Aneuploidy and Polyploidy Lecture Notes

Aneuploidy and Polyploidy

A) Aneuploidy

  • Aneuploidy and Polyploidy: Changes in chromosome number.

    • Aneuploidy: Loss or gain of one or more entire chromosomes.
      • Monosomy: Loss of one chromosome. Represented as 2n-1.
      • Trisomy: Gain of one chromosome. Represented as 2n+1.
    • Polyploidy: Gain of whole sets of chromosomes.

  • Examples of Aneuploidy Types

    • Given an example where 2n=6 with chromosomes 1, 2, and 3:
      • Euploid: 2n, e.g., 11 22 33
      • Aneuploid Monosomic: 2n-1, e.g., 1 22 33, 11 2 33, 11 22 3
      • Aneuploid Trisomic: 2n+1, e.g., 111 22 33, 11 222 33, 11 22 333

  • Phenotype of Aneuploids

    • Ranges from relatively mild to severe.
    • Depends strongly on which chromosome is affected due to varying importance of gene copy number for different genes/chromosomes.
    • More severe for autosomes than for sex chromosomes.

  • Non-Disjunction (ND)

    • Failure of chromosomes to undergo typical separation at anaphase of meiosis, a rare accident.
    • Aneuploidy is caused by non-disjunction (ND) in meiosis.
      • Non-disjunction in meiosis I: Failure of separation of a pair of homologous chromosomes – two homologues go to one pole and none to the other.
      • Non-disjunction in meiosis II: Failure of a pair of sister chromatids to separate – two chromatids go to one pole and none to the other.

  • Zygote Formation with Non-Disjunction

    • Typical zygote: n + n \rightarrow 2n
    • Monosomic zygote (from non-disjunction): (n - 1) + n \rightarrow 2n - 1
    • Trisomic zygote (from non-disjunction): (n + 1) + n \rightarrow 2n + 1
    • Leads to gametes with one more or one less chromosome than typical, joining with a typical gamete at fertilization, resulting in a zygote with an atypical chromosome number.

  • Non-Disjunction Outcomes

    • If ND occurs at anaphase I, the n + 1 gamete carries two different homologues.
    • If ND occurs at anaphase II, the n + 1 gamete carries two copies of the same homologue.

  • Determining Non-Disjunction Division

    • If an Aa individual produces an Aa gamete, ND must be at anaphase I.
    • If an Aa individual produces an AA or aa gamete, ND must be at anaphase II.

  • Consequences of Gene Product Imbalance in Aneuploids

    • Typical: 11 22 33 (balanced)
    • Trisomy 1: 111 22 33 (unbalanced)
    • Monosomy 1: 1 22 33 (unbalanced)
    • Aneuploids are phenotypically different due to the imbalance of gene products.

  • Phenotypic Effects of Aneuploidy

    1. The change in phenotype is characteristic for each individual chromosome.
    2. Monosomy is more deleterious than trisomy.
    3. Aneuploidy for larger chromosomes is more deleterious than for smaller chromosomes.
    4. Severe imbalance leads to inviability.

  • Principle of Balance: Cells or organisms with a chromosomal complement that departs from a single or multiple haploid set are phenotypically different.

  • Aneuploidy of Human Autosomes

    • Many common trisomies are spontaneously lost in pregnancy.
    • Monosomies never survive.
    • Three autosomal trisomies can survive to term: Trisomy 13, Trisomy 18, and Trisomy 21.

  • Maternal Age Effect

    • Autosomal aneuploids are more frequent among offspring of older mothers.
    • Example: Down syndrome – 1 in 700 live births overall, but 1 in 100 for mothers aged 40.

  • Down Syndrome (Trisomy 21)

    • Increased incidence with increased maternal age.
    • Most common and least detrimental (mildest phenotype) of the autosomal trisomies that give rise to live births.
      • Karyotype: 47, ##, +21 (Sex chromosomes XX or XY)
      • Incidence: 1:700 live births
      • Phenotype:
        • Moderate
        • Cardiac septal defect (15-20% die early)
        • Characteristic facial structure
        • Hirschsprung disease
        • Short stature
        • Most adults develop Alzheimer's disease (APP gene is on Chromosome 21)
      • Mental capacity: Low IQ, range from 25-75
      • Life expectancy: 50-60 years (if no cardiac defect)
      • Fertility: Reduced

B) Aneuploidy of Human Sex Chromosomes

  • More common than autosomal aneuploidies.

