L7: Human Genetic Variability And Its Consequences

Question 1

What percentage of DNA bases are identical when aligning any two human genomes?

Answer 1

Approximately 99.9%.

Example sentence: This high degree of similarity allows researchers to identify variations that may underlie diseases.

Question 2

What is the significance of “heredity having constancy and inconstancy” in human genetics?

Answer 2

It reflects the balance between stability (constancy) to pass on traits reliably, and mutation (inconstancy), which introduces genetic differences necessary for evolution and adaptation.

Question 3

Why is genetic variation important for the survival of populations?

Answer 3

It allows populations to adapt to environmental stresses and protects against being wiped out by disease. Without variation, populations are less adaptable to change.

Question 4

What are examples of large-scale germ-line genetic variations?

Answer 4

Aneuploidy, translocations, and copy number variants (CNVs).

Example sentence: These variations can have significant impacts on an individual’s health and development.

Question 5

What is aneuploidy?

Answer 5

one or more individual chromosomes being present in an extra copy or missing

Question 6

Name a well-known condition caused by aneuploidy of chromosome 21.

Answer 6

Down syndrome (Trisomy 21).

Example sentence: Down syndrome is characterized by intellectual disabilities and certain physical features.

Question 7

What is the incidence of aneuploidy (how common)

Answer 7

rare (approx 1:1000 newborns) as it is not compatible with life

Question 8

What is the clinical consequence of aneuploidy

Answer 8

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).

Question 9

Examples of viable trisomy

Answer 9

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

Question 10

Example of a viable monosomy

Answer 10

X- Turner syndrome

Question 11

What is a translocation?

Answer 11

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.

Question 12

What is the incidence of translocation

Answer 12

1:500 newborns

Question 13

Clinical consequence of translocation

Answer 13

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.

Question 14

What are copy number variants (CNVs)?

Answer 14

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.

Question 15

Incidence of CNVs

Answer 15

we all carry multiple CNVs in our genome

Question 16

What is the general size threshold for copy number variants (CNVs) to be considered pathogenic?

Answer 16

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.

Question 17

Examples of small-scale germ-line genetic variations.

Answer 17

They include SNPs, microsatellites, and insertions/deletions, most of which are benign.

Question 18

What is a Single Nucleotide Polymorphism (SNP)?

Answer 18

A single base-pair change in the DNA sequence.

Example sentence: SNPs are the most common type of genetic variation in the human genome.

Question 19

How many SNPs does the average human genome contain?

Answer 19

Around 3.5 million.

Example sentence: Studying SNPs can help identify genetic risk factors for various diseases.

Question 20

What is the clinical significance of most SNPs?

Answer 20

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.

Question 21

What are microsatellites?

Answer 21

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.

Question 22

What is the incidence of microsatellites

Answer 22

common. We have about 10,000 in our genome

Question 23

Insertions and deletions

Answer 23

Small sections of DNA that are deleted or duplicated

Question 24

What is the incidence of insertions and deletions in the human genome, and what is their usual clinical significance?

Answer 24

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).

Question 25

What is an example of a pathogenic deletion in the human genome?

Answer 25

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.

Question 26

Describe the nature of pathogenic variants in coding vs non-coding regions of the genome.

Answer 26

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).

Question 27

How do pathogenic variants alter gene function

Answer 27

- 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)

Question 28

What are the different types of small-scale pathogenic mutations?

Answer 28

Small-scale pathogenic mutations include: Non-synonymous/missense mutations Nonsense mutations Splice-site mutations Frameshift mutations

Question 29

What is genomic instability in cancer cells?

Answer 29

It allows for rapid evolution and leads to genetic changes that give a growth advantage to cancer cells. ## Footnote Example sentence: Genomic instability is a hallmark of cancer and contributes to tumor progression.

Question 30

What are "driver" mutations in cancer?

Answer 30

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. ## Footnote Example sentence: Driver mutations are potential targets for cancer therapies aimed at disrupting tumor growth.

Question 31

What is LD and how is it measured in genetic studies?

Answer 31

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.

Question 32

How are tagging SNPs used in genetic studies?

Answer 32

They leverage linkage disequilibrium patterns to characterize haplotype blocks in the genome. ## Footnote Example sentence: Tagging SNPs help researchers identify regions of the genome associated with specific traits or diseases.

Question 33

What role do microsatellites play in forensic science and genetics?

Answer 33

Microsatellites are used in DNA fingerprinting because their high variability between individuals allows for unique genetic profiling. ## Footnote Example sentence: Microsatellites are also known as short tandem repeats (STRs) and are commonly used in paternity testing.

Question 34

What are the consequences of somatic genetic variation in malignant cells?

Answer 34

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. ## Footnote Example sentence: Somatic mutations can confer resistance to chemotherapy in cancer cells, making treatment more challenging.

Question 35

What is the Hardy-Weinberg equation, and how is it applied in population genetics?

Answer 35

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. ## Footnote 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.

Question 36

What is the significance of tagging SNPs in haplotype studies?

Answer 36

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. ## Footnote Example sentence: Tagging SNPs serve as proxies for other genetic variants in haplotype blocks, streamlining the identification of disease-associated loci.

Question 37

How do haplotypes form, and why are they important in genetic studies?

Answer 37

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. ## Footnote Example sentence: Haplotypes can reveal ancestral relationships and population migrations by tracking specific genetic variants inherited together.

Question 38

What are missense/non-synonymous mutations

Answer 38

Mutations that alter the amino acid sequence of a protein

Question 39

What is a nonsense/stop mutation

Answer 39

Mutations that introduce a premature stop codon resulting in a shorter, unfinished protein product.

Question 40

What is a splice-site mutation

Answer 40

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.

Question 41

Frameshift mutations

Answer 41

a genetic mutation caused by a deletion or insertion in a DNA sequence that shifts the way the sequence is read