KCU Human Genetics: Translation, Linkage, Mitochondria, Mutations, and Cytogenetics

Vocabulary practice flashcards covering genetic code, eukaryotic translation, linkage, recombination, physical and genetic mapping, mitochondrial inheritance, mutational mechanisms, and clinical medical cytogenetics.

Isolated Congenital Asplenia (ICA)

A rare autosomal dominant condition characterized by the complete absence of a spleen at birth with no other developmental defects, predisposing patients to life-threatening bacterial infections and caused by haploinsufficiency of the ribosomal protein $RPSA$.

RPSA

A gene encoding ribosomal protein SA, an essential component of the small subunit of the ribosome ($>30$ proteins) that is subject to purifying selection and required for normal human spleen development.

One Gene, One Enzyme Hypothesis

The hypothesis originally proposed by Beadle and Tatum stating that genes function by encoding enzymes, where each individual gene encodes a separate, specific enzyme (later refined to one gene, one polypeptide).

Auxotroph

An organism or mutant strain that possesses a mutation preventing the synthesis of an essential nutritional component (such as a specific amino acid) necessary for normal growth.

Minimal Medium

A culture medium containing only the minimal nutrients necessary for colony growth, generally lacking amino acids, on which wild-type organisms can grow but auxotrophic mutants cannot without specific supplementation.

Primary Structure

The linear sequence of amino acids joined together by peptide bonds in a polypeptide chain.

Secondary Structure

The spatial configuration formed by interactions and hydrogen bonding between amino acids of the primary structure, such as an $\alpha$-helix or $\beta$-pleated sheet.

Tertiary Structure

The overall three-dimensional folding of the secondary structure into a complex globular or fibrous shape.

Quaternary Structure

The macromolecular structural organization formed when two or more separate polypeptide chains associate into a functional protein complex.

Codon

A triplet sequence of nucleotides in mRNA that specifies a particular amino acid in protein synthesis or signals the termination of translation; there are $64$ possible codons ($61$ sense codons and $3$ stop codons).

Degenerate Code

A characteristic of the genetic code in which a single amino acid can be specified by more than one distinct codon.

Synonymous Codons

Different codons that specify and encode the exact same amino acid.

Isoaccepting tRNAs

Different tRNA molecules that bind to and accept the same amino acid but possess different anticodon sequences.

Wobble Hypothesis

The hypothesis explaining nonstandard base pairing that allows the third base (at the $3\text{'}$ position) of an mRNA codon to pair flexibly with the first base (at the $5\text{'}$ position) of an anticodon on a tRNA.

Reading Frame

The specific manner in which a nucleotide sequence is divided into nonoverlapping triplets of nucleotides during translation, yielding three possible reading frames for any single mRNA sequence.

Aminoacyl-tRNA Synthetase

An enzyme responsible for attaching the correct amino acid to its cognate tRNA in an ATP-dependent two-step reaction; exactly $20$ distinct types exist in a typical cell, one for each standard amino acid.

Shine–Dalgarno Consensus Sequence

A consensus sequence in prokaryotic mRNA that pairs with the small ribosomal subunit ($30\text{S}$) to correctly align the ribosome at the translation initiation site.

Kozak Sequence

A consensus sequence in eukaryotic mRNA ($5\text{'}-\text{ACCAUGG}-3\text{'}$) surrounding the AUG start codon that facilitates identification of the initiation codon by the eukaryotic ribosome.

Release Factors

Proteins (such as $\text{RF-1}$ and $\text{RF-3}$) triggered by the presence of a stop codon in the ribosomal A site that bind to the ribosome and promote the hydrolysis and release of the completed polypeptide chain.

Haplotype

A specific set of DNA variations, markers, or polymorphisms situated on a single chromosome that tend to be inherited together as a unit.

Centimorgan ($\text{cM}$)

A unit of measuring genetic linkage (also called a map unit), defined as the distance between loci for which the expected average number of intervening crossover events in a single generation is $0.01$ ($1\%$ recombination frequency).

Coefficient of Coincidence

The ratio of the observed number of double crossovers to the expected number of double crossovers: $\frac{\text{Number of observed double crossovers}}{\text{Number of expected double crossovers}}$.

Genetic Interference

The degree to which one crossover event inhibits or suppresses the occurrence of additional crossover events nearby on the same chromosome, calculated as: $\text{Interference} = 1 - \text{Coefficient of coincidence}$.

Somatic-Cell Hybridization

A physical mapping technique in which cells from different species (such as mouse and human) are fused into hybrid cells (heterokaryons); as human chromosomes are progressively lost, the presence or absence of a gene is correlated with specific retained chromosomes.

Heterokaryon

A hybrid cell produced by membrane fusion (often facilitated by polyethylene glycol or viruses) containing two distinct nuclei from different originating cells or species.

