Chromosome Structure and Organisation in Humans Flashcards
Give a general definition and description of a chromosome.
- Chromosomes are structures consisting of chromatin fibre (DNA and protein complex) folded and complexed into a compact rearrangement. - Chromosome are constricted at a point called the centromere. This divides the chromosome into two arms, the p arm (short), and the q arm (long). - Chromosomes are only visible during cell division when the DNA becomes tightly packed.
What two elements make up a chromatin fibre?
- Chromatin fibre = DNA + Protein
How are Eukaryotic chromosomes classified?
- Eukaryotic chromosomes are classified into three major types based on the position of the centromere and further classified into groups according to size.
Chromosomes can be classified into three different categories based upon the location of their centromere - what are the names of these three classifications?
- Metacentric - p and q arms are roughly equal in length 2. Submetacentric - the p and q arms of unequal length 3. Acrocentric - the p arm is very short but still present
List the acrocentric chromosomes.
chromosomes 13, 14, 15, 21, and 22.
Outline the chromosome groupings by letter (A-G).
- Group A (Largest) - Chromosomes 1-3 - 1 and 3 are metacentric but 2 is submetacentric. - Group B (Large) - Chromosomes 4 and 5 - submetacentric chromosomes with two arms very different in size. - Group C (Medium size) - Chromosomes 6 to 12 and the X chromosome - Submetacentric chromosomes. - Group D (Medium size) - Chromosomes 13 and 14 - Acrocentric chromosomes with satellites. - Group E (Small) - Chromosome 16 is metacentric but chromosomes 17 and 18 are submetacentric. - Group F (Small) - Chromosomes 19 and 20 - Metacentric. - Group G (Small) - Chromosomes 21, 22, and Y - Acrocentric chromsomes. Chromosomes 21 and 22 have satellites whereas the Y chromosome does not.
In what order of size are autosomes numbered?
- Autosomes are numbered from largest to smallest, except that chromosome 21 is smaller than chromosome 22.
What is the centromere of a chromosome and what is its basic function?
- The centromere is a region of highly specialised chromatin that provides the foundation for kinetochore assembly and serves as a site for sister chromatid attachment. - It is easily visualised as the most constricted region of a condensed mitotic chromosome.
What is the function of the centromere?
- The centromere is essential for accurate chromosome segregation durning cell division and also provides the foundation for the assembly of the kinetochore. Microtubules of the spindle attach to the centromere via the kinetochore. - For accurate mitoses, sister chromatids must remain attached until the spindle checkpoint has been passed. The attachment of sister chromatids is mediated by the cohesin complex of proteins. As the cell progresses into anaphase the cohesion is degraded allowing the sister chromatids to be separated to opposite poles of the spindle. - Chromatid separation occurs in mitosis and meiosis II. The centromere remains intact with attached sister chromatids in the 1st meiotic division. - Defects in any of the pathways that regulate centromere assembly and function can lead to chromosome missegregation, aneuploidy, and chromosomal instability. Acentric fragments fail to attach to the mitotic spindle, segregate randomly during mitosis and are eventually lost from cells. Dicentric chromosomes are subject to fragmentation if the centromeres become attached to opposite spindle poles by way of their kinetochores.
Describe centromere structure. (Your answer should mention basic structure, and touch on any sub-domains, and associated proteins).
- The centromeres of chromosomes are composed of constitutive heterochromatin that is made up of various families of repetitive satellite DNA. - Human centromere are built on a series of head-to-tail tandem repeats of 171 bp AT rich DNA named alpha satellites, that extend several Mb and make up 3% of the genome. - There are 3 centromeric DNA sub-domains (CDEI, II, and III). Mutations in the first two have no effect upon segregation, but those in CDEIII disrupt chromosome function completely. - There are approximately 20 known proteins associated with human centromeres (known as CENPs - centromeric proteins), which play a variety of roles. CENPs can be classified into two groups depending upon their spatial positioning throughout the cycle. The first class of CENPs comprise proteins that are constitutively associated with the centromere such as CENPA, CENPB, and CENPC, which are thought to have structural roles in kinetochore formation. The second class of CENPs, known as passenger proteins, associate with the centromere transiently during the cell cycle. This class comprises proteins proteins with diverse roles in cell division such as spindle capture, metaphase to anaphase transition, and sister chromatid cohesion. - Centromeric DNA sequence is not sufficient to maintain centromere position. Centromeres are epigenetically identified. The histone H3 variant CENP-A has been demonstrated to be the epigenetic mark for centromere identity and function. CENP-A forms a unique complex with other histones (H2A, H2B, and H4). CENP-A marks active centromeres independently from DNA sequence and mediates centromere assembly through tightly regulated complex processes.
How many centromeric DNA sub-domains are there? What is the effect of mutations in each of these sub domains?
There are 3 centromeric DNA sub-domains (CDEI, II, and III). Mutations in the first two have no effect upon segregation, but those in CDEIII disrupt chromosome function completely.
What are the two main groups of proteins associated with human centromeres?
- There are approximately 20 known proteins associated with human centromeres (known as CENPs - centromeric proteins), which play a variety of roles. CENPs can be classified into two groups depending upon their spatial positioning throughout the cycle. 1). The first class of CENPs comprise proteins that are constitutively associated with the centromere such as CENPA, CENPB, and CENPC, which are thought to have structural roles in kinetochore formation. 2). The second class of CENPs, known as passenger proteins, associate with the centromere transiently during the cell cycle. This class comprises proteins proteins with diverse roles in cell division such as spindle capture, metaphase to anaphase transition, and sister chromatid cohesion.
What is the function of the protein CENP-A?
- Centromeric DNA sequence is not sufficient to maintain centromere position. - Centromeres are epigenetically identified. - The histone H3 variant CENP-A has been demonstrated to be the epigenetic mark for centromere identity and function. - CENP-A forms a unique complex with other histones (H2A, H2B, and H4). - CENP-A marks active centromeres independently from DNA sequence and mediates centromere assembly through tightly regulated complex processes.
Name 3 disorders that are associated with centromere dysfunction.
1). Premature Centromere Division (PCD) - age-dependant phenomenon occurring in women, characterised by rod-shaped X chromosome(s) without discernible centromeres, possible cause of age-dependent increase of X chromosome aneuploidy. 2). Premature Chromatid Separation (PCS) - consists of separate and splayed chromatids with discernible centromeres and involves all or most chromosomes of a metaphase. It is found in up to 2% of metaphases in cultured lymphocytes from approximately 40% of normal individuals. When PCS is present in 5% or more of cells, it is known as the ‘heterozygous PCS trait’ and has no obvious phenotypic effect, although some have reported decreased fertility and possible increase of aneuploidy in offspring. 3). Roberts syndrome - a chromosomal breakage syndrome (an example of a disease associated with centromere malfunction). Autosomal recessive. The gene ESCO2 (8p21.1), Acetyltransferase, required for the establishment of sister chromatid cohesion in S phase, holding the two sister chromatids together until the chromosomes are ready to separate. Mutation results in delayed cell division and increased cell death. Metaphase spreads show characteristic (pathognomonic) premature centromere separation, and puffing of centromeres on 1, 9, and 16. Phenotype includes pre/post growth retardation, limb malformation (reduction), craniofacial (microcephally, clefting), intellectual disability, and renal and cardiac abnormalities.
What is Premature Centromere Division (PCD)?
- Premature Centromere Division (PCD) is a disease associated with centromere dysfunction. It is an age related phenomenon that occurs in women. PCD is characterised by rod-shaped X chromosome(s) without discernibly centromeres and is a possible cause of age-dependent increase in chromosome X aneuploidy.