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18.5: Mutation and Evolution

Mutations are the raw materials of evolution. Evolution absolutely depends on mutations because this is the only way that new alleles and new regulatory regions are created. However, this seems paradoxical because most mutations that we observe are harmful (e.g., many missense mutations) or, at best, neutral, For example, "silent" mutations encoding the same amino acid. Also, many of the mutations in the vast amounts of DNA that lie between genes. Morevoer, most mutations in genes affect a single protein product (or a small set of related proteins produced by alternative splicing of a single gene transcript) while much evolutionary change involves myriad structural and functional changes in the phenotype.

So how can the small changes in genes caused by mutations, especially single-base substitutions ("point mutations"), lead to the large changes that distinguish one species from another? These questions have, as yet, only tentative answers.

One Solution: Duplication of Genes and Genomes

Mutations that would be harmful in a single pair of genes can be tolerated if those genes have first been duplicated. Gene duplication in a diploid organism provides a second pair of genes so that one pair can be safely mutated and tested in various combinations while the essential functions of the parent pair are kept intact.

Possible benefits:

  • Over time, one of the duplicates can acquire a new function. This can provide the basis for adaptive evolution.
  • But even while two paralogous genes are still similar in sequence and function, their existence provides redundancy ("belt and suspenders"). This may be a major reason why knocking out genes in yeast, "knockout mice", etc. so often has such a mild effect on the phenotype. The function of the knocked out gene can be taken over by a paralog.
  • After gene duplication, random loss of these genes at a later time in one group of descendants different from the loss in another group could provide a barrier (a "post-zygotic isolating mechanism") to their interbreeding. Such a barrier could cause speciation: the evolution of two different species from a single ancestral species.


  • Paralogous genes. Genes in one species that have arisen by duplication of an ancestral gene. Example: genes encoding olfactory receptors.
  • Duplication of the entire genome. Examples:
    • Polyploid angiosperms.
    • Genome analysis of three ascomycetes show that early in the evolution of the budding yeast, Saccharomyces cerevisiae, its entire genome was duplicated. Each chromosome of the other ascomycetes contains stretches of genes whose orthologs are distributed over two Saccharomyces cerevisiae chromosomes.
    • There is also evidence that vertebrate evolution has involved at least two duplications of the entire genome. Example: both the invertebrate Drosophila and the invertebrate chordate Amphioxus contain a single HOX gene cluster while mice and humans have four.

A Second Solution: Mutations in Regulatory Regions

Not all genes are expressed in all cells. In which cells and when a given gene will be expressed is controlled by the interaction of (1) extracellular signals turning on (or off),(2) transcription factors, which turn on (or off), and (3) particular genes. A mutation that would be lethal in the protein coding region of a gene need not be if it occurs in a control region (e.g. promoters and/or enhancers) of that gene. In fact, there is increasing evidence that mutations in control regions have played an important part in evolution. Examples:

  • Humans have a gene (LCT) encoding lactase; the enzyme that digests lactose (e.g. in milk). In most of the world's people, LCT is active in young children but is turned off in adults. However, northern Europeans and three different tribes of African pastoralists, for whom milk remains a part of the adult diet, carry a mutation in the control region of their lactase gene that permits it to be expressed in adults. The mutation is different in each of the 4 cases examples of convergent evolution.
  • There are very few differences in the coding sequences between genes of humans and chimpanzees. However, many of their shared genes differ in their control regions.
  • The story of Prx1. Prx1 encodes a transcription factor that is essential for forelimb growth in mammals. When mice have the enhancer region of their Prx1 replaced with the enhancer region of Prx1 from a bat (whose front limbs are wings), the front legs of resulting mice are 6% longer than normal. Here, then is a morphological change not driven by a change in the Prx1 protein but by a change in the expression of its gene.
  • The story of Pitx1
  • The story of Style2.1 in the domestic tomato

A Third Solution?

