Sep. 02, 2011

How Mutational and Epigenetic Changes Enable Adaptive Evolution

  • Fig. 1: Top: Gene switched ‘on’ with transcription possible with acetylated histones (red) and unmethylated cytosines (white circles). Bottom: Gene switched ‘off’ with transcription prevented with methylated cytosines (yellow circles) and deacetylated histones compacting the chromatin.Fig. 1: Top: Gene switched ‘on’ with transcription possible with acetylated histones (red) and unmethylated cytosines (white circles). Bottom: Gene switched ‘off’ with transcription prevented with methylated cytosines (yellow circles) and deacetylated histones compacting the chromatin.
  • Fig. 1: Top: Gene switched ‘on’ with transcription possible with acetylated histones (red) and unmethylated cytosines (white circles). Bottom: Gene switched ‘off’ with transcription prevented with methylated cytosines (yellow circles) and deacetylated histones compacting the chromatin.
  • Fig. 2: The synthesis of a complimentary copy of DNA (to DNA) from an RNA template, with new mutations integrated into the new DNA’.
  • Fig. 3: Model showing the key pathways involved in updating the epigenome and the genome as a result of feedback from the environment.
  • Dr Robyn A. Lindley, Melville Analytics Pty Ltd, Jindabyne, Australia

After two long centuries of evolutionary debate, it seems that we need to resurrect the ideas first put forward by Jean-Baptiste de Lamarck in 1809. The new genetics is providing us with extant evidence suggesting that nature has evolved a number of mechanisms to enable all organisms to evolve as they adapt to their environment: pondering the genesis of the epigenetic and mutational changes involved gives rise to a new theory of evolution based on the inheritance of acquired characters.

When Jean-Baptiste de Lamarck came up with the idea of acquired inheritance in 1809, he couldn't justify it [1]. However, the new genetics is providing us with molecular evidence suggesting that environmentally ‘directed' epigenetic changes, combined with targeted mutations best explains the new evolutionary model [2]. While some neo-Darwinians are still reluctant to accept a Lamarckian world view, many mainstream biologists are now openly supporting a Lamarckian view of evolution. But what mainstream scientific evidence is there to support the new theory of adaptive evolution?

Epigenetic Changes
The science of epigenetics is providing some of the most compelling evidence supporting the idea of acquired inheritance [3]. In the last decade we have discovered a number of molecular mechanisms that are used to write additional information onto the surface of our genes without altering the genomic sequence code. While some epigenetic mechanisms involve altering the surface of the individual nucleotides A, G, C or T/U, others involve changes in DNA folding patterns.
The main molecular mechanisms that mediate epigenetic regulation include DNA methylation and chromatin/histone modifications (see fig 1). Histone methylation plays a critical role in many epigenetic phenomena by producing conformational changes that switch genes to either an ‘off' state (not able to be transcribed), or an ‘on' state (able to be transcribed). These gene expression mechanisms enable the genome to rapidly adapt to a wide range of environmental changes, and they are responsible for generating diversity among individuals who may share the same DNA. Inheritance of this type of modification can occur rapidly to enable a species to adapt to sudden environmental change.

There are now a number of studies showing that what we eat, why birds suddenly build nests, the environmental stresses we are exposed to and even some subtle changes in behaviour by rat mothers can be inherited by first and subsequent generations of offspring.

One of the key questions raised by these findings is how was such a sophisticated ‘library' of genetic alternatives and cross-gene linkages created as we evolved? To answer this question, we need to evoke ways for environmental feedback to result in mutational changes in the genome.

Environmentally Directed Mutation
The inheritance of environmentally induced epigenetic change relies on a process for creating new genes or alternative gene associations in response to environmental stimuli at some stage in our evolutionary past. It implies that there are mechanisms for the creation and integration of new genomic information by generating environmentally directed mutations, and reverse transcription to integrate the favoured or selected changes into the genome (see fig 2). We now know that there are a range of environmentally directed mutations that are both time dependent and loci specific on the genome. While this view remains controversial among many scientists, there is now an expanding body of research suggesting that these processes are play an important role in generating adaptive mutations in a number of genes. A key step involves reverse transcription. The process can occur rapidly, or more slowly, and the changes can be inherited.

The antibody genes provide a wonderful example of how the genome is updated in response to an almost infinite variety of new foreign pathogens. The first clues that the antibody gene family might have developed as an adaptive process were provided through experiments conducted by Australian immunologist Ted Steele and his Canadian colleague Reg Gorczynski. To build a theoretical model to explain their predictions, Steele relied on Howard Temin's ideas on reverse transcription as the mechanism for new RNA to be integrated into the genomic DNA following exposure to a previously unknown pathogen. While it has taken almost three decades for Steele to be vindicated for proposing his Lamarckian model, we now know that the antibody genes are updated via a complex set of pathways involving targeted hypermutation and reverse transcription [4]. While some of the details of the somatic hypermutation mechanisms involved remain in dispute, the immune system provides a well studied model demonstrating how new pathogens in the environment have acted as the force guiding the evolution of the vertebrate antibody gene family.

Horizontal Gene Transfer
The discovery of horizontal gene transfer effects has also added to our understanding of how environmentally directed mutations can arise.