  • Four common aneuploidies resulting from ND in one parent:

    • 47, XXX (Triple X): Female, viable, fertile.
    • 45, X or XO (Turner): Female, viable, infertile.
    • 47, XYY (Double Y): Male, viable, fertile.
    • 47, XXY (Klinefelter): Male, viable, infertile.

  • Effects are relatively minor:

    1. Genes inactivated on all but one X chromosome.
    2. Few genes on Y chromosome.
    3. Main effect is from genes that are typically not inactivated on X.

  • Possible Sex Chromosome Aneuploidies

    • Ovum possibilities: X, XX, O
    • Sperm possibilities: X, Y, XX, YY, O
    • Combinations lead to various outcomes (XXX, XXY, XYY, etc.) with varying frequencies and viability.

  • Klinefelter Syndrome

    • Karyotype: 47, XXY
    • Phenotypic sex at birth: Male
    • Incidence: 1:1000
    • Phenotype: Mild – extra X inactivated
      • Slightly taller than average with long lower limbs
      • 30% show some breast development
    • Mental capacity: Slightly lower IQ
    • Fertility: Sterile – small testes, no sperm production

  • Turner Syndrome

    • Karyotype: 45, X or 45, XO
    • Phenotypic sex at birth: Female
    • Incidence: 1:2000 – 1:5000
    • Phenotype: Mild – only one X therefore not inactivated
      • Short stature (can be treated with growth hormone)
      • Webbed neck (thus often identified before puberty)
    • Mental capacity: Close to average
    • Fertility: Sterile – ovaries degenerate

  • Triple X (Trisomy X)

    • Karyotype: 47, XXX
    • Phenotypic sex at birth: Female
    • Incidence: 1:1000
    • Phenotype: Very mild – extra Xs are inactivated.
      • Occasional behavioral problems, but many are asymptomatic
    • Mental capacity: Can be a mild reduction in IQ
    • Fertility: Fertile – typical gametes

  • Double Y

    • Karyotype: 47, XYY
    • Phenotypic sex at birth: Male
    • Incidence: 1:1000
    • Phenotype: Very mild
    • Mental capacity: Can be a mild reduction in IQ
    • Fertility: Fertile – typical gametes

  • Fertility in Sex Chromosome Aneuploidies

    • Sterile:
      • 45, X or XO (Turner syndrome): ovaries degenerate, no meiosis
      • 47, XXY (Klinefelter syndrome): testes form but rarely spermatogonia, so very rare meiosis
    • Fertile:
      • 47, XXX: produce only typical eggs (with one X)
      • 47, XYY: produce only typical sperm (with one X or one Y)
    • During early development of the germ line the typical karyotype is restored, so oogonia are 46, XX and spermatogonia are 46, XY.

C) Autopolyploidy

  • Polyploidy: An individual with more than two sets of haploid chromosomes in their somatic cells.

  • Types of Polyploidy

    • Based on number of chromosome sets:
      • Haploid: 1n
      • Diploid: 2n
      • Triploid: 3n
      • Tetraploid: 4n
      • Hexaploid: 6n

  • Categories of Germline Polyploidy

    • Autopolyploids: More than two sets of chromosomes, all derived from one ancestral species.
    • Allopolyploids: More than two sets of chromosomes, derived from more than one ancestral species.
    • Most species are diploid, with haploid gametes but polyploids can occur, mostly in plants.

  • Somatic Polyploidy

    • Normal variation in euploidy in certain tissues in both animals and plants.
    • Examples:
      • Human liver cells can be 3n, 4n, or 8n.
      • Human megakaryocytes are also polyploid.
    • Purpose: Unclear, possibly to produce very high levels of certain gene products or to generate large cells.

