MBG block 2 lecture 4.pdf

Introduction 1.Define the following terms: acentric, dicentric, neocentromere, pseudodicentric, chromosome breakage, straddling limbo, regions of homology, interchromosomal, intrachromosomal, non allelic recombination, haploinsufficiency, and pseudodominance Acentric: A chromosome or chromos...

Introduction 1.Define the following terms: acentric, dicentric, neocentromere, pseudodicentric, chromosome breakage, straddling limbo, regions of homology, interchromosomal, intrachromosomal, non allelic recombination, haploinsufficiency, and pseudodominance Acentric: A chromosome or chromosome fragment that lacks a centromere. unstable during cell division, cannot attach to the spindle apparatus, rapidly lost and not observed unconstitutional karyotypes, excluded from daughter cells. Dicentric: A chromosome or chromosomal fragment that contains two centromeres. unstable, if opposite poles attach, two centromeres can be pulled in opposite directions during mitosis, leading to chromosome breakage or straddling limbo, excluded from daughter cells. Neocentromere: A centromere that forms at a novel location on a chromosome that was previously not centromeric via nucleosome association. can form in response to the loss or inactivation of the original centromere, sometimes function and generate kinetochores. Pseudodicentric: A chromosome that appears to have two centromeres (dicentric) but functions as if it has only one active centromere. One of the centromeres may be inactivated or non-functional, allowing the chromosome to segregate properly during cell division. Chromosome Breakage: The physical breaking of a chromosome into two or more pieces. This can result from DNA damage, errors during replication, dicentric centromeres, or mechanical forces during mitosis/meiosis. Broken chromosome fragments may result in genetic instability if not repaired correctly. Straddling Limbo: A rare term used in cytogenetics to describe chromosomal regions that span across unstable areas, such as breaks or fusion points. It refers to a liminal zone where normal chromosomal architecture is disrupted, usually as a result of dicentric chromosomes. Regions of Homology: DNA sequences that are similar or identical across different chromosomes or different regions within the same chromosome. Homologous regions facilitate genetic recombination during meiosis and repair  processes like homologous recombination. Many recurring and some sporadic rearrangements occur secondary to nonallelic recombination due to these regions Interchromosomal: Pertaining to interactions or events that occur across homologs, such as interchromosomal recombination, which involves the exchange of genetic material between non-homologous chromosomes. Intrachromosomal: Refers to processes or events occurring within or between sister chromatids (same chromosome), such as intrachromosomal recombination, where genetic material is exchanged between different regions of the same chromosome. Non-Allelic Recombination: A recombination event that occurs between similar but non-identical sequences at different loci, leading to structural rearrangements like duplications, deletions, or translocations. Haploinsufficiency: A situation in which a single functional copy of a gene is insufficient to produce a normal phenotype. This can occur when one allele of a gene is inactivated or deleted, and the remaining allele cannot compensate fully, leading to disease or abnormal development. Pseudodominance: The expression of a normally recessive allele due to the deletion or loss of the dominant allele. This can happen in cases of chromosomal deletions where the remaining allele is recessive, leading to its unexpected dominance. 2.Explain how rearrangements are possible, what features contribute to rearrangements, and how the size of a rearrangement/amount of genetic content correlates with the viability and phenotype How Chromosome Rearrangements Are Possible Breaks in DNA: Double-strand breaks (DSBs) can be improperly repaired, leading to rearrangements such as deletions, duplications, inversions, or translocations. Misalignment during recombination: Mispaired or misaligned homologous chromosomes, or even non-homologous regions, can result in unequal crossing over, leading to structural changes in chromosomes.  