Vertebrate Evolution Driven by DNA from Infectious Organisms

A prior post listed 7 assertions regarding the role of infectious organisms on the human genome. In the next few blogs we'll look at each assertion, in excerpts from Precision Medicine and the Reinvention of Human Disease. Here's the second:

Some of the key steps in the development of vertebrate animals, and mammals in particular, have come from DNA acquired from infectious organisms.

The human genome has preserved its viral ballast, at some cost. At every cell division, energy is expended to replicate the genome, and the larger the genome, the more energy must be expended. Why do we spend a large portion of the energy required to replicate our genome, on inactive sequences, of viral origin? Why doesn’t our genome simply eject the extra DNA, a biological process that is commonplace in the evolution of obligate intracellular parasitic organisms? Maybe it's because we use viral genes to our own advantage.

Two evolutionary leaps, benefiting the ancestral classes of humans, and owed to the acquisition of viral genes, include the attainment of adaptive immunity and the development of the mammalian placenta. Let’s take a moment to see how these innovations came about.

Adaptive immunity evolved at about the same time that jawed vertebrates first appeared on earth. The crucial gene responsible for the great leap to adaptive immunity, the recombination activating gene (RAG), was stolen from a retrovirus. To understand the pivotal evolutionary role of RAG, we need to review a bit of high school biology. The adaptive immune system responds to the specific chemical properties of foreign antigens, such as those that appear on viruses and other infectious agents. Adaptive immunity is a system wherein somatic T cells and B cells are produced, each with a unique and characteristic immunoglobulin (in the case of B cells) or T-cell receptor (in the case of T cells). Through a complex presentation and selection system, a foreign antigen elicits the replication of a B cell whose unique immunoglobulin molecule (i.e., so-called antibodies) matches the antigen. Secretion of matching antibodies leads to the production of antigen-antibody complexes that may deactivate and clear circulating antibodies, or may lead to the destruction of the organism that carries the antigen (e.g., virus or bacteria).

To produce the many unique B and T cells, each with a uniquely rearranged segment of DNA that encodes specific immunoglobulins or T-cell receptors, recombination and hypermutation must take place within a specific gene region. This process yields on the order of a billion unique somatic genes, and requires the participation of recombination activating genes (RAGs). The acquisition of a recombination activating gene is presumed to be the key evolutionary event that led to the development of the adaptive immune system present in all jawed vertebrates (gnathostomes). Before the appearance of the jawed vertebrates, this sort of recombination was genetically unavailable to animals. Our genes simply were not equal to the task. Retroviruses, however, are specialists at cutting, moving, and mutating DNA. Is it any wonder that the startling evolutionary leap to adaptive immunity was acquired from retrotransposons? Thus,we owe our most important defense against infections to genetic material retrieved from the vast trove of retrovirally derived DNA carried in our genome [33]. As one might expect, inherited mutations in RAG genes are the root causes of several immune deficiency syndromes [34,35].

Many millions of years later, vertebrates acquired another gene that did much to enable the evolution of all mammals. Members of Class Mammalia are distinguished by the development of the placenta, an organ that grows within the uterine cavity (i.e., the endometrium). After birth, the placenta must detach from the uterus. You can imagine the delicate balancing act between attaching firmly to the wall of the uterus and detaching cleanly from the wall of the uterus. During placental development, large, flat cells called cytotrophoblasts form the interface between placenta and uterus. To create the thin membrane that borders the lining of the uterus and that borders the blood received from the uterus in the spaces between the placental villi, the cytotrophoblasts must somehow fuse into a syncytium (i.e., multinucleate collections of cells that have fused together by dissolving their individual cytoplasmic membranes).

There is one task at which all animals excel: maintaining a clear separation between one cell and another. In point of fact, the most distinctive difference between animal cells and all other cells of eukaryotic origin happens to be the presence of cell junctions, whose purpose is to bind cells to one another without fusing cells. This being the case, you can see that the normal direction of animal evolution would preclude the appearance of a gene intended to form a huge syncytium of placental cells. Whereas animal cells are failures at fusion, viruses are champions. One of the most often-deployed methods by which viruses invade cells is through fusion at the cytoplasmic membrane. It happens that retroviral envelope genes, preserved in the human genome, do a very good job at fusing membranes. Animals captured a retroviral fusogenic envelope gene and inserted it into one of the first syncytin molecules involved the development of the placenta. Apparently, this acquisition worked out so well for mammals that later-evolving mammalian classes made their own retrovirus gene acquisitions to obtain additional syncytins, thus refining the placenta for their own subclasses [23,36].

- Jules Berman

key words: precision medicine, evolution, virus, viral, jules j berman Ph.D. M.D.