Another theoretically-possible way by which a point mutation might give rise to a new gene is if the point mutation in a previously noncoding section of DNA converts a triplet of nucleotides into ATG thus creating a new open reading frame (ORF). It is increasingly evident that much of noncoding DNA is transcribed into a heterogeneous collection of RNAs. Transcription of DNA with its newly-acquired ATG codon would produce an RNA molecule with a translation start codon (AUG). Translation of this RNA would create a protein that most likely would be useless, perhaps even harmful but might, on rare occasions, provide the starting point for the acquisition of a new useful gene.

Large Changes in Phenotype can come from small changes in Genotype

Selector Genes

The building of an organ requires the coordinated activity of many genes. However, these are often organized in hierarchies so that "upstream genes" regulate the activity of "downstream genes". The closer you get to the top with a mutation, the greater the changes affected downstream.

Follow these links to see examples of the influence of "master" (selector) genes on the phenotype.

The Story of Pitx1

Pitx1 is homeobox gene (similar to bicoid in Drosophila) with orthologs found in all vertebrates. It contains 3 exons that encode a protein of some 283 amino acids (varying slightly in different species) which is a transcription factor that regulates the expression of other genes involved in the differentiation and function of multiple features including:

  1. the anterior lobe of the pituitary gland (Pitx1 = "Pituitary homeobox1");
  2. jaw development (mutations are associated with cleft palate);
  3. development of the thymus and some types of mechanoreceptors;
  4. development of the hind limbs.

Its activity in these regions is controlled by regulatory regions (promoters and/or enhancers) specific to each region (and presumably turned on by other transcription factors in the cells of those regions).

Pitx1 is an essential gene. Mutations in the coding regions are lethal when homozygous (shown in mice). However, mutations in noncoding regions need not be. All vertebrates have a pelvic girdle with associated bones which make up the pelvic fins of fishes and the hind legs of the tetrapods. Pitx1 is needed by them all for the proper development of these structures (as well as the other functions of Pitx1).

In a remarkable study of three-spined sticklebacks published in the 15 April 2004 issue of Nature, Michael Shapiro, Melissa Marks, Catherine Peichel, and their colleagues report that a mutation in a noncoding region of the Pitx1 gene accounts for most of the difference in the structure of the pelvic bones of the marine stickleback and its close freshwater cousins.

The marine sticklebacks have prominent spines jutting out in their pelvic region (red arrow) as well as the spines along the back (that give the fish its name). These spines may help protect them from being eaten by predators. (Drawing courtesy of the Parks Administration in the Emilia-Romagna region of Italy.) The also express the Pitx1 gene in various tissues, including thymus, mechanoreceptors, and the pelvic region.

The four species of stickleback that inhabit the Atlantic coast of North America. These species are sympatric between Newfoundland, Canada and Long Island, New York, United States. Image used iwth permission (CC BY-SA 3.0; Ghegeman).

The freshwater sticklebacks have no — or very much smaller — spines in their pelvic region. They express the identical Pitx1 gene in all the same tissues except those that develop into the pelvic structures. The reason: a mutation in an enhancer upstream of the Pitx1 exons. The unmutated enhancer turns on Pitx1 in the developing pelvic area. (Mice homozygous for a mutation in this control region have deformed hind limbs.)

Here then is a remarkable demonstration of how a single gene mutation can not only be viable but can lead to a major change in phenotype - adaptive evolution. (The changes seem not to have produce true speciation as yet. The marine and freshwater forms can interbreed. In fact, that is how the differences in their hind limbs were found to be primarily due to the expression of Pitx1.)

A survey of 21 different populations of sticklebacks - both freshwater and marine - from different regions of North America, Europe, and Japan has revealed a pattern of consistent genetic differences that distinguish the freshwater from the marine forms. However, only 17% of the distinguishing mutations were found in exons that alter the amino acid sequence of the encoded proteins. All the rest were "silent" and most, 41% or more, of these occurred in intergenic regions. These results further demonstrate the importance of mutations in regulatory regions - promoters and enhancers - in the evolution of adaptive phenotypes.