The Portuguese island of Madeira is house to six different chromosomal races of mice, each with considerably lowered diploid chromosome numbers compared to mice in other places. This striking diversity, first recognized at the turn of the 21st century, can be described by the repeated blends of different chromosomes. Each race has a various set of blends, and a hybrid between 2 races would likely have actually reduced fertility or be sterilized since of issues with chromosome pairing. Such reproductive seclusion amongst populations is a key action on the roadway to speciation– and in the mices case, these chromosomal changes have all happened within the 1,000 years considering that their ancestors arrived on the island, possibly on Viking ships.The so-called Robertsonian (Rb) blends that led to these rapid karyotype modifications are relatively common chromosomal rearrangements. However their accumulation in the populations of Madeira Island and in several other separated mouse populations elsewhere is most likely due to another influencing factor: the preferential partition of the Rb fusion into the egg rather than into the disposed of polar bodies that form throughout female meiosis.We typically consider the chromosome segregation machinery as making sure unbiased, random segregation. As we discover in high school biology, if a diploid person brings 2 various alleles of a gene (i.e., is heterozygous), then either allele is equally likely to wind up in a haploid gamete. This law describes the 3:1 ratio of phenotypes that Mendel observed in his classic research studies of heredity. Researchers have understood for years, nevertheless, that self-centered genes can subvert Mendelian segregation to increase their frequency in the next generation, a phenomenon understood as meiotic drive. The Madeira mice suggest that fusion chromosomes can likewise drive unequal inheritance.Because Rb fusions are easy to determine morphologically, and since mouse oocytes are a recognized model system, studying these blends in mice provided an entry for my lab at the University of Pennsylvania to investigate the cell biology of meiotic drive, starting in 2010. Focusing on the centromere– the part of each chromosome that interacts with spindle microtubules to direct partition in mitosis or meiosis– we discovered that the structures size determines the instructions of biased partition, with bigger centromeres preferentially segregating into the egg. Centromere DNA is generally highly repeated, and we found that larger centromeres have more of the satellite repeats particular of mouse centromeres and more centromere proteins connected with that DNA. Hence, it appeared that recently formed Rb fusions might lead to bigger centromeres that would drive and become fixed in natural populations.Centromere drive depends upon a combination of asymmetries in female meiosis.Meiotic drive of Rb fusions illustrates an idea proposed more than 50 years earlier in a paper by zoologist Michael J. D. White: “It might be that the very few chromosomal rearrangements which play a critical role in speciation through the ability to produce powerful isolating mechanisms are specifically those which take place to possess a segregational advantage in the female meiosis.” Rb combinations are an example of such a rearrangement that can generate a segregational advantage (i.e., drive) through centromere expansion. The chromosomal races on Madeira Island and somewhere else reveal how drive can result in rapid karyotype change and reproductive barriers in between populations that have built up different sets of fusions.Early hints of nonrandom segregationGeneticist Marcus Rhoades introduced the concept of meiotic drive in 1942 based upon observations of unusual chromosome 10 (Ab10) in maize. Ab10 consists of an additional DNA section, described a knob, that includes a recurring DNA sequence. Rhoades revealed that Ab10 preferentially segregates into the egg in female meiosis. He also proposed a design to describe the phenomenon, involving moving the position of Ab10 toward the meiotic spindle poles in anaphase. The 4 items of meiosis are set up in a direct tetrad, and only the lower cell becomes an egg, so this polar positioning increases the probability that Ab10 winds up in the egg. This design ended up being proper, conceptually, and scientists just recently discovered a molecular motor accountable for placing Ab10.The maize knobs are not necessary for chromosomal function or even useful except in the selfish sense of increasing their own transmission through female meiosis. On the other hand, centromeres are everywhere utilized for faithful chromosome segregation throughout cellular division. As mentioned by pioneering cell biologist Dan Mazia in 1961, “The role in mitosis of the chromosome arms, which bring many of the hereditary product, may be compared with that of a remains at a funeral service: they supply the factor for the proceedings however do not take an active part in