Multifactorial Inheritance
pyloric stenosis incidence
-3/1,000 live births in US caucasians -4 times more prevalent in males than females (females have a higher threshold of liability so it takes more diseases alleles and/or environmental factors to produce the disease phenotype -tends to cluster in families -multifactorial inheritance
If MANY genes contribute to human height, many phenotypes are possible and the distribution looks like a bell-shaped curve. TRUE/FALSE
TRUE
Adopted children of biological parents unaffected with a disease
if the children develop the disease, it may have a strong environmental component, provided by the environment of the adoptive parents
4 things to take into consideration with recurrence risk calculations
(1) The more family members affected with a multifactorial disease, the higher the recurrence risk. (2) The closer the degree of relationship with the proband, the higher the recurrence risk. (3) The more severe the disease in the proband, the higher the recurrence risk. (4) Recurrence risk increases with a more severe phenotype in the proband.
threshold model
-Can be applied to qualitative traits: all-or-nothing traits, where the disease is present or it is not - model says that in order to be affected by the 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. -Before the threshold, no signs of the trait are manifested. After crossing the threshold, the trait appears.
a large component of human disease burden is caused by diseases that may involve multiple genes or differing environmental conditions
-Congenital malformations (present at birth): cleft lip/palate, pyloric stenosis, club foot, spina bifida. -Common adult diseases: coronary artery disease, obesity, alcoholism, cancer, diabetes, schizophrenia
limitations of adoption studies
-Prenatal environmental influences may be confused with genetics (maternal infections or stress during pregnancy, drug use or poor diet during pregnancy) -Adopted children may have spent some time with their biological parents. Many children aren't adopted into families as newborns, they are often older and may have been influenced by their original environment. -Adoption agencies often find adoptive parents with similar socioeconomic status to the natural parents (similar environment).
Polygenic example: Inheritance of human height
-if only one gene with two alleles- (A,a) determines height, there are three possible genotypes -if two genes with to alleles each( A, a, B, b) contribute in a similar way, nine genotypes are possible. - We assume that all dominant alleles contribute the same, and it is the number of alleles that matters. - A person would have 0, 1, 2, 3, 4 tall alleles (A or B) -The majority of the population will be of average height, and possess two dominant alleles
additive polygenic model
-multiple genes are involved in the development of a trait or disease -applied most easily to quantitative traits( aka blood pressure, height) - no continuous variation from one extreme to the other which can be represented by a bell-shaped curve
Disorders with multifactorial inheritance will be the cause of morbidity and premature mortality in nearly _______________ of individuals during their lifetime.
2/3 that is why its very important to identify the contributing factors so that development of the disease can be avoided
nature vs nurture twin studies Is the genetic component stronger in diabetes type 1 or diabetes type 2?
Diabetes type 2, since variability is higher
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
the threshold model fits all human multifactorial diseases
FALSE it does not fit all human multifactorial diseases
nature vs nurture
Family members share nature (genes) and nurture (environment). It can be difficult to distinguish which makes the stronger contribution in multifactorial disease
for the threshold model of multifactorial inheritance Who has the highest recurrence risk? Why? (a) Female relative of male proband (b) Female relative of female proband (c) Male relative of female proband (d) Male relative of male proband
Male relative of female proband A female proband (high threshold) would indicate that the family has a lot of factors required for manifesting the disease. Therefore, a male relative of a female proband, with a lower threshold, would be most likely to also manifest the disease (highest recurrence risk).
for the threshold model of multifactorial inheritance 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's family. Females have a higher liability threshold, thus she must be exposed to more disease-causing factors in order to develop the disease. There is a higher recurrence risk for pyloric stenosis in future offspring.
pyloric stenosis symptoms
Recurrent vomiting, dehydration, electrolyte imbalance. Requires surgery
calculation of recurrence risk can be assessed empirically
Risk estimate is based on previous observation of similar circumstances. • A large number of families need to be observed. • We need information for each multifactorial disease and for each population group
Caution must be applied when using twin studies or adoption studies. They will be only a preliminary indication of the extent of genetic influence on multifactorial diseases TRUE/FALSE
TRUE
More closely related individuals may also share more of the environmental factors that contribute to the disease TRUE/FALSE
TRUE
examples of nature vs nurture adoption studies
alcoholism, tendency toward criminal behavior, psychiatric illnesses--> often schizophrenia
when are adoption studies used?
