Summary Mammalian karyotypes (number and structure of chromosomes) can vary dramatically over short evolutionary time frames [1–3]. There are examples of massive karyotype conversion, from mostly telocentric (centromere terminal) to mostly metacentric (centromere internal), in 102–105 years [4, 5]. These changes typically reflect rapid fixation of Robertsonian (Rb) fusions, a common chromosomal rearrangement that joins two telocentric chromosomes at their centromeres to create one metacentric [5]. Fixation of Rb fusions can be explained by meiotic drive: biased chromosome segregation during female meiosis in violation of Mendel’s First Law [3, 6, 7]. However, there is no mechanistic explanation of why fusions would preferentially segregate to the egg in some populations, leading to fixation and karyotype change, while other populations preferentially eliminate the fusions and maintain a telocentric karyotype. Here we show, using both laboratory models and wild mice, that differences in centromere strength predict the direction of drive. Stronger centromeres, manifested by increased kinetochore protein levels and altered interactions with spindle microtubules, are preferentially retained in the egg. We find that fusions preferentially segregate to the polar body in laboratory mouse strains when the fusion centromeres are weaker than those of telocentrics. Conversely, fusion centromeres are stronger relative to telocentrics in natural house mouse populations that have changed karyotype by accumulating metacentric fusions. Our findings suggest that natural variation in centromere strength explains how the direction of drive can switch between populations. They also provide a cell biological basis of centromere drive and karyotype evolution.
Despite the existence of formal models to explain how chromosomal rearrangements can be fixed in a population in the presence of gene flow, few empirical data are available regarding the mechanisms by which genome shuffling contributes to speciation, especially in mammals. In order to shed light on this intriguing evolutionary process, here we present a detailed empirical study that shows how Robertsonian (Rb) fusions alter the chromosomal distribution of recombination events during the formation of the germline in a Rb system of the western house mouse (Mus musculus domesticus). Our results indicate that both the total number of meiotic crossovers and the chromosomal distribution of recombination events are reduced in mice with Rb fusions and that this can be related to alterations in epigenetic signatures for heterochromatinization. Furthermore, we detected novel house mouse Prdm9 allelic variants in the Rb system. Remarkably, mean recombination rates were positively correlated with a decrease in the number of ZnF domains in the Prdm9 gene. The suggestion that recombination can be modulated by both chromosomal reorganizations and genetic determinants that control the formation of double-stranded breaks during meiosis opens new avenues for understanding the role of recombination in chromosomal speciation.
These studies centre on the 'Barcelona' karyotypic race of the western house mouse (Mus musculus domesticus), first described by Adolph & Klein (1981). This is one of many races within M. m. domesticus characterized by metacentric chromosomes that have originated by repeated Robertsonian fusions, with perhaps further modification by whole-arm reciprocal translocations. Data on 111 mice from 20 sites show that the race is centred 24 km to the west of Barcelona city and has a homozygous metacentric karyotype of 2n = 28 (3.8, 4.14, 5.15, 6.10, 9.11, 12.13). The race has a small range, and mice with the standard 40-acrocentric karyotype were caught only 30 km from the race centre. Throughout the area of occurrence of metacentrics there is polymorphism (i.e. presence of acrocentrics in the population), although all six metacentrics approach fixation close to the race centre. Thus, there is a hybrid zone between the Barcelona and standard races. The centres and widths of all clines (except 3.8) were determined. Likelihood ratio tests showed that most of the cline centres differed significantly in position (i.e. the clines were staggered) and the clines for metacentrics 6.10 and 9.11 were significantly narrower than those for 4.14, 5.15 and 12.13. Overall, the clines tended to be wider the further they were from the race centre. There are various possible explanations for this hybrid zone structure and further data are needed to distinguish between them.
The spatial folding of chromosomes inside the nucleus has regulatory effects on gene expression, yet the impact of genome reshuffling on this organization remains unclear. Here, we take advantage of chromosome conformation capture in combination with single-nucleotide polymorphism (SNP) genotyping and analysis of crossover events to study how the higher-order chromatin organization and recombination landscapes are affected by chromosomal fusions in the mammalian germ line. We demonstrate that chromosomal fusions alter the nuclear architecture during meiosis, including an increased rate of heterologous interactions in primary spermatocytes, and alterations in both chromosome synapsis and axis length. These disturbances in topology were associated with changes in genomic landscapes of recombination, resulting in detectable genomic footprints. Overall, we show that chromosomal fusions impact the dynamic genome topology of germ cells in two ways: (i) altering chromosomal nuclear occupancy and synapsis, and (ii) reshaping landscapes of recombination.
One of the major challenges in evolutionary biology is the identification of the genetic basis of postzygotic reproductive isolation. Given its pivotal role in this process, here we explore the drivers that may account for the evolutionary dynamics of the PRDM9 gene between continental and island systems of chromosomal variation in house mice. Using a data set of nearly 400 wild-caught mice of Robertsonian systems, we identify the extent of PRDM9 diversity in natural house mouse populations, determine the phylogeography of PRDM9 at a local and global scale based on a new measure of pairwise genetic divergence, and analyze selective constraints. We find 57 newly described PRDM9 variants, this diversity being especially high on Madeira Island, a result that is contrary to the expectations of reduced variation for island populations. Our analysis suggest that the PRDM9 allelic variability observed in Madeira mice might be influenced by the presence of distinct chromosomal fusions resulting from a complex pattern of introgression or multiple colonization events onto the island. Importantly, we detect a significant reduction in the proportion of PRDM9 heterozygotes in Robertsonian mice, which showed a high degree of similarity in the amino acids responsible for protein–DNA binding. Our results suggest that despite the rapid evolution of PRDM9 and the variability detected in natural populations, functional constraints could facilitate the accumulation of allelic combinations that maintain recombination hotspot symmetry. We anticipate that our study will provide the basis for examining the role of different PRDM9 genetic backgrounds in reproductive isolation in natural populations.
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