A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come closest in contact. It is involved in cell division as the point of mitotic spindle attachment. The sister chromatids are attached all along their length, but they are closest at the centromere.[1]
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Each chromosome has two arms, labeled p (the shorter of the two) and q (the longer). The p arm is named for "petit" meaning 'small'; the q arm is named q simply because it follows p in the alphabet. (According to the NCBI, "q" refers to the French word "queue" meaning 'tail'.) They can be connected in either metacentric, submetacentric, acrocentric or telocentric manner.
A chromosome is metacentric if its two arms are roughly equal in length. In some cases, a metacentric chromosome is formed by balanced translocation: the fusion of two acrocentric chromosomes to form one metacentric chromosomes.
If arms' lengths are unequal, the chromosome is said to be submetacentric.
If the p (short) arm is so short that it is hard to observe, but still present, then the chromosome is acrocentric (the "acro-" in acrocentric refers to the Greek word for "peak"). The human genome includes five acrocentric chromosomes: 13, 14, 15, 21 and 22.
In an acrocentric chromosome the p arm contains genetic material including repeated sequences such as nucleolar organizing regions, and can be translocated without significant harm, as in a balanced Robertsonian translocation. The domestic horse genome includes one metacentric chromosome that is homologous to two acrocentric chromosomes in the conspecific but undomesticated Przewalski's horse.[2] This may reflect either fixation of a balanced Robertsonian translocation in domestic horses or, conversely, fixation of the fission of one metacentric chromosome into two acrocentric chromosomes in Przewalski's horses. A similar situation exists between the human and great ape genomes; in this case, because more species are extant, it is apparent that the evolutionary sequence is a reduction of two acrocentric chromosomes in the great apes to one metacentric chromosome in humans (see Karyotype#Historical note).
A telocentric chromosome's centromere is located at the terminal end of the chromosome. Telomeres may extend from both ends of the chromosome. For example, the standard house mouse karyotype has only acrocentric chromosomes.[3][4] Humans do not possess telocentric chromosomes. Some authors denote extreme acrocentric chromosomes as telocentric- 21, 22, Y.
If the chromosome's centromere is located closer to its end than to its center, it may be described as subtelocentric.
With holocentric chromosomes, the entire length of the chromosome acts as the centromere. Examples of this type of centromere can be found scattered throughout the plant and animal kingdoms,[5] with the most well known example being the nematode Caenorhabditis elegans.
There are two types of centromeres.[6] In regional centromeres, DNA sequences contribute to but do not define function. Regional centromeres contain large amounts of DNA and are often packaged into heterochromatin. In most eukaryotes, the centromere has no defined DNA sequence. It typically consists of large arrays of repetitive DNA (e.g. satellite DNA) where the sequence within individual repeat elements is similar but not identical. In humans, the primary centromeric repeat unit is called α-satellite (or alphoid), although a number of other sequence types are found in this region.
Point centromeres are smaller and more compact. DNA sequences are both necessary and sufficient to specify centromere identity and function in organisms with point centromeres. In budding yeasts, the centromere region is relatively small (about 125 bp DNA) and contains two highly conserved DNA sequences that serve as binding sites for essential kinetochore proteins.
Since centromeric DNA sequence is not the key determinant of centromeric identity in metazoans, it is thought that epigenetic inheritance plays a major role in specifying the centromere.[7] The daughter chromosomes will assemble centromeres in the same place as the parent chromosome, independent of sequence. It has been proposed that histone H3 variant CENP-A (Centromere Protein A) is the epigenetic mark of the centromere.[8] The question arises whether there must be still some original way in which the centromere is specified, even if it is subsequently propagated epigenetically. If the centromere is inherited epigenetically from one generation to the next, the problem is pushed back to the origin of the first metazoans.
The centromeric DNA is normally in a heterochromatin state, which is essential for the recruitment of the cohesin complex that mediates sister chromatid cohesion after DNA replication as well as coordinating sister chromatid separation during anaphase. In this chromatin, the normal histone H3 is replaced with a centromere-specific variant, CENP-A in humans.[9] The presence of CENP-A is believed to be important for the assembly of the kinetochore on the centromere. CENP-C has been shown to localise almost exclusively to these regions of CENP-A associated chromatin. In human cells, the histones are found to be most enriched for H4K20me3 and H3K9me3[10] which are known heterochromatic modifications.
In the yeast Schizosaccharomyces pombe (and probably in other eukaryotes), the formation of centromeric heterochromatin is connected to RNAi.[11] In nematodes such as Caenorhabditis elegans, some plants, and the insect orders Lepidoptera and Hemiptera, chromosomes are "holocentric", indicating that there is not a primary site of microtubule attachments or a primary constriction, and a "diffuse" kinetochore assembles along the entire length of the chromosome.
In rare cases in humans, neocentromeres can form at new sites on the chromosome. There are currently over 90 known human neocentromeres identified on 20 different chromosomes.[12][13] The formation of a neocentromere must be coupled with or followed or proceeded by the inactivation of the centromere since chromosomes with two functional centromeres (Dicentric chromosome) will result in chromosome breakage during mitosis. In some unusual cases human neocentromeres have been observed to form spontaneously on fragmented chromosomes. Some of these new positions were originally euchromatic and lack alpha satellite DNA altogether.
Centromere proteins are also the autoantigenic target for some anti-nuclear antibodies, such as anti-centromere antibodies.
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