Genome expansion in early eukaryotes drove the transition from lateral gene transfer to meiotic sex

Prokaryotes acquire genes from the environment via lateral gene transfer (LGT). Recombination of environmental DNA can prevent the accumulation of deleterious mutations, but LGT was abandoned by the first eukaryotes in favour of sexual reproduction. Here we develop a theoretical model of a haploid population undergoing LGT which includes two new parameters, genome size and recombination length, neglected by previous theoretical models. The greater complexity of eukaryotes is linked with larger genomes and we demonstrate that the benefit of LGT declines rapidly with genome size. The degeneration of larger genomes can only be resisted by increases in recombination length, to the same order as genome size – as occurs in meiosis. Our results can explain the strong selective pressure towards the evolution of sexual cell fusion and reciprocal recombination during early eukaryotic evolution – the origin of meiotic sex.


ABSTRACT 224
Prokaryotes generally reproduce clonally but can also acquire new genetic material via 25 lateral gene transfer (LGT). Like sex, LGT can prevent the accumulation of deleterious 26 mutations predicted by Muller's ratchet for asexual populations. This similarity between sex 27 and LGT raises the question why did eukaryotes abandon LGT in favor of sexual 28 reproduction? Understanding the limitations of LGT provides insight into this evolutionary 29 transition. We model the evolution of a haploid population undergoing LGT at a rate and 30 subjected to a mutation rate . We take into account recombination length, , and genome 31 size, , neglected by previous theoretical models. We confirm that LGT counters Muller's 32 ratchet by reducing the rate of fixation of deleterious mutations in small genomes. We then 33 demonstrate that this beneficial effect declines rapidly with genome size. Populations with 34 larger genomes are subjected to a faster rate of fixation of deleterious mutations and 35 become more vulnerable to stochastic frequency fluctuations. Muller's ratchet therefore 36 generates a strong constraint on genome size. Importantly, we show that the degeneration 37 of larger genomes can be resisted by increases in the recombination length, the average 38 We define fixation of a mutant at a locus when the least-loaded class (LLC) at that locus is 157 lost. As we neglect back-mutation, fixation of a mutant is permanent. 158

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The genome-wide mutation rate = is calculated as the product between the mutation 160 rate per locus per generation and the number of loci (we assume that the mutation rate is 161 constant across the whole genome). We introduce a new parameter L, the number of 162 contiguous genes acquired with each LGT recombination event (i.e. the size of imported 163 DNA), which has not been taken into account by previous theoretical studies ( Levin   second measure is the genome-wide rate of fixation / . This is calculated as the ratio 206 between the total number of fixed mutations over the 10,000 generations of the simulation. 207 The rate of fixation per single locus is the ratio between the genome-wide rate of fixation 208 and genome size . / is a measure of the rate of accumulation of mutations.  LGT sufficiently repress mutation accumulation in large genomes ( Figure 4B and 4D). where the strength of selection is lower, while the core genome accumulates mutations at a 267 relatively slow rate (Fig. 5). Genome size expansion results in more severe ratchet effects, 268 with a marked increase in the rate of mutations reaching fixation in the regions of the 269 genome that are under weaker selection, alongside a moderate increase in core genome 270 mutation fixation rate (Fig 5).
LGT is effective in reducing the mutational burden, both in the 271 accessory and in the core genome; but this beneficial effect is less evident in large genomes 272 than in small ones (Fig 5). Recombination across the whole genome ( = 0.2 ) completely 273 eliminates fixation in the core genome, regardless of genome size, and markedly reduces 274 the fixation rate in the accessory genome, facilitating genomic expansion (Fig 5). Asexual organisms are well known to be vulnerable to the effects of drift, which reduces the 279 genetic variation within a population, causing the progressive and inescapable accumulation 280 of deleterious mutations known as Muller's ratchet (Muller, 1964;Haigh, 1978;Otto, 2009). LGT. In small genomes, LGT is effective at preventing Muller's ratchet, with long extinction 304 times (Fig. 3) and low rates of mutation accumulation (Fig. 4), validating the results of 305 previous theoretical studies (Takeuchi et al., 2014). However, we show that large genomes 306 limit the efficiency of LGT and present a greater mutational target than smaller ones, 307 increasing the overall input of mutations to the genome. This increases the severity of the 308 ratchet leading to shorter extinction times and faster rates of mutation accumulation (Fig. 3-309   4). 310

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The increased potency of the ratchet as genome size increases is ameliorated by an increase 312 in the rate of LGT ( ; Fig. 3-4). Is this a viable option for prokaryotic species to enable them 313 to expand genome size? In a number of species, LGT has been estimated as being the same 314 what extent the rate of LGT can be modified. Our modelling suggests that larger bacterial 327 genomes are more likely to be sustained by higher rates of LGT, but the benefits of LGT as 328 actually practiced by bacteria -the non-reciprocal uptake of small pieces of DNA comprising 329 one or a few genes -are unlikely to sustain eukaryotic-sized genomes. In short, we show 330 that LGT as actually practised by bacteria cannot prevent the degeneration of larger 331

genomes. 332
Importantly, we show that the benefits of LGT also increase with recombination length ( ; 334 selection accumulating mutations at a low rate (Fig. 5-6). The ratchet effect is mainly 361 observed in the accessory genome, with mutations accumulating preferentially in loci under 362 weak selection (Fig. 5-6). Our model predicts that genome size expansion can occur in 363 populations under strong purifying selection (e.g. due to a larger effective population size). sex. In small prokaryotic genomes, LGT provides sufficient benefits to maintain genome 394 integrity, without incurring the multiple costs associated with sexual reproduction. But LGT 395 fails to prevent the accumulation of deleterious mutations in larger genomes, promoting the 396 loss of genetic information and therefore constraining genome size. Our model shows that 397 genome size expansion is only possible through a proportional increase in recombination 398 length. We considered a recombination length = 0.2 , which is equivalent to 500 genes 399 for a species with genome size of 2,500 genes -two orders of magnitude above the average 400 The benefits of LGT in maintaining genome integrity decline rapidly with genome size, 423 making large genomes vulnerable to the accumulation of mutations. This effect constrains 424 genome size in prokaryotes, and becomes even more severe with small population sizes and 425 high mutation rates. These constraints can be partially overcome by increases in LGT rate 426 and recombination length (Fig 3-4). But only recombination across the whole genome can 427 20 wholly overcome these constraints. With the massive genome expansion at the origin of 428 eukaryotes, the evolution of meiosis allowed homologous recombination across the whole 429 genome, and not only across a limited region spanning little more than a few loci, as in LGT. 430 The endosymbiosis that gave rise to the first eukaryotes led to the frequent transfer of 431 genes from the endosymbiont to the host, resulting in a large expansion in genome size, 432 likely coupled to high mutation rates. Our model shows that these conditions wrought the