8.24.16 Lecture Flashcards
What are multifactorial disorders?
Diseases that result from the influence of multiple genes, and often with the additional influence of the environment
Match the frequency of disease with the correct cause (genome/chromosome mutations, multifactorial disorders, single gene mutations): 50/1000, 6/1000, 10/1000
6/1000: disorders due to genome/chromosome mutations
10/1000: disorders due to single gene mutations
50/1000: multifactorial disorders
What are the primary characteristics of multifactorial disorders?
- Occurs more frequently in relatives of an affected individual than in the general population (relative risk ratio >1)
- Does not follow classical Mendelian inheritance patterns
- Recurrence risk for a family member is determined using empirically derived risk tables when available
Mendelian traits are ___ (present or not).
Qualitative/dichotomous
Mendelian traits are always attributable to different ___ of a single ___.
Alleles; gene (wild type or mutant)
Complex traits are either ___ or ___.
Continuous/quantitative; qualitative
Quantitative traits are described by a ___ distribution of numerical values about a population ___.
Gaussian (normal); mean
What are the x and y variables of a Gaussian distribution?
X: numerical value for quantitative trait
Y: # of individuals with a given X
What is sigma?
Standard deviation; square root of variance
What is variance?
Degree of spread to either side of the mean; sigma squared
What is the multigenic theory of quantitative traits?
Traits governed by a large number of factors (genes) would display the same type of continuous distribution as seen for quantitative traits.
What is the polygenic theory of discontinuous traits?
The concept of threshold allows for the continuous distribution of values about a mean to characterize polygenic traits.
Family members share a greater number of identical ___ of genes than unrelated individuals
Alleles
The ___ for a genetic disorder within a family exceeds the frequency of the disease in the general population.
Recurrence risk
What is relative risk ratio?
Lambda R; a quantitative measure of the degree of familial aggregation of a disease; quantity>1 suggests genes contribute to the disease
What does relative risk ratio equal?
Prevalence of disease in relatives of affected person/Prevalence of disease in general population
Family members may also share ___ in common.
Environmental factors
What is concordance?
Likelihood that an individual will share a common phenotype with another family member (have the same disease)
The number of alleles two family members share in common is determined by ___.
The degree of relatedness
Because concordance rates are not 100% and 50% in monozygotic and dizygotic twins respectively, it is likely that…
…other factors are contributing.
What is strong evidence of a genetic component to a specific disease with respect to twins?
Monozygotic twins show greater concordance than dizygotic twins.
What suggests that genetic factors are more important than environmental factors to a specific disease?
Similar concordance rates for MZ twins reared together and apart
Variance is related to the contribution of ___ and ___ to the trait.
Genes; environment
When variance is due to different causes, they are ___.
Additive
variance = ?
v(environment) + v(genes)
What is heritability and what does it equal?
The proportion of the total variance due to genes
h^2 = v(genes)/[v(environment)+v(genes)]
What is the variance of MZ twins?
v(MZ) = v(environment) because there is not variance in genes
What is the variance of DZ twins?
v(DZ) = v(environment) + v(genes)
h^2 can also be written as = ___ with respect to twins.
[v(DZ)-v(MZ)]/v(DZ)
What does heritability of 0 indicate? Of 1?
0 - variability due to environment exclusively
1 - variability due to genes exclusively
What is Digenic Retinis Pigmentosa?
Incurable eye condition that progresses from night blindness to tunnel vision to legal blindness by middle age
Describe the multigenic nature of Digenic Retinis Pigmentosa.
- Simplest example of multigenic trait - determined by additive effect of genotypes at multiple loci
- No known environmental factors
What are the 2 photoreceptor proteins lost in Digenic Retinis Pigmentosa due to the 2 genes that produce these proteins?
Peripherin and ROM1
True or false - Digenic Retinis Pigmentosa is present with only one mutation.
False - need mutation in both genes to cross the threshold
What is Hirschsprung Disease (HSCR)?
Loss of some or all ganglion cells of the colon that control peristalsis, resulting in severe constipation, symptoms of intestinal obstruction, and gross dilation of the colon above the aganglionic segment.
HSCR occurs in ___ newborns.
1/5000
What is the relative risk ratio in siblings of someone affected by HSCR?
200
What causes HSCR?
Additive affects of susceptibility loci; loss of a number of different genes (locus heterogeneity), including RET gene
HSCR behaves as ___, ___, or ___.
Dominant; recessive; multigenic
Males have a ___ risk of HSCR compared with females in the same family.
2-fold higher
How is HSCR treated?
Surgical removal of aganglionic section of colon
What is Type I diabetes?
Autoimmune disease with a strong genetic component that typically develops in childhood and shows family aggregation
What is the relative risk ratio for siblings of someone with IDDM? Concordance in MZ?
35; 40%
___ locus plays a role in IDDM. Why?
MHC; contains several families of related genes that participate in priming lymphocytes to mount an immune response
The gene cluster ___ is implicated in IDDM.
HLA-DR
More shared ___ increase the likelihood of having IDDM.
DR haplotypes
What is Idiopathic Cerebral Vein Thrombosis?
Clots form in venous system of brain, cause catastrophic occlusion of cerebral veins in absence of inciting event; typically affects young adults
What are the three common factors in Idiopathic Cerebral Vein Thrombosis?
- Mutant allele of factor V (decreases factor V degradation)
- Mutant allele of prothrombin (increases mRNA stability and plasma levels of prothrombin)
- Oral contraceptives (increase plasma levels of factor X and prothrombin)
What is Alzheimer Disease?
Most common cause of dementia in the elderly; accumulation of abnormal protein aggregates within neurons and in the extracellular spaces in the brain; fatal neurodegenerative disease
True or false - men are more likely to be affected by AD than women.
False - woman are more likely to be affected
What is dementia?
Progressive loss of memory and other intellectual functions
What are the most significant risk factors for AD?
Age, gender, family history
Late onset forms of AD have complex causes. Describe these.
Those with at least one copy of e4 allele of apolipoprotein E (APOE) are 2-3 times more likely to have AD than those who lack it. e4 is likely a predisposing allele, does not predestine
What is APOE?
A constituent of AD amyloid plaques
What are multifactorial congenital malformations?
Isolated defects, not part of a syndrome, caused by complex genetic factors
What do anencephaly (incomplete brain development) and spina bifida have in common?
Neural tube defects, folic acid deficiency increases likelihood of disease (environmental effect)
When risk tables are unavailable, it is possible to estimate risk of recurrence for relatives in a family for multigenic disorders. How is this done?
Disease incidence in population = P 1st degree relative = P^1/2 2nd degree relative = P^3/4 3rd degree relative = P^7/8 4th+ degree relative = P