  • Autotetraploidy

    • Arises due to an accident during mitosis when chromosomes replicate but cell division does not occur, leading to a 4n cell.
    • 2n = 2, Mitosis results in 4n = 4.
    • If 4n cells are part of germ line, gametes that arise will be diploid (2n) – balanced, viable.
    • Can fertilize each other to give a fully autotetraploid zygote and individual, 4n, which is viable and fertile.
    • In plants, if it occurs in one cell, all descendant cells are irreversibly autotetraploid.

  • Phenotype of Autotetraploids

    • Chromosomal complement is balanced – in plants often fully viable, also in some animals, but not mammals.
    • Cells/tissues/organs/body larger, slower growing.
    • Otherwise closely resembles diploid.
    • Usually fully fertile.

  • Autotriploidy

    • Arises if a diploid gamete (2n) joins with a haploid gamete (1n) resulting in a 3n zygote.
    • Haploid gamete comes from a typical diploid.
    • Diploid gamete may come from:
      • an autotetraploid (2n gamete), or
      • a diploid unreduced gamete (2n) arising during meiosis.
    • Usually completely sterile because meiosis in 3n leads to unbalanced gametes.

  • Phenotype of Autotriploids

    • Chromosomal complement is balanced – in plants often fully viable, also in some animals, but not mammals.
    • Cells/tissues/organs/body larger, slower growing (intermediate between diploid and tetraploid).
    • Closely resembles parent species.

  • Evolution by Autopolyploidy

    • Once produced, an autotetraploid is an 'instant' new species.
    • If 4n x 2n results in a 3n sterile offspring, then the tetraploid is reproductively isolated from its diploid ancestor.
    • New 4n species closely resembles 2n ancestor, but larger, slower growing, and may colonize new habitats.

D) Allopolyploidy

  • Allopolyploidy: Chromosome sets derived from more than one ancestral species.

  • Origin: Formation of inter-species hybrids.

  • Hybrid: Allodiploid – one set of chromosomes from each species (n1 + n2) or AB.

  • Usually only closely related species will form a viable hybrid.

  • Most inter-species hybrids that survive are sterile, i.e., no offspring, because:

    • meiosis does not occur, or
    • the two sets of chromosomes do not pair.

  • Allotetraploidy

    • If the chromosome number is doubled during mitosis to form allotetraploid (2n1 + 2n2 or AABB), then in the resulting cell all the chromosomes can form bivalents at meiosis.
    • Balanced diploid gametes result, rendering the plant fertile.
    • Such allopolyploid events are mostly confined to plants.

  • Allopolyploid mammals are not usually viable.

  • In plants it is possible if rare chromosome duplication without cell division occurs in somatic tissues of the hybrid (hybrid is AB).

    • All descendent cells are irreversibly allotetraploid.

  • Phenotype of Allotetraploids

    • Chromosomal complement is balanced – in plants often fully viable and fertile (not in mammals).
    • Resembles a blend of phenotypes of each diploid parent species.

  • Evolution by Allopolyploidy

    • Once produced, an allotetraploid represents an 'instant' new species, resembling a blend of the two parent species.

  • Key Differences Between Autopolyploidy and Allopolyploidy

    • Autopolyploidy:
      • One ancestral species.
      • Resembles parent species.
      • Original hybrid is fertile.
      • Backcross to either parent species gives sterile progeny.
    • Allopolyploidy:
      • More than one ancestral species.
      • Resembles a blend of the parent species.
      • Original hybrid is sterile.
      • Backcross to either parent species gives sterile progeny.

Summary of Lecture

  • Aneuploidy: Loss or gain of one or more entire chromosomes. Caused by non-disjunction during meiosis. More severe for autosomes than for sex chromosomes. Three viable autosome aneuploidies: Patau (13), Edwards (18) and Down (21) syndrome. Four common sex aneuploidies: Turner, Trisomy X, Klinefelter's, Double Y
  • Polyploidy: Gain of whole sets of chromosomes.
  • Autopolyploids: More than two sets of chromosomes, all derived from one ancestral species.
  • Allopolyploids: More than two sets of chromosomes, derived from more than one ancestral species.