Quiz 3 special topics class

Why was the the Finnish population used in the study of genetic variants ?

• It experienced a population bottleneck, leading to an enrichment of certain recessive variants

The standard GWAS model typically assumes an ______ inheritance model, meaning it does not account for purely ______ effects.

additive , recessive

What were the findings in the paper about mono and biallelic variants effects ?

• Some recessive disease mutations also have effects in heterozygous carriers (AB).Ex. SERPINA1 mutation increased lung disease risk even in heterozygotes.

• Some homozygous mutations cause disease earlier and more severely than previously thought Ex. CASP7 mutation caused early-onset cataracts.

• Some variants classified as "benign" actually influence disease risk.

One of the novel recessive associations found in this study was in the ______ gene, which was associated with ______.

CASP7 gene , cataracts

How did the recessive GWAS model improve disease variant discovery compared to the additive model?

It found recessive disease associations that the additive model overlooked

What was the significance of the SCN5A gene finding in mono and biallelic genetic variants study?

• Homozygous individuals had a high risk of severe cardiac arrhythmia, but heterozygotes were protected from mild arrhythmia

Explain the significance of Figure 1 in the study. How do the five different inheritance models presented challenge traditional genetic assumptions?

• Figure 1 shows five different inheritance patterns, including dominant, recessive, and additive models.

• The study challenges the assumption that recessive variants only cause disease in homozygous individuals (biallelic mutations).

• Some heterozygous (monoallelic) carriers also showed mild disease effects, meaning some recessive variants don’t behave strictly as recessive.

The study identified a genetic variant in the ______ gene that correlates with higher-pitched voices.

ABCC9

The ABCC9 gene influences the production of an ion channel that affects ______ and ______, two proteins essential for tissue flexibility

collagen, elastin

People with the ABCC9 mutation linked to high-pitched voices were also more likely to have ______, a cardiovascular risk factor.

high blood pressure

Which of the following describes the role of the ABCC9 gene?

It helps form an ion channel that influences the flexibility of vocal cords.

Define what genetic mosaicism means ?

• The presence of different cells in a person’s body that have different genetic makeup, even though they all come from the same original fertilized egg (zygote)

• The process of DNA replication isn't perfect, and some copying mistakes slip through, leading to genetic changes in different cells.

Where does the body prevent mutations from happening and why ?

• Reproductive cells , as these are responsible for passing genetic material to future generations.

A group of cells with the same mutation that outcompetes others in a tissue is known as a

clone

The accumulation of somatic mutations in blood cells increases the risk of _______ and _______ but may reduce the risk of Alzheimer's disease.

cancer, heart disease

Mutations in the _______ gene in esophagus cells appear to suppress tumor formation rather than promote it.

NOTCH1

Why was the discovery of widespread somatic mutations in the skin surprising to researchers?

• Many normal-looking skin cells carried cancer-linked mutations

Why is the discovery of somatic mosaicism significant for aging research?

• It suggests that mutations accumulating in cells over time may drive aging

What is one reason researchers propose testing multiple tissue types (blood, skin, saliva) instead of just blood when diagnosing diseases like ALS?

• Some mutations are only present in specific tissues, meaning a blood test alone may miss them

What role does V(D)J recombination play in mosaicism?

• It introduces genetic variability in immune system cells.

In some cases, genetic mosaicism can lead to spontaneous correction of a disease-causing mutation, a phenomenon known as _______ mosaicism.

Revertant

Extrachromosomal circular DNA is often observed in _______ cells and contributes to their ability to evolve rapidly.

Cancer

In which of the following genetic disorders is mosaicism often observed, leading to varying severity of symptoms?

• Turner syndrome

• Down syndrome

• McCune-Albright syndrome

What is a key characteristic of obligatory somatic mosaicism?

It is necessary for survival because the mutation would be lethal in all cells.

Which of the following best describes second-hit mosaicism?

• A somatic mutation that inactivates the second copy of a tumor suppressor gene.

Which sequencing technology has allowed researchers to detect low-frequency somatic mutations with high sensitivity?

• Next generation sequencing

Why is single-cell sequencing a valuable tool for studying mosaicism?

It can detect mutations in individual cells, avoiding the dilution effect of bulk sequencing.

Explain the difference between chromosomal mosaicism and single-nucleotide mosaicism, and provide an example of each.

• Chromosomal mosaicism involves large structural changes in chromosomes, like missing or extra copies (e.g., mosaic Down syndrome).

• Single-nucleotide mosaicism involves small mutations affecting only one or a few DNA bases (e.g., mosaic mutations in cancer driver genes).

What are mobile element insertions, and how do they contribute to genetic mosaicism?

• Mobile elements like LINE-1 can randomly insert into genes, sometimes disrupting their function and contributing to diseases.

The primary challenge of studying the human brain at the genomic level is its __________, due to the variety of specialized cell types.

Heterogeneity

What is WGCNA(Weighted Gene Co-expression Network Analysis)?