Fluorescence In Situ Hybridization (FISH)

A cytogenetic technique in which a fluorescently labeled DNA probe is hybridized to denatured chromosomal DNA in interphase nuclei or metaphase spreads to visualize, identify, or map specific genomic regions, microdeletions, or duplications.

Genome-Wide Association Study (GWAS)

An experimental approach that assays hundreds of thousands to millions of sequence variants (typically SNPs) across the whole genome in large cohorts of cases and controls to identify variants significantly associated with specific traits or diseases.

Polygenic Risk Score (PRS)

An individualized estimate of genetic predisposition to a complex trait or disorder, calculated by weighting and summing genotypes across multiple risk-associated loci by their effect sizes.

Efferocytosis

The clearance and phagocytic uptake of apoptotic and dead cells by macrophages (including brain microglia), a multistep process essential for immune tolerance, tissue homeostasis, and inflammation resolution implicated in Alzheimer's disease.

Endosymbiotic Theory

The evolutionary proposal that mitochondria and chloroplasts originated approximately $1.0\text{–}1.5\,\text{billion}$ years ago when free-living aerobic eubacteria (such as an $\alpha$-proteobacterium) and photosynthetic cyanobacteria were engulfed by primitive eukaryotic host cells.

Replicative Segregation

The random partitioning and distribution of organellar genomes (such as mitochondria) during cell division into progeny cells.

Heteroplasmy

The cellular condition characterized by the coexistence of two or more genetically distinct types of organellar DNA (e.g., normal and mutated mtDNA) within the same cell or individual.

Homoplasmy

The cellular condition in which all copies of the organellar DNA (mtDNA or chloroplast DNA) within a cell or organism are genetically identical.

Petite Mutations

Yeast mutations characterized by small colony size caused by large deletions in mitochondrial DNA that impair oxidative phosphorylation, preventing growth on nonfermentable carbon sources like glycerol.

Human Mitochondrial Genome

A circular, double-stranded DNA molecule comprising $16{,}569\,\text{bp}$ that encodes $2\,\text{rRNAs}$, $22\,\text{tRNAs}$, and $13\,\text{protein}$ subunits of oxidative phosphorylation enzymes.

Leigh Syndrome

A neurometabolic disorder characterized by central nervous system degeneration (e.g., necrosis of basal ganglia) and psychomotor regression, commonly associated with the maternally inherited mitochondrial mutation $\text{m.8993T}>\text{G}$ in the $ATP6$ gene.

MERRF Syndrome

Myoclonic epilepsy with ragged red fibers, a maternally inherited heteroplasmic mitochondrial disorder caused most commonly by an $\text{m.8344A}>\text{G}$ variant in the $MT\text{-}TK$ gene encoding $\text{tRNA}^{\text{Lys}}$.

LHON (Leber Hereditary Optic Neuropathy)

A mitochondrial disorder causing rapid onset of blindness in early adulthood due to optic nerve atrophy, showing a strong male bias and homoplasmic maternal inheritance commonly through the $\text{m.11778A}>\text{G}$ variant in $ND4$.

Spindle Transfer

A reproductive technology (mitochondrial replacement therapy) where the nuclear spindle-chromosome complex from a patient's unfertilized metaphase II oocyte is transferred into an enucleated donor oocyte containing healthy mitochondria prior to fertilization.

Somatic Mutation

A mutation that arises in non-germline tissues; it is propagated during mitotic cell divisions to clone daughter cells within the individual, but cannot be transmitted to offspring.

Germ-Line Mutation

A mutation occurring in reproductive germline cells (producing eggs or sperm) that can be passed down to subsequent generations, being present in every cell of the offspring.

De Novo Mutation

A new genetic alteration occurring for the first time in a family member as a result of a mutation in a parental gamete or in the fertilized egg itself, absent from both parental somatic genomes.

Transition

A base substitution mutation in which a purine is replaced by another purine ($\text{A} \leftrightarrow \text{G}$) or a pyrimidine is replaced by another pyrimidine ($\text{T} \leftrightarrow \text{C}$).

Transversion

A base substitution mutation in which a purine is replaced by a pyrimidine or a pyrimidine is replaced by a purine (e.g., $\text{A} \leftrightarrow \text{C}$, $\text{A} \leftrightarrow \text{T}$, $\text{G} \leftrightarrow \text{C}$, $\text{G} \leftrightarrow \text{T}$).

Frameshift Mutation

An insertion or deletion of a number of nucleotides not divisible by three within a coding sequence, which shifts the reading frame and completely alters all downstream amino acids.

Expanding Nucleotide Repeats

A class of mutations where the number of tandem copies of a specific nucleotide sequence increases dynamically across successive cell divisions or generations (as seen in Huntington disease, Fragile X, and ALS).

