Biochemistry 5 Flashcards
Historically, single-gene disorders were the first to be recognized as?
inherited
A much larger component of human disease burden is formed by
- congenital malformations (present at birth): cleft lip/palate, pyloric stenosis, club foot, spina bifida
- Common adult diseases: coronary artery disease, obesity, alcoholism, cancer, diabetes, infantile autism, schizophrenia
Congenital malformations and common adult diseases are expected to?
become the largest % of a physician’s cases in the future
Polygenic or multigenic
trait in which variation is thought to be caused by a combined effect of MULTIPLE GENES (not environmental contribution yet)
Multifactorial =
polygenic + environmental factors
Multifactorial can be distinguished from a single gene
-Can occur in isolation, which no clear Mendelian pattern
-Can occur more in one sex than in the other, with no clear sex-linked pattern
-Can occur more in a certain ethnic group
-Environmental factors change the risk of the disease
If a pregnant woman neglects to take folate supplements, her child will be born with spina bifida.
FALSE
If a pregnant woman takes folate supplements before and during the pregnancy, her child will not be born with spina bifida
false
Additive polygenic or multigenic model
Can be applied to quantitative traits, traits that are measurable. There is continuous variation from one extreme to to the other, which can be represented by a bell-shaped curve.
Examples of additive polygenic or multigenic model
BP, serum, LDL cholesterol
Example of polygenic or multigenic
inheritance of human height
If only one gene with two alleles (A, a) determines height, how many possible genotypes are there?
three
If there are two genes with two alleles each (A, a, B, b), how many genotypes are possible?
Nine
We assume that all dominant alleles contirbute?
the same, and it is the number that what matters
A person would have 0,1,2,3,4 tall alleles…
0: aabb
1: aaBb or AaBb
2: aaBB or AAbb or AaBb
3: AaBB or AABb
4: AABB
The majority of the population will be (height wise)
average height, with two dominant alleles
If many genes contribute to human height, many what are possible?
Phenotypes are possible and the distribution looks like a bell-shaped curve. Each individual gene follows mendelian inheritance.
Threshold model can be applied to:
all or nothing traits, where the disease is either present or not
In order to be affected by a multifactorial disease, a person must exceed?
a certain threshold of liability
For a specific population the threshold does
not change
liability changes depending on
genetic and environmental factors
Liability changes depending on
genetic and environmental factors
Before the threshold, ______ signs of the trait are manifested
no
After crossing the threshold, the trait
appears
threshold of liability vs. liability
threshold of liability does not change for individuals in the same population
liability
changes due to exercise and diet
the threshold liability may change in
different populations
(different genders, different ethnic groups, etc)
the threshold of human multifactorial inheritance fits for many human diseases
- infantile autism
- neural tube defects
- some forms of congenital heart disease
- isolated cleft lip/palate
- club foot
- hypertension
the threshold model does not fit for
diabetes type 1
pyloric stenosis is an example of the
threshold model
Due to hyperplasia of the muscles at the pylorus of the stomach, it produces
obstruction of gastric emptying
symptoms of pyloric stenosis
Recurrent vomiting, dehydration, electrolyte imbalance. It requires surgical incision.
Pyloric stenosis male vs. female
4 times more prevalent in males than females
Threshold model females vs. females in pyloric stenosis
females (different population) have a higher threshold of liability (takes more of the disease alleles and/or environmental factors to produce the disease phenotype)
-Males are more affected with the disease
Lower threshold =
occurrence risk higher
Bob was the first child in his family with pyloric stenosis (male proband). Martha was the first child in her family with pyloric stenosis (female proband). Which family has higher recurrence risk?
Martha. Females have a higher liability threshold, thus she must be exposed to more disease causing factors in order to develop the disease.
Occurence risk w/ poly/multi traits
easy in monogenic or Mendelian traits, not even attempted with polygenic or multifactorial traits
recurrence risk
empirical risk = empirical recurrence risk
Recurrence risk is based on
previous observation of similar circumstances
Recurrence risk - a large number of what needs to be observed?
Families need to be observed. We need information for each multifactorial disease and for a similar population group.
the more family members affected, the
higher the recurrence risk
The less of the degree of relationship with the proband, the?
less the recurrence risk
the more severe the disease in the proband, the
higher chances to transmit the disease
Criteria to differentiate multifactorial inheritance
- recurrence risk increases with more than 1 family member affected
- recurrence risk increases if the proband is of the less commonly affected sex
- recurrence risk increases with a more severe phenotype in the proband
- recurrence risk decreases with the degree of relatedness
some genetic diseases have both a single gene and a?
multifactorial component ex: diabetes and glucokinase, or obesity and leptin gene
Family members share nature (genes) and?
nurture (environment)
Determining the influence of each component will help to better understand?
the etiology of the disease and to apply proper emphasis on public health strategies (lung and breast cancer)
Two methods used to differentiate between genes and environment contribution
- twin studies
- adoption studies
Twin studies based on comparison between
MZ and DZ twins
MZ twins
-Originated when original embryo divides to form two embryos
-Genetically identical
DZ/Fraternal twins
originated from a double ovulation followed by fertilization of each egg with a different sperm cell
50% identical, as any other sibling
if both members of a twin pair share a trait they are
concordant
if both members of a twin pair do not share a trait they are
discordant
Cmz an Cdz represent
the concordance value for MZ and DZ twins respectively
Cmz means that in 79% of cases, two MZ twins
share the disorder
In theory, the influence of environment is _______ in MZ and DZ twins, but they are genetically different
similar in MZ and DZ twins, but they are genetically different
heritability
represents the proportion the variation in a disease trait that can be attributed to genes
heritability equation
h=2(Cmz - Cdz)
The higher the value of h, the greater the?
genetic influence
The environmental contribution is represented by
1-h
h = 0.58 indicates that
58% of the trait is genetic, and 1-h = 0.42 means that 42% is environmental
High or low concordance says nothing about
heritability and contribution of genetics
Is the genetic component stronger in T1DM or T2DM
Type 1
Limitations of the twin studies
- Difference in the uterine environment
- Somatic mutations in only one of the twins
- Underestimation of environmental contribution (overestimation of genetic condition) (in many cases MZ twins are treated more similarly than DZ twins)
Adoption studies
