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Genetics and Reproduction

An Advanced Review for Pre-Medical Students

Table of Contents>

I. Mendelian Genetics Basics

This section covers the fundamental principles of heredity as discovered by Gregor Mendel, which form the bedrock of classical genetics. Understanding these laws is essential for predicting patterns of inheritance.

A. Key Terminology

TermDefinition
GeneA specific sequence of nucleotides in DNA that is located on a chromosome and that is the functional unit of inheritance.
AlleleOne of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome.
LocusThe specific physical location of a gene on a chromosome.
GenotypeThe genetic makeup of an organism, represented by the combination of alleles it possesses (e.g., TT, Tt, tt).
PhenotypeThe observable physical or biochemical characteristics of an organism, determined by its genotype and environmental factors (e.g., tall, short).
HomozygousHaving two identical alleles for a particular gene (e.g., TT or tt).
HeterozygousHaving two different alleles for a particular gene (e.g., Tt).
Dominant AlleleAn allele that expresses its phenotypic effect even when heterozygous with a recessive allele (e.g., T).
Recessive AlleleAn allele that only expresses its phenotypic effect when two copies are present (homozygous) (e.g., t).
Homologous Chromosomes with Alleles

Homologous Chromosomes with Alleles

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B. Mendel's Laws

LawCore PrincipleAssociated CrossKey Ratios (F2 of heterozygote cross)
Law of SegregationDuring gamete formation (meiosis), the two alleles for a heritable character separate from each other so that each gamete ends up with only one allele.Monohybrid Cross (examines one trait)Phenotypic: 3:1, Genotypic: 1:2:1
Law of Independent AssortmentAlleles of genes on non-homologous chromosomes assort independently during gamete formation. The inheritance of one character has no effect on the inheritance of another.Dihybrid Cross (examines two traits)Phenotypic: 9:3:3:1
Punnett Square for Monohybrid Cross (Tt x Tt)

Punnett Square for Monohybrid Cross (Tt x Tt)

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Punnett Square for Dihybrid Cross (RrYy x RrYy)

Punnett Square for Dihybrid Cross (RrYy x RrYy)

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C. Non-Mendelian Inheritance

Many traits do not follow simple Mendelian patterns. These exceptions provide a more nuanced understanding of genetics.

PatternDescriptionExample
Incomplete DominanceThe heterozygous phenotype is an intermediate blend of the two homozygous phenotypes.Red (CRCR) and white (CWCW) snapdragons produce pink (CRCW) offspring.
CodominanceBoth alleles are fully and separately expressed in the heterozygous phenotype.Human ABO blood group system, where alleles IA and IB are both expressed in type AB blood.
Incomplete Dominance in Snapdragon Flowers

Incomplete Dominance in Snapdragon Flowers

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Codominance in Human ABO Blood Types

Codominance in Human ABO Blood Types

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D. Human Genetics Tools

Analyzing inheritance in humans requires specialized tools due to ethical and practical constraints on experimental breeding.

ToolDescription & Use
Pedigree ChartA family tree diagram that shows the inheritance of a trait over several generations. Used to determine the mode of inheritance (autosomal dominant/recessive, X-linked) and to calculate probabilities of inheriting a trait.
KaryotypeAn organized profile of a person's chromosomes. Used to diagnose chromosomal abnormalities, such as aneuploidy (e.g., Trisomy 21 - Down Syndrome) or large structural changes.
Example of a Pedigree Chart (Autosomal Dominant)

Example of a Pedigree Chart (Autosomal Dominant)

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Human Karyotype

Human Karyotype

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II. Molecular Genetics

This section explores the molecular mechanisms that underpin heredity: the structure and function of DNA, and how the genetic code is expressed as functional proteins.

A. DNA Replication

Before a cell divides, it must accurately duplicate its entire genome. This process, known as DNA replication, is semiconservative and relies on the coordinated action of several key enzymes.

