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.