them.” Rather, the action is at the centromere, which moderates the chromosomes interactions with spindle microtubules.Because the core centromere function of linking to the spindle is highly conserved across eukaryotes, we expect that centromere components would likewise be conserved. Contrary to this expectation, numerous centromeric proteins progress quickly in numerous eukaryotic lineages, with patterns of amino acid modifications recommending favorable selection. The repeated DNA at centromeres, which does not code for any proteins, is likewise extremely variable even between carefully associated types. This fast advancement of both the protein and DNA components of the centromere, regardless of the structures conserved function, appears paradoxical.Investigating centromeres or other self-centered loci as”pathogens” in the context of hereditary conflict can supply an unique window into the biology of chromosome segregation and inheritance.To describe this paradox, in 2001, researchers proposed the idea that centromeres could play a function in meiotic drive. According to the centromere drive hypothesis, centromere DNA series (like the maize knobs)can act like self-centered genetic components, promoting their transmission to the next generation by pirating the chromosome partition machinery. This centromere drive may enforce fitness costs, such as an increased possibility of segregation mistakes that produce aneuploid gametes. These expenses enforce a selective pressure for adaptive evolution of centromere proteins to suppress the fitness costs.But the repeated, noncoding DNA at centromeres continuously changes, putting the rest of the genome, where centromere proteins are encoded, under recurrent pressure to adapt. This consistent hereditary conflict is comparable to immune elements progressing under pressure from a constantly altering pathogen, however with an essential chromosomal locus as the pathogen. The outcome is centromeric DNA and proteins that are extremely variable even between closely related types. For this reason, the drive theory suggests that proteins adjusted to centromeres in one population might not work optimally when challenged with divergent centromeres from another population, causing hybrid incompatibilities, reproductive isolation, and speciation, analogous to the isolation induced by distinctions in karyotype.Initial assistance for the centromere drive theory originated from observations in yellow monkeyflowers (Mimulus spp.)published in 2008. In these plants, an expanded centromere, with more copies of the centromeric DNA repeat, exhibits a dramatic transmission bias. It can end up in offspring as much as 98 percent of the time when plants are heterozygous for this expanded centromere. Plants homozygous for the broadened centromere display reproductive physical fitness costs, nevertheless, in the type of minimized seed and pollen production, although the underlying systems are unclear. Subsequent findings have shown that the magnitude of the transmission bias differs across different hereditary backgrounds. Specifically, research study indicate a version of the H3 histone protein as a prospective suppressor of drive. This variation, understood as CENP-A or CenH3, plays a crucial function in packaging centromeric DNA and acts as the structure for the kinetochore, a multiprotein complex that binds the spindle microtubules.These observations are consistent with the centromere drive hypothesis and raise interesting mechanistic concerns for cell biologists: How do selfish centromeres predisposition their partition? How might adjustments of centromere proteins avoid drive or otherwise suppress the expenses of nonrandom segregation? And what does all this mean for the evolution of species and populations? THE SCIENTIST STAFFSeparating UnequallyRandom partition leads to each of moms and dads alleles having an equal chance(0.5 possibility)of being given. This can be visualized in a standard Punnett square(left), which causes a 3:1 ratio of offspring phenotypes and a 1:2:1 ratio of offspring genotypes (represented by orange, dark blue, and light blue shading, respectively ). If there is a meiotic drive, those ratios are shifted, sometimes dramatically (right ). PDFMechanisms of prejudiced segregationCentromere drive depends upon a mix of asymmetries in female meiosis. First, there is the cell fate asymmetry that leads to the development of one functional gamete while the other haploid cells are deteriorated and are therefore evolutionary dead ends. Second, there is the uneven positioning of the spindle close to the cell cortex, a thin layer of actin and other proteins just beneath the plasma membrane, causing production of a big egg and a little polar body. Half of the chromosomes are attached to the cortical side of the spindle and are thus predestined for the polar body. Third, there is practical asymmetry in between the centromeres of homologous chromosomes, with selfish centromeres most likely to stay in the