Intergenomic conflict can occur between different species that antagonistically coevolve, such as predator and their prey, or hosts and pathogens. Intragenomic conflict arises when some genetic elements behave selfishly in the context of the rest of the genome: promoting their own spread without benefitting, and indeed often to the detriment of, the host [1], [2], [3], [4]. Classic examples of intragenomic selfish elements include transposable elements and driving elements such as homing endonucleases (sequence-specific nucleases that can cleave non-driving alleles, leading to repair from the driving allele in heterozygous hosts) [5]. Selfish elements, whether transmitted horizontally like many viruses, or vertically like transposable elements, are parasitic elements that rely on their hosts for survival, while conferring a cost to that host. Host variation that minimizes selfish element success, or the fitness costs associated, will be advantageous and can lead to positive selection or balancing selection in populations [6], [7], [8], [9], [10], [11]. For example, mammalian antiviral factors are sometimes observed to be under positive selection, while in flies antimicrobial peptides can exhibit balancing selection [12], [13], [14].

Why then do selfish elements persist in the face of host counteradaptation? In some cases, in spite of the fitness cost, a selfish element may be challenging for a host to lose. A classic example might be driving elements, which promote non-mendelian inheritance of themselves even when associated with a host fitness decrease. The second possibility is that hosts might experience a condition-specific benefit for having a selfish element. Many bacterial plasmids carry cargo genes that benefit the host under certain conditions, such as antibiotic resistance genes, even though they carry their own metabolic cost. A third, and somewhat related possibility, is that the fitness cost itself of a selfish element may be variable depending on the genetic context as well as the environmental context: varying by either host or parasite genotype, or both.

Whether these conflicts occur within a genome or between genomes, hosts are under selective pressures to minimize the costs and restrict proliferation of the antagonist. However, the ability of selfish elements to counter-adapt and overcome host defenses can lead to molecular arms race dynamics, shaping evolution and giving rise to sometimes surprising biological novelty. Notably these instances violate the assumption that important functions will remain well-conserved over evolutionary time, or that genes that spread in a population are always beneficial to the host. This novelty can manifest even in processes that are essential for an organism’s survival, including development [15], chromatin, and cell division [16], [17]. Beyond being a source of selective pressure, selfish elements sometimes drive novelty just by being mutagenic. Integrating elements such as transposons can be a source of increased rates of mutagenesis when derepressed [18], [19], [20], [21], [22], while exogenous elements can be a rich source of new genetic material when captured in a new genome, even if by chance.

The molecular interfaces where host and parasite directly and physically interact (such as protein-protein interactions, or DNA binding proteins, etc.) are the frontlines where selection most often leads to rapid evolution and signatures of positive selection. Host factors that directly interact with a genetic parasite often fall into two classes: susceptibility factors and host-protective restriction factors. Susceptibility factors are typically encoded by the host cell and fulfill a function for the host, but are also utilized by the parasite for its own survival, such as replication or translation machinery [10], [11], [23], [24]. Restriction factors are generally host cellular immune factors that actively interfere with selfish element functions within the host, which can also serve host homeostatic functions, such as degradation of RNAs or proteostasis [25], [26], [27], [28], [29], [30]. Because genetic parasites often hijack host-essential components, functional constraint can make evolutionary escape harder for the host. Variation that allows for host survival and parasite exclusion can be beneficial and drive innovation in otherwise constrained processes.

Conflict can be challenging to study systematically in many organisms. An ideal system would have molecular tools facilitating mechanistic study, but also have evolutionary resources available. Experimentally tractable systems allow for the identification of causal mutations and testing of molecular mechanisms underlying phenotypes of interest. Evolutionary studies complement traditional molecular approaches in laboratory models: comparative genomics and phenotypic profiling give context for natural variation in extant populations. These retrospective studies of what has happened in natural populations are also complemented well by prospective studies via experimental evolution in the laboratory [21]. Through applying known and controlled selective pressures and profiling adaptive mutations, we can build a better understanding of which mutations are adaptive in which contexts. Evolutionary approaches can be one way to explore mutations that might otherwise not be sampled during traditional genetic studies. Genetic approaches often favor null mutants, while evolution can give rise to different alleles through a spectrum of mutational mechanisms, facilitating the discovery of separation of function mutants. This makes evolutionary studies complimentary to classical genetic and molecular approaches and may provide additional insights into the fundamental biology of genes involved in several cellular processes.

However, not all organisms or parasites are well-supported for genetic and molecular studies, and of the model systems available to work with in the laboratory, not all have sufficient evolutionary resources. Even in systems that do have molecular tools and multiple species/isolates sequenced and available to work with in the laboratory already, it is often still challenging to tie observations of what has happened in the past (through comparative genomics experiments) to specific selective pressures or known conflicts. In species with rapid generation times that can be propagated in the laboratory, experimental evolution is a powerful tool for associating selective pressures to observed adaptive outcomes. It has been most often used in the context of abiotic selection in budding yeast and many other organisms, and less often, but with compelling results, in studies of biotic conflict [31], [32], [33], [34], [35]. Not all host/parasite systems are tractable for ‘real time’ laboratory evolution experiments though, often due to long generation times.