Enzyme/ProteinFunction in DNA Replication
HelicaseUnwinds the DNA double helix at the replication fork.
Single-Strand Binding Proteins (SSBs)Bind to and stabilize single-stranded DNA, preventing it from re-pairing.
TopoisomeraseRelieves the torsional strain ahead of the replication fork caused by unwinding.
PrimaseSynthesizes a short RNA primer, providing a 3'-OH end for DNA polymerase to start synthesis.
DNA Polymerase III(In prokaryotes) The main replication enzyme, synthesizing the new DNA strand by adding nucleotides to the 3' end.
DNA Polymerase I(In prokaryotes) Removes the RNA primers and replaces them with DNA nucleotides.
DNA LigaseJoins the Okazaki fragments on the lagging strand to create a continuous DNA strand.
DNA Replication Fork

DNA Replication Fork

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B. From Gene to Protein: The Central Dogma

The central dogma of molecular biology, proposed by Francis Crick, describes the two-step process, transcription and translation, by which the information in genes flows into proteins: DNA → RNA → Protein.

1. Transcription

This is the synthesis of an RNA copy of a segment of DNA. In eukaryotes, this process occurs in the nucleus and involves several steps, including post-transcriptional modification of the primary transcript (pre-mRNA) into mature mRNA.

Transcription Process

Transcription Process

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2. Translation

This is the synthesis of a polypeptide, using the information in the mRNA. The process occurs on ribosomes in the cytoplasm. The mRNA sequence is read in codons (groups of three bases), and tRNA molecules bring the corresponding amino acids to the ribosome.

Translation at the Ribosome

Translation at the Ribosome

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C. Mutations

A mutation is a permanent alteration in the DNA sequence. They are the ultimate source of genetic variation but can also be the cause of genetic diseases.

Types of Gene (Point) Mutations
Substitution (Silent)A base change that results in a codon that codes for the same amino acid. No effect on the protein.
Substitution (Missense)A base change that results in a codon that codes for a different amino acid. Can have minor or major effects (e.g., sickle cell anemia).
Substitution (Nonsense)A base change that results in a premature stop codon. Leads to a truncated, usually nonfunctional, protein.
Insertion/Deletion (Frameshift)Addition or loss of nucleotides (not in a multiple of three) that shifts the reading frame, altering all subsequent amino acids and often creating a premature stop codon.
Gene Mutations (Point Mutations)

Gene Mutations (Point Mutations)

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Chromosomal Mutations

Chromosomal Mutations

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III. Genetic Technology

The understanding of molecular genetics has led to powerful technologies that allow us to analyze and manipulate DNA.

TechniquePrinciple and Key Applications
Recombinant DNA Technology
  • Principle: Combining DNA from different sources using restriction enzymes (to cut) and DNA ligase (to paste). Plasmids are often used as vectors to carry the foreign DNA into a host (like E. coli).
  • Applications: Production of therapeutic proteins (e.g., insulin, human growth hormone), creation of genetically modified organisms (GMOs), gene therapy research.
Polymerase Chain Reaction (PCR)
  • Principle: A three-step cycle (Denaturation, Annealing, Extension) that exponentially amplifies a specific segment of DNA in vitro. Requires a thermostable DNA polymerase (Taq polymerase).
  • Applications: Medical diagnostics (detecting viral/bacterial pathogens), forensic science (DNA fingerprinting), genetic testing, cloning genes.
CRISPR-Cas9 Gene Editing
  • Principle: A system using a guide RNA (gRNA) to direct the Cas9 enzyme to a specific sequence in the genome, where it creates a double-strand break. The cell's natural repair mechanisms can then be used to introduce changes (delete, insert, or replace DNA).
  • Applications: Basic research (studying gene function), developing therapies for genetic diseases, agricultural improvements.
Recombinant DNA Technology Flowchart

Recombinant DNA Technology Flowchart

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Polymerase Chain Reaction (PCR) Cycle

Polymerase Chain Reaction (PCR) Cycle

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CRISPR-Cas9 Gene Editing Mechanism

CRISPR-Cas9 Gene Editing Mechanism

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IV. Eukaryotic Gene Regulation

Unlike prokaryotes, eukaryotic gene expression is regulated at multiple levels, allowing for complex control of cell differentiation and function. This intricate system ensures that the right genes are expressed at the right time and in the right place.