Non-homologous end joining (NHEJ): This error-prone DNA repair mechanism can cause random joining of chromosome fragments, leading to structural abnormalities. Features That Contribute to Rearrangements Repetitive Sequences: Sequences like direct or inverted repeats (e.g., transposable elements, segmental duplications) facilitate misalignment during recombination or repair, increasing the likelihood of rearrangements. Chromosomal Fragility: Fragile sites—specific regions prone to breakage—are hotspots for chromosome rearrangements. Errors in DNA Repair Mechanisms: Defective or misregulated DNA repair processes, such as faulty homologous recombination or NHEJ, can result in improper chromosome repair. Size of Rearrangement and Genetic Content Correlation with Viability and Phenotype Small Rearrangements: Tend to have less severe effects, especially if they do not disrupt essential genes or regulatory regions. These may be viable and result in minor or no phenotypic consequences. Large Rearrangements: These can significantly impact viability and phenotype, as larger segments of the genome may be affected. If important genes or large gene sets are deleted, duplicated, or relocated, this can lead to developmental issues, genetic disorders, or lethality. ○ Balanced Rearrangements: Involve no loss or gain of genetic material (e.g., inversions, translocations). These may have little effect on the carrier’s phenotype but can cause problems in gametes, potentially leading to infertility or abnormal offspring. ○ Unbalanced Rearrangements: Result in a net loss or gain of genetic material (e.g., deletions, duplications). These typically have more severe consequences, often correlating with gene dosage imbalances, resulting in developmental disorders, physical abnormalities, or reduced viability. 3.List the types of rearrangement that can occur and explain how they both occur and contribute to final chromosome architecture Interchromosomal Recombination: This occurs during meiosis when homologous chromosomes (chromosomes from the same pair, one from each parent) exchange genetic material through a process called "crossing over." This type of recombination happens between non-sister chromatids of homologous chromosomes, typically in Prophase I of meiosis. The result is a new combination of alleles on each homologous chromosome, which contributes to genetic diversity in gametes (sperm and egg cells). Intrachromosomal Recombination: This type of recombination occurs within or between sister chromatids of the same chromosome. Since sister chromatids are genetically identical (produced by DNA replication), this process generally does not lead to new genetic variation. However, intrachromosomal recombination can play a role in DNA repair or in cases where minor sequence differences arise between sister chromatids. It typically occurs in somatic cells during DNA repair mechanisms, such as homologous recombination, but is not a source of genetic diversity like interchromosomal recombination. Unexpected/Abnormal Recombination: Nonallelic recombination events Exchanges occur between different loci Homologous Chromosomes Recombination: across homologs, altered alignment so that loci/alleles are not exchanged evenly Sister Chromatids Recombination: Within one single chromatid or across chromatids unevenly Nonhomologous chromosomes Recombination: Inappropriate recombination 1. Direct Repeats and Homologues Recombine How It Occurs: Homologous recombination typically takes place between two similar or identical sequences (direct repeats) on homologous chromosomes during meiosis. When the recombination occurs between non-allelic regions (i.e., direct repeats at different loci), this can lead to unequal crossing over.  Contribution to Chromosome Architecture: Unequal crossing over between homologs can result in duplications on one chromosome and deletions on the other. This reshuffling can alter gene dosage and contribute to disorders, such as gene copy number variations (CNVs) that can be linked to developmental disorders or cancer. 2. Direct Repeats and Sister Chromatids Recombine How It Occurs: Recombination between identical direct repeats on sister chromatids can occur during DNA replication or repair processes, especially during mitosis. This event is called sister chromatid exchange. Contribution to Chromosome Architecture: Although sister chromatid recombination typically doesn't introduce genetic variation (because sister chromatids are identical), it can cause deletions, duplications, or inversions when misalignment occurs between repeats. This can lead to chromosomal instability, which is often seen in cancer cells. 3. Inverted Repeats and Homologues Recombine How It Occurs: Homologous recombination between inverted repeats on homologous chromosomes can lead to the formation of inversions. This occurs when an inverted repeat on one homologous chromosome misaligns with a matching sequence on the other homolog during recombination. Contribution to Chromosome Architecture: Inversions alter the gene order within a chromosome without changing the total amount of genetic material. However, this structural change can cause problems during meiosis by leading to the production of abnormal gametes due to improper pairing and recombination of homologous chromosomes. 4. Inverted Repeats and Sister Chromatids Recombine How It Occurs: Recombination between inverted repeats on sister chromatids can result in the flipping of a segment within one sister chromatid relative to the other, forming an inversion. Contribution to Chromosome Architecture: This rearrangement can disrupt gene function if important regulatory sequences or coding regions are inverted. If the inversion includes the centromere (pericentric inversion), it can also affect chromosome segregation during cell division. 