Chromosome Abnormalities Notes

Genetic Disorders

• Genetic disorders can be categorized into three main types:
  • Single gene disorders
  • Chromosomal abnormalities
  • Multifactorial disorders

Single Gene Disorders

• Recessive Disorders:
  • Albinism
  • Tay-Sachs disease (Lethal)
  • Phenylketonuria
• Dominant Disorders:
  • Hypercholesterolemia
  • Huntington’s disease
  • Polydactylia
• X-linked Disorders:
  • Color Blindness (recessive)
  • Hemophilia (recessive)
  • Duchenne’s disease (recessive)
  • Goltz’s syndrome (dominant)

Single Gene Disorder Inheritance

• Recessive Disorders:
  • One chance in four of having an affected child if both parents are carriers.
• Dominant Disorders:
  • A fifty-fifty chance of having an affected child if one parent is affected.
• X-Linked Disorders:
  • Males are at risk because they have only one X chromosome.

Chromosomal Disorders

• Associated with various chromosomal abnormalities.
  • Down Syndrome
  • Turner Syndrome
  • Klinefelter Syndrome
  • Patau Syndrome
  • Edward’s Syndrome

Chromosomal Abnormalities

• Changes in the total number of chromosomes:
  • Missing chromosomes
  • Extra chromosomes
• Chromosomal rearrangements:
  • Duplication of chromosome segments
  • Deletion of chromosome segments
  • Inversion of chromosome segments
  • Translocation of chromosome segments

Variation in Chromosome Number

• Aneuploidy: $2n "+/- " x$ chromosomes
• Monosomy: $2n - 1$
• Disomy: $2n$
• Trisomy: $2n + 1$
• Tetrasomy, pentasomy, etc.: $2n+2$, $2n + 3$, etc.
• Euploidy: Multiples of $n$
• Diploidy: $2n$
• Polyploidy: $3n, 4n, 5n,…$
• Triploidy: $3n$
• Tetraploidy, pentaploidy, etc.: $4n, 5n$, etc.
• Autopolyploidy: Multiples of the same genome
• Allopolyploidy (amphidiploidy): Multiples of closely related genomes

Euploidy

• Change in the number of haploid chromosome sets ($n$).
• Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes in each cell.
• Cells with one additional set of chromosomes, for a total of 69 chromosomes, are called triploid.
• Euploidy is generally not tolerated in humans; deviation from diploidy ($2n$) with haploid gametes ($n$) is usually lethal.
• Euploidy is more common in other organisms like plants, where it may be part of their normal cell cycle.

Aneuploidy

• Gain or loss of one or more chromosomes but not a complete set.
  • Aneuploidy: $2n "+/-" x$ chromosomes
  • Monosomy: $2n - 1$
  • Disomy: $2n$
  • Trisomy: $2n + 1$
  • Tetrasomy, pentasomy, etc.: $2n+2$, $2n + 3$, etc.

Causes of Aneuploidy

• Aneuploidy is typically caused by nondisjunction, a random error during gamete production.
• Nondisjunction occurs when paired homologs fail to separate properly during segregation in Anaphase I or Anaphase II, leading to different final results.

Nondisjunction

• Can occur during the first or second meiotic division.
• First-division nondisjunction: None of the offspring is normal.
• Second-division nondisjunction: Half of the offspring is normal.

Monosomy

• Lack of a single chromosome ($2n-1$).
• Not tolerated in humans because the lack of a chromosome renders all genes contained in the other homolog as the only copy of the gene.
  • Haploinsufficiency: The single gene cannot provide adequate function for the organism.
  • Exposure of recessive alleles: Some may be lethal and were previously masked by the presence of the dominant allele in the other chromosome.

Y Chromosome

• Determinant of maleness but void of essential genes.
• Contains a gene encoding TDF (testis-determining factor) that promotes the formation of testes in the undifferentiated region of gonadal tissue in the embryo.
• The presence or absence of the Y chromosome determines gender differentiation.

