Chromosome Abnormalities, Extranuclear Inheritance, and Biochemical Genetics: Study Guide

Chromosome Abnormalities

Overview of Chromosome Abnormalities

Chromosome abnormalities refer to changes in chromosome structure or number, often resulting from errors during cell division, DNA breakage, or faulty repair mechanisms. These abnormalities can be lethal early in development, but some survivors exhibit characteristic syndromes.

• Structural abnormalities: Deletions, duplications, inversions, and translocations.

• Numerical abnormalities: Changes in chromosome number, such as aneuploidy and polyploidy.

Chromosome Counts: "Somy" vs. "Ploidy"

Human cells are normally diploid (2n = 46). Chromosome number can vary due to errors in cell division:

Condition	Chromosome Number	Description
Haploidy (n)	23	One set of chromosomes
Triploidy (3n)	69	Three sets of chromosomes
Pentaploidy (5n)	115	Five sets of chromosomes
Monosomy (2n - 1)	45	One chromosome missing
Trisomy (2n + 1)	47	One extra chromosome
Pentasomy (2n + 3)	49	Five copies of one chromosome

• Euploidy ("-ploidy"): Addition or loss of whole sets of chromosomes (e.g., triploid, tetraploid). Gene balance is maintained.

• Aneuploidy ("-somy"): Addition or loss of individual chromosomes (e.g., trisomy 21, monosomy X). Causes gene dosage imbalance and is usually more harmful.

Chromosome Mutations and Aberrations

There are four basic types of structural chromosome changes:

Type	Description	Consequence
Deletion	Loss of a segment	Loss of genes, unmasking of recessive alleles (pseudodominance), often lethal if large
Duplication	Segment present twice	Gene dosage imbalance, raw material for evolution
Inversion	Segment flipped 180°	Usually no gene loss, but can affect meiosis and gene expression (position effects)
Translocation	Segment moves to a nonhomologous chromosome	Can be balanced or unbalanced; may cause disease or affect fertility

• Reciprocal translocation: Exchange between two nonhomologous chromosomes; carriers are often normal but can produce unbalanced gametes.

• Robertsonian translocation: Fusion of two acrocentric chromosomes; can result in carriers with 45 chromosomes and lead to conditions like translocation Down syndrome.

• Position effect: Gene expression may change if a gene is relocated near heterochromatin or a new regulatory region (e.g., variegation in Drosophila, MYC in Burkitt lymphoma).

Variation in Chromosome Number

Term	Meaning	Example
Euploidy	Whole sets of chromosomes	Haploid (n), diploid (2n), triploid (3n), tetraploid (4n)
Monoploid	One basic set (x)	Male bee (drone)
Polyploidy	More than two complete sets	Wheat (hexaploid, 6x)
Autopolyploid	Extra sets from same species	Seedless watermelon (triploid)
Allopolyploid	Sets from different species	Triticale (wheat x rye)
Aneuploidy	Gain/loss of individual chromosomes	Down, Turner syndromes
Monosomy	2n - 1	Turner (45,X)
Trisomy	2n + 1	Down (+21)
Nullisomy	2n - 2	Lethal in diploids
Tetrasomy	2n + 2	48,XXXX
Mosaicism	Two or more cell lines with different karyotypes	Mosaic Down syndrome

Nondisjunction in Meiosis

Nondisjunction is the failure of chromosomes to separate properly during meiosis, leading to gametes with abnormal chromosome numbers.

• Meiosis I nondisjunction: Homologs fail to separate; all gametes are abnormal (two n+1, two n-1).

• Meiosis II nondisjunction: Sister chromatids fail to separate; two normal gametes, one n+1, one n-1.

Feature	Meiosis I	Meiosis II
Defective separation	Homologs	Sister chromatids
Abnormal gametes	100% (4/4)	50% (2/4)
Extra chromosomes in n+1 gamete	Two different homologs	Two identical copies

• Examples: Trisomy 21 (Down syndrome), Turner syndrome (45,X), Klinefelter syndrome (47,XXY), XYY syndrome.

• Mosaicism: Results from mitotic nondisjunction early in development.

Gene Duplication Hypothesis

Gene duplication provides a spare copy of a gene, allowing one copy to maintain its original function while the other accumulates mutations and potentially acquires a new function. This is a major source of new genes in evolution.

• Mechanisms: Unequal crossing over, retrotransposition, tandem duplication, whole-genome duplication (polyploidy).

• Examples: Globin gene family, vertebrate Hox clusters, opsin genes, olfactory receptors.

• Disease: Gene duplication can cause disorders (e.g., CMT1A) due to dosage imbalance.

Types of Inversions and the Inversion Loop

Type	Centromere Location	Arm Lengths
Paracentric	Not inside inverted segment	Unchanged
Pericentric	Inside inverted segment	Can change

• Inversion heterozygotes: Form an inversion loop during meiosis I to align homologous regions.

• Paracentric inversion crossover: Produces dicentric and acentric chromatids; only parental types are viable.

• Pericentric inversion crossover: Produces chromatids with duplications and deletions; only parental types are viable.

