Human Genetic Diversity: Mutation and Polymorphism

Human Genetic Diversity: Mutation and Polymorphism

Overview of Human Genetic Diversity

• General Population Disparity: Despite the high level of genetic similarity (99.9%) among humans, about 3.2 million base differences exist within the human genome. These variations are crucial as they contribute to the genetic diversity seen in populations worldwide and can influence various traits, susceptibility to diseases, and responses to environmental factors.

Mutation as a Source of Genetic Variation

• Types of Mutations:

  • Base-Pair Substitution: A change in a single nucleotide base in the DNA sequence.

  • Insertion/Deletion: Additions or losses of one or more nucleotide bases in the DNA sequence. These can severely alter gene function.

  • Promoter Mutation: Changes that affect the region of DNA that initiates transcription, potentially altering the expression levels of genes.

  • Splicing Mutation: Affect the splicing process of pre-mRNA, leading to different protein products that may alter functionality.

  • Mobile Element Insertion: Involves the insertion of transposable elements that can disrupt gene sequences or regulatory regions.

  • Expanded Repeats: Involves sequences of nucleotides that are repeated more times than normal, leading to conditions such as Huntington's disease.

• Mutation Rates:

  • Mutation Hot Spots: Certain regions of the genome that have a higher frequency of mutations, often due to their structural properties or sequence context.

  • Paternal Age Effects: Observed increases in mutation rates correlating with older paternal ages, significantly impacting the likelihood of certain genetic disorders being passed down.

• Causes of Mutations:

  • Induced Mutations: Result from environmental factors, such as radiation, chemicals, and viruses, leading to various forms of DNA alterations.

  • Spontaneous Mutations: Arise from normal cellular processes that can lead to errors during DNA replication or repair processes.

• Consequences of Mutations:

  • Gain of function: Mutations that enhance the activity or expression of a gene, often associated with dominant genetic disorders.

  • Loss of function: Result in a gene product that is completely inactive, commonly leading to recessive conditions.

  • Dominant negative mutations: Produce a variant protein that hinders the function of the normal protein, often seen in disorders involving structural proteins or complexes.

The Human Genome

• Each somatic cell contains 2 copies of the nuclear genome derived from parents; gametes contain only 1 copy, crucial for sexual reproduction.

• Chromosomal Composition: Humans have a total of 22 pairs of autosomes plus a pair of sex chromosomes (XX or XY), essential for sex determination.

• Genome Size: The human genome is approximately 2 meters long when stretched out, comprised of 3.2 billion base pairs. It consists of roughly 25,000 protein-coding genes and more than 20,000 non-coding genes that play essential regulatory roles.

Alleles and Locus

• Definitions:

  • Allele: Different forms of a gene that may produce variations in a trait.

  • Locus: The specific, fixed position of a gene or DNA sequence on a chromosome, serving as a point of reference.

Mutation and Polymorphism

• Mutation: A relatively rare (<1%) heritable alteration that can lead to genetic diversity.

• Polymorphism: Presence of two or more alleles at a locus in a population where the frequency of at least one allele is greater than 1%, essential for evolutionary processes and population genetics.

Types of Mutations

1. Base-Pair Substitution

• Classifications:

  • Silent substitution: Does not change the amino acid sequence due to redundancy in the genetic code.

  • Missense mutation: Changes one amino acid in the protein product, potentially affecting function.

  • Nonsense substitution: Introduces a stop codon, resulting in a truncated protein which may lead to loss of function.

2. Insertion and Deletion

• Can disrupt the reading frame of the gene, especially when the number of inserted or deleted bases is not a multiple of three, altering subsequent amino acid sequences.

3. Promoter Mutations

• Alterations in the promoter region can significantly affect the binding of transcription factors and RNA polymerase, leading to changes in gene expression levels.

4. Splicing Mutations

• Affect the ability of spliceosomes to properly excise intronic sequences, leading to incorrectly assembled proteins and potential diseases.

5. Transposable Elements

• Transposons: Mobile genetic elements that can change their position within the genome, causing mutations and altering the function of neighboring genes.

6. Expanded Repeats

• Associated with various genetic disorders like myotonic dystrophy or fragile X syndrome due to the instability of these repeated sequences during DNA replication.

Molecular Consequences of Mutations

• Gain-of-Function Mutations: Often linked to dominant diseases, these mutations result in abnormal protein activities, such as regulating cell growth.

• Loss-of-Function Mutations: Typically recessive, resulting in the absence or dysfunction of proteins crucial for normal biological processes.

• Dominant Negative Mutations: Can disrupt normal cellular functions by preferentially binding to normal proteins, impacting multimeric protein complexes.

Causes of Mutations

1. Induced Mutations

• Mutagens: Agents like UV light, ionizing radiation, certain chemicals, and biological agents that can induce changes in DNA. Examples include:

  • Base analogs: Molecules that resemble DNA bases and get incorporated during DNA synthesis, leading to base substitution.

  • Acridine dyes: Chemicals that intercalate between DNA bases, causing frameshift mutations through misincorporation.

  • Deamination Agents: Cause altered base pairing, leading to transition mutations.

2. Spontaneous Mutations

• Arise naturally from errors during DNA replication or from endogenous processes that can alter DNA structure, such as oxidative stress and replication errors.

Repair Mechanisms

• DNA Repair Systems: Critical for maintaining genetic integrity, involving various mechanisms:

  • Nucleotide Excision Repair: Repairs bulky DNA adducts and helix-distorting lesions. For example, people with Xeroderma Pigmentosum lack this repair mechanism, rendering them sensitive to UV light and increasing skin cancer risk.

Mutation Rates and Paternal Age Effect

• Mutation Rate: Typically estimated at around 1 in 10^8 base pairs per generation; however, certain regions of the genome, particularly CG dinucleotides, exhibit much higher mutation frequencies.

• Paternal Age Effect: Refers to the observation that increased paternal age correlates with heightened risk for new mutations in offspring, impacting various single-gene disorders and explaining the age-related rise in conditions such as achondroplasia.