Chromosome Mutations: Aneuploidy and Polyploidy

Introduction to Chromosome Mutations

• Most members of diploid species typically possess two haploid sets of chromosomes
• Chromosomal mutations or aberrations deviate from this pattern
• Known variations include alterations in total chromosome number, deletions or duplications of genetic segments, and rearrangements within or among chromosomes
• These changes can lead to phenotypic variations and can be lethal

Specific Terminology Describing Variations in Chromosome Number

• Variations in chromosome number are known as aneuploidy, referring to instances where an organism gains or loses one or more chromosomes, but not a complete set
• In euploidy, complete haploid sets of chromosomes are present
• Polyploidy occurs when more than two sets of chromosomes are present

Aneuploidy

• Aneuploidy is represented by 2n ± x chromosomes
• Monosomy is represented by 2n - 1
• Disomy is represented by 2n
• Trisomy is represented by 2n+1
• Tetrasomy and pentasomy are represented by 2n + 2 and 2n + 3, respectively

Euploidy

• Euploidy is represented by multiples of n chromosomes
• Diploidy has 2n chromosomes
• Polyploidy has 3n, 4n, 5n, ... chromosomes
• Triploidy has 3n chromosomes
• Tetraploidy and pentaploidy has 4n and 5n, respectively
• Autopolyploidy has multiples of the same genome type
• Allopolyploidy (amphidiploidy) has multiples of closely related genome types

Causes of Chromosomal Variation

• Chromosomal variation can arise from nondisjunction, where chromosomes or chromatids fail to separate properly during meiosis I or II
• Nondisjunction disrupts normal chromosome distribution into gametes
• Fertilization of abnormal gametes with normal gametes results in zygotes with three members (trisomy) or only one member (monosomy) of a chromosome

Monosomy and Trisomy Effects

• Loss of one chromosome (2n - 1) can lead to severe phenotypic effects
• Monosomy for the X chromosome exists in humans and results in Turner syndrome
• Monosomy is any of the autosomes isn't usually tolerated in humans and other animals
• Death may be a result from lethals being unmasked
• A single recessive gene may be insufficient to provide life-sustaining function for the organism; this is called haploinsufficiency

Trisomy Effects

• Trisomy (2n + 1 chromosomes) is more viable than the loss of a chromosome
• Autosomal trisomies generally have severe effects and are lethal during development
• Trisomic plants can be viable but can have altered phenotypes
• Datura has many trisomic conditions, where each trisomy produces a unique capsule
• Trisomic rise for the longer chromosome grows very slowly

Down Syndrome: Trisomy 21 (47, 21+)

• This is the only human autosomal trisomy in which an individual can survive longer than a year past birth, with an average life expectancy of 50 years
• Occurs in approximately 1 in 800 live births: ~250,000 US individuals
• Individuals exhibit 6-8 of 12-14 characteristics, including a prominent epicanthic fold in each eye
• Other characteristics are a flat face, round head, short stature with protruding tongue, and short, broad hands with a characteristic palm and fingerprint pattern
• A person with Down Syndrome changes how the persons body and brain develop, which can cause both mental and physical challenges for the baby.
• People with Down syndrome usually have a measure of intelligence in the mildly-to-moderately low range and are slower to speak than other children
• Children with Down Syndrome are prone to respiratory disease and heart defects
• A higher incidence of leukemia can occur with down syndrome
• Death in older individuals often occurs earlier due to Alzheimer's disease compared to the normal population

Chromosome 21 and Down Syndrome

• A critical region of chromosome 21 contains genes responsible for Down syndrome phenotypes, and are sensitive to changes in dosage
• DSCR is the Down syndrome critical region
• Three copies of the gene are involved in the production of the Down syndrome phenotype
• The associated protein has 1.5 times greater concentration in individuals with Down syndrome compared to normal levels
• Extra copy of the DSCR1 (VEGF overexpression) is associated with a decreased risk of some cancers from extra copy of VEGF: Vascular endothelial growth factor
• Approximately 10% reduction in cancer mortality

Origin of the Extra 21st Chromosome in Down Syndrome

• In 95% of Down syndrome cases, the extra chromosome 21 originates from the sperm or the egg, resulting from nondisjunction during meiosis I
• The ovum is the source in about 95% of trisomy cases
• The incidence of Down syndrome increases with maternal age in women
• The risk of Down syndrome increases dramatically as childbearing women exceed 45 years of age

Maternal Age and Down Syndrome

• In females, all primary oocytes are formed by birth
• Ovulation starts at puberty
• Arrest process restarts after ovulation, requiring fertilization for completion
• Each released ovum has undergone meiosis I arrest ~1 month longer than the preceding cycle
• Women between the ages of 30 and 40 produce significantly older ova

Genetic Counseling

• Genetic counseling is recommended for women who are pregnant late in their reproductive years
• diagnostic testing may also be recommended
• Diagnostic testing uses fetal cells obtained from amniotic fluid or placental chorion
• Noninvasive prenatal genetic diagnosis (NIPGD) is a new approach to deriving cells from maternal circulation
• Fetal cells are cultured, and the karyotype can be determined by cytogenetic analysis

Down Syndrome and Nondisjunction

• Down syndrome is caused by a random error known as a nondisjunction of chromosome 21, so the disorder isn't inheritable
• In familial Down syndrome, translocation of the bottom part of chromosome 21 onto another chromosome (14) can cause it to occasionally run in families

