Genetics of Common disorders-with complex inheritane-Personalized Med Flashcards
Polymorphisms facts
1% of genome that separates us as people
can be small, or single
most are silent
small are functional and effect expression or activity of protein
Mutation defintion
DNA change that severely alters activity or expression of gene
SilentPolymorphism definition
Silent change in DNA that does not alter expression or activity of gene/protein
Functional polymorphism defintion
subtle changes that alter levels of activity on gene-still in normal range
-somewhat diffferent but not completely different
Relative risk
Pre of disease in relatives of affected person
/
Prevalence of disease in general population
Heritiability-what it means and how to calc
(Variance in dizygotic pairs-variacne in monozygotic pairs)/variance in dizygotic pairs
0-trait not due to heritability
1-trait is due completely to heritability
Genetic linkage analysis
Marker co-segregates with disease
Can say mutation is somewhere near to marker
Then sequence genes in area and look for mutation of family/different families, then confirmm mutation affects expression or activity of gene
Deep resequencing of human genome
Next gen sequencing allows identification of rare/individual mutations because so fast and cheap
HSCR
Hirschsprungs Disease
Neural crest defect for cells that go on to form enteric nervous system
-mutations in receptor/ligand needed for neural crest migration
Enlarged colon with no nerves
Complex hereditary
- males 2x more likely than females w/i fam
- MZ does not show perfect concordance
Found 3 alleles that somehow, together make disease
Phenotypic overlap of MS, survival bone marrow transplant, T1 diabetes
Autoimmunity
Phenotypic overlap of schizo, autism, biopolar
neurodev disorder
Multifactorial defintion and evidence
Refers to inheritance of phenotypic trait that is attributale to two or more genes and/or epigenetic
not simple recessive/dom
twin studies
Polygenic defintion and vs…
Character determined by combined action of number of genetic loci vs monogenic
Risk for genetic common/rare disease
functional polymorphism
mutations
Risk for epigenetic diseases
covalent mods to DNA or chrom
Influenced by non-genetic environmental factors
definitions for rare/common disease
common=5%=less phenotypic effect but effect more population
rare-significant phenotype bu lesson general population
Association studies for common variants
if polymorphism is co-ineritbed with disease alley, then the polymorphism should be inherited more frequently in individuals with disease
-other WT nucleotide where polymorpishm is should be inherited more often by unaffected siblings
GWAS-how to do and problems
Recruit many with disease
Isolate DNA and genotype whole genome
Stats-identify SNP allele coinherited with disease
Problems with reproducibility and functionality
How are Snps inhierted
in blocks
ENCODE project
Determined 80% of genome is involve din at least one biochemical event
99% of it is somewhat close to ENCODE identified event
Far reaching expression methods
long distance promotoers, reg RNAs
Noncoding functional effects
Epigenetic hypthesis
due to epimutations
non-genetic
interface between environment and gene expression
Heterogenous
Provide basis for heterogenity
epigenetic technology (2)
IP CH3 DNA taken from indies ten hybridieed to DNA
Degree of hybridization indicates methylation status
Bisulfite seq-methylatio of particular DNA can then be determined by standard molecular approaches
many genes that lead to cancer have epigenetic alterations
ommics
look at something-take expression pattern
parse into different subgroups that respond to dif pathways
metabolome-nice pocket-easy to target
sequence/find total amounts of whatever your looking at-see how patient is effected-what (omics thing) causes disease