egg. Centromere drive depends upon coupling these asymmetries. The spindle provides spatial cues suggesting which side leads to the egg versus the polar body, and self-centered centromeres communicate with the spindle such that they preferentially orient far from the polar body and toward the egg.For the past eight years, my associates and I have actually used mice to question these characteristics, and have actually discovered that spindle asymmetry is undoubtedly paired with cell fate asymmetry. Previous studies had revealed that activation of a GTPase called Ran, by GTP binding, is caused by chromosomes and creates a diffusible signal that the cortex spots, leading to the cells polarization. Another GTPase, Cdc42, is enriched on the polarized cortex near the spindle. In 2017, we showed that the combination of spindle positioning, polarization-triggering Ran signaling, and Cdc42 signaling from the cortex back to the spindle leads to asymmetry within the spindle. This spindle asymmetry is based upon distinctions in a post-translational adjustment of tubulin, the protein that makes up microtubules. The cortical side of the spindle is enriched for tyrosinated α-tubulin, which contains a C-terminal tyrosine, while the egg side is improved for detyrosinated α-tubulin, from which the tyrosine has actually been gotten rid of by a peptidase. We evaluated the significance of this asymmetry in a hybrid mouse model made by crossing a pressure that has larger centromeres with a stress that has smaller centromeres. When homologous chromosomes pair in female meiosis in the hybrid, larger and smaller sized centromeres complete for transmission to the egg. We revealed that larger, selfish centromeres capitalize on the spindle asymmetry to preferentially orient towards the detyrosinated side predestined for the egg.Preferential orientation depends on the third asymmetry: practical differences in between centromeres of homologous chromosomes. Selfish centromeres make use of the well-studied equipment that prevents segregation errors in every cellular division. In mitosis, for instance, centromeres of sibling chromosomes can attach to the same spindle pole, an error that would cause partition of both sibling chromosomes into one child cell. To correct the error before segregation can take place, microtubule destabilizing proteins at centromeres moderate detachment from spindle microtubules, supplying an opportunity for one centromere to connect to the opposite pole. In 2019, we showed that self-centered centromeres in hybrid mouse models hire more of these destabilizers relative to the homologous chromosome. From the viewpoint of a selfish centromere, accessory to the cortical side of the spindle is detrimental due to the fact that it leads to the polar body. The destabilizers resolve this concern by preferentially detaching the selfish centromere from tyrosinated microtubules and reorienting it towards the egg side.DRIVEN TO SURVIVEDuring oogenesis, just one of the haploid cells developed by meiosis makes it through. The others, called polar bodies, pass away. This establishes a chance for”cheating,”or nonrandom partition, for example during the very first round of meiosis when bivalents are divided into paired chromosomes, as chromosomes with centromeres dealing with far from the cell cortex are kept in the future egg cell. One example of this is that larger centromeres hijack the machinery that connects to the spindle, resulting in them dealing with away from the cortex preferentially(zoom ). See complete infographic: WEB
Centromere DNA is usually highly repeated, and we discovered that bigger centromeres have more of the satellite repeats characteristic of mouse centromeres and more centromere proteins associated with that DNA. These expenses impose a selective pressure for adaptive evolution of centromere proteins to suppress the fitness costs.But the repeated, noncoding DNA at centromeres constantly changes, putting the rest of the genome, where centromere proteins are encoded, under frequent pressure to adjust. PDFDefending against centromere driveThe fitness costs to organisms of centromere drive are still uncertain, however we anticipate that these costs depend on practical distinctions in between the paired centromeres of homologous chromosomes: differential interaction of these centromeres with spindle microtubules, for example, may lead to partition errors. Lowering these distinctions would minimize fitness costs to the organism.Functional equalization of different centromeres might take place in two ways: by damaging the pathway selfish centromeres exploit to hire destabilizing proteins, and/or by reinforcing another recruitment pathway that is equivalent at all centromeres. Alternatively, when we weakened the heterochromatin path by knocking out the centromere protein CENP-B, which contributes to development of heterochromatin near the centromere, we discovered that centromeres became functionally more different (i.e., more off center ).