When Albrecht von Kolliker proved that sperm cells arose as differentiated tissue cells in 1941, few realized the evolutionary implications [5]. Yet, for decades scientists continued to believe that the Weissmann's barrier existed between the heritable information in somatic cells and the reproductive germline cells, thus preserving the integrity of the genes we inherit. Since then, we have discovered that undifferentiated bone marrow stem cells are used to differentiate into ova in adult females and sperm cells in males. When the new cells are formed they are able to integrate somatically updated DNA.
One of the earliest experiments showing that foreign DNA can become integrated into the genome was reported by French biologists Jacques Benoit and Pierre Leroy in 1960. They injected pure DNA extracted from Khaki Campbell ducks into purebred Pekin ducklings. The ducklings bred to the next generation of purebred Pekin ducklings showed some of the phenotypic features of the Khaki Campbell ducks. Other experiments using Ephestia produced similar results.

More recently experiments have been conducted to demonstrate the speed with which new genetic information can be integrated into the germline and inherited. Patrick Fogarty of the biopharmaceutical company Tosk Inc. in California, showed that when he injected mice with vectors carrying foreign DNA, the new genetic cargo became integrated into almost all of the somatic cells tested [6]. Progeny from mice that were injected as early as two days prior to mating unexpectedly produced transgenic progeny. The new genome remained stable for the first four generations tested. Fogarty concluded that mature germ cells could readily integrate the new genetic cargo.

When tiny gold pellets coated with foreign DNA are fired into the chromosomes of a plant, the plants molecular machinery is also ready and able to integrate the foreign DNA into their chromosomes. The next generation of plants are then cultivated with the new genes and the acquired features that these confer.

The Sire Effect
Among the eukaryotes, the sire effect is another curious form of acquired inheritance involving the integration of foreign DNA: it involves genetic transfer from the sire that first breeds with a female to future offspring fathered by another male. That is, a female's sexual partners may be able to provide genetic material that is inherited by future offspring she may bear to other males. While this idea has influenced some animal breeding practices for centuries, there is some molecular evidence to verify the phenomenon. In the 1980s, experiments by Reg Gorczynski and his colleagues in Canada reported that the phenomenon was observed in the immune system [7]. They used a group of normal female mice that had at least three litters with males that had received a skin graft and been inoculated so that rejection of the graft was significantly delayed. They showed that these females continued to produce some offspring showing the same delayed rejection of a skin graft, even when the new father was a normal non-grafted male.

Other experiments verifying the sire effect phenomenon were conducted using rabbits. To understand how wild rabbit populations might develop resistance to the Myxomatosis virus faster than predicted, Bill Sobey and Dorothy Connolly conducted a number of controlled breeding experiments at the Australia's Commonwealth Scientific and Industrial Research Organisation (CSIRO) laboratories [8]. They reported evidence suggesting that recovered bucks which acquired immunity were able to pass their immunity to offspring when mated with a doe who had not previously been exposed to the Myxomatosis virus. When they later mated a non-immune buck to the same does, they found that their offspring were also born with immunity to the virus.

Acquired Inheritance Effects in Bacteria and Fungi
It is also well known that acquired inheritance effects involving epigenetic and environmentally directed mutation phenomena occur in bacteria and fungi. In 1944 Oswald MacLeod and Maclyn McCarty showed that when you feed a non-encapsulated pneumonococcus bacterial strain with pure nucleic acid carefully extracted from a more virulent and lethal encapsulated strain that has a protective coating on its surface, the bacteria that were fed the nucleic acid were transformed into the more lethal fully encapsulated strain [9].

Another key experiment that has helped to further the acceptance of acquired inheritance effects in bacteria was performed by John Cairns and a group of other scientists at Oxford University in 1988 [10]. Cairns concluded that he had found evidence suggesting that bacteria could somehow select which mutations to produce. When they placed a sample of E. Coli that was unable to consume lactose into an environment where lactose was the only food source available, they observed that the genetic makeup of the bacteria rapidly changed so that the next generations of the original bacteria were able to effectively use lactose as a food source. The bacteria use various forms of hypermutation in response to environmental stress to enhance their search for the most appropriate new mutations for integration into their DNA.

Experiments using other microbial test systems have since confirmed that acquired inheritance phenomena like these examples are widespread in single celled organisms like yeast and bacteria.

All bacteria, yeast, fungi, plants and eukaryotes are designed to evolve as they interact with the environment. If the environmental conditions change suddenly, then genes possess the molecular mechanisms to throw up a range of new possibilities, and the resulting directed epigenetic or mutational changes occurring can be rapidly passed on to future generations. This new view of evolution based on epigenetic and directed mutation phenomena demands that we adopt a much more sophisticated view of evolution: the new view needs to accommodate the Lamarckian idea that our genome is able to adapt to environmental stimuli with at least some of the changes inherited by the next generation.

[1] Lamarck J.: Zoological Philosophy (1809)
[2] Lindley R.: The Soma (2010)
[3] Jablonka E., Lamb M.: Evolution in Four Dimensions (2007)
[4] Steele E., Lindley R., Blanden R: Lamarck's Signature (1998)
[5] Johnson J. et al.: Cell 122 (2005)
[6] Fogarty P.: J. Drug Discovery Today 1, 3 (2002)
[7] Gorczynski R. et al.: J. of Immunology 131 (1983)
[8] Sobey W., Conolly: Australian Wildlife Research 13 (1986)
[9] Avery O. et al.: J. Experimental Medicine 79, 2 (1944)
[10] Cairns J. et al.: Nature 335 (1988)

Dr Robyn A. Lindley
Melville Analytics Pty Ltd, Jindabyne, Australia

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