Why does hybrid sterility occur

Thus Prdm9 could control a particular case of a more universal mechanism that enables new species to form. Hybrid sterility HS is a postzygotic reproductive isolation mechanism that enforces speciation by restricting gene flow between related taxa. HS is a universal phenomenon observed in many eukaryotic inter-species hybrids, including examples in yeast, plants, insects, birds, and mammals Coyne and Orr, ; Maheshwari and Barbash, In the early days of genetics, HS was difficult to accommodate in Darwin's theory of evolution by natural selection.

In time, however, the Bateson—Dobzhansky—Muller incompatibility BDMI hypothesis Muller and Pontecorvo, ; Dobzhansky, ; Orr, explicated HS, and more generally any hybrid incompatibility, as a consequence of the independent divergence of mutually interacting genes resulting in aberrant interaction of the new alleles that have not been tested by natural selection.

HS has several common features across various sexually reproducing eukaryotic species. Haldane's rule posits that if one sex of the F 1 offspring of two different animal races is absent, rare, or sterile, it is the heterogametic sex XY or ZW Haldane, Another common feature refers to the disproportionately large role of Chr X compared to that of autosomes in reproductive isolation Presgraves, More recently, interaction between selfish genomic elements causing meiotic drive and their suppressors has been implicated in some instances of reproductive isolation Orr, ; Zhang et al.

The molecular mechanisms underlying HS remain an unresolved question. Historically, genic and chromosomal mechanisms of HS had been hypothesized, but the latter were soon dismissed as unlikely on the grounds that large chromosomal rearrangements do not segregate with HS genetic factors Dobzhansky, Other possible forms of non-genic chromosomal HS were not considered because of the limited knowledge of the carrier of genetic information at the time.

Thus, for the past 80 years or so, the focus on the genic control of HS prevailed Dobzhansky, ; Orr, ; Forsdyke, The low success rate of the positional cloning of HS genes was explained by the oligogenic or polygenic nature of HS phenotypes and by the inherent difficulty in genetically dissecting the phenotype that prevents its own transfer to progeny.

Over 40 years ago, we introduced the house mouse Mus musculus as a mammalian model for the genetic analysis of HS. Most of the tested laboratory inbred strains share either the Prdm9 Dom2 or the Prdm9 Dom3 allele Parvanov et al. The former allele was found in inbred strains producing sterile male hybrids when crossed with PWD females, whereas the Prdm9 Dom3 was observed in the strains that yielded quasi-fertile males in the same type of inter-subspecific crosses Forejt et al.

Any other tested allelic combination of these two major HS genes yields fully fertile or subfertile male hybrids Dzur-Gejdosova et al. Initially, we explained this 'missing heritability' by assuming the genic interaction of three or more additional HS genes with a small effect that had escaped the genetic screen Dzur-Gejdosova et al.

However, an alternative, non-genic explanation emerged from the analysis of meiotic phenotypes of sterile hybrids. The asynapsis was accompanied by disturbed transcriptional inactivation of sex chromosomes at the first meiotic prophase Bhattacharyya et al.

The failure of intersubspecific homologs to synapse was clearly dependent on interhomolog interactions, and we suggested that their fast-evolving nongenic DNA divergence could be the causal factor. Because meiotic asynapses of different origin are known to compromise the normal progression of the first meiotic division Forejt, , ; Mahadevaiah et al. Such hotspots were designated as asymmetric DSB hotspots. Chromosome-specific quantification of asymmetry correlated well with the asynapsis rate across five arbitrarily chosen chromosomes of PB6F 1 hybrids Davies et al.

Another, non-exclusive interpretation of DMC1 ChIP-seq data pointed to significant enrichment of PRDM9-independent hotspots in the PB6F 1 hybrid testis, which occurs in promoters and other regulatory motifs and which is characteristic of spermatogenic arrest in Prdm9 knockout males Smagulova et al. Recently, one third of PRDM9-dependent DSBs were reported within sequences that have at least some repetitive character, indicating that inappropriately high DSB levels in transposons and other repetitive elements may contribute to the infertility seen in some mouse hybrids Yamada et al.