Turner Syndrome (XO)

• Monosomy of the sex-determining chromosome, with only one X chromosome present.
• Individuals are female, but their ovaries do not develop properly, and they do not ovulate.
• Prevalence is 1 in every 2,500 newborn girls but is more common among stillbirths and miscarriages.

Trisomy

• Presence of an extra chromosome ($2n+1$).
• Not well-tolerated in humans, except for a few exceptions, mainly involving small chromosomes.
  • Down Syndrome (47, 21+)
  • Patau Syndrome (47, 13+)
  • Edward’s Syndrome (47, 18+)
  • Klinefelter Syndrome (47, XXY)
  • XYY Condition (47, XYY)

Syndromes Associated with Trisomy

• Down syndrome: 1 in every 800 newborns
• Klinefelter syndrome: 1 in every 660 newborn boys
• XXY Condition: 1 in every 1000 newborn boys
• Edward syndrome: 1 in every 5000 newborns
• Patau syndrome: 1 in every 16000 newborns
• Only 5-10% of newborns survive the first year of life.
• ~30% of spontaneous abortions have chromosomal abnormalities.
• Studies of spontaneous abortions have recovered trisomies for every chromosome but not monosomies (except for XO), suggesting embryos with monosomies die very early.

Down Syndrome

• Extra chromosome 21 (47, 21+).
• Life expectancy: 50-60 years.
• Increased risk for heart malformations and higher incidence of leukemia and Alzheimer’s disease.
• 75% of the trisomy comes from non-disjunction in Meiosis I.
• 95% originated from the non-disjunction event in the mother.

Down Syndrome: Risk Increase with Mother's Age

• Risk increases with maternal age.
• All eggs are produced in the fetus and arrested in Meiosis I (prophase I) until puberty.
• After puberty, eggs are arrested in Meiosis II until fertilization.

Klinefelter Syndrome

• 47, XXY.
• Males, usually with long arms and legs.
• Rudimentary testes that do not produce enough testosterone, causing sterility.
• Shortage of testosterone leads to incomplete suppression of feminine sexual development, such as enlargement of the breast, round hips, and lack of facial hair.
• Increased risk for breast cancer and lupus.

XYY Condition

• 47, XYY.
• Very rare condition with very little effect on affected individuals.
• Males with XYY have normal sexual development and are fully fertile.

Patau and Edward Syndrome

• The only known autosomal trisomies detected.
• Patau (47, 13+)
• Edward (47, 18+)
• Very severe conditions with a low survival rate: 5-10% do not survive the first year of life.

Human Mosaics

• Individuals with patches of tissues with different genetic compositions.
• Human mosaics have been reported with patches of XX and XO.
• Generated by the loss of an X or Y chromosome early in the life of an embryo.

Cancer as Mosaic Tissue

• Many cancers induce genome instability that results in significant chromosomal rearrangements.
• Affected individuals can be considered mosaics, containing tissues with different genetic makeups.

X Inactivation

• Most genes on the X chromosome function as a single copy; otherwise, females would have a double dosage compared to males.
• To achieve this, one of the X chromosomes undergoes inactivation and remains highly compacted, forming a structure called the Barr Body.
• Which of the two X chromosomes gets inactivated is a random process that occurs early in embryogenesis.
• All cells derived from a single cell will have the same X chromosome inactivated, leading to the production of mosaics.

Chromosomal Rearrangements

• Changes in the total number of chromosomes:
  • Chromosomes missing
  • Extra chromosomes
• Chromosomal rearrangements:
  • Duplication of chromosome segments
  • Deletion of chromosome segments
  • Inversion of chromosome segments
  • Translocation of chromosome segments

Chromosomal Rearrangements and DNA Breaks

• DNA breaks occur constantly, either spontaneously or due to exogenous agents (radiation, UV light, chemical agents, etc.).
• Most of the time, these breaks are properly repaired, but in other cases, they are not repaired correctly, which can lead to all kinds of chromosomal rearrangements.

