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Questions and Answers
Missense mutations cause no change in the sequence of the encoded protein.
Missense mutations cause no change in the sequence of the encoded protein.
False
Nonsense mutations occur when a nucleotide substitution converts an amino acid codon into a stop codon.
Nonsense mutations occur when a nucleotide substitution converts an amino acid codon into a stop codon.
True
Silent mutations always lead to a change in the encoded protein.
Silent mutations always lead to a change in the encoded protein.
False
Dynamic mutations involve expansions of repeat sequences within the DNA.
Dynamic mutations involve expansions of repeat sequences within the DNA.
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Deletions and insertions of a small number of bases account for 50% of disease-causing mutations.
Deletions and insertions of a small number of bases account for 50% of disease-causing mutations.
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Long-range regulatory mutations are common in human genetic disease.
Long-range regulatory mutations are common in human genetic disease.
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RNA processing mutations can destroy consensus splice sites.
RNA processing mutations can destroy consensus splice sites.
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Nucleotide substitutions are the most prevalent type of mutation, accounting for 60% of all disease-causing mutations.
Nucleotide substitutions are the most prevalent type of mutation, accounting for 60% of all disease-causing mutations.
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Hotspots of mutation are locations in the genome where mutations occur more frequently than expected.
Hotspots of mutation are locations in the genome where mutations occur more frequently than expected.
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There are only two types of mutations, which are base pair substitutions and deletions.
There are only two types of mutations, which are base pair substitutions and deletions.
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Nonhomologous end-joining repair involves a precise matching of the broken ends of DNA before they are joined.
Nonhomologous end-joining repair involves a precise matching of the broken ends of DNA before they are joined.
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The overall mutation rate due to replication errors in the human genome is approximately 10 mutations per cell division.
The overall mutation rate due to replication errors in the human genome is approximately 10 mutations per cell division.
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Nucleotide substitutions can occur due to spontaneous chemical processes and may not always be accurately repaired.
Nucleotide substitutions can occur due to spontaneous chemical processes and may not always be accurately repaired.
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Transitions involve changes from purine to purine or pyrimidine to pyrimidine.
Transitions involve changes from purine to purine or pyrimidine to pyrimidine.
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Transversions are more prevalent than transitions in the human genome as a result of random nucleotide substitutions.
Transversions are more prevalent than transitions in the human genome as a result of random nucleotide substitutions.
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Methylation of cytosine residues in the human genome is responsible for generating the majority of mutations.
Methylation of cytosine residues in the human genome is responsible for generating the majority of mutations.
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Hotspots of mutation in the human genome do not show significant preference for specific types of nucleotide substitutions.
Hotspots of mutation in the human genome do not show significant preference for specific types of nucleotide substitutions.
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The estimated average rate of new mutations in human genomes is about 1.2 × 10−8 mutations per base pair per generation.
The estimated average rate of new mutations in human genomes is about 1.2 × 10−8 mutations per base pair per generation.
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More than 30% of single nucleotide substitutions arise from spontaneous deamination.
More than 30% of single nucleotide substitutions arise from spontaneous deamination.
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DNA repair mechanisms are highly efficient in correcting nucleotide changes resulting from DNA damage.
DNA repair mechanisms are highly efficient in correcting nucleotide changes resulting from DNA damage.
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Mutation rates can vary from gene to gene and from individual to individual.
Mutation rates can vary from gene to gene and from individual to individual.
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C>T transitions are equally common as G>A transitions among single base pair substitutions.
C>T transitions are equally common as G>A transitions among single base pair substitutions.
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The CG doublet is not considered a hotspot for mutations in the human genome.
The CG doublet is not considered a hotspot for mutations in the human genome.
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Frameshift mutations can occur only when a deletion of three nucleotides takes place.
Frameshift mutations can occur only when a deletion of three nucleotides takes place.
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Capping, polyadenylation, and splicing are essential modifications needed during the conversion of RNA transcripts to mature mRNAs.
Capping, polyadenylation, and splicing are essential modifications needed during the conversion of RNA transcripts to mature mRNAs.
