Ancient genome function persists despite frequent mutations

Every time a cell divides, its chromosomes must be distributed correctly between the two daughter cells. Central to this process is the centromere, a specialised region of the chromosome that serves as the attachment site for the cellular machinery pulling the chromosomes apart. Centromeres thus perform an essential function in cell division that emerged very early in eukaryotic evolution. Remarkably, although this function has been retained over almost two billion years of evolution, the DNA sequences underlying centromeres have evolved at an extraordinarily rapid rate. An international research team led by Professor Dr Korbinian Schneeberger, head of the Institute of Crop Biology at Heinrich Heine University (HHU) Düsseldorf, together with the Max Planck Institute for Plant Breeding Research (MPIPZ) in Cologne, has now discovered how relatively small mutations can give rise to the enormous differences between centromeres. The researchers report their findings in the scientific journal Nature, in a study that also involved researchers from Tübingen, Karlsruhe, Munich and Sheffield.

While the fundamental function of centromeres is highly conserved, their DNA sequences are not: centromeres can differ dramatically between species and even between individuals of the same species. This apparent contradiction is known in biology as the centromere paradox, and it raises the question of how a structure that has retained such an ancient function can contain DNA that changes so rapidly. The research team used the model plant thale cress (Arabidopsis thaliana) to directly investigate the mutations that occur within centromeres from one generation to the next. The study showed that centromeres exhibit a characteristic pattern of mutation: point mutations, changes affecting just a single nucleotide, essentially one letter of the genome, occur at an almost tenfold higher rate than in the chromosome arms. Insertions and deletions also occur frequently, typically involving hundreds to several thousand DNA letters.

These mutations are not random disruptions of the centromere. In Arabidopsis, centromeres consist largely of a basic DNA sequence approximately 178 letters in length that is repeated thousands of times. The newly identified insertions and deletions almost always added or removed complete copies of these repeat units, thereby maintaining the centromere’s repetitive architecture. Xiao Dong, a doctoral researcher at the MPIPZ and first author of the study, explains that centromeres are far more dynamic than one might expect for a region of the genome with such an essential function. At the same time, the mutations are remarkably structured: they alter the centromere while preserving its basic repetitive organisation.

The researchers were particularly interested in one of the most striking features of centromeres: their repetitive DNA is organised into vast blocks, which are sometimes millions of DNA letters in length, with repeats that are highly similar. These blocks can differ drastically between individuals. Professor Schneeberger, senior author of the study, notes that it was previously thought that structures of this size required large mutations or long-range rearrangements to form. The study shows that this is not the case. The researchers demonstrated this through simulations in which they modelled the evolution of centromeres over many thousands of generations, using experimentally measured mutation rates and types. In the simulations, relatively small mutations, mostly affecting only a few thousand DNA letters, gradually generated large blocks comprising hundreds of thousands to millions of DNA letters that closely resembled the structures found in natural centromeres.

This difference in scale is remarkable. In natural centromeres, vast patterns extend over millions of DNA letters. They did not emerge as a result of similarly enormous changes, though, but rather through the accumulation of many relatively small mutations. The study thus connects two very different evolutionary scales: local mutations that occur from one generation to the next and the enormous differences between centromeres that have emerged over thousands of generations of evolution. Since researchers began studying spontaneous mutation rates in plants almost 20 years ago, they have wondered whether different parts of the genome mutate in different ways. This study shows that centromeres are indeed different. Their unusual mutational dynamics help explain why centromeres stand out so strikingly when the genomes of different individuals and populations are compared.

The study was carried out by researchers from the Max Planck Institute for Plant Breeding Research in Cologne, the Max Planck Institute for Biology Tübingen, the Joseph Gottlieb Kölreuter Institute for Plant Sciences at Karlsruhe Institute of Technology, LMU Munich, the University of Sheffield and Heinrich Heine University Düsseldorf through its CEPLAS Cluster of Excellence. The work illuminates how a genomic structure performing one of the most ancient and essential functions in eukaryotic biology can simultaneously be among the most rapidly evolving regions of the genome, resolving a long-standing puzzle in evolutionary genomics through direct measurement of mutation and computational modelling of centromere evolution across thousands of generations.