• Human example: Pericentric inversion of chromosome 9 (common, usually harmless).

Fragile Sites and Fragile X Syndrome

Type	Features	Examples
Rare fragile sites	Inherited, caused by expanded repeats	FRAXA (FMR1), FRAXE, FRA16B
Common fragile sites	Present in everyone, late-replicating	FRA3B (FHIT), FRA16D (WWOX)

• Fragile X syndrome: Caused by CGG repeat expansion in the FMR1 gene, leading to gene silencing and loss of FMRP protein. X-linked, more severe in males.

• Symptoms: Intellectual disability, long face, large ears, macroorchidism, autism features.

• Expansion: Occurs mainly through maternal transmission (anticipation).

Extranuclear Inheritance

Overview of Extranuclear (Cytoplasmic) Inheritance

Extranuclear inheritance involves genes located in organelle genomes (mitochondria, chloroplasts) or other cytoplasmic elements, leading to non-Mendelian inheritance patterns.

• Uniparental (usually maternal) transmission: The egg provides most cytoplasm and organelles.

• Reciprocal crosses: Yield different results; offspring phenotype depends on the mother.

• Heteroplasmy: Mixture of mutant and normal organelle genomes in a cell.

• Homoplasmy: All organelle genomes are identical.

• Replicative segregation: Random distribution of organelles during cell division.

• Threshold effect: Symptoms appear only when mutant fraction exceeds a threshold (often 60–90%).

Types and Examples of Extranuclear Inheritance

1. Organelle inheritance:

   • Mitochondrial inheritance: Human mtDNA diseases, yeast petite mutants.

   • Chloroplast inheritance: Plant ctDNA, e.g., leaf variegation in Mirabilis jalapa.

2. Maternal effect: Mother's nuclear genotype determines egg cytoplasm (e.g., snail shell coiling, bicoid in Drosophila).

3. Infectious/symbiotic agents: Kappa particles in Paramecium, sigma virus in Drosophila.

Mitochondrial and Chloroplast Disorders

Disease	Mutation	Features
LHON	Point mutations in complex I genes	Sudden central vision loss, more often in males
MELAS	m.3243A>G in tRNA-Leu	Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes
MERRF	m.8344A>G in tRNA-Lys	Myoclonic epilepsy, ragged red muscle fibers
Kearns-Sayre syndrome	Large single mtDNA deletion	Ophthalmoplegia, retinitis pigmentosa, heart block
NARP/Leigh syndrome	m.8993T>G/C in ATP6	Neuropathy, ataxia, retinitis pigmentosa; Leigh is severe in infants

• Pedigree rule: Affected mothers transmit to all children (variable severity with heteroplasmy); affected fathers transmit to none.

• Therapies: Supportive care, cofactors, mitochondrial replacement therapy ("three-parent baby").

Chloroplast Disorders

• Cause: Mutations in ctDNA or nuclear genes affecting plastids.

• Symptoms: Variegation, albino or pale sectors in plants (e.g., Mirabilis jalapa).

• Inheritance: Usually maternal in angiosperms; can be biparental or paternal in some species.

Comparison of mtDNA and ctDNA

Feature	mtDNA (human)	ctDNA (plants)
Shape	Circular, double-stranded	Circular (some linear), double-stranded
Size	16,569 bp	120–160 kb
Genes	37 (13 proteins, 22 tRNAs, 2 rRNAs)	100–120 (photosynthesis, rRNAs, tRNAs, ribosomal proteins)
Copies per cell	Hundreds to thousands	Many per chloroplast
Structure	Few introns; D-loop control region	Inverted repeats, introns present
Inheritance	Maternal	Usually maternal
Other	Different genetic code, no histones, high mutation rate	Most proteins encoded in nucleus

• Most organelle proteins are nuclear-encoded and imported.

Ribosomal Variations

Ribosome	Size	Subunits and rRNAs
Bacterial	70S	30S (16S), 50S (23S, 5S)
Eukaryotic cytoplasmic	80S	40S (18S), 60S (28S, 5.8S, 5S)
Chloroplast	70S	Like bacterial
Mammalian mitochondrial	55S	28S (12S), 39S (16S)

Reactive Oxygen Species (ROS) and DNA Damage

• ROS: Superoxide (O2-), hydrogen peroxide (H2O2), hydroxyl radical (OH), mainly from the electron transport chain.

• DNA damage: Oxidized bases (e.g., 8-oxoguanine), strand breaks, crosslinks.

• mtDNA vulnerability: Proximity to ROS, lack of histones, limited repair.

• Repair/defense: Base excision repair, SOD, catalase, antioxidants.

• Consequences: Mutations, cancer, aging, neurodegeneration.

Endosymbiotic Theory

This theory proposes that mitochondria and chloroplasts evolved from free-living bacteria engulfed by ancestral eukaryotic cells, becoming permanent symbionts.

• Evidence: Double membranes, own circular DNA, 70S ribosomes, binary fission, phylogenetic similarity to bacteria, endosymbiotic gene transfer.