We report the restoration of synapsis of intersubspecific chromosome pairs in the presence of 27 Mb or more of consubspecific sequence, and the reversal of HS by targeted suppression of asynapsis in the four most asynapsis-sensitive chromosomes.

Our findings point to the chromosomal basis of Prdm9 -directed hybrid male infertility as a nonexclusive alternative to a widely accepted concept of hybrid sterility driven by multiple genic incompatibilities. Altogether, pachynemas from 40 PB6F1 hybrid males were analyzed.

All autosomes of hybrid males displayed a certain degree of asynapsis, classified as complete, partial, or intermingled more than two tangled univalents within labeled chromatin cloud , with frequencies ranging from 2.

Recently, SPO11 oligos released during the processing of DSBs were sequenced, mapped and quantified at chromosome-wide scale in male mice of the B6 laboratory inbred strain Lange et al. Thus, our findings suggest that synapsis of a pair of homologous chromosomes depends on the presence of a certain minimum number of symmetric DSBs, as we elaborate further using a simulation described in the 'Discussion'.

A Partial arrowheads and complete arrows asynapsis of Chr 19 and See also Figure 1—video 1. E based on GLMM model. Chromosome-scale comparison of expected DSBs in symmetric hotspots and asynapsis rate.

We propose that the absence of active euchromatin is a consequence of the meiotic synapsis failure of intersubspecific chromosomes, known as meiotic silencing of unsynapsed chromatin MSUC [ Burgoyne et al. To do that, we crossed the male hybrids between two B6. Altogether, chromosomes from over 12, pachynemas were examined. All male progeny of the 2-chr crosses were fully sterile, with low testis weight and the absence of sperm in the epididymis.

The analysis of data from six recombinant chromosomes revealed the common features described below. A The F 1 hybrid males of two consomic strains generation 1 G 1 , Chr 5 and Chr 12 shown here were crossed to PWD females to produce generation 2 G 2 sterile F 1 hybrids with random recombinant consomic chromosomes 5 and The localization of PWD homozygous sequence with respect to centromere, interstitial part of the chromosome or telomere, or on both ends is distinguished by color see also Figure 3—source data 1 — 6.

The average length between the minimum and maximum of the consubspecific sequence is plotted. The mean asynapsis rate of a given chromosome is regularly higher in PB6F 1 hybrids dashed line than in 2-chr cross. For explanation see Figure 4 and the section on the trans- effect-dependent variation in asynapsis rate. The efficiency of synapsis rescue was gradual with an apparent change point Figure 3B. To describe the pattern in the data, a segmented regression model was used see 'Materials and methods'.

The model based on the data pooled from all 2-chr crosses was selected as the best model with an estimated change point at The slope of the decrease of asynapsis in the region of consubspecific intervals shorter than In spite of the known role of subtelomeric bouquet association in chromosome pairing Ishiguro et al. To check the causal relationship between meiotic chromosome asynapsis and HS, we attempted to reverse HS by reducing the asynapsis in the four most asynapsis-prone chromosomes.

As predicted, a significant fraction of hybrid males did indeed show partial rescue of spermatogenesis. A Scheme of a four-generation cross resulting in F 1 hybrids with four recombinant consomic chromosomes. The localization of PWD homozygous sequence with respect to the centromere, the interstitial part of the chromosome, or the telomere, or on both ends is distinguished by color see also Figure 4—source data 3.

C Number of sperm in epididymis is a function of the probability of synapsis of all four consomic chromosomes. See Figure 6—figure supplement 2. Eleven G 3 male parents selected for the 4-Chr cross experiment. Eighteen G 4 males were deliberately selected according to their fertility parameters, 13 with HS partial rescue, displaying sperm cells in the epididymis 0.

