Kevin -Centromeres are considered to be epigenetically defined chromosomal loci-examanswer PDF

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Centromeres are considered to be epigenetically defined chromosomal loci. Discuss the evidence for this hypothesis and the key experimental data that have contributed to this concept Chromosomes act as the functional unit of inheritance that contains DNA and must segregate efficiently in order to ac...

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Centromeres are considered to be epigenetically defined chromosomal loci. Discuss the evidence for this hypothesis and the key experimental data that have contributed to this concept Chromosomes act as the functional unit of inheritance that contains DNA and must segregate efficiently in order to achieve and maintain accurate chromosome delivery. Within eukaryotes, mitosis involves sister chromatids being bidirectionally orientated towards the microtubule-based spindle poles that allow the movement of complete sets of chromosomes to each daughter cell. This function is mediated by the kinetochore, a proteinaceous structure that forms during mitosis at the microtubule/chromosome interface. Kinetochore assembly is localised to a specific chromosomal locus known as the centromere, which confers the transmission function to chromosomes. Defects associated with the functionality of the centromere or the kinetochore can lead to segregation errors which, in turn, can lead to aneuploidy resulting in cellular stress and greater genomic instability. The centromere has been defined genetically as a site of suppressed meiotic recombination on each linkage group. They have also been defined cytogenetically as the primary constriction site of condensed mitotic chromosomes. However, defining the molecular features that confer the function of the centromere is an ongoing pursuit. Classic experiments from Clarke and Carbon in budding yeast defined the centromere as a small 125bp sequence-specific region of DNA. However, for most eukaryotes the centromere is much larger and is not defined by a particular DNA sequence but rather by epigenetic mechanisms. For both simple and complex centromeres, there is a core centromeric chromatin at the foundation of the kinetochore where specialised nucleosomes are held containing the histone H3 variant centromere protein (CENP) A. This core is comprised of homogenous ordered repeats. There is also a surrounding specialized heterochromatin domain, known as the pericentromere, required for sister-chromatid cohesion. Both of these components are essential for successful chromosome transmission at cell division. The centromere is typically located within a region of repetitive satellite DNA in diverse plant and animal phyla. In humans, the predominant centromeric satellite, α-type 1, consists of repeats of 171bp monomers that extend for several megabases at most centromeres. In humans and other great apes, monomers are arranged head-to-tail to form higher-order repeats that are themselves reiterated across the centromere core. The human pericentromere contains flanking monomers that lack higher-order repeats and that have reduced identity between monomers. Despite this correlating localisation, several instances have supported the concept of the epigenetic manner of centromeres. The first evidence of this came from human patient samples containing dicentric chromosomes in which one centromere was functionally inactivated without changes to its underlying DNA sequence. Centromere inactivation is also observed in Robertsonian fusions and in isodicentric Y chromosomes generated by sister chromatid recombination of Y palindromes. It has also been identified that centromeres form at atypical sites over evolutionary time subsequent to a speciation event without transposing the surrounding genetic markers. This is a phenomenon known as centromere repositioning which creates neocentromeres. Specifically, the genus Equus has exhibited numerous centromere repositioning events during evolution. This has permitted the development of several centromeres in the equid line that have been shown to lack α-satellite repeats. Centromere repositioning has been

identified to have occurred at least six times in Equus asinus during evolution, while 3 other repositioning events have occurred throughout the genus, further suggesting the epigenetic characteristics of centromeres. In 1993, routine karyotyping of a human patient revealed that a chromosome fragment had lost its centromeric DNA but was nonetheless stably maintained in mitosis, assembled a functional kinetochore and mediated sister chromatid cohesion in the absence of canonical underlying DNA repeats. Neocentromeres have also been identified to be inherited, demonstrating that these structures are stable in both mitosis and meiosis. As well as this, neocentromeres have been generated experimentally in diverse organisms by selecting for their ability to rescue acentric chromosomal fragments. Similarly, two human cases have described instances where a centromere relocated within an intact chromosome 3 or 4 respectively, from the original location to a new location on the chromosome arm. It was identified that this new location was able to persist in multiple family members for at least two generations. In most eukaryotes, the defining feature of centromeres is the presence of nucleosomes containing CENP-A. CENP-A was first identified as a centromere-specific antigen recognised by antibodies from human patients with the autoimmune disease CREST syndrome. CENPA nucleosomes share homology with histone H3 and have been identified in diverse eukaryotes, making it a prime candidate for an epigenetic mark of centromere identity. CENP-A is also found at all identified neocentromeres, as well as at the active centromeres of dicentric chromosomes....