1. Evolution of individual genes in humans
Are there any examples of genes that are actively evolving in
humans (but which are static in other primates)?
If so, how do we distinguish genes that are under
POSITIVE SELECTION from those that are under
PURIFYING SELECTION?

2. Four papers to read:
Balter, M Are human brains still evolving? SCIENCE 309:
Evans, P.D. et al Reconstructing the evolutionary history of
microcephalin, a gene controlling human brain size. Human
Molecular Genetics 13:
Vallender, E.J. and B.T. Lahn Positive selection on the human
genome. Human Molecular Genetics 13: R245-R254.
Evans, P.D. et al Microcephalin, a gene regulating brain size,
continues to evolve adaptively in humans. SCIENCE 309:

3. POSITIVE SELECTION (ACCELERATING EVOLUTION)
The traditional way of determining whether a gene is under
PURIFYING SELECTION (NEGATIVE SELECTION) or
POSITIVE SELECTION (ACCELERATING EVOLUTION)
Ratio of Synonymous (Ks) vs Non-synonymous (Ka) substitutions
in a comparison between species or races or populations
Ka/Ks

4. Synonymous substitutions are not subject to Natural Selection
Definitions of Ka and Ks and Ka/Ks
Ks = frequency of synonymous substitutions, i.e.,
the ratio of synonymous substitutions per synonymous site, e.g.,
Leu (L) --> Leu CTT --> CTA, TTA --> TTG, etc
Cys (C) --> Cys TGT --> TGC
Arg (R) --> Arg (R) CGG --> AGG
Synonymous substitutions are not subject to Natural Selection

5. Non-synonymous substitutions are subject to Natural Selection
Ka = frequency of non-synonymous substitutions, i.e.,
the ratio of nonsynonymous substitutions per nonsynonymous site, e.g.,
-- any nucleotide substitution that causes an amino acid substitution
Val (V) - Leu (L) GTT --> CTT
Val (V) - Glu (E) GTA --> GAA
Thr (T) - Pro (P) ACC --> CCC
Leu (L) - Phe (F) CUU --> UUU
Ser (S) - Arg (R) AGC --> AGA
Non-synonymous substitutions are subject to Natural Selection
i.e., they are usually deleterious and thus they are seen much
more rarely than synonymous substitutions

6. What the Ka/Ks ratio means
What this means
Ka/Ks = 1.0 Neutral evolution
Ka/Ks < 1.0 Purifying selection
(negative selection)
-- the typical form of selection for all life
Non-synonymous substns
are selected against
Ka/Ks > 1.0 Positive Selection
(accelerating evolution)
At least some non-synonymous
substns are selected for

7. Most genes are under purifying selection.
Apolipoprotein E appears to be an exception

8. Example calculations from Table 3.3
Human/Rabbit -globin: Ka/Ks = / =
Human/Rabbit Apo E: Ka/Ks = / = 1.06

10. Ka/Ks ratios show positive selection within primate lineage

11. Some “controls” to show
primate-specific
and human-specific
adaptive (accelerated)
evolution of MCPH

12. Sliding window profile of Ka/Ks in MCPH gene from different
groups of organisms to highlight primate-specific accelerated
evolution

13. + 33 more, including ASPM and Microcephalin and BRCA1
Vallender and Lahn Positive selection on the human genome.
Human Molecular Genetics 13: R245-R254.
+ 33 more, including ASPM and Microcephalin and BRCA1