EHJ352H1 Lecture Notes - Lecture 9: Gamma Distribution, Intron, Genetic Load

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26 Jan 2013
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Lecture 9+10: Human mutation load
Mutations happen, most are deleterious and thus all populations contain deleterious
mutations
At mutation-selection balance:
Frequency of deleterious allele (q) = u/s
The mean fitness depend on mutation rate: equilibrium frequency of deleterious
allele = u/hs. If mutation is really deleterious there will not be many at equilibrium,
its average effect is rather small. If a minor deleterious allele will have more copies.
Thus selection will either make the effect really big and amount of alleles really
small, or the bigger effect on the mean fitness due to the large amount of copies but
small individual effect
W=1-2u, W is almost equal to 1. Only 1 gene and if multiple by all genes then the
result is rather big.
Selection decreases the number of mutations and mutation increases the number of
mutations
Haldane: Weq = e^-U, U is the average number of new deleterious mutation rate
each time the offspring is produced, per generation
Mutation load: extent by which mean fitness is reduced due to mutation.
L=1-e^-U
If there was 1 new bad mutation per generation, then the Weq = 0.37. The
accumulative effect of rare alleles in the entire population
If there were 3 bad mutations per generation, then Weq will be 0.05
If we have such a high mutation load, how are we a thriving species?
1. The prediction is right: we are a lot less fit than we could be
2. The prediction is right; however it does not really affect our productivity as a
species. We are mainly limited by competition with each other, others have bad
alleles also!
3. The prediction is wrong as some of the simplifying assumptions used in the model
are violated, however he gives a decent estimate and the simplifying assumptions
might not even make the load smaller
Phenomena that may be influenced by deleterious mutations: inbreeding depression,
variation in fitness (health) and genome size and complexity
Evidence of deleterious alleles:
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1. Explicit genetic disease
Type 2 diabetes, breast cancer, myopia and migraine etc.
Perhaps 50% of the highest death rates (heart disease, cancer etc.) have
genetic factor, 42.5% of deaths due to deleterious mutations
2. Inbreeding depression
Inbreed individuals tend to be less fit than outbreed individuals
Most deleterious alleles are at least partially recessive. The a allele may be
rare in the population but common in the family, thus when 2 close
members mate then the deleterious recessive allele will be passed on,
increase the chances of producing homozygous offspring
Fruit fly: 71% less fit
Mouse: 100% less fit
Beetle: 37% ID
Flower: 83% less fit
Humans: 70% ID, usually first cousin mating and extrapolate them into full
inbreeding
3. Loss of Function
Typical individual have: 190-210 in-frame, 80-100 nonsense, 40-50 splice
site disrupting, 220-250 off-frame deletions
340-400 assumed LOF mutations per individual
Estimated that each genome is heterozygous for 50-100 variants classified
by the database as causing inherited disorders.
However a later (2012) study estimated 100 high confidence LOFs, after
eliminating false positives
LOF genes: less evolutionary conserved, thus higher than average values of
Ka/Ks.
High Ka/Ks can be due to adaptive evolution or relaxed selection
Lower than average conservation in promoter regions
LOFs have more closely related genes (paralogs) than other genes: perhaps
more functional redundancy
Compared to derived variants (from ancestral) at synonymous sites, high
confidence LOFs should be rarer,
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