The Way We Were: Origins of Meiosis and Sex

Sex is as foundational for eukaryotes as are mitochondria and internal membranes. Why and how did it happen?

Sexual reproduction is a rather expensive proposition. The anxiety, the dating, the weddings- ugh! But biologically as well, having to find mates is no picnic for any species. Why do we bother, when bacteria get along just fine just dividing in two? This is a deep question in biology, with a lot of issues in play. And it turns out that bacteria do have quite a bit of something-like-sex: they exchange DNA with each other in small pieces, for similar reasons we do. But the eukaryotic form of sex is uniquely powerful and has supported the rapid evolution of eukaryotes to be by far the dominant domain of life on earth.

A major enemy of DNA-encoded life is mutation. Despite the many DNA replication accuracy and repair mechanisms, some rate of mutation still occurs, and is indeed essential for evolution. But for larger genomes, the mutation rate always exceeds the replication rate, (and the purifying natural selection rate), so that damaging mutations build up and the lineage will inevitably die out without some help. This process is called Muller's ratchet, and is why all organisms appear to exchange DNA with others in their environment, either sporadically like bacteria, or systematically, like eukaryotes.

An even worse enemy of the genome is unrepaired damage like complete (double strand) breaks in the DNA. These stop replication entirely, and are fatal. These also need to be repaired, and again, having extra copies of a genome is the way to allow these to be fixed, by processes like homologous recombination and gene conversion. So having access to other genomes has two crucial roles for organisms- allowing immediate repair, and allowing some way to sweep out deleterious mutations over the longer term.

Our ancestors, the archaea, which are distinct from bacteria, typically have circular, single molecule genomes, in multiple copies per cell, with frequent gene conversions among the copies and frequent exchange with other cells. They routinely have five to twenty copies of their genome, and can easily repair any immediate damage using those other copies. They do not hide mutant copies like we do in a recessive allele, but rather by gene conversion (which means, replicating parts of a chromosome into other ones, piecemeal) make each genome identical over time so that it (and the cell) is visible to selection, despite their polyploid condition. Similarly, taking in DNA from other, similar cells uses the target cells' status as live cells (also visible to selection) to insure that the recipients are getting high quality DNA that can repair their own defects or correct minor mutations. All this ensures that their progeny are all set up with viable genomes, instead of genomes riddled with defects. But it comes at various costs as well, such as a constant race between getting lethal mutation and finding the DNA that might repair it. 

Both mitosis and meiosis were eukaryotic innovations. In both, the chromosomes all line up for orderly segregation to descendants. But meiosis engages in two divisions, and features homolog synapsis and recombination before the first division of the parental homologs.

This is evidently a precursor to the process that led, very roughly 2.5 billion years ago, to eukaryotes, but is all done in a piecemeal basis, nothing like what we do now as eukaryotes. To get to that point, the following innovations needed to happen:

• Linearized genomes, with centromeres and telomeres, and >1 number of chromosomes.
• Mitosis to organize normal cellular division, where multiple chromosomes are systematically lined up and distributed 1:1 to daughter cells, using extensive cytoskeletal rearrangements and regulation.
• Mating with cell fusion, where entire genomes are combined, recombined, and then reduced back to a single complement, and packaged into progeny cells.
• Synapsis, as part of meiosis, where all sister homologs are lined up, damaged to initiate DNA repair and crossing-over.
• Meiosis division one, where the now-recombined parental homologs are separated.
• Meiosis division two, which largely follows the same mechanisms as mitosis, separating the reshuffled and recombined sister chromosomes.

This is a lot of novelty on the path to eukaryogenesis, and is just a portion of the many other innovations that happened in this lineage. What drove all this, and what were some plausible steps in the process? The advent of true sex generated several powerful effects:

1. A definitive solution to Muller's ratchet, by exposing every locus in a systematic way to partial selection and sweeping out deleterious mutations, while protecting most members of the population from those same mutations. Continual recombination of the parental genomes allows beneficial mutations to separate from deleterious ones and be differentially preserved.
2. Mutated alleles are partially, yet systematically, hidden as recessive alleles, allowing selection when they come into homozygous status, but also allowing them to exist for limited time to buffer the mutation rate and to generate new variation. This vastly increases accessible genetic variation.
3. Full genome-length alignment and repair by crossing over is part of the process, correcting various kinds of damage and allowing accurate recombination across arbitrarily large genomes.
4. Crossing over during meiotic synapsis mixes up the parental chromosomes, allowing true recombination among the parental genomes, beyond just the shuffling of the full-length chromosomes. This vastly increases the power of mating to sample genetic variation across the population, and generates what we think of as "species", which represent more or less closed interbreeding pools of genetic variants that are not clones but diverse individuals.

