Preaching about the converted: how meiotic gene conversion influences genomic diversity

Abstract

Meiotic crossover (CO) recombination involves a reciprocal exchange between homologous chromosomes. COs are often associated with gene conversion at the exchange site where genetic information is unidirectionally transferred from one chromosome to the other. COs and independent assortment of homologous chromosomes contribute significantly to the promotion of genomic diversity. What has not been appreciated is the contribution of another product of meiotic recombination, noncrossovers (NCOs), which result in gene conversion without exchange of flanking markers. Here, we review our comprehensive analysis of recombination at a highly polymorphic mouse hotspot. We found that NCOs make up ∼90% of recombination events. Preferential recombination initiation on one chromosome allowed us to estimate the contribution of CO and NCO gene conversion to transmission distortion, a deviation from Mendelian inheritance in the population. While NCO gene conversion tracts are shorter, and thus have a more punctate effect, their higher frequency translates into an approximately two-fold greater contribution than COs to gene conversion-based allelic shuffling and transmission distortion. We discuss the potential impact of mammalian NCO characteristics on evolution and genomic diversity.

Figure 1

Meiotic recombination pathways. DSBs are induced preferentially at hotspots located throughout the genome. Resection of the DSB from 5′ to 3′ generates 3′ single-stranded tails, which invade the intact homolog (black) creating a D-loop intermediate. DNA repair synthesis (dashed lines) is primed by the invading 3′ end and templated by the homolog. In synthesis-dependent strand annealing (SDSA), the newly synthesized 3′ tail is displaced from the homolog, whereupon it anneals to the second, homologous 3′ end of the DSB. Subsequent repair synthesis and ligation reseals the DSB and generates a noncrossover (NCO). In double-strand break repair (DSBR), the D-loop captures the second end of the DSB and a double Holliday junction (dHJ) is formed. Resolution of the dHJ can generate a crossover (CO). Both NCOs and COs can result in gene conversions, as indicated, where sequences of the homolog that receives a DSB (gray) are converted to the genotype of the intact homolog (black).

Figure 2

Recombination at the A3 hotspot. (A) CO activity in centimorgans (cM) per Mb in A/J × DBA/2J F1 hybrids. When amplifying COs in the DBA/2J to A/J orientation, exchange points cluster to the left (top), while in the A/J to DBA/2J orientation, exchange points cluster to the right (bottom). The offset in exchange points is due to preferential DSB formation on the DBA/2J chromosome. Dashed lines indicate the distribution center of each orientation, and the offset between them is used to estimate the mean CO gene conversion tract length of 500 bp. (B) NCOs (as % of total NCOs detected) in all F1 hybrids on the DBA/2J chromosome. Ticks at the top of graphs represent tested polymorphisms. The x-axis scale for (A) and (B) is in kilo bases.

Figure 3

Transmission distortion and allelic fixation at the A3 hotspot. (A) Percent A/J transmission for A/J × DBA/2J F1 hybrids from COs (black bars and line) and NCOs (gray bars). The dotted line at 50% is Mendelian transmission. Circles above the bars demarcate polymorphisms analyzed in B. (B) Monte Carlo simulations (Wright-Fisher model) to determine the number of generations to fixation for the three indicated polymorphisms, with the simplified assumption that the polymorphism is causative for the DSB bias. Calculated gametic ratios are indicated.