Mutations and Polymorphisms

Flashcards covering definitions and key concepts of genetic mutations, polymorphisms, triplet repeat expansion diseases, structural variations, and genome-wide association studies (GWAS) from the lecture.

Locus

A specific DNA segment that occupies a defined position on a chromosome.

Alleles

Alternative versions of DNA sequence at a specific locus, with maternal and paternal copies present in each individual.

Wild-type Allele

The single prevailing or most common allele at a specific genomic locus in a population.

Polymorphic Locus

A genomic locus that has more than two common alleles present in a population.

Private Alleles

Rare genetic variants that are confined to individual families.

Zygosity

The degree of allele similarity at a single locus in an organism.

Homozygous

Having two identical copies of the same allele at a specific locus.

Heterozygous

Having two different alleles at a specific locus.

Genotype

The specific genetic information or allele combination present at a locus.

Phenotype

The observable physical or functional appearance of an organism determined by its genotype.

Reference Sequence

The most common DNA sequence in a population used as a genomic standard.

Euploidy

A chromosome mutation involving the multiplication of an entire chromosome set, such as tetraploidy.

Aneuploidy

A chromosome mutation characterized by the presence of additional or missing individual chromosomes, such as trisomy or monosomy.

Subchromosomal Mutations

Structural changes involving portions of chromosomes, including copy number variations and structural rearrangements.

DNA Mutations

Small genetic changes including base substitutions, deletions, and insertions up to $100\,bp$.

Germline Mutations

Heritable genetic changes inherited from parents or de novo mutations transmitted to offspring.

Somatic Mutations

Non-heritable genetic changes specific to body tissues, frequent in cancer and highly proliferative cells.

Mutation Frequency

The number of mutations per locus per cell division, determined by base change rates, repair probability, and detection probability.

Hot Spots

Specific regions of DNA that mutate differently or at significantly higher rates than average genomic regions.

Disease-causing Mutation Rate

The incidence of new cases of a genetic disease not present in parents and caused by a single mutation.

Regional Mutations

Chromosomal portion changes resulting from homologous recombination between fragments with high homology or repair of double-strand breaks.

Synonymous Mutation

A nucleotide substitution that specifies the same amino acid, leaving the translated protein unaltered.

Missense Mutation

A single nucleotide substitution that replaces one codon with a codon specifying a different amino acid.

Transition

A point mutation involving a base change between two purines ($\text{A} \rightleftharpoons \text{G}$) or two pyrimidines ($\text{T} \rightleftharpoons \text{C}$).

Transversion

A point mutation involving a base change between a purine and a pyrimidine ($\text{A} \rightleftharpoons \text{C}$, $\text{A} \rightleftharpoons \text{T}$, $\text{G} \rightleftharpoons \text{C}$, or $\text{G} \rightleftharpoons \text{T}$).

Nonsense Mutation

A point mutation resulting in the replacement of an amino acid-coding codon by a stop codon.

Splicing Pattern Alterations

Mutations affecting mRNA processing that abolish or create alternative intron-exon junctions.

Dynamic Mutations

Unstable amplifications of simple trinucleotide repeats in coding or untranslated genomic regions.

Huntington Disease (Triplet Repeat)

A triplet expansion disease involving $\text{CAG}$ (Glutamine) repeats in the HTT gene with a disease threshold of $>35$ repeats.

Spinocerebellar Ataxia Type 1

A triplet expansion disease involving $\text{CAG}$ (Glutamine) repeats in the ATXN1 gene with a disease threshold of $>49$ repeats.

Machado-Joseph Disease

A triplet expansion disease involving $\text{CAG}$ (Glutamine) repeats in the ATXN3 gene with a disease threshold of $>55$ repeats.

Kennedy Disease

A triplet expansion disease involving $\text{CAG}$ (Glutamine) repeats in the AR gene with a disease threshold of $>38$ repeats.

Fragile X Syndrome (Triplet Repeat)

A triplet expansion disease involving $\text{CGG}$ (Arginine) repeats in the FMR1 gene with a disease threshold of $>230$ repeats.

