Chromosomal Mutations and Structure

Chromosomal Mutations Overview

• Chromosomal mutations are alterations in the structure or number of chromosomes.
• These mutations can profoundly affect an organism's phenotype.
• Chromosomal mutations can cause developmental abnormalities, diseases, and syndromes.
• Researching chromosomal mutations provides insights into genetic disorders, identifies causative factors, and aids in developing diagnostic and therapeutic strategies.

Human Chromosome Structure

• A chromosome is a threadlike structure of nucleic acids and protein found in the nucleus of most living cells.
• Chromosomes carry genetic information in the form of genes.
• The word "chromosome" means "colored body".
• Human cells typically contain 23 pairs of chromosomes, totaling 46.
• In non dividing cells chromosomes aren't visible under a microscope
• They become visible during cell division as DNA becomes more tightly packed

Chromosome Arms

• Each human chromosome has two arms: a short arm (p) and a long arm (q).
• The centromere separates these arms.

Centromere

• The centromere is a specialized DNA sequence linking sister chromatids.
• Spindle fibers attach to the centromere via the kinetochore during mitosis.
• In humans, the centromere contains repeats of a 171-base DNA sequence called an alpha satellite.
• Centromeres also contain centromere-associated proteins, and centromere associated protein form the Kinetochore.

Telomere

• Telomeres are specialized repeated DNA sequences (TTAGGG) that protect the ends of chromosomes.
• Subtelomeres are chromosome parts between protein reach areas and telomeres.
• During chromosome replication the lagging DNA strand end is left unreplicated which telomerase extends, before DNA polymerase completes the strand.

Chromosome Classification

• Chromosomes are classified based on centromere position: telocentric, metacentric, submetacentric, or acrocentric.

Chromosomal Number

• The number of chromosome pairs varies by species; humans have 23 pairs.

Cytogenetics

• Cytogenetics links chromosome variations to specific traits and illnesses.
• Cytogeneticists use stains and dyes to contrast dark heterochromatin (mostly repetitive DNA sequences) with lighter euchromatin (more protein-encoding genes).

Karyotyping

• A karyotype is an individual's collection of chromosomes.
• The human karyotype consists of 46 chromosomes: 22 pairs of autosomes and one pair of sex chromosomes (XX or XY).
• Karyotyping involves pairing and ordering chromosomes to provide a genome-wide snapshot.

Chromosome Banding

• G banding technique, involves the use of Giemsa dye to stain chromosomes after pre-treatment with trypsin.
• Chromosome bands result from DNA and protein interactions with thiazine and eosin components of the stain.

Chromosome Nomenclature

• Geneticists use letters and numbers to describe a gene's cytogenetic location on a chromosome.
• The chromosome number is the 1st number or letter
• "p" or "q" indicates the arm, with other numbers describing the region, band, and sub-band.

FISH (Fluorescence in situ Hybridization)

• FISH identifies specific chromosomal aberrations or maps chromosomal genes using fluorescence.
• The process involves fixed chromosomes on a microscope slide, denatured DNA, and fluorescently labeled DNA probes.
• Two probes are used: one as a control hybridizing outside the targeted region, and another to a target location on the individual's DNA sequence.
• Chromosome painting uses many probes to detect structural abnormalities.

rDNA

• rDNA is DNA encoding ribosomal RNA (rRNA).

Chromosome Abnormalities

• Constitutive abnormalities are present in all tissues, while acquired abnormalities are in one organ.
• Homogeneous abnormalities occur when all cells studied carry the anomaly, mosaic: only some cells carry.
• Numerical abnormalities involve changes in the total number of chromosomes whereas structural abnormalities include missing, extra, or translocated genetic material.

Numerical Chromosomal Abnormalities

• Euploidy refers to the normal number and sets of chromosomes.
• Polyploidy is the presence of three or more complete sets of chromosomes.
• Aneuploidy is the presence of additional or missing individual chromosomes.

Types of Polyploidy and Aneuploidy

• Triploidy involves three sets of chromosomes (23 x 3 = 69)
• Tetraploidy involves four sets of chromosomes (23 x 4 = 92).
• Monosomy is one less chromosome (23 x 2) – 1 = 45
• Trisomy is one additional chromosome (23 x 2) + 1 = 47.
• Nullisomy occurs when a pair of homologous chromosomes is missing which is 22 x 2 = 44.

Aneuploidy Details

• Aneuploidy mainly consists of trisomies which can be mosaic or nonmosaic.
• It often results from meiotic non-disjunction or errors in meiotic segregation during Anaphase I (Meiosis I), especially in human females.
• Autosomal aneuploidy involves chromosomes, excluding the sex chromosomes
• Sex chromosome aneuploidy involves the sex chromosomes.

Common Aneuploidies

• Trisomy 21 (Down syndrome): incidence is 1/800 live births with 1/60 spontaneous losses.
• Trisomy 18 (Edwards syndrome): incidence is 1/3000 live births with 1/140 spontaneous losses.
• Trisomy 13 (Patau syndrome): incidence is 1/5000 live births with 1/60 spontaneous losses.
• 45,X (Turner syndrome): incidence is 1/5000 live births with 1/16 spontaneous losses.
• 47,XXY (Klinefelter syndrome): incidence is 1/1000 live births with 1/400 spontaneous losses.