Eukaryotic Gene Expression Regulation

Eukaryotic Gene Expression Regulation

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Level of RegulationMechanismExample/Supplement
Pre-TranscriptionalControl of DNA accessibility through chromatin modification. Tightly packed heterochromatin is generally silent, while loosely packed euchromatin is transcriptionally active.
  • Histone Acetylation: Neutralizes the positive charge of histones, loosening their grip on DNA and promoting transcription.
  • DNA Methylation: Addition of methyl groups to cytosine bases, often in promoter regions, which typically leads to gene silencing.
TranscriptionalThe primary control point, involving the binding of transcription factors to specific DNA sequences to initiate or block transcription.
  • Promoters & Transcription Factors: RNA Polymerase II requires general transcription factors to bind to the promoter (e.g., TATA box).
  • Enhancers & Silencers: DNA sequences far from the gene that can be bound by specific transcription factors (activators or repressors) to dramatically increase or decrease transcription rates.
Post-TranscriptionalModification and processing of the primary RNA transcript (pre-mRNA) in the nucleus before it is exported to the cytoplasm.
  • Alternative Splicing: Different exons can be selectively included or excluded, allowing a single gene to code for multiple protein isoforms.
  • 5' Capping & 3' Poly-A Tail: These modifications are crucial for mRNA stability, export from the nucleus, and recognition by ribosomes.
TranslationalRegulation of the rate at which mRNA is translated into protein.
  • microRNAs (miRNAs): Small non-coding RNAs that bind to complementary sequences on mRNA, forming a RNA-induced silencing complex (RISC) that either degrades the target mRNA or blocks its translation.
Post-TranslationalModification of the polypeptide chain after synthesis to make it a functional protein.
  • Chemical Modifications: Phosphorylation, glycosylation, etc., can activate or deactivate proteins.
  • Proteolytic Cleavage: Cutting a polypeptide into smaller, active forms (e.g., insulin).
  • Ubiquitination: Tagging proteins with ubiquitin marks them for destruction by the proteasome.
Histone Acetylation and Chromatin Remodeling

Histone Acetylation and Chromatin Remodeling

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V. Advanced Molecular Processes

A deeper look into the eukaryotic-specific mechanisms of DNA replication reveals key differences from the prokaryotic model, particularly in managing linear chromosomes and ensuring high fidelity.

Eukaryotic DNA Replication Details

Eukaryotic Replication Fork with Polymerase Switching

Eukaryotic Replication Fork with Polymerase Switching

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FeatureDescription in Eukaryotes
Multiple Origins of ReplicationTo replicate the vast eukaryotic genome in a timely manner, DNA synthesis is initiated at many points (origins) simultaneously. These are recognized by the Origin Recognition Complex (ORC).
Specialized DNA PolymerasesEukaryotes use a larger, more complex set of DNA polymerases with distinct roles:
  • Polymerase α (alpha): Works with primase to synthesize the initial RNA/DNA hybrid primer.
  • Polymerase δ (delta): Synthesizes the lagging strand and has proofreading capabilities.
  • Polymerase ε (epsilon): Synthesizes the leading strand and has proofreading capabilities.
The End-Replication Problem & TelomeraseDNA polymerase cannot fully replicate the 3' end of the lagging strand, leading to progressive shortening of linear chromosomes with each cell division. The enzyme Telomerase, a reverse transcriptase with its own RNA template, extends the repetitive DNA sequences at the ends (telomeres), counteracting this shortening in germline cells, stem cells, and many cancer cells.
Action of Telomerase

Action of Telomerase

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VI. Gene Mutations & Molecular Basis of Disease

Specific types of mutations at the DNA level can have profound clinical consequences, leading to a wide range of genetic disorders by altering protein structure and function.