assessing the genetic contribution to diseases that could potentially be learned or induced behaviors, or result from abuse or neglect.
nature vs nurture adoption studies
based on comparing rates of diseases in adopted offspring of affected biological parents vs. adopted offspring on unaffected biological parents
twin studies
based on comparisons of MZ and DZ twins
why is recurrence risk for multifactorial diseases is higher in individuals who are more closely related to each other
because they share more of their genetic information
even between identical twins, gene expression can start to vary over time due to ______________ that occur in one twin but not the other this leads to complications in older twin pairs
epigenetic changes
pyloric stenosis
example of threshold model Due to hyperplasia of the muscles at the pylorus of the stomach, it produces obstruction of gastric emptying
for the threshold model of multifactorial inheritance Is the occurrence risk higher for males or females
higher for males since they have a lower threshold
Adopted children of biological parents affected with a disease
if the children still develop the disease in their adoptive environment, the disease may have a strong genetic component
In theory, the influence of environment is similar in MZ and DZ twins (raised together), but they are genetically different TRUE/FALSE
in monozygotic-its 100% genes + environment in dizygotic- its 50% genes + environment
Example study of schizophrenia
indicates genes may be involved. • 8-10% of children adopted from families where schizophrenia was present (but adopted into families with no schizophrenia) will develop schizophrenia. • 1% of adopted children born of unaffected parents become schizophrenic (this mirrors the general risk of schizophrenia in the population). • This means that the disease status of the biological parents has a strong influence on the development of the disease in the child, regardless of environment, indicating a strong genetic component.
lung cancer vs. breast cancer causes
lung cancer- strong environmental contribution breast cancer- strong genetic contribution
what were the first disorders to be recognized as inherited?
monogenic or single-gene disorders
which two types of inheritance can be more difficult to distinguish
multifactorial inheritance from single gene inheritance with reduced penetrance or variable expressivity
common multifactorial disease characteristics
multiple occurrences in a family with no recognizable Mendelian pattern of inheritance disease can occur more in one sex than the other, with no clear sex-linked pattern there is a large amount of variation in the severity of the condition environmental factors like diet degrees of relatedness single abnormal gene for the disease has not been found
obesity and the leptin gene
obesity(usually multifactorial) leptin (leptin deficiency result in obesity-stritly a monogenic disease)
dizygotic twins(DZ) =fraternal twins
originated from a double ovulation followed by fertilization of each egg with different sperm 50% identical , the same as any other siblings have separate placentas
monozygotic twins= identical
originated when original embryo divides to form two embryos genetically identical 100% may share a placenta or have separate placentas
multifactorial
polygenic + environmental factors
heritability
represents the proportion of the variation in a disease trait that can be attributed to genes. h = 2 (CMZ-CDZ) the higher the (h) value, the greater the genetic influence
polygenic
trait in which variation is through to be caused by a combined effect of multiple genes
what two methods are used to differentiate between genetic and environmental contributions?
twin studies adoption studies
CMZ and CDZ
• CMZ and CDZ represent the concordance value for MZ and DZ twins, respectively. • Ex: CMZ = 0.79 indicates that in 79% cases, two MZ twins share the disorder. • Ex: CDZ = 0.24 indicates that in 24% cases, two DZ twins share the disorder.
what are limitations of twin studies?
• Differences in the uterine environment are not accounted for (different placentas). • Somatic mutations can occur in only one of the twins. • There is an underestimation of environmental contribution.
calculation of occurrence risk
• Easy in monogenic or Mendelian traits. • Calculation not usually attempted with polygenic or multifactorial traits.
concordance vs. discordance
• 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.
threshold model of human multifactorial inheritance fits for many human diseases
• Infantile autism • Neural tube defects (spina bifida, anencephaly) • Some forms of congenital heart disease • Isolated cleft lip/palate • Club foot • Hypertension
basic characteristics of multifactorial disease than can sometimes help to differentiate multifactorial inheritance from single gene inheritance
• Researchers have been unable to identify a single gene that is always mutated in the individuals with the disease, despite many attempts to do so. • Researchers have linked multiple genes to the manifestation of the disease.