The meiotic analysis of over pachynemas from the genotyped males confirmed the prediction based on the results of 2-chr crosses. All recombinant chromosomes with consubspecific intervals of sufficient length Figure 4—source data 3 ; see Figure 3—source data 7 for change point estimates effectively restored synapsis. Moreover, the presence of sperm cells corresponded with the rescue of synapsis of consomic chromosomes. Chrs 16, 18, and 19 contributed the strongest effect Figure 4—source data 3.

Provided that the probability of failure of the synapsis of each chromosome was completely independent of the rest of the hybrid genome, then the asynapsis rate of a particular nonrecombinant intersubspecific chromosome pair would be the same in F 1 hybrids, 2-chr crosses, and the 4-chr cross.

Moreover, the frequency of pachynemas with all chromosomes synapsed could be predicted by multiplication of the observed frequencies of the synapsis of individual chromosomes see Figure 2—source data 2. Such predicted values would be close to the values directly read from the meiotic spreads and would lie along the diagonal in Figure 5.

As shown below, both types of analysis clearly revealed that the asynapsis rate of a particular chromosome depends on the synapsis status of other chromosomes. First, in PB6F 1 hybrids, the observed The trans effect was more pronounced in 2-chr cross and 4-chr cross experiments.

On average, if the predicted synapsis rate of three chromosomes is increased by ten percent, we can expect a 4. However, for the chromosomes with at least The expected rate of synapsed pachynemas was calculated for each mouse in 2-chr cross and 4-chr cross experiments by multiplication of observed synapsis rates i.

Chrs 15, 16, 18 and 19 in 4-chr cross and the observed PB6F 1 synapsis rates of the remaining autosomes. Asynapsis rate was calculated as a complement to synapsis rate.

The difference between expected and observed overall asynapsis is most pronounced in 4-chr cross males with the lowest expected overall asynapsis rate. SC is sperm count. The relation between observed and calculated rate of pachytene asynapsis and fertility parameters. To conclude, the trans effect is the second non-genic effect modifying the asynapsis rate primarily caused by the cis -acting inter-homolog incompatibility in PB6F 1 primary spermatocytes.

The significance and the magnitude of the trans effect depends on the cis -acting inter-homolog incompatibility. The males remained sterile, but the synapsis of the particular consubspecific pair was completely restored Bhattacharyya et al. Davies et al. This asymmetry could be explained in part by erosion of the PRDM9-binding sites due to preferential transmission to progeny of the altered hotspots motifs Boulton et al.

In a parallel study, Smagulova et al. These Prdm9 -independent hotspots may represent the late-forming DSBs on unsynapsed chromosomes and, as such, they may be a consequence rather than the cause of meiotic asynapsis see Kauppi et al. We found that meiotic asynapsis affects each autosomal pair in PB6F 1 intersubspecific hybrids at distinctively unequal rates, with shorter chromosomes affected more often than longer ones.

A similar pattern of higher sensitivity of smaller autosomes to the synapsis failure was observed in mice with lowered dosages of SPO11 Kauppi et al. Provided that a shortage of symmetric hotspots Davies et al. We found that chromosomes with 27 Mb or longer stretches of consubspecific sequence always rescued full synapsis in hybrid males.

The position of the consubspecific interval along the chromosome was not critical for synapsis rescue, in accordance with the finding that synaptonemal complexes nucleate at multiple recombination sites in each chromosome Zickler and Kleckner, ; Finsterbusch et al.

Allowing for the assumptions enumerated in the 'Results' section, the number of DSBs necessary for proper synapsis of a given chromosome can be estimated on the basis of the expected distribution of symmetric DSB hotspots on all autosomes and their asynapsis ratios in sterile F 1 hybrids Figure 2—source data 2.

Polyploid hybrids are interfertile among themselves, but reproductively isolated by the mismatch in chromosome numbers from the parental species; they are therefore well defined new species. Privacy Policy. Speciation - What is hybrid speciation? Hybrid speciation There is one type of sympatric speciation which is uncontroversial and well known to exist: hybrid speciation which regularly occurs in plants.

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