Centromeres Take Flight: Alpha Satellite and the Quest for the Human Centromere

At first glance, there are significant advantages for the individual cell and organism to contain centromeres that are dependent entirely on primary DNA sequence; given the importance of centromeres to cell and organismal viability, there should be no room for gain or loss of centromere function. Then why would centromeres utilize epigenetic mechanisms of regulation? Perhaps because it is adaptive and advantageous during evolution.Epigenetic mechanisms could help buffer organisms from frequent and possibly detrimental changes to the DNA sequence. In addition to frequent base changes, satellite arrays readily expand and contract, changing the relative representation of neighbors (Figure 4Figure 4A). A primary sequence-independent, self-propagation mechanism would tolerate changes in DNA sequence, because the centromere would simply follow the rule “love the one you're with…” Alternatively, an epigenetic mechanism may even be adaptive. For example, if centromere function per se results in recombination suppression, the resulting accumulation of ephemeral satellites in the centromeric region would then favor evolution of sequence-independent mechanisms of centromere specification.Figure 4Evolutionary Changes in Centromeric Sequences and FunctionOrange and red denote different satellite arrays.View Large Image | View Hi-Res Image | Download PowerPoint SlideCentromere plasticity could also facilitate chromosome evolution. Related species frequently differ in the arrangement and association of chromosome arms, even when the DNA sequences are nearly identical. Chromosome parts are exchanged by fusion and fission events—the requirement for one, and only one, centromere would render many of the resulting dicentric and acentric chromosome rearrangements useless unless centromeres could be inactivated and neocentromeres activated (Figure 4Figure 4B). Thus, the ability to move the centromere from one DNA sequence to another, by spreading, hopping, or activation (Figure 4Figure 4A and Figure 4Figure 4B) may expedite chromosome evolution. Do centromeres move within a chromosome, in evolutionary or even cellular timescales? Perhaps our perception of the absolute stability of centromere location is false. Most centromeres have been localized by light microscopy, which does not provide the resolution necessary to answer this question. Functional centromeric DNAs need to be identified and mapped precisely within populations, and within extensive phylogenies that contain both closely related and distant species that are accessible to experimental manipulation.Lessons learned from centromere studies may be relevant to understanding other chromosomal functions, such as homolog pairing, long-distance regulation of gene expression, and replication. For example, replication origins in S. cerevisiae are competent to function when cloned and reintegrated into chromosomes; this does not appear to be true for mammalian origins. Perhaps other chromosomal functions in higher eukaryotes have, like centromeres, been resistant to comprehension because these biological processes are determined by epigenetic mechanisms; if so, new tools and ways of thinking need to be developed before we can completely understand chromosome behavior and inheritance. The determinants of centromere identity and function are being investigated intensively in humans and other eukaryotes, and in the coming years we expect to gain a deeper understanding of this essential and complex biological function.