Mutation Rate & Quantitative Aspects Flashcards
What is the typical spontaneous mutation rate in humans?
The estimated spontaneous mutation rate in humans is ~1 × 10⁻⁹ per nucleotide per generation, meaning that in a diploid human genome (~6 billion bases), about 60-70 new mutations arise per individual per generation.
How do mutation rates vary between different organisms?
✔ Bacteria & Viruses → Higher mutation rates (~10⁻⁶ to 10⁻⁸ per nucleotide per replication cycle).
✔ Humans & Mammals → Lower mutation rates (~10⁻⁹ per nucleotide per generation).
✔ Mitochondrial DNA (mtDNA) → Higher mutation rate than nuclear DNA due to lack of efficient repair mechanisms.
What factors influence mutation rates?
1️⃣ DNA replication fidelity → DNA polymerase proofreading efficiency.
2️⃣ DNA repair mechanisms → More repair = fewer mutations.
3️⃣ Environmental mutagens → Radiation, chemicals, UV exposure.
4️⃣ Repetitive sequences → Higher mutation rates in microsatellites due to replication slippage.
What is the difference between germline and somatic mutations in terms of mutation rates?
✔ Germline mutations occur in reproductive cells and are passed to offspring (mutation rate ~10⁻⁹ per base per generation).
✔ Somatic mutations occur in body cells and accumulate over a lifetime (linked to aging and cancer).
What is the difference between a single-origin mutation and a recurrent mutation?
✔ Single-Origin Mutation → Mutation appears once in a single ancestor and is inherited by all descendants.
✔ Recurrent Mutation → The same genetic change appears independently in different lineages.
How can haplotype analysis distinguish between single-origin and recurrent mutations?
✔ Single-Origin Mutation → All individuals with the mutation share the same haplotype (genetic markers around the mutation).
✔ Recurrent Mutation → Individuals with the mutation have different haplotypes, meaning the mutation occurred multiple times in evolution.
Why are CpG dinucleotides hotspots for recurrent mutations?
Methylated CpG sites (5mC) are highly prone to spontaneous deamination, converting cytosine (C) into thymine (T), which often escapes DNA repair, leading to recurrent mutations in the genome.
✔ Deamination Process:
Unmethylated C → Uracil (U) → Quickly repaired ✅
Methylated 5mC → Thymine (T) → Often not repaired ❌
✔ Mutation Hotspots: CpG sites mutate 10–50× faster than other sequences, making them frequent sites of disease-causing mutations (e.g., p53, BRCA1).
✔ Recurrent Mutations: The same C → T transition can arise independently in different individuals, leading to recurrent changes in the genome over evolution.
What is admixture in population genetics?
Admixture occurs when two or more genetically distinct populations interbreed, leading to new allele combinations and increased genetic diversity.
How does gene flow from migration affect allele frequencies in a population?
✔ Increases genetic diversity by introducing new alleles.
✔ Reduces genetic differentiation between populations.
✔ Can introduce advantageous or deleterious alleles, altering evolutionary trajectories.
What is admixture mapping, and how is it used in genetics?
✔ Admixture mapping identifies genomic regions with ancestry-specific variation to find disease-associated genes.
✔ Used in studies of polygenic traits (e.g., diabetes, hypertension in mixed populations).
How does population structure affect GWAS results in admixed populations?
✔ Population structure can create false-positive associations in GWAS if ancestry is not properly controlled.
✔ Local ancestry analysis is needed to separate true associations from background genetic differences.
What is compound heterozygosity?
Compound heterozygosity occurs when an individual inherits two different mutated alleles at the same gene locus—one from each parent—resulting in a heterozygous state with two distinct mutations rather than a single identical mutation on both alleles.
How does compound heterozygosity differ from simple heterozygosity?
✔ Simple heterozygosity → One normal allele + One mutant allele (heterozygous carrier).
✔ Compound heterozygosity → Two different mutant alleles at the same locus, leading to potential disease phenotypes even without homozygosity.
Are all splicing variants pathogenic?
No, not all splicing variants cause disease. Some changes in intronic or exonic splicing enhancers may be silent, while others disrupt normal splicing and cause disease.
How can splicing variants lead to disease?
✔ Exon Skipping → A mutation in a splice donor/acceptor site can cause exon loss, leading to an altered or truncated protein.
✔ Intron Retention → If splicing is disrupted, intronic sequences may be retained, introducing premature stop codons.
✔ Cryptic Splice Site Activation → Mutations can create new splice sites, leading to abnormal transcripts.
✔ Frame Disruptions → If splicing errors shift the reading frame, they may result in nonsense-mediated decay (NMD) or a dysfunctional protein.
Can intronic variants affect phenotype and cause disease?
Yes, intronic variants can affect gene expression and function in several ways:
✔ Disrupting Splice Sites → If an intronic variant affects a donor/acceptor site, it can interfere with proper splicing (e.g., Beta-thalassemia).
✔ Creating Cryptic Splice Sites → Some intronic mutations introduce alternative splicing patterns, resulting in aberrant proteins.
✔ Altering Enhancer or Silencer Binding → Regulatory sequences in introns may control transcription rates (e.g., intronic mutations in FGFR2 affect craniosynostosis).
✔ Impacting RNA Stability → Some intronic mutations affect mRNA degradation or secondary structure, leading to reduced gene expression.
Can synonymous variants be pathogenic?
Yes, even though synonymous variants do not change the amino acid sequence, they can still affect gene function.
What are unstable repeats in genetics?
Unstable repeats are repetitive DNA sequences, typically short tandem repeats (STRs) or trinucleotide repeats, that can expand or contract during DNA replication, leading to genetic instability.
What types of unstable repeats exist in the genome?
✔ Trinucleotide Repeats → Example: CAG, CGG, CTG expansions in diseases like Huntington’s disease.
✔ Tetranucleotide Repeats → Example: CCTG in myotonic dystrophy.
✔ Microsatellites → Short repeat sequences scattered throughout the genome, prone to expansion/contraction.
How do unstable repeats cause disease?
Repeat expansions can lead to:
✔ Loss of protein function → Large expansions disrupt normal gene expression (e.g., Fragile X syndrome).
✔ Toxic gain of function → Expanded RNA or protein aggregates cause cellular toxicity (e.g., Huntington’s disease).
✔ Epigenetic silencing → Repeat expansions trigger DNA methylation and histone modifications, shutting down gene expression.
How can repeat expansions alter transcription?
✔ Transcriptional Silencing → Large repeat expansions in promoters trigger methylation and reduce transcription.
✔ RNA Toxicity → Expanded repeats in mRNA form secondary structures, sequestering RNA-binding proteins.
✔ Chromatin Changes → Repeats can recruit repressive histone marks (H3K9me3, H3K27me3), shutting down genes.
What is anticipation in repeat expansion disorders?
Anticipation refers to the worsening of disease severity and earlier onset in successive generations due to repeat expansion.
✔ Example: Myotonic dystrophy, where CTG repeats increase in length across generations, leading to more severe symptoms.
