作者：Jacob Dooley 1 年以前
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Refer to concept of previous lecture on population genetics and Hardy- Weinberg equilibrium. Assumes no evolution, and focus on random mating. Goes against idea of random assortment (principal of mendelian genetics)
Mainly: Linakge = mendilion and Association=complex diseases
**there exist correlations between the marker you genotyped and the functional polymorphism (due to LD)**
Key concept: Exploring associations between the variations in a gene and a trait assumes:
Current high throughput genotyping allows us to inexpensively genotype large numbers* of genetic markers(or variants) across the genome
Dissimliar to candidate gene appraoach
across entire genome
Similar to linkage analysis
Quantitative: BMI, Fasting glucose
Qualitative: Obesity, T2D, Asthma, CVD
Dense genotyping
Large study pop (case/control unrelated)
Mendelian disorders
Good for high heritability
Estimate Heritability of twins: H2= 2 x (rmz-rdz)
MZ/DZ graph
DNA finger printing
Use fam Studies: Use twin studies- MZ and DZ
(higher heritability, greater contribution of genetic diff. 0= no genetic contrib 1=genotype is responsible (totally)
Quantitative: Correlation and Heritability
Coefficient of Correlation (r)
Larger rrr, greater fam ag (greater than 1)
Measures: RR and Fam hx case-control
DMD
X linked rec, mutation rate 10^-4
Muscle weakness at 3-5 yoa, heart and resp are also affected
Duchenne Muscular Dystrophy
Cystic Fibrosis
CFTR only gene assoc with CF
Genocopy: Similar phenotypes show varying genotypes on different loci
Principal effects in lungs and exocrine pancreas increase in sweat sodium and Cl concentration
Familial Hypercholesterolemia
Gene dosage: earlier manifestation and sev.
LDLR mutations are auto semidom trait Both homo and heterogeneity phenotypes
Group of metabolic disorders chracterized by elevated plasma lipids carried by apolipoprotein B
PKU and Tay-Sachs
Tay-Sachs: Lysosomal storage disease Pseudodeficiency Alleles: clinically benign allele that has a reduction in function activity detected by in vitro assays but has suffiecnt activity
Example of allelic Heterogeneity: Over 1557 mutations world wide found in patients with PKU Variant and non-variant PKU
PKU: mutation in PAH--> neg impact on degre of phenylalanine PAH expressed in liver, damage CNS First genetic defect to cause intellectual disability normal at birth, microcephaly, hyperactivity, seizures, and learning disability Phenyalaline--> Tyrosine, with help from BH4 (cofactor) and PAH
Mendelian diseases are not really “simple” • Reduced penetrance • Heterogeneity (allelic, phenotypic) • Genotyping errors leads to spurious recombinants → loss of power • The multi-locus map helps to detect this error by checking for unusual double recombinants
1-theta=Pr (no recom)
theta: Pr (recombination
Log Likelihood ratio
Z(theta) = log 10 (L(theta)/L(theta=0.5))
Test if a genetic marker & disease locus are linked • Genotypes at disease locus are unknown but phenotype (affection status) is known
Goal: Identify a chromosomal region linked to a disease within families that exceeds the null expectation, which enable localization of disease gene in the genome
Recombination happens in prophase
Why Linkage:
• In most cases little is known about the genomic location of genes contributing to disease • Thus, the study design usually consists of systematically surveying the entire genome • The extent of linkage is a function of the physical distance between the loci on the chromosome • Based on recombination between loci 10
use fam with disease, identify regions that co-seg with phenotype
Posostionlal cloning
Mutations increase in freq if they increase in number of offspring
Mutations spread by migration
Mutations may change in frequency by chance events
New Traits arise via chance mutations in DNA
Practical:
The most common forms of α-Thalassemia are the result of gene deletions. Rationalize the high frequency of deletions in mutational carriers.
a- Thalassemia: -Two identical a-globin genes on each chromosome (16) Tandem homologous a-globin genes facilitates misalignment between domains
Hereditary persistence of fetal hemoglobin
A group of clinically benign conditions that impair perinatal switch: y-globin --> B-globin synthesis Ex: Hb F
Thalassemias
Diseases that result from decreased abundance of one or more of globin chains Ex: B-thalassemias
Structural variants
Alters AA sequence of globin PP--> alter properties of the protein Ex: Sickle Cell and Methemoglobin
Locus Control Region (LCR): req for expression of all genes in B-globin cluster areas of "open" DNA gives TF access to reg elements that mediate expression
Temporal switches of globin synthesis are accompanied by changes in the principal site of erythropoiesis
a, b, and y: Globin switching changes in expression of global molecules during development
Sickle cell disease and B-thalassemeia each result from distinct B-globin gene mutations.
Ex: thalassemia. genes at diff loci (16 a-globin and 11 B-globin gene both causing thalassemia
Assosiation of more than one locus with clinical phenotype
B-Thalassemia: HBB: chromosome 11p15.4 over 200 disease causing mutations identified
The occurrence of more than one allele at a locus Diff mutation at same gene
Alleles present at that locus
One of several alternative forms of sequence at a locus 2 alleles per locus, one per chromosome
A measurable unit on a chromosome single nucleotide polymorphism (SNP)
Position on the chromosome: Disease Locus & Marker Locus
Sickle Cell Anemia: Hemoglobin chains aggregate. E6V (AA Sub)
Enhance one or more of the functions of the protein Increase in amount of function or abundance of the protein
May alter coding, regulatory, or other regions Can have range of effects if residual function is maintained