Trisomy 21 (Down Syndrome)

• Characterized by mild to moderate learning difficulties, distinct facial features, and cardiac defects (40% of cases).
• It occurs in 1:700 live births, translocation accounts for 5%.
• At maternal age 43 the rate is 1:50, and 60% abort spontaneously.
• Primary trisomy 21 accounts for 95% of cases (47,XX,+21 or 47,XY,+21).

Monosomy X (Turner Syndrome)

• Karyotype is 45, X or 45, X0.
• Individuals have normal intelligence, a dysmorphic presentation (webbed neck, broad chest with widely spaced nipples), primary amenorrhoea, and lack of secondary sexual characteristics (streak ovaries at birth).
• It has a 1:5000 live births incidence, normal lifespan, 99% abort spontaneously with no maternal age effect, 80% are paternal in origin.

Klinefelter Syndrome

• Karyotype is 47, XXY
• Sufferers have normal intelligence, are unusually tall, have disproportionately long limbs, and face 30-50% gynaecomastia and infertility/Azoospermia.
• It has an incidence of 1/1000, and I.Q may be reduced relative to sibs.

Structural Chromosome Abnormalities

• These include deletion, duplication, inversion, and translocation from causes such as errors in recombination.
• Gene dosage effects & regulatory region disruption are why they lead to disease.

Structural Abnormality Abbreviations

• del: Deletions
• dup: Duplications
• rcp t: Reciprocal translocation
• rbt: Robertsonian translocation
• peri inv: Pericentric inversions
• para inv: Paracentric inversion
• ins: Insertions
• r: Rings
• i: Isochromosome
• rea: Rearrangement
• dic: Dicentric
• ace: Acentric
• mar: Marker
• dm: Doubleminute
• hsr: Homogeneously staining region
• p: Short arm
• q: Long arm
• +: Gain
• -: Loss

Structural Abnormalities - Deletions

• Deletions involve missing portions of a chromosome.
• Microdeletions are chromosomal deletions too small to be detected by light microscopy
• Known disorders in humans include Wolf-Hirschhorn syndrome (46,XX,del(4)(p16.3)), Jacobsen syndrome (46,XX,del(11)(q23)), and Smith Magenis syndrome (46,XX,del(17)(p11.2)).

Structural Abnormalities - Duplications

• There is a portion of the chromosome is duplicated, resulting in extra genetic material
• Known human disorders include Charcot-Marie-Tooth disease type 1A.

Structural Abnormalities - Translocations

• A portion of one chromosome is transferred to another chromosome
• Reciprocal translocation is when segments from two different chromosomes have been exchanged
• The entire chromosomal arm has been attached to another chromosome's arm at or close to the centromere
• Robertsonian translocations, in humans, only occur with chromosomes 13, 14, 15, 21, and 22.

Structural Abnormalities - Inversions

• A portion of the chromosome broken off & turned upside-down, before being reattached, is referred to as an inversion
• Paracentric inversions (para inv) do not include the centromere
• Pericentric inversions (peri inv)include centromere

Structural Abnormalities - Insertions

• An insertion refers to the insertion of a larger sequence into a chromosome
• In insertion, translocation can occurs when a piece of one chromosome breaks off and attaches to another chromosome.

Structural Abnormalities - Ring Chromosome

• Ring chromosomes are when a portion of a chromosome has broken off and formed a circle or ring.
• This can happen with or without loss of genetic material.

Structural Abnormalities - Isochromosome

• Isochromosomes are formed by the mirror image copy of a chromosome segment including the centromere.

Uniparental Disomy

• Cases where two copies of a chromosome come from the same parent are Uniparental disomy
• Angelman syndrome and Prader-Willi syndrome are examples of disorders can be caused by uniparental disomy.

Trinucleotide Repeats

• Unusual genetic alterations can cause genetic conditions, from the expansion of a DNA nucleotide segment
• A dynamic or unstable mutation is the triplet repeat which allows the gene is passed on to offspring, and makes the triplicates get longer.
• The condition can worsen, or become more severe, causing and earlier onset. genetic anticipation will worsen from prior generations
• fragile X syndrome, myotonic muscular dystrophy, and Huntington's disease are examples caused by triplet repeat expansions.

DNA Repair Defects

• A Dna repair deficiency disorder is a medical condition where there are reduced functionalities in the repair process.
• Ataxia telangiectasia, bloom syndrome, cockayne syndrome, cronin anemia, progeria (hutchinson-gliford program syndrome
• Rothmund-thomson syndrome, trichothiodystrophy, warmer syndrome and xeroderma pigmentosum are some DNA repair defects

Transposable Elements

• TE, transposon, or jumping gene are Transposable elements- transposes or jumping genes.
• These can change the position of nucleotides with in the genome.
• Altering the cells - genetic ID, or how big the genome is.
• Some TransPosition's in duplications of the same nucleotides can cause issues for some jumping results are deleterious- so harmful to the human
• Transposes can drive the evolution of genomes by facilitating translocation of genetic regions with double stranded brakes can then be repaired after exons are moved - insertion and transportation alter general regulatory regions and phenotypes

Synteny and Evolution

• Synteny refers to the conservation of the relative order of genes or genetic markers across different species' genomes.
• It signifies the presence of homologous chromosomal segments or regions that share similar gene arrangements and orientations
• In other words, synteny reflects the retention of gene order between related organisms over evolutionary time
• Synteny is important in the world of evolutional genomics.
• Synteny is widely used in studying complex genomes, as comparative genomics allows the presence and possibly function of genes in a simpler, model organism to infer those in a more complex one.