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The 5' donor and 3' acceptor sites are critical for the proper splicing of introns from unprocessed RNA.
The 5' donor and 3' acceptor sites are critical for the proper splicing of introns from unprocessed RNA.
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Insertions and deletions causing mutations typically involve very large segments of DNA.
Insertions and deletions causing mutations typically involve very large segments of DNA.
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Point mutations in the untranslated regions of mRNA can significantly alter protein production levels.
Point mutations in the untranslated regions of mRNA can significantly alter protein production levels.
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Alternative donor or acceptor sites created by intron base substitutions are beneficial for normal RNA splicing.
Alternative donor or acceptor sites created by intron base substitutions are beneficial for normal RNA splicing.
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Substantial segments of genes can be deleted, inverted, or duplicated without any noticeable effects on the organism.
Substantial segments of genes can be deleted, inverted, or duplicated without any noticeable effects on the organism.
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Southern blotting is primarily used to detect small nucleotide changes in DNA sequences.
Southern blotting is primarily used to detect small nucleotide changes in DNA sequences.
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Frameshift mutations can lead to the production of completely different proteins by altering the downstream reading frame.
Frameshift mutations can lead to the production of completely different proteins by altering the downstream reading frame.
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Nucleotide substitutions can occur without any effect on RNA splicing.
Nucleotide substitutions can occur without any effect on RNA splicing.
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Polymorphisms occur in randomly chosen segments of human DNA approximately 1000 bp in length with an average of one base pair difference between homologous chromosomes inherited from unrelated parents.
Polymorphisms occur in randomly chosen segments of human DNA approximately 1000 bp in length with an average of one base pair difference between homologous chromosomes inherited from unrelated parents.
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Chromosome mutations involve alterations that affect only single nucleotides without changing the overall structure of the chromosomes.
Chromosome mutations involve alterations that affect only single nucleotides without changing the overall structure of the chromosomes.
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Regional mutations can involve changes in the copy number of subchromosomal segments, affecting large sections of chromosomes.
Regional mutations can involve changes in the copy number of subchromosomal segments, affecting large sections of chromosomes.
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Most sequence polymorphisms have significant consequences on gene functioning.
Most sequence polymorphisms have significant consequences on gene functioning.
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The assessment of whether a variant is a polymorphism is based solely on its frequency in a population, needing to exceed 1% of alleles.
The assessment of whether a variant is a polymorphism is based solely on its frequency in a population, needing to exceed 1% of alleles.
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Nucleotide substitutions are the only type of mutation that can affect the coding sequence of genes.
Nucleotide substitutions are the only type of mutation that can affect the coding sequence of genes.
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Polymorphisms can be useful as markers for tracking inheritance in genetic studies.
Polymorphisms can be useful as markers for tracking inheritance in genetic studies.
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Gene or DNA mutations can involve alterations in DNA sequences that range from a single nucleotide up to approximately 100 kb.
Gene or DNA mutations can involve alterations in DNA sequences that range from a single nucleotide up to approximately 100 kb.
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The concept of genetic polymorphism does not take into consideration the demonstrable effects on the individual.
The concept of genetic polymorphism does not take into consideration the demonstrable effects on the individual.
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Increased mutation rates have no established link to human diseases.
Increased mutation rates have no established link to human diseases.
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Study Notes
Human Genetics Diversity: Mutation and Polymorphism
- The study of genetic and genomic variation is crucial in medicine and human genetics.
- Evolution's steady influx of nucleotide variation ensures high genetic diversity and individuality. This applies across human and medical genetics.
- Genetic diversity includes variations in genome organization, nucleotide sequence changes, copy numbers of DNA segments, protein structure/amount variations in tissues, and clinical disease contexts.
Genetic Diversity
- Variation exists in the organization of the genome
- Variations in the nucleotide sequence of the genome
- Variations in the copy number of large genomic DNA segments
- Variations in the structure or amount of proteins found in different tissues
- Any variation in the context of clinical disease
The Sequence of Nuclear DNA
- The sequence of nuclear DNA is approximately 99.5% identical between unrelated humans.
- Most DNA sequence differences have little to no effect on appearance, while others directly cause disease.