Deletions

• A missing region in a chromosome.
• Only tolerated when the missing region is small.

Cri-du-chat Syndrome

• Example of a disease caused by a deletion.
• Individuals with this syndrome have intellectual disability and possess a high-pitched cry that sounds like a cat.
• Caused by a small deletion in the short arm of chromosome 5 (46, 5p-).
• It has an incidence of 1 in every 25,000-50,000 births.
• The missing region contains genes like TERT (involved in telomere maintenance) and CTNND2 (associated with mental retardation).

Duplications

• A repeated region in a chromosome.
• When a piece of a chromosome is present, repeated in the genome, it creates extra copies for the genes located in the duplicated region.
• Duplications have been a great driving force during evolution.
• Duplicated genes allow the evolution of one of them while preserving the other.
• It has led to the formation of families of genes that resemble each other and that all have a common ancestor who underwent duplication.

Charcot-Marie-Tooth Disease

• Example of a disease caused by duplication.
• CMT is a neuropathy caused by progressive demyelination of peripheral nerves, causing nerve impulses to go more slowly.
• CMT-affected individuals have mobility problems.
• Type 1A of CMT is associated with a duplication of a region containing the gene PMP22.
• Having an extra copy of PMP22 causes the observed phenotypes for unknown reasons.

Inversions

• When a chromosome segment is turned around 180°.
• Do not involve loss of genetic information.
• If the inverted segment contains the centromere, it is called pericentric; otherwise, it is called paracentric.

Inversions: What's the Risk?

• Because there is no loss of genetic material, inversions do not normally lead to phenotypic changes unless:
  • The break point disrupts genes in the middle.
  • The rearrangement of material silences expressing genes or expresses silencing genes.
• The major problem for individuals with inversions is during meiosis pairing, which can lead to faulty gamete formation.
• Crossing over within the inversion loop during meiosis can lead to non-viable gametes due to missing genes.

Translocations

• Relocation of chromosome fragments.
• Two major types:
  • Reciprocal Translocation
  • Robertsonian Translocation
• Reciprocal translocation involves the exchange of genetic material between two chromosomes.
• If no genetic information is lost, it is called a 'balanced translocation'.
• If a translocation reshuffles the centromeres between the two chromosomes, it may not be viable, even if there has not been a loss of genetic material.

Robertsonian Translocations

• Exchanges between acrocentric chromosomes.
• Acrocentric chromosomes in humans are 13, 14, 15, 21, and 22, and they have a long arm and a very tiny short arm.
• The exchange involves the loss of two short arms and the fusion of two long arms at the centromere.
• Although there is a loss of genetic material, the 'p' arm is so tiny that cells seem to tolerate its loss.

Problems with Balanced Translocations

• The breakpoint may disrupt important genes or create fusions between two genes.
  • Example: Philadelphia chromosome, present in 95% of all chronic myeloid leukemia cases. It is caused by a balanced translocation between chromosomes 9 and 22.
• In mitosis, even if they are balanced, it can lead to a lack of viability if dicentric and acentric chromosomes are formed; otherwise, mitosis occurs normally.
• The big problem occurs during meiosis because it will form gametes that can give rise to offspring with unbalanced translocation (loss and duplication of genetic material), which can lead to infertility.

Reciprocal Translocations: Problems in Meiosis

• Balanced reciprocal translocations can lead to a lot of non-viable gametes.
• Some gametes produced can pass the balanced translocation to the next generation, creating balanced carriers.
• It is estimated that 1 in every 930 people have balanced translocations.

Familial Down Syndrome

• 5% of Down syndrome cases do not result from non-disjunction in the mother's gamete but rather from a rare familial form where the disease 'runs in the family'.
• A Robertsonian translocation between chromosomes 14 and 21 is the cause of this familial form of Down syndrome.