Centromeres occupy a peculiar position in the genome. They are the one region that every chromosome absolutely requires for faithful inheritance, yet they are also among the least conserved stretches of DNA known. Evolutionary biologists have long noted that the proteins which bind centromeric DNA are far more similar across distantly related species than the DNA sequences themselves, a pattern that has fuelled decades of debate about what drives centromere change. The new findings from Arabidopsis thaliana speak directly to this debate by showing that the raw material of centromere evolution, the spontaneous mutations arising in each generation, is itself unusual in both quantity and kind.

The roughly tenfold elevated rate of point mutations in centromeres is notable because mutation rates elsewhere in the genome are generally assumed to be relatively uniform, shaped by shared repair machinery and similar chromatin environments. Centromeres, however, sit in a distinctive chromatin context marked by specialised histone variants, and their repetitive structure may itself complicate DNA replication and repair. Whether the elevated mutation rate reflects the intrinsic difficulty of accurately copying long arrays of tandem repeats, or a reduced efficiency of repair pathways in this region, remains an open question that the study’s data can now help address.

Equally significant is the finding that insertions and deletions in centromeres tend to add or remove whole repeat units rather than arbitrary fragments of sequence. This constraint means that mutation does not erode the repetitive architecture that centromeres depend on; instead, it reshuffles and resizes the repeat array while leaving its fundamental organisation intact. In effect, the mutational process behaves like a stochastic expansion and contraction of a template library, generating diversity in copy number and arrangement without destroying the underlying repeat. This provides a mechanistic explanation for why centromeres from different individuals can look radically different at the sequence level while still performing an identical cellular role.

The simulation work carries particular weight because it bridges measurement and prediction. Rather than merely cataloguing mutation rates, the researchers fed experimentally observed rates and mutation types into models running over many thousands of generations and asked whether the resulting structures resembled real centromeres. The fact that small-scale mutations, each affecting only a few thousand DNA letters, could accumulate into blocks spanning hundreds of thousands to millions of letters suggests that no special large-scale rearrangement mechanism is needed to explain centromere architecture. Gradual accumulation, given enough generations and the right mutational biases, is sufficient.

This conclusion has implications beyond plant biology. Centromeres in animals and fungi share the same general features: essential function, repetitive sequence composition, and rapid evolution. If the mutational dynamics observed in Arabidopsis prove general, they may explain a broader pattern of genome organisation across eukaryotes. They may also bear on practical questions, since centromere defects underlie chromosome missegregation events that contribute to infertility, developmental disorders and cancer, and centromere repeat variation has been implicated in hybrid incompatibilities between species.

The study also illustrates the value of long-term experimental programmes in genetics. The observation that different genomic regions mutate in different ways emerged from decades of work measuring spontaneous mutation in plants, work that initially seemed unlikely to resolve questions about structures as large and complex as centromeres. Combining those direct measurements with modern genome assembly methods, which have only recently made the repetitive centromeric regions of individual genomes readable, allowed the researchers to connect generation-by-generation mutation to evolutionary outcomes at the scale of millions of DNA letters.

For evolutionary theory, the work reframes the centromere paradox. The paradox dissolves if one accepts that the function of a centromere resides not in its precise DNA sequence but in its repetitive organisation and the chromatin it recruits. Sequence can drift rapidly, copy numbers can expand and contract, and blocks can turn over between generations, all without compromising the role the centromere plays in cell division. What the study demonstrates is that the pace of this drift is not an anomaly but a direct consequence of mutational processes that are measurably different in centromeres than in the rest of the genome, and that these processes, operating over thousands of generations, are sufficient to produce the extraordinary diversity observed among natural centromeres today.

Subject of Research: Mutational dynamics of centromeres in Arabidopsis thaliana

Article Title: Ancient genome function persists despite frequent mutations

Article References: Ancient genome function persists despite frequent mutations. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: centromeres, cell division, Arabidopsis thaliana, mutation rates, genome evolution, Nature, repeat units, eukaryotic evolution, chromosome segregation, genomics, Ancient, genome