The Nature of Genetic Variation
- Alleles are alternative versions of DNA sequence at a particular locus.
- Many genes have a single predominant allele (wild-type/common allele) present in more than half of a population.
- Variant/mutant alleles differ from the wild-type due to mutations (permanent changes in DNA sequence or arrangement).
- Mutations refer to DNA changes but not the individuals carrying the mutated alleles.
Polymorphism
- A locus exhibiting polymorphism has two or more relatively common alleles (defined as > 1% frequency) in a population.
- Most variant alleles are infrequent enough to not qualify as polymorphisms. Some are extremely rare ("private alleles").
The Concept of Mutation
- A study of mutations begins with single nucleotide changes up to entire chromosome alterations.
Useful Databases
- The Human Genome Project's 2003 completion provided a reference genome sequence in 2004.
- Data are accessible through these websites:
- dbSNP (Single Nucleotide Polymorphism Database) and dbVar (Structural Variation Database) are databases for small-scale and large-scale variations (e.g. single nucleotide variants, microsatellites, indels, CNVs).
- http://www.ncbi.nlm.nih.gov/snp/
- http://www.ncbi.nlm.nih.gov/dbvar/
- The 1000 Genomes Project sequences large numbers of individuals to create a comprehensive resource for genetic variation.
- www.1000genomes.org
- The Human Gene Mutation Database (HGMD) catalogs germline mutations associated with inherited human diseases (over 120,000 mutations in 4400 genes). www.hgmd.org
- The Database of Genomic Variants (DGV) is a catalogue of structural variations in the human genome (over 400,000 entries, including 200,000 CNVs, 1000 inversions, 34,000 indels, as of 2012). http://dgv.tcag.ca
- JSNP Database reports SNPs from the Millennium Genome Project. http://snp.ims.u-tokyo.ac.jp/
Mutations at Three Different Levels
- Chromosome mutations change chromosome numbers in a cell
- Subchromosomal/regional mutations change parts of a chromosome (copy number changes, rearrangements).
- Gene/DNA mutations alter DNA sequence (substitutions, deletions, insertions).
The Concept of Genetic Polymorphism
- A randomly chosen 1000 bp segment of human DNA typically has only one base pair difference between homologous chromosomes (unrelated parents).
- Whether a variant is a polymorphism depends on its frequency (>1% in a population), not the type of mutation, size of the mutated segment, or effect on the individual.
Polymorphisms Located
- Most sequence polymorphisms are located between genes or within introns and are insignificant to gene function.
- Some reside in protein-coding regions, leading to different protein variants and human population differences.
- Others are regulatory regions, having vital effects on transcription or RNA stability.
Polymorphisms as Tools
- Polymorphisms are crucial for human and medical genetics.
- Identifying different inherited gene forms/genome segments provide tools for research and clinical application.
- Polymorphisms are used in research (mapping genes, linkage analysis, disease detection), prenatal diagnostics, genetic disease carriers, blood banking/organ transplantation, forensic applications (paternity, victim identification, suspect matching).
Inherited Variation and Polymorphism in DNA
- The Human Genome Project (and related studies) yields comprehensive DNA sequence information.
- This data allows characterization of types and frequencies of polymorphic variation in the human genome.
- DNA polymorphism classification based on DNA sequence variations between alleles.
Types of Variation in the Human Genome
- Single nucleotide polymorphism (SNP): usually two alleles differing by a single nucleotide; common, often every 1000 bp.
- Insertion/deletions (indels): 2-100 nucleotides; number in hundreds of thousands; simple (two alleles) or multiallelic (variable number of repeated segments).
- Microsatellites (STRPs): repeats of short tandem nucleotide sequences (2-4 bp); many alleles; readily determined by PCR.
- Minisatellites (VNTRs): repeats of longer tandem sequences; many alleles; used for DNA fingerprinting.
- Mobile element insertion polymorphisms: insertion of mobile genetic elements. Common Alu and LINE families.
- Copy number variants (CNVs): variation in the number of copies of larger segments (200 base pairs - 2 megabases.)
