Genetic Variation in Populations Flashcards
What is the Hardy-Weinberg rule
= genetic variation in a population will remain constant from one generation to the next in the absence of disturbing factors.
p² + 2pq + q² = 1
(p = frequency of allele A in population)
(q = frequency of allele a in population
AA = p²
aa = q²
Aa = 2pq
p + q =1
= can be expressed as decimal or 1 in x
Working out probability of having affected child?
Probability of both being carries
x
Probability of two carriers having an affected child
What are the assumptions of the Hardy-Weinberg Rule?
Mating is random
(= but humans mate assortively)
No inbreeding
Allele frequencies remain constant across generations (with no:)
= mutations
= selection (e.g. heterozygote advantage)
= genetic drift (random changes in population)
(EXTRA READING)
= also no gene flow, infinite population size
What are the measures of inbreeding?
Coefficient of relationship (R)
= proportion of alleles shared by 2 people by having common ancestors (identity by descent)
= sum of (1/2)ⁿ
= n = number of links through a common ancestor between 2 individuals
= for full siblings = R = (1/2)² + (1/2)² = 1/2
Coefficient of inbreeding (F)
= proportion of loci at which individual is expected to be homozogous
= 1/2(R) of parents
= if parents cousins = F = 1/2 ( 1/2⁴ + 1/2⁴ ) = 1/16
Inbreeding and risk of recessive disease?
Risk for first cousins increases the rarer the recessive disease
e.g. Charles II of Spain - many closed loops - very disabled
How do mutations normally appear?
One mutation per 30 b.p (per generation)
= 100 per genome
Average of one protein-coding per generation
= can be non-harmful
Persistence of mutation depends on:
= type of mutation (different selection pressures)
(dominant, recessive, X-linked)
= selection
(positive, neutral, negative)
What is the persistence of deleterious mutations?
= balanced by de novo mutations
Dominant lethal
= single generation
Dominant conditions affecting reproductive success
= one to a few generations
Late onset dominant
= many generations (e.g. Huntington’s - already have reproduced)
X-linked lethal
= 1/3 lost per generation
Autosomal recessive
= several to many generations but mostly eventually lost
(dependent on population size, selective disadvantage)
What is the heterozygote advantage?
EXTRA READING
= when individuals who carry 2 different alleles have selective advantage over those who are homozygous
= leads to maintenance of genetic diversity
= e.g. sickle cell anaemia + malaria
= e.g. cystic fibrosis gene + resistance to typhoid fever
= e.g. HLA gene + immune function
What is the founder effect?
= reduces variability and increases the frequency of previous rare alleles
EXTRA READING
= when new population is established by small number of individuals who are genetically different from their original population
= results in loss of genetic diversity (new population have limited genetic variation)
= often seen in small, isolated populations
= genetic disorders become more prevalent
= BUT can also have beneficial traits
What are examples of multifactorial traits?
Height
Weight
Skin Colour
SUSCEPTIBILITY TO DISEASE
Response to drugs
EXTRA READING
= traits influenced by both genetics and environmental factors
= often do not follow simple pattern of inheritance
What is the difference for complex genetic diseases? (compared to Medelian disorders)
There is no clear pattern of inheritance
BUT tend to ‘run’ in families
Few large pedigrees of multiple affected individuals
Most people have no known family history
What is heritability?
= how much of the observed VARIATION in a trait is caused by genetics
Highly penetrant, single gene disorders should have heritability of 0 (no genetic variation)
BUT there is nearly always some variability
(effected of modifier genes , environment = risk factors?)
Estimating heritability?
(a) Runs in families?
λs = risk to sib / population risk
? shared family environment
(b) Twin Concordance
monozygotic > dizygotic
environmental affects controlled
(c) Adoption
biological > adoptive
= as seen in evidence showing genetic contribution to risk to relatives of having disorders such as depression, ADHD, Bipolar etc.
EXTRA READING
= family studies
= twin studies
= can then use statistical methods to calculate heritability coefficient
(represents proportion of variation in disorder attributed to genetic factors)
What are some examples of λs?
λs = fold greater chance of having disease if sibling is affected
What is the liability model?
= how to get to heritability from observed risks to relatives (in complex disease)
= using normal distribution theory
= percentage of the variance in liability in attributable to genetic factors
EXTRA READING
= explains complex interplay between genetic and environmental factors
= e.g. schizophrenia and autism
= helps to explain variability in disease manifestation even in individuals with similar genetic or environmental risk factors
What are some examples of drugs producing serious side effects in some people?
= e.g. warfarin response = genetic variants in metabolising genes (Cytp450) and target (VKOR)
low metabolisers
= metabolise drug very slowly
= lower doses requires
= danger of overdose
ultra-rapid metabolisers
= clear drug very quickly
= require greater doses
CYP2D6 = converts codeine to morphine
CYP2C9 = inactivates warfarin
CYP2C19 = metabolites >10% of drug
EXTRA READING
= VKORC1 gene = encodes protein that warfarin targets to inhibit blood clotting
= variants can result in decreased amount of protein = more sensitive to warfarin = lower doses
= other genetic factors = vitamin K metabolism + transport, genes involved in drug transport and metabolism
