54 Questions
What is the primary source of germline single nucleotide variants (SNVs)?
Male germline
What is the approximate frequency of variants in the human genome?
1 variant per 1000 bp
What determines the amount of DNA shared between individuals?
Their population histories
What is the percentage of gametes carrying a heterozygous germline variant?
50%
What is the characteristic of rare germline variants?
They are unique to a single individual
What is true about the male and female germline lineages?
The male germline undergoes many more cell divisions
What is the main effect of genetic drift on allele frequency?
It changes the frequency of alleles due to chance.
What is the result of a recessive phenotype?
It only occurs when all chromosome copies carry the variant.
What is an example of balancing selection?
Heterozygote advantage
What is the term for a newly arising variant in the germline?
De novo germline mutation or variant
What is the effect of a genetic bottleneck on a population?
All members of the population will derive from a small number of ancestors.
What is the term for a change in the frequency of a variant in a population due to a change in fitness?
Selection
What is the result of a frameshift variant?
It leads to premature truncation of a protein.
What is the term for a variant that alters splicing donor or acceptor sites?
Splicing variant
What is the term for the two inherited copies of each chromosome?
Homologues
What is the result of positive selection on a phenotype?
It increases the frequency of a variant.
What type of variant can occur if a structural variant disrupts a gene, leading to protein truncation?
Gene truncation via structural variant
What is the term for an allele present on one of two homologous chromosomes?
Heterozygous
What type of selection acts on a phenotype to increase the frequency of a variant in a population?
Positive selection
What is the term for a phenotype that leads to a non-viable embryo?
Embryonic lethal
What is the lineage of cells that contributes to the production of gametes?
Germline lineage
When do PGCs arise in humans?
Approximately two weeks after conception
How many cell divisions do male germline cells undergo per year at puberty?
23 times
What percentage of germline SNVs are introduced via the male germline?
~70-80%
In what percentage of cases of Down syndrome does the additional copy of chromosome 21 come from the mother?
>90%
What is the term for a variant that does not generate a measurable phenotype?
Neutral variant
What is the difference between dominant and recessive variants?
Dominant variants generate a phenotype with one copy, while recessive variants generate a phenotype with two copies.
What is an example of a fitness advantage that is caused by human intervention?
Dog breeding
What is negative selection, also known as?
Purifying selection
What is an example of balancing selection?
Heterozygote advantage
What determines the relative importance of selection and genetic drift?
Population size and strength of selection
What is the effect of negative selection on allele frequencies?
Decreases allele frequencies in populations
What is an example of a trait that is under positive selection in one environment but negative selection in another?
MC1R alleles and vitamin D production
What is the effect of genetic drift on variants that cause phenotypes?
Genetic drift affects such variants, but the impact depends on population size
What is the primary factor that influences the increase in cytogenetic abnormalities with maternal age?
Segregation errors
What is the probability that a de novo germline variant in a spermatogonial stem cell (SSC) will be passed to the next generation?
50%
How much DNA is shared between an individual and their grandparent?
25%
What is the typical difference in germline DNA between two unrelated individuals?
~3 million positions
What are common variants in the context of germline DNA?
Variants frequent across populations
What can patterns of allele frequencies help reconstruct?
The migration histories of humans and animals
Which force can cause a newly arising de novo germline variant to become rare or die out?
Genetic drift
What is the probability that a de novo germline variant in a zygote will be present in the gametes of the resulting individual?
50%
How often does a newly arising de novo germline variant become common?
Rarely
What proportion of DNA do full siblings share with each other?
50%
What is a common characteristic of genetic bottlenecks?
They drastically reduce population size
What process is described by the phenomenon where disease-causing alleles become common due to chance?
Genetic drift
Which type of genetic variant involves the introduction of a premature stop codon?
Nonsense
How can non-coding variants impact gene expression?
By modifying protein product levels
What is a primary feature of the founder effect?
A small number of individuals starting a new colony
What genetic phenomenon was key to the high frequency of the BRCA1 indel allele in the Ashkenazi population?
Genetic drift
How do frameshift mutations exert their impact on proteins?
By altering the reading frame and causing premature termination
In the context of genetic drift, why might small populations experience significant shifts in allele frequencies?
Due to chance fluctuations
What type of structural variant leads to gene truncation?
Gene truncation via rearrangement
Which example illustrates an impact of genetic drift during breed formation in dogs?
High frequency of some disease alleles
Study Notes
Germline Lineage
- The germline lineage involves cells that give rise to gametes (sperm and egg cells) and their precursors
- The male germline undergoes many more cell divisions than the female germline
- Germline single nucleotide variants (SNVs) primarily arise in the male germline, and their number depends on the father's age
- Cytogenetic variants frequently arise in the female germline, and are more common in older women
Inheritance
- A heterozygous germline variant is carried by 50% of gametes
- The amount of DNA shared between relatives can be calculated, given that a child inherits 50% DNA from each parent
- Unrelated people in the population on average differ at 3 million positions in the genome, with an average of ~1 variant per 1000 bp
- The amount of DNA shared between individuals depends on their population histories; germline variants allow us to reconstruct population histories
Variants
- Common germline variants are shared by many individuals and may have occurred many generations ago
- Rare germline variants are shared by few individuals, or may be unique to a single individual, and likely occurred in the germline of a recent ancestor
- All germline variants start off as rare, and selection and genetic drift determine if they become common
Selection and Genetic Drift
- Genetic drift is the change in allele frequency due to chance, and is particularly important in small populations
- Selection is the change in allele frequency due to a change in fitness, which acts on phenotypes
- Phenotypes can be dominantly or recessively inherited, and can be conferred by changing the amino acid composition of a protein or by altering the amount of a gene product
Phenotypes
- Coding variants can cause changes in the amino acid composition of a protein, leading to phenotypes
- Non-coding variants and copy number variants can cause changes in the amount of protein product that is produced, leading to phenotypes
- Examples of variants that can cause phenotypes include missense, nonsense, in-frame insertion or deletion, frameshift, splicing, and gene truncation via structural variants or transposable element insertions
Selection
- Positive selection acts on a phenotype to increase the frequency of a variant in a population
- Negative selection acts on a phenotype to decrease the frequency of a variant in a population
- Balancing selection is an interaction between positive and negative selection that acts to maintain several alleles in the population
Learn about the differences between male and female germline lineages, how genetic variations arise, and their dependence on age. Understand the role of germline variants in gametes and their impact on offspring.
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