Microsatellites
- Repeats of di-, tri-, or tetra-nucleotide sequences (e.g. TGTG, CAACAA).
- Allele differences due to variations in repeat number, thus called short tandem repeat polymorphisms or STRPs.
Minisatellites
- Repeated nucleotide sequences 10–100 bp in length.
- Variation in the number of repeats causes different alleles.
Mobile Element Insertion Polymorphisms
- Mobile genetic elements (Alu, LINE families) form nearly half of the human genome.
- These repetitive sequences can affect gene function.
Copy Number Polymorphisms (CNVs)
- Variations in the number of larger DNA segments within a genome (200bp to 2 Mb).
- Can have two alleles or multiple alleles (different copy numbers).
- Detected currently by comparative genome hybridization.
Inversion Polymorphisms
- Inversions involve inverting a DNA segment within a chromosome.
- In their balanced form, have little effect but homologous recombination can cause deletion/duplication of linked regions.
Origins and Frequency of Mutation Types
- Mutations arise during DNA replication, repair, recombination, cell division.
- Mutation frequency per locus per cell division (genome/chromosome) is a measure of error proneness, but is less significant for medical geneticists than mutation frequency per locus per generation.
Categories of Human Mutation (Based on a table provided)
- Genome mutations: arise from chromosome missegregation.
- Chromosome mutations: arise from chromosome rearrangements.
- Gene mutations: caused by base pair mutations.
Mutation Consequences (based on a tabular presentation):
- Nucleotide Substitutions broadly include missense, nonsense, silent, frame shift mutations, etc.
- Deletions and Insertions include a broad spectrum of indels, insertions, deletions including larger scale rearrangements of genes.
DNA Replication Errors
- Most replication errors are promptly corrected (proofreading) by DNA repair enzymes.
- Despite this, a small number of errors occur; estimated one mutation of a base pair per 10^10 per cell division in humans).
Repair of DNA Damage
- Spontaneous chemical processes can damage nucleotides.
- Repair mechanisms may introduce errors during the repair process.
- Damage/repair processes are a major source of permanent mutations.
Hotspot Mutations
- Transition mutations (i.e A-G substitutions) are more common than transversions.
- Spontaneously occurring deamination of methylcytosine is responsible for the high frequency of C-T transitions (methyl-CG is a hotspot).
Sex Differences in Mutation Rates
- New mutations occur in germline during mitotic and meiotic divisions in gametogenesis (spermatogenesis and oogenesis).
- Female gametes (oogenesis): oocytes in meiosis develop before birth; they remain there until ovulation; more susceptible to mutations due to extended duration.
- Male gametes (spermatogenesis): continuous processes throughout life; thus more divisions mean higher exposure to mutations
Variation in Individual Genomes
- Large-scale genome sequencing helps track amount and type of variation expected in individual genomes.
- Tens of thousands of human genomes are now sequenced, providing insights into genetic diversity and disease.
Variation Detected in a Typical Human Genome
- Provides an array of mutations in typical human genomes. (5-10 million SNPs, 25,000–50,000 rare variants, 75 new base pair mutations, 3-7 CNVs, 200,000-500,000 indels, 200-250 frameshift and more)
Clinical Sequencing Studies
- Determining the extent of genome variation (sequence/expression) impacting disease onset/progression is needed for genomic medicine.
- Genomes influence various aspects in the natural history of disease and management.
Sequencing Studies Target
- Whole-genome and whole-exome sequencing assists in identifying de novo mutations causing certain conditions (e.g. autism, schizophrenia, intellectual disability).
- Clinical studies may target germline or somatic variants in the context of cancer.
Other Important Concepts
- Regional Mutations: mutations affecting genome structure due to homologous recombination between similar sequences, or spontaneous DNA breaks.
- Dynamic Mutations: these mutations involve repeated nucleotide sequences, and repeat expansion during gametogenesis may drive disease, through interference with RNA processes.
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Description
Explore the different types of genetic mutations and their implications on protein encoding. This quiz covers missense, nonsense, silent, and dynamic mutations, along with the concept of mutation hotspots and DNA repair mechanisms. Test your understanding of how these mutations contribute to genetic diseases.