Human Aneuploidy

• Besides Down syndrome, only two human trisomies survive to term, along with no monosomies that survive to term
• Patua syndrome (trisomy 13) can occur
• Edwards syndrome (trisomy 18) can occur
• Both trisomies survive to term
• Manifest severe malformations and early lethality

Polyploidy

• Polyploidy involves more than two haploid sets of chromosomes present
• A triploid has 3n sets
• A tetraploid has 4n sets
• A pentaploid has 5n sets
• Rare in animal species but found in fish, lizards, amphibians and very common in plant species
• Uneven number of homologs often does not produce genetically balanced gametes

Polyploidy in Humans

• In humans, it can occur in the form of triploidy, 69 chromosomes, i.e. called 69,XXX, or tetraploidy with 92 chromosomes, i.e. called 92,XXXX
• Those human forms die shortly after birth
• Polyploidy can originate with one or more sets of chromosomes identical to the haploid complement species or a combination of chromosome sets from different species as a consequence of interspecific matings

Autopolyploidy

• Autopolyploids have additional sets of chromosomes (identical to the parent species)
• Triploids are AAA
• Tetraploids are AAAA
• Autotriploids can arise if a diploid (nondisjunction) is fertilized by a hapoid or when two sperm fertilizes an ovum that results in a triploid zygote
• Diploids that are crossed with tetraploids that are under experimental conditions can also give triploids

Autotetraploids

• Because they have an even number, autotetraploids (4n) are theoretically more likely to be found in nature than autotriploids (3n)
• Tetraploids are more likely to produce balanced gametes
• Tetraploids begin with replicated or non-replicated chromosomes entering interphase and duplicating chromosome number

Experimentally inducing Autopolyploidy

• Applying heat or cold shock to diploid cells undergoing meiosis or applying colchicine to somatic cells undergoing mitosis can induce it, too
• Autopolyploid flowers and fruits are often increased in size, making such varieties of greater horticultural/commercial value
• Potatoes, winesap apples, commercial seedless bananas, seedless watermelon, and so on are examples
• They are often propagated asexually

Research in Autopolyploidy

• Research shows, as polyploidy increases, gene expression either increases or decreases at tenfold
• Two genes that come from G1 Cyclins are expressed when ploidy increases
• The polyploid cell stays in the G1 phase longer and grows to a larger

Allotetraploid and Amphidiploid

• An allotetraploid/amphidiploid results from hybridization of two closely related species
• Polyploid contains four haploid genomes derived from separate species
• Sterlie hybrids can undergo a natural or induced chromosomal doubling that can produce fertile amphidiploids
• Amphidiploid plants can also be produced by somatic cell hybridization

Endopolyploidy

• Condition where only certain cells in diploid organism are polyploidy
• The set of chromosomes replicates repeatedly without nuclear division
• Vertebrate liver cell nuclei, including human ones, often have 4n, 8n, or 16n chromosome sets
• Although the role of endopolyploidy is not clear, the proliferation of chromosome copies often occurs in cells where high levels of certain gene products are required

Chromosome Composition and Arrangement

• There are two primary ways in which the structure of chromosomes can be altered
  • The total amount of genetic information in the chromosome can change
    • Deletions
    • Duplications
• The genetic material remains the same, but is rearranged
  • Inversions
  • Translocations (reciprocal and nonreciprocal)

An aberration is found in one homolog, but not the other, and the individual is heterozygous for the aberration

Chromosome Breakage

• If no loss or gain of genetic material occurs, individuals bearing the aberration heterozygously are likely to be unaffected phenotypically
• In many cases, structural changes are due to one+, chromosomal axis break along with loss or rearrangement Breakages can occur spontaneously or from chemical or radiation exposure
• Alterations that happen in gametes are heritable

A Deletion

• A chromosome breaks in one or more locations and a portion of it is lost
• The missing piece is referred to as a deletion or a deficiency
• The deletion can occur near one end, and is called a terminal deletion, or from the interior of the chromosome, which is called an intercalary deletion

Synapsis

• Synapsis to occur between chromosomes with large intercalary deletion that's paired to a normal homolog involves unpaired region of the normal homolog that"buckel" out into deletion and compensation loop
• Small deletions do not usually have adverse effects, effect, and can sometimes occur

Cri du Chat Syndrome

• Cri du chat syndrome results from a segmental deletion of a small terminal portion of the short arm of chromosome 5
• The condition can be irregularly inherited from chromosomal material loss in gametes Severity varies with length of deletion
• An eerie cry similar to a cat's meowing and anatomical malformations, including gastrointestinal and cardiac complications
• Those affected have abnormal glottis and larynx development and are mostly mentally retarted
• The chromosome is missing contains the TERT gene, which encodes telomerase reverse transcriptase Responsible for catalyzing the addition of nucleotides (TTAGGG)

Duplication

• Duplications happen from unequal crossing over in synapses chromosomes in meiosis Duplication results in:
  • gene redundancy.
  • phenotypic variation -genetic variability during evolution

Gene Redundancy

• Multiple copies of genes encode for ribosomal RNA genes (rRNA)
• This DNA is called rDNA
• E. coli's haploid genome is 0.7% rDNA (seven copies)
• Drosophila at 0.3% (130) gene copies.

The Bar Mutation

• It's caused from duplications that result in Bar-eyed flies that have narrow, slit-like eyes versus normal oval-shaped eyes