1

… and what about positive Darwinian selection?

2

We have already discussed a test based on the ratio of fixed

to polymorphic differences

We note that the McDonald-Kreitman test requires data from many individuals from two populations or species. Let’s assume we only have one sequence from each species.

3

4

The KA/KS test requires two aligned sequences only.

5

6

The assumptions of this method are: (1)all synonymous mutations are neutral, i.e., they do not affect the fitness of the organism, (2) nonsynoymous mutations can be advantageous, neutral, or deleterious, (3) nonsynonymous mutations that are advantageous will undergo fixation in a population much more rapidly than neutral mutations.

If advantageous selection plays a major role in the evolution of a protein, then the rate of nonsynonymous substitution should exceed the rate of synonymous substitution.

7

If positive selection predominates, then KA/KS > 1

If neutrality predominates, then KA/KS << 1

8

Prevalence of positive selection

3,595 groups of homologous sequences

In 17 gene groups, the ratio of nonsynonymous to synonymous substitution was significantly larger than 1.

Endo T, Ikeo K, Gojobori T. 1996. Large-scale search for genes on which positive selection may operate. Mol. Biol. Evol. 13:685-690.

~ 0.45%~ 0.45%

9

Prevalence of positive selection

7,645 homologous gene groups from human, chimpanzee, and mouse.

In 6 groups, the ratio of nonsynonymous to synonymous substitution was significantly larger than 1, i.e., experienced positive Darwinian selection (Clark et al. 2003). ~ 0.08%~ 0.08%

10

The vast majority of The vast majority of molecular evolution molecular evolution is neutral.is neutral. Change = EquivalenceChange = Equivalence

11

Examples of extreme KA/KS values (>>1):

(1) Glycophorin C = a red-cell membrane protein that serves as the receptor for a Plasmodium falciparum erythrocyte-binding protein, hence mediating one of P. falciparum’s invasion pathways in humans. Selective factor? Malaria.

(2) Granulysin = a protein secreted by cytotoxic T cells when they attach to infected body cells. It creates holes in pathogens, such as Mycobacterium tuberculosi, and destroys them. Granulysin also induces apoptosis in infected cells. Selective factor? Tuberculosis.

12

Elevated KA/KS ratios are frequently found in sex-related genes, e.g., genes involved in mating behavior, fertilization, spermatogenesis, ejaculation, or sex determination.

13

Sperm lysin

Red: Nonsynonymous/Synonymous >> 1Green: Nonsynonymous/Synonymous ~ 1Gray: Nonsynonymous/Synonymous << 1

14

One of the highest KA/KS ratios (= 5.15) for a full-length protein was found in the 18-kilodalton protein in the acrosomal vesicle at the anterior of the sperm cell of several abalone species.

15

It is thought that sex-related genes are subject to positive selection for short periods of time during speciation as a means of erecting reproductive barriers that restrict gene flow between the speciating populations.

16

17

“A total of 585 of the 13,454 human-chimpanzee orthologs (4.4%) have observed KA/KS > 1.”

“Simulations show that estimates of KA/KS > 1 would be expected to occur simply by chance in at least 263 cases, if purifying selection is allowed to act non-uniformly across genes.”

€

583−263

13,454×100 = 2.4%

18

Methodological caveats: (1) The KA/KS test can only detect positive selection if the proportion of nonsynonymous substitutions that are adaptive is >70%. (2) The KA/KS test can only detect positive selection if it occurred recently.(3) The KA/KS test can only detect positive selection if there are few reversals (e.g., A to T to A).

19

20

21

In the KA/KS test we assumed that all synonymous changes are neutral.

It is possible, however, that not all synonymous changes are neutral.

22

For example, the fitness effects of synonymous and nonsynonymous mutations were experimentally shown to exhibit almost identical distributions in two protein-coding genes of Salmonella typhimurium (Lind et al. 2010).

In other words, a synonymous mutation was as likely to be deleterious as a nonsynonymous one.

23

24

What is the proportion of synonymous mutations by codon position?

First codon position = 6%Second codon position = 0% Third codon position = 69%

What is the proportion of neutral mutations by codon position?

First codon position = 21%Second codon position = 7% Third codon position = 42%

25

What is the proportion of synonymous mutations by codon position?

Second codon position = 0% Third codon position = 69%

What is the proportion of neutral mutations by codon position?

Second codon position = 7% Third codon position = 42%

26

What is the proportion of synonymous mutations by codon position?

Second codon position = 0% Third codon position = 69%

What is the proportion of neutral mutations by codon position?

Second codon position = 7%Third codon position = 42%

some

nonsynon

ymous

substitu

tions

are comp

letely

neutralSome synonymous substitutions are deleterious

27

28

29

Homoplasy = A structural resemblance that is due to parallelism or convergent evolution, rather than to common ancestry.

30Are the horns homologous or homoplastic structures?

31

Hair Bone

32

33

34

35

Pisciformy(fish shape)

36

Myrmecophagy(ant-eating)

37

Active flight has evolved at least four times (in insects, pterosaurs, birds, and bats).

Bioaerial locomotion

38

39

Evolution of

lysozymesin

ruminants, langurs

& hoatzins

40

41

Foregut fermenters are not herbivores, they are bacteriovores!

Food for bacteria

42

Foregut fermentation has arisen independently at least three times in the evolution of placental mammals, at least once in marsupials, and at least once in birds.

43

Ruminants (e.g., cows, deer, sheep, giraffes)

44

Colobus guereza

Colobine monkeys (e.g.,

langurs)

45

46Opisthocomus hoazin

Hoatzin (pronouced Watson), an enigmatic South American bird (most probably related to the cuckoos).

47Choloepus didactylus

48

QuokkaSetonix brachyurus

49

Convergent amino-acid replacements in lysozymes from the foregut of cow and langur. Only convergent replacements are shown, denoted by a one-letter abbreviation of the resultant amino acid followed by the position number at which the replacement occurred.

50

Adaptive replacements contribute to a better performance of lysozyme at low pH and confer protection against the proteolytic activities in the stomach.

51

Position 87

52

Position 87

53