Genetics of Common Disorders with Complex Inheritance Flashcards
Polymorphisms:
- the 1% of the genome that differs between individuals
- can be small insertions/deletions, differences in number repeats, or single nucleotide differences
- most polymorphisms are silent, a small percentage are functional
What do functional polymorphisms affect?
- either the expression of a gene or the activity of a protein
Mutation definition:
- a DNA change that severely alters the activity or expression of a gene
Silent Polymorphism definition:
- a silent change in the DNA that does not alter the expression or activity of the gene
Functional polymorphism definition:
- subtle changes that alter the levels or activity of a gene, but still in the NORMAL range
Relative risk equation:
Heritability equation:
- 0 = trait NOT due to heritability
- 1 = trait due completely to heritability
- DZ = dyzygotic twins
- MZ = monozygotic twins
Regarding twins, a 100% heritable trait will be passed on to:
both monozygotic twins
Penetrance definition:
“all or none”
- the amount of people in the population who have the mutation and demonstrate the phenotype.
- if <100% of people who have the mutation express the phenotype, then incomplete penetrance exists.
Expressivity definition:
“phenotype severity”
- when the severity of the phenotype among individuals with the same disease-expressing genotype differs
Dominant inheritance:
- passed on to 50% of progeny
- no carriers
Recessive Inheritance:
- carriers exist
Semi-dominant disease:
- when heterozygous for dominant trait, lesser phenotype.
- when homozygous for dominant traint, more severe phenotype.
What kind of pedigree is this?
Incomplete Penetrance
- When some people with the a dominant mutation do not develop features of the disorder.
What kind of pedigree is this?
(assume all are homozygotes)
differential expressivity
- people with varying phenotype despite same genotype
Genetic Linkage:
- detects the polymorphic region that shows linkage to a disease
- it is present in a majority or all of those with the disease and not in those without the disease
Genetic Linkage detects a polymorphic region linked to a disease. How do you then identify the causative gene?
- sequence all the genes in the polymorphic region and look for mutation that segregates disease in all pedigrees
- look for presence of different mutations in different families
- confirm mutation affects expression or activity of gene
Hirschsprung’s Disease:
- neural crest defect for cells that go on to form the enteric nervous system of the intestines
- result: enlarged colon
- complex inheritance
- three individual mutations from different loci all have to be inherited in order to have the disease
- RET gene and two unknown genes
Phenotypic overlap of common diseases:
- some major common diseases share mutations in the same genes.
- co-inheritance of other mutations will push someone toward developing a specific disease.
Multifactorial inheritance definition:
- inheritance of a phenotypic characteristic (trait) that is attributable to two or more genes, or interaction with the environment, or both.
Polygenic definition:
- a trait whose phenotype is influenced by more than one gene, and is the result of the combined action of multiple genetic loci
Mendelian disorders are caused by mutations in how many genes?
1
Where does evidence for polygenic diseases come from?
- genetic studies
- disease phenotype does not follow simple recessive or dominant inheritance pattern
- twin studies
- disease does not demonstrate clear heritability
The three risks for common polygenic diseases:
-
genetic
- mutations and polymorphisms
-
epigenetic
- methylation; can be influence by environment
-
non-genetic environmental factors
- hormones, diet, infection can alter cell pathways
Common variants regarding the overall population:
- functional polymorphisms
- occur frequently in the population
- less individual risk, more population risk
Rare variants regarding the overall population:
- mutations
- more individual risk, less population risk
Single nucleotide polymorphisms:
- sequence variation occurring commonly within a population in which a single nucleotide differs between members of a biological species or paired chromosomes.
Common single nucleotide polymorphisms are identified via:
association studies
Genome wide association analysis process:
- do microarrays with thousands of affected individuals and thousands of controls
- find common variants for disease of interest
- If certain genetic variations are found to be significantly more frequent in people with the disease compared to people without disease, the variations are said to be “associated” with the disease.
Three types of regulatory RNAs that affect gene expression:
- enhancer RNAs
- miRNAs
-
long-noncoding mRNAs
- possible anti-sense function
How do you identify common variants?
association studies
How do you identify rare variants?
genome sequencing
What does the Epigenetic Hypothesis state?
- risk of common disease are due to epimutations
- changes in the epigenetic signature that affects gene regulation
- provide interface between environmental factors and gene expression
- provide basis for phenotype heterogeneity
What is the transcriptome?
- the transcriptional profile of certain diseases
- can be the basis of diagnosis and treatment options
What is the proteome?
- the proteins produced by a disease
- can be utilized to determine the basis of disease and treatment options by targeting specific proteins related to disease
What is metabolomics?
- Understand the metabolic profile of diseased cells.
- Target the metabolic pathways contributing to the disease phenotype with specific drugs.
