stimulates fat cells to secrete leptin
• Leptin travels to the brain and signals it to
  supress appetite and increase metabolism to
  digest the food
• Low levels of leptin indicate starvation, which
  triggers hunger and decreases the metabolic rate

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LEPTIN

• Remaining 85 of participants produced normal
  amounts of leptin but they had defective leptin
  receptors
• A few severely obese children with leptin
  deficiency have attained normal weight with daily
  injections of leptin
• 9 year old girl who only ate about 1/2 a meal a
  day and weighed 200 pounds
• After 4 years of leptin injections her weight is
  normal

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ENVIRONMENTAL EFFECTS ON BODY WEIGHT

• The Pima Indian population separated into 2
  groups in the Middle Ages.
• One group settled in the Sierra Madre mountains
  of Mexico
• The other group settled in southern Arizona
• 1970 the Arizona population no longer had an
  agricultural lifestyle and consumed 40 of their
  calories from fat
• They developed the highest prevalence of obesity
  of any population
• 1/2 of them suffered from diabetes by age 35

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Congenital heart disease

• Structural abnormalities present at birth
• Three major problems are
• left to right shunts
• blood moves from left side of heart to right
  bypassing systemic circulation),
• right to left shunts
• blood moves from right side of heart to left
  bypassing the lungs'blue baby'
• stenosis (narrowing) of a part of the heart or
  vessel
• E.g aortic or pulmonary stenosis

• Complex 1.5 per 1000 live births
• Simple 4.5 per 1000 live births
• Treatment usually by surgery.

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• Heart begins to develop at around 3 weeks
  gestation
• formation of heart tube and its subdivisions
• formation of septa between chambers
• Development is complex and involves
• proliferation
• Migration
• Differentiation
• Interaction between cells of different embryonic
  origin

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• In a heart with an Atrial Septal Defect (ASD)
  there is communication between the right and left
  atria which causes a left to right shunting of
  blood due to the lower pressure in the pulmonary
  circulatory system. Consequently there is a
  mixing of oxygenated (systemic) and deoxygenated
  (pulmonary) blood.

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• The ventricular septal defect (VSD) is the most
  common of all congenital heart anomalies
• there is a left to right shunting of blood and
  pulmonary hypertension

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Normal parents 1 affected child
1 affected parent
Population
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Which genes?

• Development of any organ is complex
• proliferation
• Migration
• Differentiation
• Interaction between cells of different embryonic
  origin
• High susceptibility of the heart to defects
  reflects the complexity
• depends on orchestrated switching on and off of
  key genes
• This is regulated by transcription factors
• Knock them out in a mouse lethal phenotype

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TBX5 and Holt Oram syndrome (HOS)

• Autosomal dominant developmental disorder
  affecting the heart (ASD or VSD) and upper limbs
• Linkage studies, showed the gene was located on
  12q21.3-q22.
• A translocation at 12q2 defined the interval
  containing the HOS locus
• From the critical region they likewise isolated a
  gene with a high degree of homology to mouse Tbx5
  and identified several mutations in TBX5 in
  affected members of HOS families
• TBX5 associates with NKX2-5 and synergistically
  promotes cardiomyocyte differentiation. Both
  directly bind to the promoter of the gene
  encoding cardiac-specific natriuretic peptide
  precursor type A (NPPA)

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TXB5
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Next week

• 4.30pm Mayfield House
• Meet in the board room of the BSMS block
• Level 3