Mutation TypeMolecular ConsequenceClassic Disease Example
MissenseA single nucleotide substitution results in a codon that codes for a different amino acid. The effect can range from benign to severe depending on the new amino acid's properties and location.Sickle Cell Anemia: A single A-to-T substitution in the β-globin gene replaces the hydrophilic Glutamic acid (Glu) with the hydrophobic Valine (Val), causing hemoglobin to polymerize under low oxygen.
NonsenseA nucleotide substitution results in a premature STOP codon (UAA, UAG, UGA), leading to the synthesis of a truncated, and typically non-functional, protein.Duchenne Muscular Dystrophy: Many cases are caused by a nonsense mutation in the dystrophin gene, which is crucial for muscle fiber integrity. The resulting truncated protein leads to progressive muscle wasting.
FrameshiftAn insertion or deletion of a number of nucleotides that is not a multiple of three. This alters the triplet reading frame of the codons, usually leading to a completely different downstream amino acid sequence and often a premature stop codon.Tay-Sachs Disease: A common cause is a 4-base insertion in the HEXA gene. This frameshift results in a non-functional hexosaminidase A enzyme, causing a fatal buildup of lipids in brain cells.
Splice-SiteA mutation at an intron-exon boundary (splice donor or acceptor site) disrupts the normal splicing of pre-mRNA. This can lead to the retention of an intron or the exclusion of an exon in the mature mRNA, altering the protein product.β-Thalassemia: Certain mutations in the HBB gene occur at splice sites, leading to incorrect splicing of the β-globin pre-mRNA. This results in a deficient production of functional hemoglobin, causing severe anemia.
Sickle Cell Anemia Mutation

Sickle Cell Anemia Mutation

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Effect of Dystrophin Mutation in DMD

Effect of Dystrophin Mutation in DMD

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VII. Chromosomal Abnormalities & Diagnostics

Large-scale changes at the chromosomal level, involving number or structure, can also cause significant genetic syndromes. Various cytogenetic and molecular techniques are used for their diagnosis.

Abnormality TypeDescriptionExampleDiagnostic Techniques
Numerical (Aneuploidy)Gain or loss of one or more entire chromosomes, typically resulting from non-disjunction during meiosis I or II.
  • Trisomy 21 (Down Syndrome): 3 copies of chromosome 21.
  • Monosomy X (Turner Syndrome): A single X chromosome in females.
Karyotyping: Visualizes full chromosome set.
FISH: Uses fluorescent probes for specific chromosomes.
StructuralAlterations affecting parts of a chromosome, such as deletions, duplications, inversions, or translocations (exchange of segments between non-homologous chromosomes).
  • Cri-du-chat Syndrome: Deletion on the short arm of chromosome 5.
  • Philadelphia Chromosome: A reciprocal translocation between chr. 9 and 22, often found in Chronic Myeloid Leukemia (CML).
Karyotyping: Detects large structural changes.
Array CGH: Detects small deletions/duplications (microdeletions/microduplications) with high resolution.
Fluorescence In Situ Hybridization (FISH)

Fluorescence In Situ Hybridization (FISH)

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Array CGH (aCGH) Workflow

Array CGH (aCGH) Workflow

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VIII. Advanced Genetic Technologies & Applications

Beyond the foundational techniques, several advanced methods are crucial in modern research and diagnostics, enabling personalized medicine and deeper biological insights.

TechniquePrinciplePrimary Application
Quantitative PCR (qPCR)Also known as real-time PCR, this technique uses fluorescent dyes or probes to measure the amount of amplified DNA in real-time during a PCR reaction. The rate of fluorescence increase is proportional to the initial amount of target DNA.Gene expression analysis (by reverse transcribing mRNA to cDNA first), viral load quantification (e.g., HIV, COVID-19), and pathogen detection.
RNA Sequencing (RNA-Seq)A high-throughput, next-generation sequencing (NGS) method that captures a snapshot of the entire transcriptome (all RNA molecules) in a cell or tissue. It provides information on which genes are expressed and at what levels.Comprehensive gene expression profiling, discovering novel genes and transcript isoforms, identifying biomarkers for diseases like cancer, and understanding cellular responses to stimuli.
SNP Analysis & GWASDetecting Single Nucleotide Polymorphisms (SNPs), which are the most common type of genetic variation. Genome-Wide Association Studies (GWAS) scan the genomes of many individuals to find SNPs associated with a particular trait or disease.Identifying genetic risk factors for complex diseases (e.g., diabetes, heart disease), predicting individual drug responses (pharmacogenomics), and ancestry tracing.
Quantitative PCR (qPCR) Amplification Plot

Quantitative PCR (qPCR) Amplification Plot

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RNA-Sequencing (RNA-Seq) Workflow

RNA-Sequencing (RNA-Seq) Workflow

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GWAS Manhattan Plot for identifying SNPs

GWAS Manhattan Plot for identifying SNPs

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