L7: Human Genetic Variability And Its Consequences Flashcards
What percentage of DNA bases are identical when aligning any two human genomes?
Approximately 99.9%.
Example sentence: This high degree of similarity allows researchers to identify variations that may underlie diseases.
What is the significance of “heredity having constancy and inconstancy” in human genetics?
It reflects the balance between stability (constancy) to pass on traits reliably, and mutation (inconstancy), which introduces genetic differences necessary for evolution and adaptation.
Why is genetic variation important for the survival of populations?
It allows populations to adapt to environmental stresses and protects against being wiped out by disease. Without variation, populations are less adaptable to change.
What are examples of large-scale germ-line genetic variations?
Aneuploidy, translocations, and copy number variants (CNVs).
Example sentence: These variations can have significant impacts on an individual’s health and development.
What is aneuploidy?
one or more individual chromosomes being present in an extra copy or missing
Name a well-known condition caused by aneuploidy of chromosome 21.
Down syndrome (Trisomy 21).
Example sentence: Down syndrome is characterized by intellectual disabilities and certain physical features.
What is the incidence of aneuploidy (how common)
rare (approx 1:1000 newborns) as it is not compatible with life
What is the clinical consequence of aneuploidy
Gene dosage refers to the number of copies of a gene. In aneuploidy, too many or too few copies of genes on certain chromosomes can lead to severe developmental issues. Chromosomes with fewer genes (e.g., sex chromosomes) tend to be more tolerant of dosage changes than others (e.g., chromosome 1).
Examples of viable trisomy
Trisomy 21 (down syndrome)
Trisomy 13 (Patau syndrome)
Trisomy 18 (Edwards syndrome)
XXY (Kleinefelters)- less severe as there are fewer genes on X and Y chromosomes
Example of a viable monosomy
X- Turner syndrome
What is a translocation?
The exchange of DNA between two different chromosomes during meiosis. Caused by non-homologous recombination
Example sentence: Translocations can lead to genetic disorders or predispose individuals to certain conditions.
What is the incidence of translocation
1:500 newborns
Clinical consequence of translocation
The clinical impact depends on whether there is a net gain or loss of genetic material or if important genes are disrupted, which can lead to developmental disorders or fertility issues.
What are copy number variants (CNVs)?
Deletions or duplications of DNA that are greater than 1000 base-pairs in size.
Example sentence: CNVs can result in changes to gene dosage and expression levels.
Incidence of CNVs
we all carry multiple CNVs in our genome
What is the general size threshold for copy number variants (CNVs) to be considered pathogenic?
CNVs larger than 1 million base-pairs tend to be pathogenic. They tend to be pathogenic, leading to conditions like learning disabilities, autism, or epilepsy.
Examples of small-scale germ-line genetic variations.
They include SNPs, microsatellites, and insertions/deletions, most of which are benign.
What is a Single Nucleotide Polymorphism (SNP)?
A single base-pair change in the DNA sequence.
Example sentence: SNPs are the most common type of genetic variation in the human genome.
How many SNPs does the average human genome contain?
Around 3.5 million.
Example sentence: Studying SNPs can help identify genetic risk factors for various diseases.
What is the clinical significance of most SNPs?
The vast majority are benign and do not cause disease as it is only a single bp change. In rare conditions though, they can be disease-causing
Example sentence: Benign SNPs are important for understanding normal genetic variation.
What are microsatellites?
Short (2-5 bp) repeated units of DNA, commonly found in non-coding regions of the genome.
Example sentence: Microsatellites are used in DNA fingerprinting and forensic analysis.
What is the incidence of microsatellites
common. We have about 10,000 in our genome
Insertions and deletions
Small sections of DNA that are deleted or duplicated
What is the incidence of insertions and deletions in the human genome, and what is their usual clinical significance?
The human genome contains approximately 20,000 insertions and deletions per person, most of which are benign unless they affect coding regions of genes (exons).
What is an example of a pathogenic deletion in the human genome?
The CFTR delta F508 mutation, where the deletion of phenylalanine causes cystic fibrosis by preventing the protein from leaving the endoplasmic reticulum for further processing.