Fragile X-E Syndrome

A triplet expansion disease involving $\text{CCG}$ (Proline) repeats in the AFF2 gene with a disease threshold of $>200$ repeats.

Myotonic Dystrophy (Triplet Repeat)

A triplet expansion disease involving $\text{CTG}$ (Leucine) repeats in the DMPK gene with a disease threshold of $>50$ repeats.

Friedreich's Ataxia (Triplet Repeat)

A triplet expansion disease involving $\text{GAA}$ (Glutamic acid) repeats in the FXN gene with a disease threshold of $>100$ repeats.

Frameshift Mutation

An insertion or deletion of nucleotides not in a multiple of 3, altering the reading frame and resulting in a functionally altered protein.

Gain-of-Function Mutation

A mutation resulting in overproduction or inappropriate production of a novel or excess protein product.

Loss-of-Function Mutation

A mutation that reduces or eliminates the expression or functional activity of a protein product.

Haploinsufficiency

A state in heterozygotes where 50% of the normal protein product from a single normal allele is insufficient for proper function.

Dominant Negative Mutation

A mutation in which an abnormal protein product inhibits or interferes with the normal protein produced by the normal allele in heterozygotes.

Genetic Polymorphism

A genetic mutation or variation with a frequency exceeding 1% of all alleles in a population.

Single Nucleotide Polymorphism (SNP)

A single base pair change occurring on average 1 in every 1000 base pairs, totaling 5 to 10 million per genome.

CpG Hot Spots

Adjacent CG dinucleotide sites in DNA that exhibit a 25-fold higher rate of mutation into single nucleotide polymorphisms.

Insertion-Deletion Polymorphisms (Indels)

Genetic variants up to $1000\,bp$ involving the presence or absence of a short DNA sequence fragment.

Microsatellites (STRs)

Short tandem repeat polymorphisms with variable numbers of repeated short segments (2, 3, or 4 nucleotides) generating multiple alleles.

DNA Fingerprinting

A method to infer familial relationships by examining microsatellite alleles across 13 specific genomic loci.

Copy Number Variants (CNVs)

Large genomic variants extending up to hundreds of kilobases that alter gene dosage by duplicating or deleting segments containing dozens of genes.

Inversion Polymorphisms

Structural variants (few bp to Mb) formed by homologous recombination at edge sequence homologies, resulting in balanced DNA without net gain or loss.

Discovery Phase (Variant Detection)

Initial variant identification performed by whole genome or whole exome sequencing and comparison against a reference sequence.

Validation Phase (Variant Detection)

A replication assay conducted in a larger population cohort to rule out sequencing errors and confirm statistical occurrence.

Screening Phase (Variant Detection)

High-throughput analysis evaluating thousands of SNPs across multiple individuals using high-density DNA arrays (SNP arrays).

Linkage Analysis

A family-based genetic mapping approach used to identify disease variant positions.

Association Analysis

A population-based genetic analysis method used to evaluate statistical correlations between genetic loci and specific disease phenotypes.

Genome-Wide Association Studies (GWAS)

A molecular technique analyzing hundreds of thousands to millions of markers to identify unbiased susceptibility variants for complex traits without prior hypothesis.

Genotype Imputation

The process of predicting ungenotyped neighbor SNP variants based on reference genomes and known linkage disequilibrium.

Linkage Disequilibrium

The non-random association of alleles at linked loci, reflecting the tendency of specific alleles to be inherited together as haplotypes.

Haplotypes

Sets of closely linked single nucleotide polymorphisms located on the same chromosome that tend to be inherited together.

Manhattan Plot

A scatter plot used in GWAS that plots statistical significance ($-\log_{10}(P)$) on the y-axis against genomic chromosomal coordinates on the x-axis.

GWAS Significance Threshold

The standard statistical significance p-value threshold of $P = 5 \times 10^{-8}$ required in GWAS due to multiple hypothesis testing.