Missense Mutation

A single nucleotide substitution that changes a sense codon so that it directs the incorporation of a different amino acid in the encoded protein.

Nonsense Mutation

A point mutation that converts a sense codon encoding an amino acid into a premature stop (termination) codon (such as UAA, UAG, or UGA), truncating the protein product.

Silent Mutation

A base substitution that alters a codon to a synonymous codon specifying the exact same amino acid, leaving the translated protein's amino acid sequence unchanged.

Neutral Mutation

A missense mutation that substitutes an amino acid but does not measurably alter the biochemical function, folding, or fitness of the resulting protein.

Base Analog

A mutagenic chemical substance with molecular structure sufficiently similar to normal nitrogenous bases that it can be erroneously incorporated into DNA by polymerases during replication.

5-Bromouracil ($5\text{-Bu}$)

A thymine base analog bearing a bromine atom at the 5-carbon position in place of a methyl group; it normally pairs with adenine, but when ionized pairs with guanine, driving $\text{TA} \rightarrow \text{CG}$ transition mutations.

Alkylating Agent

A mutagenic chemical (such as ethylmethylsulfonate [EMS] or mustard gas) that transfers alkyl groups (such as methyl or ethyl groups) to nitrogenous bases, modifying their base-pairing specificity.

Pyrimidine Dimer

A covalent linkage formed between adjacent pyrimidine bases (predominantly thymines) on the same DNA strand induced by ultraviolet (UV) radiation, which distorts the double helix and blocks DNA replication.

Ames Test

A biological assay using histidine-auxotrophic ($\text{his}^-$) Salmonella strains exposed to liver metabolic extracts and test chemicals to evaluate a compound's mutagenic capacity by measuring reverse mutation rates back to histidine prototrophy.

Nucleotide-Excision Repair (NER)

A major DNA repair pathway that recognizes and removes bulky helix-distorting lesions, such as ultraviolet-induced pyrimidine dimers and modified bases, by excising an oligonucleotide fragment and resynthesizing the strand.

Xeroderma Pigmentosum

A rare autosomal recessive disorder resulting from defective nucleotide-excision repair enzymes, leading to extreme sensitivity to sunlight, freckle-like skin lesions, and a massive predisposition to sunlight-induced skin cancers.

PolyPhen-2

An in silico tool that predicts the potential damaging impact of human nonsynonymous single nucleotide polymorphisms (missense substitutions) on protein structure and function using sequence, phylogenetic, and structural features via a Naive Bayes classifier.

MutationTaster

A free web-based application that evaluates the disease-causing potential of sequence variants by performing automated computational tests at both DNA and protein levels, accommodating nonsynonymous, synonymous, intronic, and splice-site variants.

c. (HGVS Prefix)

The standard Human Genome Variation Society (HGVS) nomenclature prefix designating a variant positioned relative to a coding DNA reference sequence.

p. (HGVS Prefix)

The standard Human Genome Variation Society (HGVS) nomenclature prefix designating a variant described at the translated protein reference level.

Medical Cytogenetics

The branch of clinical medicine and laboratory genetics that analyzes the structure, number, morphology, and clinical relationship of human chromosomes to genetic disease.

G-Banding Chromosome Analysis

A classic cytogenetic method employing trypsin digestion and Giemsa staining to produce characteristic light and dark band patterns along metaphase chromosomes with a standard resolution limit of $5\text{–}10\,\text{Mb}$.

Array Comparative Genomic Hybridization (aCGH)

A molecular cytogenetic microarray platform that co-hybridizes patient and control DNAs labeled with different fluorophores to detect genome-wide unbalanced copy number variations (losses and gains) down to approximately $>10\,\text{kb}$.

Ring Chromosome

A structurally abnormal circular chromosome formed when breaks occur on both the short and long arms, followed by fusion of the broken ends with concomitant loss of terminal chromosomal material, as observed in $46,\text{XY},\text{r}(18)(\text{p}11.2\text{q}23)$.

Isodicentric Y [$\text{idic(Y)}$]

A structural Y chromosome abnormality possessing two centromeres formed by homologous recombination between opposing arm palindromes, leading to duplication of the short arm, loss of distal long arm material, and mitotic instability manifesting as $45,\text{X}$ mosaicism.

Chimerism

A condition in which an individual organism or tissue contains two or more genetically distinct cell lines originating from the fusion of different independent zygotes, such as in $46,\text{XX}/46,\text{XY}$ chimerism.

Philadelphia Chromosome ($\text{Ph}$)

A shortened derivative chromosome 22 resulting from the balanced reciprocal translocation $t(9;22)(q34;q11.2)$, fusing the $BCR$ gene to the $ABL1$ tyrosine kinase oncogene, classically driving chronic myelogenous leukemia (CML).