1 MCB 502A - 2015. Lecture #3 Genome evolution. DNA replication The two major types of genome evolution The cross-hybridization studies of DNA from different species that we discussed at the end of the previous lecture revealed certain patterns that are easier to discuss at the level of "total DNA information content of the cell", also known as "genome". In particular, the differences between genomes of different species highlighted the phenomenon of "genome evolution" that we will discuss next. For a long time genome evolution was thought to be driven by point mutations: one-nucleotide changes in the DNA sequence to gradually adapt to a stable environment, with occasional genome scrambling by rearrangements to get a foothold in an entirely new habitat. The hybridization studies like the one we discussed, and more recently the whole-genome sequencing, painted an entirely different picture for bacterial genomes. The bacterial genomes turned out to be much more dynamic and adaptable, but in an unexpected way: there is a significant “flow of genes” from the environment through the genomes, as genes are frequently lost, forcing their homologs to be picked up from the environment by selection. Bacteria internalize relatively long uninterrupted chunks of foreign DNA, apparently for food, but sometimes this food ends up being inserted into the chromosome, becoming part of the genome ("you are what you eat" is the slogan of the prokaryotic genome evolution.). This process of "horizontal gene transfer" produces “mosaic genomes” in close relatives; such genomes, if compared pairwise, are mostly homologous in that they have the common “frame”, but also contain interspersed homeologous and completely heterologous patches of DNA. It is remarkable to observe how stable these genomic frames are through the millions of years of bacterial evolution. The reason for their stability (referred to as "high synteny" or high degree of gene colocalization) remains a mystery. How is this mode of evolution different from the classic “gradually mutate and occasionally scramble” mode that produces familiar "evolutionary trees"? The continuous gene flow through bacterial genomes means the the mode of evolution is changed from branching to "festooning". Horizontal gene transfer allows for a faster adaptation to a new environment, as the newcomer bacterium can pick up all the necessary genes to survive in the new habitat from aboriginal microbes, as long as the new proteins can be "plugged into" the newcomer's metabolism. The now classic example is the benign resident of our gut, E. coli (with a typical genome size in the 4.2-4.7 Mbp range and a minimal genome of 3.7 Mbp), which has enteropathogenic relatives causing food poisoning and other diseases throughout our body, with genome sizes up to 5.4 Mbp that, apparently, have picked up pathogenic islands of “really nasty genes” from some other, unrelated pathogens, allowing these now dangerous E. coli to colonize various habitats within our body. This adaptational utility of horizontal gene transfer is further enhanced by the “mobilome” — a collection of genes on the extrachromosomal elements (plasmids and phages) and on mobile elements within the chromosome, staying for a few, or a few thousand, generations within prokaryotic cells. The mobilome genes are typically not required for cell propagation and are easily lost. However, whenever an adaptation-important gene gets into a mobilome, it is rapidly spread among the local microbes. In this way, prokaryotic genome evolution is accelerated by mobilome. Mobilome is also responsible for bacterial speciation,2 allowing host bacteria to colonize new niches. The two classic examples are the Bacillus cereus — Bacillus antracis lethal differences in the resident plasmids and the Vibrio cholerae deadly lysogenic conversion by the XTS prophage. Thus, a bacterial genome can take up and accommodate a lot of foreign DNA (in the above case of E. coli, up to 50% of its minimal value). At the same time, the circularity of bacterial chromosome puts severe restriction on gross chromosomal rearrangements, making many of them nonviable. By the way, because mobile element movement stimulates rearrangements, this indirectly but severely restricts the number of mobile elements in the microbial genomes, by killing off lineages that cannot control their multiplication. The general patterns of archaeal genome evolution are similar to those of bacteria and are dominated by rapid gene loss and re-acquisition via horizontal gene transfer, combined with intolerance for active mobile elements (repeats). This predictably results in high synteny between related archaeal genomes. In contrast to bacteria and archaea, eukaryotic genome evolution is immune to horizontal gene transfer and instead is dominated by rearrangements. The reason horizontal gene transfer does not work in eukaryotes is that their DNA is kept in a separate compartment (the nucleus), while their cytoplasmic routing of exogenous DNA specifically avoids the nucleus, so the exogenous DNA is degraded by cytoplasmic DNases before it has a chance to get to the nucleus and incorporate into the genome. The major type of exogenous DNA that has any chance of inserting into the eukaryotic genome is the cDNA of retroviruses. Retroviruses are single-stranded RNA (ssRNA) viruses that replicate only in the nucleus via duplex cDNA intermediates integrated into the host genome. Since retroviruses have to get to the nucleus to replicate, while no other exogenous DNA can, retroviral infections is the major source of exogenous DNA in eukaryotes. In addition, because of the unique biology, retroviral infections are a major driver of the eukaryotic genome evolution. The small sizes of the retroviral genomes, the one-enzyme mechanism of retroviral cDNA formation, and the rampant recombination during cDNA synthesis breed ever-changing families of simplistic mobile retroelements that infest eukaryotic genomes with thousands of repeats each. These retroelements and the layers of their decaying remnants comprise the bulk of noncoding DNA in the eukaryotic genomes (up to 60% in the mammalian genomes, up to 90% in plant genomes). The amazing tolerance of eukaryotic genomes to infestation with mobile elements comes from split genes (it is OK to insert into introns) and because of the alternative splicing, which alleviates detrimental inserts into exons
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