Genetics of Common Disorders with Complex Inheritance and Personalized Medicine Flashcards
What percent of the genome is identical between individuals?
99%
1% of the DNA sequence between individuals is different. These DNA differences are called
Polymorphisms
Can be small insertions/deletions, differences in the number of repeats, or single nucleotide differences (SNPs)
Polymorphisms
Most polymorphisms are silent, meaning they exert no functional
Difference
The entire genome is equivalent to a book, each chromosome is equivalent to a chapter, each gene is equivalent to a paragraph, and each nucleotide is equivalent to a
Letter
A DNA change that severely alters the activity or expression of a gene
Mutation
Silent change in the DNA that does not alter the
expression or activity of the gene.
Polymorphism
Subtle changes that alter the levels or activity of a gene, but the gene is still in NORMAL range
Functional Polymorphism
How do we find relative risk?
Prevalence in affected / prevalence in unaffected
The variance within pairs of dizygotic (DZ) twins will be similar to that seen within monozygotic (MZ) twins, and heritability (h^2) will approach 0 if the variability of the trait is determined chiefly by the
Environment
If the variability is determined chiefly by the environment, the heritability will approach
0
If the variability is determined exclusively by genetic makeup, than the variance of MZ pairs is 0 and the heritability is
1
A single gene disorder named after Gregor Mendel
Mendelian Disorder
What are the three modes of inheritance for the Mendelian disorder?
- ) Recessive
- ) Dominant
- ) semi-dominant
To identify the causative gene, we want to sequence all the genes in the region and look for a mutation that segregates with disease in all
Pedigrees
To find the causative gene, we want to look for the presence of different mutations in different
Families
To identify the causative gene, we want to confirm that the mutation affects expression or activity of a
Gene
Deep sequencing, the next generation of sequencing, allows for sequencing the entire genome in a cheap and relatively fast manner. We can sequence the
Genome, Exome, or Transcriptome
Neural crest defect for cells that go on to form the enteric nervous system of the intestines
-leads to enlarged colon
Hirschsprung’s disease (HSCR)
The frequency of HSCR is
1/5000
Does not follow a simple recessive or dominant inheritance pattern
HSCR
The relative risk for siblings to get HSCR is about
-Monozygotic twins do not show perfect concordance
200
How much more likely are males within the family to get HSCR than females?
2x
HSCR is caused by a mutation in the tyrosine kinase receptor needed for neural crest migration known as
RET
Scanning of the genome for 67 siblings that both have HSCR showed that 55/67 siblings shared alleles at
10q11.2 (RET), 3p21, and 19q12
Are major health concerns and therefore understanding the biological basis of these disorders so new treatments can be developed is necessary
Common diseases
The phenotypic overlap of Multiple sclerosis (MS), type 1 diabetes, and survival bone marrow transplant is
Autoimmunity
The phenotypic overlap of schizophrenia, bipolar disorder, and autism is
Neurodevelopmental disorder
Refers to inheritance of a phenotypic characteristic (trait) that is attributable to two or more genes, or interaction with the environment, or both
Multi-factorial inheritance
A character determined by the combined action of a number of genetic loci
Polygenic
Caused by mutations in single genes
-ex: Cystic fibrosis and Duchene Muscular Dystrophy
Monogenic (Mendelian) disorders
Do not follow simple recessive or dominant inheritance patterns
Multi-factorial diseases
What are the risks for common diseases
- ) Genetic
- ) Epigenetic
- ) Non-genetic environmental factors
What are two types of genetic risks for common diseases?
Functional polymorphisms (common variants) and mutations (rare variants)
Hormones, diet, or infections that alter cell biological pathways
Non-genetic environmental factors
Common diseases occur frequently in the population; some of the genetic susceptibility alleles are then likely to be
Common (>5%)
Are likely to have less of a phenotypic effect per individual but would affect more individuals within the population
Common variants (functional polymorphisms)
Would have a significant phenotypic effect per
individual but contribute less to general population
Rare variants (mutations)
If we have two polymorphisms, A and G, and the A polymorphism is co-inherited with a disease allele, then the A polymorphism should be inherited more frequently in
Affected individuals
If we have two polymorphisms, A and G, and the A polymorphism is co-inherited with a disease allele, then the G polymorphism should be inherited more frequently in
Unaffected individuals
The previous polymorphism example was an example of an
Association study
SNPs are co-inherited as blocks or bins. Panels are created with tagged SNPs for each bin. Thousands of people with the disease are recruited and their DNA is isolated and genotyped for their whole genome
Genome Wide Association Analysis (GWAS)
Once the recruits have been genotypes, we then do statistical analysis to identify the
SNP alleles co-inherited with disease
What are some problems with GWAS?
Reproducibility and functionality
49% of variants in individuals affected with ASD are
Common inherited (A)
Seeks to identify all functional elements in the human genome
ENCODE
Identified protein coding regions contained in approximately 20,000 genes
-discovered that protein coding regions made up only 1% of genomeq
Human genome project
Aims to characterize other functional DNA elements
ENCODE
ENCODE discovered that what percent of the genome is involved in at least one biochemical event?
> 80%
ENCODE discovered that 95% of the genome is within 8kb of a
DNA protein interaction
What percent of the genome is within 1.7kb of an ENCODE identified event?
99%
A substantial proportion of variants are annotated as having predicted functional effects in the
Non-coding category
Affects the epigenome, transcriptome, proteome, and metabolome
Environment
Says that risks of commmon diseases are due to epimutations
Epigenetic hypothesis
Changes in the epigenetic signature
-affects gene regulation
Epimutation
Contribute to non-genetic components of diseases
Epimutations
Epimutations provide an interface between environmental factors and
Gene expression
For many common diseases cause by epimutations, phenotypes are very
Heterogeneous
The metabolic state of a cell is not invariant and is directly linked to
Cellular function
The observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.
Warburg effect
What most human diseases are, where if you get one allele, you have a certain clinical phenotype, but if you get two mutant alleles, you have a much worse phenotype
Semi-dominant
Looks like AD, but may appear to skip a generation
Incomplete penetrence
Identifying pieces of DNA that are co-inherited with the mutation
Genetic linkage
A handful of mutations cause these diseases as opposed to just one
-Ex: HSCR
Simple complex disorders
Pose less individual risk, but more population risk
Common varaints
Tell us how the cell is functioning
Metabolites
