Chromosomal Mutations and Structure

Chromosomal Mutations

• Mutations visible using a light microscope or fluorescent probes can involve missing, extra, or moved DNA, including structural variants.
• Large-scale chromosomal abnormalities disrupt or halt prenatal development.
• Only 0.65% of newborns have chromosomal anomalies that produce symptoms.
• Cytogenetics links chromosome variations to specific traits, including illnesses.

Chromosome Structure

• A chromosome is composed of sister chromatids.
• Heterochromatin is darkly staining and consists mostly of repetitive DNA.
• Euchromatin is lighter-staining and contains most protein-encoding genes.
• Telomeres are chromosome tips composed of many repeats of TTAGGG.
• Telomeres shorten with each cell division.

Telomere and Cancer

• Telomeres become too short in cancer cells, leading to cell division problems and the development of a malignant tumour.
• Telomerase, the enzyme that maintains telomere length, is activated in cancer cells.

Karyotype

• A karyotype is a chart of chromosomes arranged by size and structure.
• Humans have 24 chromosome types.
• Autosomes are numbered 1 to 22 by size.
• Sex chromosomes are X and Y.

Karyotyping Techniques

• Karyotyping is typically performed on cells during mitotic metaphase.
• Karyotypes are useful for confirming clinical diagnoses, determining effects of environmental toxins, and understanding evolutionary relationships.
• Common methods include amniocentesis and chorionic villus sampling (CVS).
• A newer approach is cell-free fetal DNA testing.

Centromere Positions

• Telocentric: Centromere at the tip.
• Acrocentric: Centromere close to the center.
• Submetacentric: Centromere off-center.
• Metacentric: Centromere at the center.

Detecting Chromosomes

• Chromosomes can be imaged from any type of human cell with a nucleus (red blood cells do not have a nucleus).
• Prenatal diagnosis is a common application of human chromosome testing.
• Chromosome testing can be utilized for relatives who have atypical chromosomes to understand infertility, diagnose cancers, or track cancers' development.
• Older techniques include amniocentesis and chorionic villus sampling (CVS).
• Newer techniques include cell-free fetal DNA testing.

Amniocentesis

• A small sample of amniotic fluid is taken from a pregnant woman's uterus using a needle, guided by ultrasound.
• Fetal cells suspended in the fluid are sampled.

Chorionic Villus Sampling (CVS)

• Cells from the chorion are sampled, providing earlier results than amniocentesis.
• There is a higher risk of spontaneous abortion.

Maternal Age Effect

• Amniocentesis was historically limited to women over 35 as the risk of miscarriage equals the risk of the procedure as maternal age increases.

Cell-Free Fetal DNA Testing

• In a pregnant woman, about 20% of small DNA pieces in the blood come from the placenta, representing the fetus.
• Cell-free fetal DNA tests are done at 10 weeks or later and are replacing older techniques.
• This method is called noninvasive prenatal diagnosis or testing.
• Fetal DNA is analyzed based on proportions, and entire genomes can be reconstructed from the DNA fragments.

Chromosomal Shorthand

• Chromosomal shorthand is a way to succinctly describe chromosome structure, number, and any abnormalities in a karyotype or genetic analysis.
• After short hand notation, numbers (and sub-numbers) indicate bands and sub-bands to identify genes.
• 46,XX denotes a chromosomally normal female.
• 46,XY denotes a chromosomally normal male.

Atypical Chromosomes

• Karyotypes may be atypical (abnormal) in terms of chromosome number or structure.
• Atypical chromosomes are present in at least 50% of spontaneous abortions, with only 0.65% of newborns having them.
• Most of these embryos and fetuses stop developing before birth.

Atypical Chromosomes—Types

• Polyploidy: Extra chromosome sets.
• Aneuploidy: Extra or missing chromosomes.
• Monosomy: One chromosome is missing.
• Trisomy: One extra chromosome.
• Deletion: Part of a chromosome is missing.
• Duplication: Part of a chromosome is present twice.
• Translocation: Two chromosomes join or exchange parts.
• Inversion: Chromosome segment is reversed.
• Isochromosome: A chromosome with identical arms.
• Ring chromosome: Chromosome forms a ring due to telomere deletions.
• Chromothripsis: One or more chromosomes break apart.

