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?

Four papers to read:

1. Balter, M. 2005. Are human brains still evolving? SCIENCE 309:1662 - 1663.

2. Evans, P.D. et al. 2004. Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size. Human Molecular Genetics 13: 1139-1145.

3. Vallender, E.J. and B.T. Lahn. 2004. Positive selection on the human genome. Human Molecular Genetics 13: R245-R254.

4. Evans, P.D. et al. 2005. Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans. SCIENCE 309: 1717-1720.

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) substitutionsin a comparison between species or races or populations

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

Definitions of Ka and Ks and Ka/Ks

Synonymous substitutions are not 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 --> CTTVal (V) - Glu (E) GTA --> GAAThr (T) - Pro (P) ACC --> CCCLeu (L) - Phe (F) CUU --> UUUSer (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

What the Ka/Ks ratio means

Ka/Ks = 1.0 Neutral evolution

Ka/Ks < 1.0 Purifying selection (negative selection)

-- the typical form of selection for all life

Ka/Ks > 1.0 Positive Selection (accelerating evolution)

What this means

Non-synonymous substnsare selected against

At least some non-synonymoussubstns are selected for

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

Example calculations from Table 3.3

Human/Rabbit -globin: Ka/Ks = 0.015/0.294 = 0.051

Human/Rabbit Apo E: Ka/Ks = 0.114/0.108 = 1.06

Ka/Ks ratios show positive selection within primate lineage

Some “controls” to showprimate-specificand human-specificadaptive (accelerated)evolution of MCPH

Sliding window profile of Ka/Ks in MCPH gene from differentgroups of organisms to highlight primate-specific accelerated evolution

+ 33 more, including ASPM and Microcephalin and BRCA1

Vallender and Lahn. 2004. Positive selection on the human genome. Human Molecular Genetics 13: R245-R254.