Evolution, 4th Edition

184 CHAPTER 7

saw that a selective sweep leaves a region of depressed polymorphism in the region

of chromosome near where a selective sweep occurred (see Figures 5.15 and 5.16).

Here we will look at three more methods that are widely used to study adaptation

at the level of the genes. Other approaches are discussed in the Suggestions for

Further Reading [30-32, 36].

Synonymous versus nonsynonymous differences

The BRCA1 locus has an important place in human health. Women who carry cer-

tain mutations in BRCA1 have greater than a 50 percent chance of developing breast

cancer and a 39 percent chance of developing ovarian cancer before age 70 [28].

Some women who find they carry this mutation make the courageous decision to

have a double mastectomy rather than risk developing cancer (FIGURE 7.20).

This locus also has an interesting evolutionary story: it has evolved rapidly

by positive selection in primates, particularly in the last few million years of

human history [22]. The signs of positive selection can be seen by comparing

the sequences of this gene from two species. We count the number of differ-

ences that are nonsynonymous, then divide that number by the number of DNA

sites in the gene where nonsynonymous mutations could occur. This gives us

the number of nonsynonymous differences per nonsynonymous site, which we

refer to as dN. We then repeat this procedure for the synonymous differences to

get dS, the number of synonymous differences per synonymous site. Finally, we

divide the two numbers to find the dN/dS ratio. We can calculate this ratio using

data from just a single individual sampled from each of two species, and for that

reason it is widely used.

How does this ratio inform us about selection? For many species, the synony-

mous sites are expected to evolve neutrally because changes to the DNA sequence

at those sites do not alter the protein. Those sites should accumulate differences

between species by random genetic drift (as predicted by Equation 7.2). Now con-

sider the nonsynonymous sites. If positive selection is at work, they will evolve

more quickly than the neutral synonymous sites, and differences between species

will build up more rapidly. Then the dN/dS ratio will be greater than 1. Another

Futuyma Kirkpatrick Evolution, 4e

Sinauer Associates

Troutt Visual Services

Evolution4e_07.20.ai Date 01-12-2017

Human

Bonobo

Angelina Jolie

Chimpanzee

Gorilla

8 Mya 6 Mya 2 Mya Today

Sites with disease-causing mutations

** ** *

Sites of positive selection

2.79

0.00

0.76

0.76

2.66

0.71

(A)

(B)

(C)

FIGURE 7.20 The BRCA1 gene, which is responsible

for many cases of breast cancer, shows evidence of

rapid evolution by positive selection in our recent

evolutionary past. (A) A phylogeny of great apes

showing the ratio of nonsynonymous to synony-

mous substitutions, dN/dS, along each branch. Ratios

in bold are significantly greater than 1, suggesting

evolution by positive selection. The dN/dS ratios on

the branches leading to humans and to chimps have

the highest values observed. (B) Schematic of BRCA1,

showing sites of mutations known to cause disease in

humans and sites that have recently evolved under

positive selection. The colored bands correspond

to domains of the BRCA1 protein. (C) The actress

Angelina Jolie made the brave decision to undergo

a double mastectomy after learning she had an 80

percent risk of developing breast cancer as a result of

her genotype at BRCA1. (After [22].)

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