Variations in Chromosome Number

• Euploidy: One or more complete sets of chromosomes (normal or abnormal).
• Polyploidy: An increase in chromosome sets (abnormal).
• Aneuploidy: Changes in chromosome numbers, gaining or losing a single chromosome (abnormal).
• Monosomy (2n-1): Loss of a single chromosome.
• Trisomy (2n+1): Gain of a single chromosome.

Polyploidy

• Triploid (3N) cells have three sets of chromosomes (common result of fertilization of one egg by two sperm).
• Polyploidy accounts for 17% of all spontaneous abortions and is usually fatal within a month.

Aneuploidy

• Aneuploidy, most commonly arising from nondisjunction, is often lethal.
• Autosomal monosomy is rarely observed in live births.
• Autosomal trisomy accounts for about half of chromosomal abnormalities in miscarriages and only some result in live birth—with trisomies 13, 18, and 21 being commonly observed.
• Trisomy 21, Down syndrome, is the only type that allows survival to adulthood.

Nondisjunction

• Nondisjunction is a chromosomal error where chromosomes fail to separate properly during cell division.
• It results in gametes with either too many or too few chromosomes.
• Nondisjunction can occur during meiosis I or meiosis II, affecting different aspects of homologous and chromatid separation.

Autosomal Aneuploids

• Most autosomal aneuploids stop developing before birth.
• Common trisomies in newborns include those of chromosomes 21, 18, and 13.
• These chromosomes carry fewer genes than other autosomes.

Trisomy 21

• Down syndrome is the most common trisomy in newborns.
• Down syndrome results in distinctive facial and physical problems.

Trisomy 18

• Edwards syndrome, is characterized by serious mental and physical disabilities.
• An odd, clenched fist is a distinctive feature of trisomy 18.

Trisomy 13

• Patau syndrome is characterized by significant intellectual and physical disabilities.
• A fusion of the developing eyes, a notable feature, is found in individuals with trisomy 13.

Sex Chromosome Aneuploids

• Sex chromosome aneuploidies are more common than autosomal aneuploidies.
• They involve X and Y chromosomes and affect human survival.
• Most individuals with X and Y chromosome abnormalities are eliminated early in pregnancy.

Turner Syndrome (XO)

• About 1 in 2,500 female births.
• The characteristic feature and symptoms include short stature, neck webbing, incomplete sexual development (infertility).
• Individuals who are mosaics may have children.

Klinefelter Syndrome (XXY)

• About 1 in 500 male births.
• Incomplete sexual development, rudimentary testes and prostate, long limbs, large hands and feet, and sometimes breast tissue development.

47, XYY Syndrome

• About 1 in 1000 male births.
• Results from nondisjunction in the male.
• Often phenotypically normal but may have increased height.
• Acne, subtle speech, reading disabilities, and aggressive behaviors (not definitively supported).

Atypical Chromosome Structure

• A chromosome can have either too much or too little genetic material.
• Stretches of DNA can be inverted or moved and inserted into a different type of chromosome.

Deletions and Duplications

• Deletions and duplications are CNV variants often not inherited; rather, they arise de novo.
• The severity of the associated syndrome increases as the number of genes affected becomes higher. Cri-du-chat syndrome is characterized by a deletion in chromosome 5, causing a characteristic cat-like cry.

Duplications in Chromosome 15

• Duplications in chromosome 15 can result in a range of symptoms, differing by duplication type.

Translocation

• Reciprical and Robertsonian translocation are two main types.
• Reciprocal translocation involves the exchange of segments between non-homologous chromosomes.
• Robertsonian translocation involves the fusion of two acrocentric chromosomes, resulting in the loss of the tips and a change in chromosome number.

Robertsonian Translocation

• The most common type of structural chromosome abnormality observed.
• Frequency—1 live-birth in 1000.
• It affects two acrocentric chromosomes.

This quiz explores key concepts related to chromosomal mutations, including their structural variants and implications for human health. It discusses the composition of chromosomes, the role of telomeres, and their significance in cancer development. Test your knowledge of cytogenetics and the relationship between chromosome anomalies and diseases.