The hotspot conversion paradox and the evolution of meiotic recombination

Abstract

Studies of meiotic recombination have revealed an evolutionary paradox. Molecular and genetic analysis has shown that crossing over initiates at specific sites called hotspots, by a recombinational-repair mechanism in which the initiating hotspot is replaced by a copy of its homolog. We have used computer simulations of large populations to show that this mechanism causes active hotspot alleles to be rapidly replaced by inactive alleles, which arise by rare mutation and increase by recombination-associated conversion. Additional simulations solidified the paradox by showing that the known benefits of recombination appear inadequate to maintain its mechanism. Neither the benefits of accurate segregation nor those of recombining flanking genes were sufficient to preserve active alleles in the face of conversion. A partial resolution to this paradox was obtained by introducing into the model an additional, nonmeiotic function for the sites that initiate recombination, consistent with the observed association of hotspots with functional sites in chromatin. Provided selection for this function was sufficiently strong, active hotspots were able to persist in spite of frequent conversion to inactive alleles. However, this explanation is unsatisfactory for two reasons. First, it is unlikely to apply to obligately sexual species, because observed crossover frequencies imply maintenance of many hotspots per genome, and the viability selection needed to preserve these would drive the species to extinction. Second, it fails to explain why such a genetically costly mechanism of recombination has been maintained over evolutionary time. Thus the paradox persists and is likely to be resolved only by significant changes to the commonly accepted mechanism of crossing over.

Figure 1

Meiotic recombination in yeast and its consequences. (a) Two homologs of a single chromosome with a single recombination hotspot; r⁺ is an active hotspot allele (black), and r⁻ is an inactive allele (gray). The chromosomes have replicated before meiosis; each black line represents a single chromatid. (b) One active hotspot allele undergoes a double-strand DNA break. (c) The broken chromatid undergoes recombinational repair, using a homologous chromatid as a template. In the process the broken hotspot is replaced with a copy of its homolog. (d) The recombining chromatids resolve, and completion of meiosis I and II produces four gametes: If resolution of the repair intermediate has produced a crossover, segregation is accurate and each gamete receives a single chromosome. If there has been no crossover, chromosomes may be distributed randomly at meiosis I, giving either four functional gametes or four aneuploid gametes.

Figure 2

The computer simulation model. A deterministic population was simulated using matlab (Student version 4a) on a Macintosh PowerPC 7200. Viability selection acts on diploids, mutation on gametes. The complete model is available by anonymous FTP at: ftp://ftp.zoology.ubc.ca/pub/redfield.

Figure 3

Decrease in frequency of the r⁺ allele due to conversion. M_r = 10⁻⁸, M_ab = 0, no viability selection on a, b, or r. □, C = 0.2; ▪, C = 0.1; ▵, C = 0.05; ▴, C = 0.02. (A) Conversion not opposed by selection (X = 0). The inset is an enlargement of the first 100 generations, with the dotted line showing the effect of mutation alone. (B) Conversion opposed by fertility selection (X = 0.5). With C = 0.02 the frequency of the r⁺ allele had decreased to 0.01 at generation 1813.

Figure 4

Effect of selection against a⁻ and b⁻ mutations on frequency of the r⁺ allele. M_r = 0, C = 0.2, X = 0.5, M_ab = 0.1, conversion at r and fertility selection inactivated. ○, multiplicative selection (W_ab = 0.85ⁱ); •, additive selection (W_ab = 1 − 0.15i); ▴, quadratic selection (W_ab = 1 − 0.04i − 0.02i²).

Figure 5

Effect of viability selection against r⁻ mutations on frequency of the r⁺ allele. M_r = 10⁻⁸, C = 0.1, X = 0, M_ab = 0, no viability selection on a or b. ○, S_r = 0; •, S_r = 0.1; □, S_r = 0.2; ▪, S₄ = 0.4. (A) W_r⁺⁺ = W_r⁺⁻ = 1, W_r⁻⁻ = 1 − S_r; (B) W_r⁺⁺ = 1, W_r⁺⁻ = 1 − 0.5S_r, W_r⁻⁻ = 1 − S_r.

Figure 6

Combined effects of fertility selection and viability selection against a⁻, b⁻, and r⁻ mutations on frequency of the r⁺ allele. C = 0.1, M_r = 10⁻⁸, X = 0.5, M_ab = 0, quadratic selection against a⁻ and b⁻, (see legend to Fig. 4). ○, S_r = 0; •, S_r = 0.1; □, S_r = 0.2; ▪, S_r = 0.4. W_r⁺⁺ = W_r⁺⁻ = 1, W_r⁻ = 1 − S_r.