5. Direct Repeats and Intrachromosomal Recombination How It Occurs: When recombination occurs between direct repeats on the same chromosome (intrachromosomal recombination), a segment of the chromosome between the repeats can be excised. This results in a deletion of the intervening segment. Contribution to Chromosome Architecture: This event reduces the size of the chromosome and can lead to loss of gene function if important genes are within the deleted region. Depending on the size of the deletion, it can lead to developmental disorders or genetic diseases. 6. Inverted Repeats and Intrachromosomal Recombination How It Occurs: Recombination between inverted repeats on the same chromosome can cause a segment of the chromosome to flip, resulting in an intrachromosomal inversion. Contribution to Chromosome Architecture: This alters the gene order on the chromosome and can disrupt genes at the inversion breakpoints. Such inversions can affect regulatory regions and create complications during homologous recombination in meiosis, potentially leading to unbalanced gametes. 9. Non-Allelic Homologous Recombination (NAHR) How It Occurs: NAHR happens when recombination occurs between homologous sequences that are located at non-allelic positions on the same chromosome or on different chromosomes. This often involves repeated sequences like segmental duplications or transposable elements. Contribution to Chromosome Architecture: NAHR can lead to structural rearrangements such as deletions, duplications, inversions, and translocations. These rearrangements often result in genomic disorders like DiGeorge syndrome (22q11.2 deletion), Williams syndrome, or other microdeletion/microduplication syndromes. 10. Non-Homologous Recombination (Random) How It Occurs: Non-homologous recombination can occur between non-homologous chromosomes or regions of chromosomes that do not share  sequence similarity. This event is rare but can be induced by DNA breaks and improper repair mechanisms, such as NHEJ or fork stalling in replication. Contribution to Chromosome Architecture: This type of recombination results in chromosomal translocations and complex rearrangements that can lead to genetic disorders or cancer. An example is the fusion of BCR and ABL genes resulting in the Philadelphia chromosome, a hallmark of chronic myeloid leukemia Summary of Contribution to Chromosome Architecture: Gene dosage effects: Duplications and deletions alter the number of copies of certain genes, leading to overexpression or underexpression, which can result in developmental abnormalities or diseases. Chromosomal instability: Rearrangements like translocations, inversions, and fusions can cause issues with chromosome segregation during mitosis or meiosis, potentially leading to infertility or genetic disorders. Evolutionary impact: Rearrangements can create new gene combinations or even novel genes, contributing to evolutionary changes in populations. Cancer development: Many chromosomal rearrangements, particularly translocations and gene fusions, play critical roles in oncogenesis by creating oncogenic fusion proteins or altering the regulation of cancer-related genes. 4.Compare and contrast balanced and unbalanced rearrangements in terms of phenotypic consequences Balanced Rearrangements: no net loss or gain of genetic information, phenotypically normal with positional effects leading to any observable phenotype Unbalanced Rearrangements: additional and/or missing material, Clinically affected degree dependent on amount gained or lost Molecular cytogenetic techniques: allow us to view changes and balanced vs. unbalanced rearrangements, The more apparent the change (i.e. larger, swapping hetero and euchromatin, etc…), the more likely it is to be detected 5. Compare and contrast de novo and familial rearrangements in terms of inheritance and phenotypic consequences De Novo Rearrangements: No family history; arises spontaneously during gametogenesis (sperm or egg formation) or early embryonic development. Phenotypic Consequences of De Novo Rearrangements: : ranging from no effect (if the rearrangement is benign) to severe developmental or health problems (if key genes are disrupted). Risk for abnormal phenotype is higher for an individual with even apparently balanced de novo rearrangements than for an individual who has inherited a similar rearrangement from a parent Familial Rearrangements: Inherited from a parent; may have a history in the family. parents may be unaffected carriers (if the rearrangement is balanced, meaning no loss or gain of genetic material). Familial Rearrangements Phenotypic Consequences: Balanced rearrangements often have no phenotypic effect in carriers, but can lead to unbalanced rearrangements in offspring, potentially causing developmental disorders, congenital abnormalities, or reproductive issues such as infertility or recurrent miscarriages.