Mutation and Evolution

Mutations are the raw materials of evolution.

Evolution absolutely depends on mutations because this is the only way that new alleles are created.

• 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
    • mutations in noncoding DNA (e.g. "junk" DNA).
• most mutations 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?

The Problem of Harmful Mutations

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.

Evidence:

• 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. [View]

A Second Solution: Mutations in Regulatory Regions

• extracellular signals turning on (or off)
• transcription factors, which turn on (or off)
• particular genes

The Problem of How 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.

• Embryonic Development: Getting Started
  (especially the story of bicoid and nanos)
• Organizing the Embryo: The Central Nervous System
• Organizing the Embryo: Segmentation
  (more on bicoid and nanos)
• Embryonic Development: Putting on the finishing touches
  (especially the discussion of homeobox genes)

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

• 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.

• 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.)
• express the Pitx1 gene in various tissues, including
  • thymus
  • mechanoreceptors, and
  • the pelvic region.

• have no — or very much smaller — spines in their pelvic region;
• express the identical Pitx1 gene in all the same tissues except those that develop into the pelvic structures.
• The reason: a mutation in the vicinity of the Pitx1 exons but not in them. The sequence mutated is as yet unknown but presumably has occurred in a promoter or enhancer of Pitx1 that 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.)