Mutations and Polymorphisms Study Notes

Flashcards covering definitions, classification of mutations, dynamic repeat expansions, functional consequences, types of genetic polymorphisms, GWAS design, and clinical guidelines based on the lecture notes.

How is a locus defined in genetics?

A locus is a DNA segment that occupies a specific position on a chromosome.

What is the prevailing or most common allele at a locus in a population called?

The wild-type or common allele (with the most common sequence across a population referred to as the reference sequence).

What characterizes a polymorphic locus?

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

What are "private" alleles?

Rare genetic variants that are confined to specific families.

What percentage of DNA sequence identity is shared among human individuals?

Approximately $99.9\%$, with the remaining $0.1\%$ accounting for genetically determined variability.

How do euploidy and aneuploidy differ in chromosome mutations?

• Euploidy involves the multiplication of an entire chromosome set (e.g., tetraploidy),

• Aneuploidy involves gain or loss of individual chromosomes (e.g., trisomy, monosomy).

How is the rate of disease-causing mutations defined?

As the incidence of new cases of a genetic disease that were not present in the parents and were caused by a single mutation.

What is the estimated rate of replication errors during cell division?

Less than $1$ mutation per genome per cell division.

Based on base structure changes, how do transitions and transversions differ?

• Transitions swap a purine for another purine ($A \leftrightarrow G$) or a pyrimidine for another pyrimidine ($T \leftrightarrow C$ )

• Transversions swap a purine for a pyrimidine or vice versa ($A \leftrightarrow C$, $A \leftrightarrow T$, $G \leftrightarrow C$, $G \leftrightarrow T$).

What is the functional difference between synonymous and missense mutations?

• Synonymous mutations alter a nucleotide without changing the amino acid.

• Missense mutations substitute a nucleotide to specify a different amino acid.

What defines a nonsense mutation?

A point mutation that replaces an amino acid-coding codon with a stop codon, resulting in truncated protein synthesis.

What are dynamic mutations?

Amplifications of simple trinucleotide repeats in coding regions or untranslated regions of genes.

Which repeated codon, gene, and disease threshold define Huntington disease?

Codon repeat $CAG$ (coding for Gln) in the $HTT$ gene, with a normal repeat range of $11\text{--}35$ and a disease threshold of $>35$ repeats.

What are the repeated codon, gene, and disease threshold associated with Fragile X syndrome?

Codon repeat $CGG$ (coding for Arg) in the $FMR1$ gene, with a disease threshold of $>230$ repeats (normal range $5\text{--}54$).

Which repeated codon and gene cause Friedreich's ataxia, and what is its threshold for disease?

Codon repeat $GAA$ (coding for Glu) in the $FXN$ gene, with a disease threshold of $>100$ repeats.

How does a frameshift mutation alter protein expression?

An insertion, deletion, or rearrangement of nucleotides in a number not divisible by $3$ alters the reading frame, resulting in a functionally altered protein.

How do gain-of-function and loss-of-function mutations differ in protein expression?

• Gain-of-function mutations lead to overproduction or inappropriate production of a protein.

• Loss-of-function mutations reduce or eliminate protein production.

What is haploinsufficiency?

A condition in which $50\%$ of normal protein production from a single normal allele is insufficient to maintain standard cell function.

What is a dominant negative mutation?

A mutation where the mutated protein product interferes with or inhibits the function of the normal protein product encoded by the wild-type allele in a heterozygote.

How do germline and somatic mutations differ regarding heritability?

• Germline mutations are inherited or de novo mutations transmitted to offspring.

• Somatic mutations are restricted to non-germline tissues and are not passed to next generations.

What minimal population frequency defines a genetic polymorphism?

A mutation frequency exceeding $1\%$ of all alleles in a population.

How frequently do SNPs occur in the human genome, and what is the mutation rate at CpG sites?

SNPs occur on average $1$ per every $1000\,bp$ ($5\text{--}10$ million total per genome), with a $25\times$ higher mutation rate at adjacent CG (CpG) hot spots.

Approximately how many SNPs are located within protein-coding genes?

Approximately $100{,}000$ SNPs.

What are microsatellites, and how are they applied in human genetics?

Microsatellites (short tandem repeat polymorphisms) consist of repeated units of $2$, $3$, or $4$ nucleotides, generating multiple alleles used to infer familial relationships by DNA fingerprinting across $13$ loci.

What size range can copy number variants (CNVs) reach, and what is their primary functional impact?

CNVs can extend up to hundreds of kilobases ($kb$), often encompassing dozens of genes and altering gene dosage.

Why are inversion polymorphisms considered balanced structural variants?

Because inversion occurs via sequence homology at the edges without causing a net loss or gain of genomic DNA.

What are the three main steps in the detection process of genetic polymorphisms?

1. Discovery: (WGS/WES and reference sequence comparison).

2. Validation: (replication assay and population prevalence).

3. Screening: (high-density DNA arrays/SNP arrays).

What is the primary objective of a Genome-Wide Association Study (GWAS)?

To simultaneously analyze hundreds of thousands or millions of genomic DNA variations to identify unbiased loci associated with complex phenotypes without requiring a prior hypothesis.

What key sample quality control checks are performed during a GWAS?

1. Sample quality

2. Relatedness

3. Population stratification

What standard statistical significance threshold is used in GWAS Manhattan plots?

$p = 5 \times 10^{-8}$, which accounts for multiple testing across hundreds of thousands of genetic markers.

How is linkage disequilibrium defined?

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

What is a haplotype?

A set of closely linked SNPs located on the same chromosome that tend to be inherited together.

How does genotype imputation predict ungenotyped SNPs?

By matching known genotyped SNPs to reference population panels (e.g., HapMap) based on linkage disequilibrium patterns to fill in unmeasured variants.

What three underlying reasons can account for a SNP significantly associated with a disease in GWAS?

1. A direct causal relationship exists between the SNP and the disease.

2. The SNP is a marker in linkage disequilibrium with the true causal locus.

3. The finding is a false positive.

Which codon repeat, gene, and disease threshold correspond to Myotonic dystrophy?

Codon repeat $CTG$ (coding for Leu) in the $DMPK$ gene, with a disease threshold of $>50$ repeats.

What are the typical ages of disease onset for Glaucoma and Retinitis pigmentosa?

Glaucoma typically begins over age $40$ (except congenital forms affecting infants), while Retinitis pigmentosa begins between ages $10$ and $30$.

What are examples of traits and carrier statuses reported by direct-to-consumer testing like 23andMe?

Traits: Cilantro aversion, hairline, photic sneeze reflex, and bitter taste preference

Carrier statuses: Cystic fibrosis, BRCA1, sickle cell anemia, and glycogen storage disease.

What is the AAO 2013 recommendation on direct-to-consumer (DTC) genetic testing for eye diseases?

Avoid direct-to-consumer genetic testing kits and guide patients toward approved, accredited clinical testing facilities.

What are the typical onset ages for Uveal melanoma compared to Polypoidal choroidal vasculopathies?

Uveal melanoma onset is typically between ages $50$ and $80$, whereas Polypoidal choroidal vasculopathies onset occurs between ages $50$ and $65$.

What are the four major types of genetic polymorphisms?

1. Single nucleotide polymorphisms (SNPs)

2. Insertion-deletion polymorphisms (indels, including microsatellites)

3. Copy number variants (CNVs)

4. Inversion polymorphisms.