Describe the nature of pathogenic variants in coding vs non-coding regions of the genome.
Pathogenic variants in coding regions directly affect protein function (e.g., changing amino acids), while most non-coding variants are benign since 98% of the genome is non-genic (non-coding).
How do pathogenic variants alter gene function
- knock-out or increase copy number of a gene (CNV)
- rearrange multiple genes (translocation)
- change the amino acid sequence non-synonymous variant)
- lead to premature stop of translation (non-sense variant)
- alter splicing (splice-site variant)
What are the different types of small-scale pathogenic mutations?
Small-scale pathogenic mutations include:
Non-synonymous/missense mutations
Nonsense mutations
Splice-site mutations
Frameshift mutations
What is genomic instability in cancer cells?
It allows for rapid evolution and leads to genetic changes that give a growth advantage to cancer cells.
Example sentence: Genomic instability is a hallmark of cancer and contributes to tumor progression.
What are “driver” mutations in cancer?
Critical mutations that give cancer cells a growth advantage and allow them to bypass safety mechanisms like apoptosis (programmed cell death), leading to tumor progression and metastasis.
Example sentence: Driver mutations are potential targets for cancer therapies aimed at disrupting tumor growth.
What is LD and how is it measured in genetic studies?
The non-random association of alleles at different loci. LD is quantified by the statistic “D,” which measures the deviation from expected allele combinations, and “r²,” a more commonly used metric that normalizes D.
How are tagging SNPs used in genetic studies?
They leverage linkage disequilibrium patterns to characterize haplotype blocks in the genome.
Example sentence: Tagging SNPs help researchers identify regions of the genome associated with specific traits or diseases.
What role do microsatellites play in forensic science and genetics?
Microsatellites are used in DNA fingerprinting because their high variability between individuals allows for unique genetic profiling.
Example sentence: Microsatellites are also known as short tandem repeats (STRs) and are commonly used in paternity testing.
What are the consequences of somatic genetic variation in malignant cells?
Somatic variation in cancer cells leads to genomic instability, which allows cancer cells to evolve rapidly. This instability enables mutations that promote unchecked growth, division, and metastasis.
Example sentence: Somatic mutations can confer resistance to chemotherapy in cancer cells, making treatment more challenging.
What is the Hardy-Weinberg equation, and how is it applied in population genetics?
The Hardy-Weinberg equation
p2+2pq+q2=1p2+2pq+q2=1. It is used to predict allele and genotype frequencies in a population, assuming no evolution is occurring (for mendelian traits). It helps estimate carrier frequencies for diseases like cystic fibrosis.
Example sentence: The Hardy-Weinberg principle is used to study genetic equilibrium in populations and detect deviations that may indicate genetic drift or selection pressure.
What is the significance of tagging SNPs in haplotype studies?
Tagging SNPs are used to reduce the complexity of genetic studies by identifying patterns of linkage disequilibrium within a population, allowing researchers to track genetic variations across haplotypes without genotyping every SNP.
Example sentence: Tagging SNPs serve as proxies for other genetic variants in haplotype blocks, streamlining the identification of disease-associated loci.
How do haplotypes form, and why are they important in genetic studies?
Haplotypes form as blocks of genetic material that are inherited together due to low recombination rates. They are important for studying inheritance patterns and disease association within populations.
Example sentence: Haplotypes can reveal ancestral relationships and population migrations by tracking specific genetic variants inherited together.
What are missense/non-synonymous mutations
Mutations that alter the amino acid sequence of a protein
What is a nonsense/stop mutation
Mutations that introduce a premature stop codon resulting in a shorter, unfinished protein product.
What is a splice-site mutation
A genetic alteration in the DNA sequence that occurs at the boundary of an exon and an intron (splice site). This change can disrupt RNA splicing resulting in the loss of exons or the inclusion of introns and an altered protein-coding sequence.
Frameshift mutations
a genetic mutation caused by a deletion or insertion in a DNA sequence that shifts the way the sequence is read
