Lecture 3 Flashcards
Explain the hardy weinberg law
Allele Frequencies:
Frequency of allele A in population (p) = number of A alleles/total number of alleles
Frequency of allele a in population (q) = number of a alleles/total number of alleles
p+q=1
Genotype frequencies:
AA = p2
aa = q2
Aa = 2aq
So p2 + 2pq + q2 = 1
When does the hardy weinberg rule apply?
If mating is random and population is stable
Assumptions of hardy weinberg rule
- Mating is random
- No inbreeding
- Alleles frequencies remain consistent across generations:
Can change due to mutations in small populations, selection e.g. heterozygote advantage, and genetic drift (random changes in population)
Explain the two measures of inbreeding
Coefficient of relationship (R): proportion of alleles shared by two people by having common ancestors
- Sum of (1/2)^n where n is number of links through a common ancestor between 2 people.
- For full sibling (1/2)^2 + (1/2)^2=1/2
Coefficient of inbreeding (F): proportion of loci at which individual is expected to be homozygous:
1/2R if parents
If parents are cousins: F = 1/2(1/2^4 + 1/2^4) = 1/16
Inbreeding and the risk of recessive disease
q=0.01
0.005
0.001
q2=1 in 10,000 for unaffected parents
1 in 40,000
1 in 1,000,000
q/16 = 1 in 1600 for first cousin marriage
1 in 3200
1 in 16,000
Relative risk for first cousins
1/16q = 6.25
12.5
62.5
Inbreeding and fitness - general fertility
The inbreeding coefficient for runs of homozygosity (FROH) is associated with deleterious changes in 32/100 traits tested using 1.4 million people
These changes are not associated with common variant homozygosity - suggests genetic variants with inbreeding depression are predominantly rare
FROH equivalent to first cousins having children shows a 55% decrease
What percentage of child deaths are caused by parent relations
20%
What are the 5 categories that can be affected by inbreeding
- Reproductive success
- Risky behaviours e.g. drinking
- Cognitive ability
- Body size
- Health
Especially in males
Explain the frequency and persistence of mutations
- One mutation per 30 million base pairs per generation (100 per genome).
- Average of one protein-coding gene per generation
Persistence depends on:
- Mutation type (dominant, recessive, X-linked)
- Selection (positive, neutral, negative)
Persistence of deleterious mutations
- Dominant lethal: single generation
- Dominant conditions affecting reproductive success: one to a few generations
- Late onset dominant (e.g. Huntington’s): many generations
- X-linked lethal: 1/3 lost per generation
Autosomal recessive: several-many generations but mostly eventually lost, depending on pop size and selective disadvantage
Explain heterozygote advanatge
Can decrease frequency of deleterious mutations including sickle cell and malaria
Aa -> aa (-X-> Sickle cell), Aa, AA (-X-> Malaria)
Also CF allele and resistance to tuberculosis
Founder effect
Variety of mutant alleles in source population
Founders of new population increase the frequency of previously rare alleles and reduce variability
Explain multifactorial traits and heritability
Traits can be affected by a single gene or can be polygenic
Traits can also be affected by either environmental factors or genetic factors (heretability: the proportion genetic variation that explains phenotypic variation)
Phenotypic variation = genetic variation + environmental variation
v2=VG/VP
v2 = heretability
VG - genetic variation
VP - phenotypic variation
How do complex genetic diseases differ to mendelian ones
- No clear pattern of inheritance
- Run in families
- Few large pedigrees of multiply affected individuals
- Most people have no known family history
Explain heretability
- How much of an observed variation is caused by genetics
- Highly penetrant, single gene disorders have heritability of 0 (no variation)
Usually nearly always some variability (effects of modifier genes and environment)
Schizophrenia risk factors
Family history is major factor
Other factors include Rubella, CNS damage, bereavement
What diseases and disorders are more likely if a first degree relative has had it?
Major depression
ADHD
Schizophrenia
Bipolar
Autism
What are the fold greater chances of having a disease if sibling is affected
Cystic fibrosis - 500
HD - 5000
MS - 25
Late onset Alzheimer’s - 4
Effects of drugs
Serious side effects: 1 in 15 hospital admissions
Sensitivity to drugs: 20X variation is safe, effective dose of warfarin:
pharmacokinetics affect absorption, metabolism and excretion
pharmacodynamics effect target tissue
Variation in above is combination of genetic and environmental factors - Pharmacogenetics
Explain the liability model of heritability
In a phenotypic liability sample from a population, only proprotion K are affected which determines threshold in a normal standard deviation
Jn the phenotypic liability of relatives of affected individuals, Kr (risk to relatives of affected individuals) is greater and aR is the mean liability shift.
Azathioprine
Immunosuppressant
Side effect: Neutropenia
Causes low TPMT activity
Fluorouracil
Cancer treatment
Side effect: nervous system toxicity
Causes lack of dihydropyrimidine dehydrogenase
Succinylcholine
Muscle relaxant
Side effect: Prolonged apnea
Causes low butrylcholinesterase activity
Warfarin
Anticoagulant
Side effect: Excessive bleeding
Causes: Low CYP2C9 activity, variations in VKOR
Cytochrome P450 enzymes
low metabolisers (3-10% of population)
Lower doses required to achieve effect
Danger of over dose
Ultra-rapid metabolisers clear drug quickly from system, and require greater doses to achieve the same effect