Genetic Anticipation

Definition and Molecular Basis

Genetic anticipation is the phenomenon where a disease appears earlier and/or more severely in successive generations, often due to trinucleotide repeat expansions.

Disease	Repeat	Gene	Notes
Huntington disease	CAG	HTT	Expansion mainly paternal; 36+ repeats pathogenic
Myotonic dystrophy 1	CTG	DMPK	Congenital form after maternal transmission
Fragile X	CGG	FMR1	Premutation expands to full mutation maternally
Friedreich ataxia	GAA	FXN	Recessive
Spinocerebellar ataxias	CAG	Various

Biochemical Genetics

One Gene-One Enzyme vs. One Gene-One Polypeptide Theory

• One gene-one enzyme: Each gene encodes an enzyme controlling a step in a metabolic pathway (Beadle and Tatum, 1941).

• One gene-one polypeptide: Each gene encodes a single polypeptide, which may be a subunit of a protein (e.g., hemoglobin alpha and beta chains).

• Modern view: One gene can produce multiple products via alternative splicing; some genes encode functional RNAs.

Types of Genetic Tests

• Cytogenetic: Karyotype, FISH, chromosomal microarray (detects number and large structural changes).

• Biochemical: Enzyme activity or metabolite levels (e.g., Phe in PKU, hexosaminidase A in Tay-Sachs).

• Molecular (DNA): PCR, RFLP, ASO hybridization, Sanger/next-generation sequencing, MLPA, microarrays.

RFLP (Restriction Fragment Length Polymorphism)

• DNA is cut with restriction enzymes; mutations altering restriction sites change fragment sizes.

• Fragments are separated by gel electrophoresis and detected by Southern blot or PCR-RFLP.

• Uses: Detect known mutations, carrier/prenatal diagnosis, linkage mapping, forensics.

ASO (Allele-Specific Oligonucleotide) / SNP Genotyping

• Short labeled probes match either the normal or mutant allele.

• Sample DNA is hybridized; only perfect matches bind at high stringency.

• Uses: Detect specific point mutations (e.g., sickle cell, cystic fibrosis), carrier screening, prenatal diagnosis.

Genotype	Normal ASO	Mutant ASO
Normal homozygote	Signal	No signal
Heterozygote	Signal	Signal
Mutant homozygote	No signal	Signal

DNA Microarrays

• Chips with thousands of DNA probes; patient DNA is labeled and hybridized.

• Signal intensity reveals copy number (CGH arrays) or genotype (SNP arrays).

• Uses: Detect deletions, duplications, copy-number variants, genotype many SNPs for GWAS, ancestry, disease risk.

Expression Microarrays / Transcriptome Analysis

• mRNA is converted to labeled cDNA and hybridized to a chip with gene probes.

• Fluorescence indicates gene expression levels; can compare conditions (e.g., tumor vs. normal).

• Uses: Identify gene expression changes in disease, classify tumors, predict prognosis or drug response.

Amniocentesis and Chorionic Villus Sampling (CVS)

• Amniocentesis: Needle withdraws amniotic fluid; fetal cells are cultured for karyotyping, biochemical, and DNA tests.

• Uses: Detect aneuploidy, structural abnormalities, metabolic diseases, known familial mutations.

• CVS: Samples placenta earlier (10–13 weeks); cannot measure alpha-fetoprotein.

Metabolic Disorders

Phenylketonuria (PKU)

• Biology: Autosomal recessive deficiency of phenylalanine hydroxylase (PAH).

• Pathway: Phenylalanine --(PAH)--> Tyrosine --> melanin, dopamine, thyroxine, epinephrine.

• Symptoms: High Phe is toxic to the brain; untreated leads to intellectual disability, seizures, microcephaly, musty odor, light skin/hair.

• Treatment: Lifelong low-Phe diet, Phe-free formula, tyrosine supplementation; avoid aspartame.

• Maternal PKU: High maternal Phe during pregnancy can harm the fetus.

Alkaptonuria (AKU)

• Biology: Autosomal recessive deficiency of homogentisate 1,2-dioxygenase (HGD).

• Symptoms: Accumulation of homogentisic acid, dark urine, ochronosis (pigmentation), early arthritis, heart valve disease.

• Treatment: Symptom management, joint replacement, nitisinone, diet.

Sickle Cell Disease

• Genetics: Autosomal recessive; HBB gene mutation (GAG to GTG, Glu6Val) produces hemoglobin S (HbS).

• Pathophysiology: HbS polymerizes when deoxygenated, causing sickled, rigid RBCs that block vessels and are destroyed early (hemolytic anemia).

• Symptoms: Vaso-occlusion, pain, anemia.

• Heterozygote advantage: Sickle cell trait (HbA/HbS) confers resistance to severe malaria.

• Diagnosis: Hemoglobin electrophoresis, HPLC, newborn screening, prenatal DNA testing (RFLP, ASO, sequencing).

Additional info: For all genetic disorders, understanding inheritance patterns, molecular mechanisms, and available diagnostic methods is crucial for clinical genetics and genetic counseling.