The time point of 2.5 billion years ago is significant because this is the general time of the great oxidation event, when cyanobacteria were finally producing enough oxygen by photosynthesis to alter the geology of earth. (However our current level of atmospheric oxygen did not come about until almost two billion years later, with rise of land plants.) While this mainly prompted the logic of acquiring mitochondria, either to detoxify oxygen or use it metabolically, some believe that it is relevant to the development of meiosis as well. 

There was a window of time when oxygen was present, but the ozone layer had not yet formed, possibly generating a particularly mutagenic environment of UV irradiation and reactive oxygen species. Such higher mutagenesis may have pressured the archaea mentioned above to get their act together- to not distribute their chromosomes so sporadically to offspring, to mate fully across their chromosomes, not just pieces of them, and to recombine / repair across those entire mated chromosomes. In this proposal, synapsis, as seen in meiosis I, had its origin in a repair process that solved the problem of large genomes under mutational load by aligning them more securely than previously. 

It is notable that one of the special enzymes of meiosis is Spo11, which induces the double-strand breaks that lead to crossing-over, recombination, and the chiasmata that hold the homologs together during the first division. This DNA damage happens at quite high rates all over the genome, and is programmed, via the structures of the synaptonemal complex, to favor crossing-over between (parental) homologs vs duplicate sister chromosomes. Such intensive repair, while now aimed at ensuring recombination, may have originally had other purposes.

Alternately, others suggest that it is larger genome size that motivated this innovation. This origin event involves many gene duplication events that ramified the capabilities of the symbiotic assemblage. Such gene dupilcations would naturally lead to recombinational errors in traditional gene conversion models of bacterial / archaeal genetic exchange, so there was pressure to generate a more accurate whole-genome alignment system that confined recombination to the precise homologs of genes, rather than to any similar relative that happened to be present. This led to the synapsis that currently is part of meiosis I, but it is also part of "parameiosis" systems on some eukaryotes, which, while clearly derived, might resemble primitive steps to full-blown meiosis.

It has long been apparent that the mechanisms of meiosis division one are largely derived from (or related to) the mechanisms used for mitosis, via gene duplications and regulatory tinkering. So these processes (mitosis and the two divisions of meiosis) are highly related and may have arisen as a package deal (along with linear chromosomes) during the long and murky road from the last archaeal ancestor and the last common eukaryotic ancestor, which possessed a much larger suite of additional innovations, from mitochondria to nuclei, mitosis, meiosis, cytoskeleton, introns / mRNA splicing, peroxisomes, other organelles, etc.  

Modeling of different mitotic/meiotic features. All cells modeled have 18 copies of a polypoid genome, with a newly evolved process of mitosis. Green = addition of crossing over / recombination of parental chromosomes, but no chromosome exchange. Red = chromosome exchange, but no crossing over. Blue = both crossing over and chromosome exchange, as occurs now in eukaryotes. The Y axis is fitness / survival and the X axis is time in generations after start of modeling.

A modeling paper points to the quantitative benefits of the mitosis when combined with the meiotic suite of innovations. They suggest that in a polyploid archaean lineage, the establishment of mitosis alone would have had revolutionary effects, ensuring accurate segregation of all the chromosomes, and that this would have enabled differentiation among those polyploid chromosome copies, since they would be each be faithfully transmitted individually to offspring (assuming all, instead of one, were replicated and transmitted). Thus they could develop into different chromosomes, rather than remain copies. This would, as above, encourage meiosis-like synapsis over the whole genome to align all the (highly similar) genes properly.

"Modeling suggests that mitosis (accurate segregation of sister chromosomes) immediately removes all long-term disadvantages of polyploidy."

Additional modeling of the meiotic features of chromosome shuffling, and recombination between parental chromosomes, indicates (shown above) that these are highly beneficial to long-term fitness, which can rise instead of decaying with time, per the various benefits of true sex as described above. 

The field has definitely not settled on one story of how meiosis (and mitosis) evolved, and these ideas and hypotheses are tentative at this point. But the accumulating findings that the archaea that most closely resemble the root of the eukaryotic (nuclear) tree have many of the needed ingredients, such as active cytoskeletons, a variety of molecular antecedents of ramified eukaryotic features, and now extensive polyploidy to go with gene conversion and DNA exchange with other cells, makes the momentous gap from archaea to eukaryotes somewhat narrower.

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