10-2. Eukaryotic Chromosome Abnormalities and Molecular Organization

10-2. Eukaryotic Chromosome Abnormalities and Molecular Organization

10.1 Chromosome Number and Shape Vary among Organisms

Chromosome number, genome content, and chromosome morphology are species-specific and fundamental to genetic analysis. Understanding these differences is essential for interpreting genetic variation and abnormalities.

• Genome Content and Chromosome Number: Each species has a characteristic number of chromosomes and genome size. Closely related species tend to have similar chromosome numbers.

• Chromosome Morphology: Each chromosome pair in a diploid genome has a distinct size, shape, and genetic content.

• Visualization: Chromosomes can be visualized using various cytogenetic techniques, especially during metaphase when condensation is maximal.

Table 10.1: Chromosome Number in Selected Animal Species

Species	Diploid Chromosome Number (2n)
Carp (Cyprinus carpio)	104
Cat (Felis catus)	38
Chicken (Gallus gallus)	78
Chimpanzee (Pan troglodytes)	48
Cow (Bos taurus)	60
Dog (Canis familiaris)	78
Fruit fly (Drosophila melanogaster)	8
Horse (Equus caballus)	64
Human (Homo sapiens)	46
Mouse (Mus musculus)	40
Rhesus monkey (Macaca mulatta)	42

Chromosomes in Nuclei

Chromosomes are not randomly distributed within the nucleus. Their organization is crucial for gene regulation and inheritance.

• Chromosome Territories: During interphase, chromosomes occupy distinct regions called chromosome territories.

• Historical Insight: Early cytogeneticists (Wilson, Sutton, Boveri) observed that chromosome behavior during meiosis mirrored gene transmission.

Dynamic Chromosomes

Chromosomes are dynamic structures, especially during interphase, where they are confined to territories but remain active.

• Once confined to a territory, a chromosome does not leave until mitosis begins.

• Chromosomes move, twist, and turn during transcription and DNA replication.

• Centromeres anchor chromosomes within their territories.

• Interchromosomal Domains: Regions between territories that allow movement of proteins, enzymes, and RNA molecules.

• Larger, gene-rich chromosomes are generally near the nucleus center; smaller, gene-poor chromosomes are near the periphery.

Chromosome Visualization and Karyotypes

Chromosome visualization is essential for identifying chromosomal abnormalities and for genetic diagnosis.

• Metaphase Chromosome Condensation: Chromosomes are most condensed and visible at metaphase.

• Karyotype: An organized visual display of chromosomes, used to identify abnormalities in number or structure. Autosomes are numbered 1–22; sex chromosomes are identified separately.

• Chromosomes may be stained with different compounds to distinguish them.

Chromosome Shape and Classification

Chromosome shape is determined by centromere position, which divides chromosomes into arms of unequal length.

• p arm: Short arm

• q arm: Long arm

• Shapes:

  • Metacentric: Centromere near the middle

  • Submetacentric: Centromere between center and tip

  • Acrocentric: Centromere close to one end

  • Telocentric: Centromere at the tip (no p arm)

Fluorescent In Situ Hybridization (FISH)

FISH is a molecular technique used to detect specific DNA sequences on chromosomes using fluorescently labeled probes.

• Probes can be gene-specific and labeled with compounds emitting different wavelengths of light.

• Allows simultaneous detection of multiple sequences.

Chromosome Banding Techniques

Chromosome banding is used to identify individual chromosomes based on their unique banding patterns.

• G (Giemsa) Banding: The standard for human chromosomes; produces distinct, reproducible patterns.

• Preparation involves cell culture, metaphase arrest, and slide preparation.

Heterochromatin and Euchromatin

Chromatin condensation varies along chromosomes, affecting gene expression.

• Euchromatin: Less condensed, gene-rich, and actively transcribed regions.

• Heterochromatin: Highly condensed, gene-poor, and transcriptionally inactive regions.

10.2 Nondisjunction Leads to Changes in Chromosome Number

Nondisjunction is the failure of chromosomes or sister chromatids to separate properly during cell division, leading to abnormal chromosome numbers.

• Results in aneuploidy (abnormal number of chromosomes).

• Phenotypic effects are usually severe in animals, less so in plants.

Key Terms

• Euploid: Having a complete set of chromosomes (e.g., n, 2n, 3n).

• Aneuploid: Having a chromosome number that is not an exact multiple of the haploid set.

Nondisjunction in Germ-Line Cells

• Produces aneuploid gametes, leading to aneuploid zygotes.

• Meiosis I nondisjunction: Failure of homologs to separate; gametes are n+1 or n–1.

• Fusion with normal gametes produces trisomic (2n+1) or monosomic (2n–1) offspring.

Nondisjunction in Meiosis II

• Failure of sister chromatids to separate.

• Among four gametes, two are normal (n), one is n+1, and one is n–1.

Gene Dosage Alteration

Changes in chromosome number alter the dosage of all genes on the affected chromosome, leading to phenotypic effects.

• Example: Datura stramonium (jimson weed) has 12 distinct trisomic lines, each with unique phenotypes due to gene dosage changes.

Table 10.2: Human Aneuploidies and Frequencies at Birth

Aneuploidy	Syndrome	Frequency at Birth	Syndrome Characteristics
Trisomy 13	Patau syndrome	1 in 15,000	Mental retardation, developmental delay, polydactyly, heart defects, etc.
Trisomy 18	Edwards syndrome	1 in 8,000	Mental retardation, developmental delay, clenched fists, heart defects, etc.
Trisomy 21	Down syndrome	1 in 700	Mental retardation, characteristic facial features, heart defects, etc.
45, X	Turner syndrome (female)	1 in 5,000	Short stature, infertility, webbed neck, etc.
47, XXY	Klinefelter syndrome (male)	1 in 1,000	Tall stature, infertility, mild cognitive impairment, etc.
47, XYY	Jacob syndrome (male)	1 in 1,000	Tall stature, learning difficulties, etc.
47, XXX	Triple X syndrome (female)	1 in 1,000	Tall stature, mild cognitive impairment, etc.

Aneuploidy in Humans

• Humans are highly sensitive to gene dosage changes; most aneuploidies are lethal.

• Only trisomies of chromosomes 13, 18, and 21 are seen in live births; no autosomal monosomies are observed.

• Sex chromosome aneuploidies are more tolerated.

• About half of all conceptions abort spontaneously, with more than half of these due to chromosomal abnormalities.

Trisomy 21 (Down Syndrome)

• Most common autosomal trisomy in live births.

• Risk increases with maternal age.

• Symptoms are linked to a small number of genes on chromosome 21.

Table 10.3: Risk of Down Syndrome (Trisomy 21) by Maternal Age

Maternal Age Range	Total Live Births Studied	Trisomy 21 Births	Rate per 1000 Births
15–19	30,272	17	0.49
20–24	117,393	66	0.56
25–29	108,742	72	0.66
30–34	48,079	67	1.39
35–39	18,032	61	3.38
40–44	3,064	49	16.00
45–49	84	3	35.71

Critical Region on Chromosome 21

• DSCR (Down syndrome critical region): Correlated with most Down syndrome symptoms.

• DYRK gene: Dosage-sensitive; contributes to learning defects.

• DSCAM gene: Involved in heart and nervous system formation.

Turner Syndrome

• Monosomy of the X chromosome (XO).

• Single copy of the SHOX gene is insufficient for normal development (haploinsufficiency).

• Symptoms include short stature, infertility, and other developmental abnormalities.