• Used to group genes based on similar activity patterns across different cell types and conditions.

One major caveat of single-cell RNA sequencing (scRNA-seq) is that it only provides a __________ snapshot of gene expression.

• Static

What is the main advantage of using single-cell RNA sequencing (scRNA-seq) in neuroscience?

• It identifies gene expression at a single-cell resolution

Neurodegenerative diseases, such as Alzheimer's, have been linked to specific disruptions in __________ networks.

Gene regulatory .

Which of the following methods is used to study chromatin accessibility in brain cells?

scATAC-seq

In Figure 1, what do the UMAP plots primarily illustrate?

• Clustering of brain cells based on transcriptomic and epigenomic features

What is a major limitation of brain transcriptomic studies?

• Single-cell transcriptomics often lacks spatial context, making it hard to link gene expression to anatomical location

What fMRI do ?

Functional MRI (fMRI) helps correlate genetic variations with brain function.

What are the disadvantages in studying synapses ?

• Synapes are tiny

• mapping synapses to their original neurons

• measuring synapse function is still indirect .

How can we be able to map where synapses originate from ?

Tracing tools (like engineered viruses) can help map which neurons are connected . Eg : Rabies virus

What is a way to test the prediction of which genes are important form WGCNA and GRNs ?

• Human-derived brain organoids (mini-brains grown from stem cells) allow some experimental validation.

What does the FigR computational approach do ?

• Designed to link chromatin accessibility with gene expression.

What are DORCS( disease-associated domains of regulatory chromatin )

• chromatin regions specifically linked to genetic risk factors for diseases,

The authors observed that changes in __________ accessibility often occur before changes in gene expression.

• chromatin

In this study, immune cells were stimulated using different treatments,

• LPS

• IFN-y

• PMA + ionomycin

One key limitation of scRNA-seq alone is that it does not capture __________ modifications, which are crucial for understanding gene regulation.

• Epigenetic

Why did the authors develop scOptMatch?

• To improve the accuracy of pairing scRNA-seq and scATAC-seq data

• Ensuring that gene expression and chromatin accessibility are correctly matched to the same cells.

What was observed about the relationship between chromatin accessibility and gene expression over time?

Chromatin accessibility changes often occur before gene expression changes, priming cells for activation

What is the difference between the three different life cycles of the annelids in the study ?

1. Owenia fusiformis – Indirect development with a planktotrophic (feeding) larva.

2. Capitella teleta – Indirect development with a lecithotrophic (non-feeding) larva.

3. Dimorphilus gyrociliatus – Direct development (no larval stage).

What is the difference between indirect and direct developers ?

-Indirect development: Animals go through a larval stage before becoming an adult. Others have direct development, skipping the larval stage.

Which of the following best describes the role of heterochrony in Owenia fusiformis development?

It delays trunk development until late larval stages.

The regulatory motif most responsible for the delayed activation of Hox genes in O. fusiformis is:

HOX/CDX/EVX motif

According to Figure 4, what is the most likely ancestral state of bilaterian life cycles?

• A head-dominant feeding larva with delayed trunk development

In O. fusiformis, what developmental process correlates most strongly with changes in chromatin accessibility in the Hox cluster?

• The transition from competent larva to juvenile

  Chromatin accessibility changes most strongly during the transition to a competent larva, when Hox genes are activated.

Unlike Capitella teleta and Dimorphilus gyrociliatus, O. fusiformis delays trunk development by postponing the activation of _________ genes until the pre-metamorphic stage.

Hox genes

According to Figure 3, the activation of Hox genes in O. fusiformis occurs only after the larva reaches the ______________ stage, whereas in C. teleta, Hox genes are expressed immediately after gastrulation.

Competent larval

Explain how heterochrony contributes to the unique developmental pattern of O. fusiformis compared to other annelids.

• Heterochrony in O. fusiformis delays trunk development until late larval stages, meaning the larva initially forms an enlarged head region while suppressing trunk formation.

• This differs from other annelids, where trunk development begins much earlier in embryogenesis.

Describe two key differences between the direct development of D. gyrociliatus and the indirect development of O. fusiformis in terms of gene expression

• D. gyrociliatus expresses trunk patterning genes much earlier, almost immediately after gastrulation, while O. fusiformis does not activate them until the late larval stage.

• D. gyrociliatus has no distinct larval transcriptomic signature, while O. fusiformis has a clear larval gene expression phase before juvenile transformation.

True or False

In O. fusiformis, Hox genes are spatially arranged but not expressed during embryogenesis.

TRUE

• Hox genes in O. fusiformis are only expressed in the trunk rudiment after larval growth.

True or False

The gene expression profile of the mitraria larva of O. fusiformis is most similar to the pluteus larva of sea urchins and the planula larva of cnidarians.

TRUE

• The gene expression profile of the mitraria larva resembles that of other head-dominant bilaterian larvae.

What is the main advantage of sequencing whole genomes compared to exome sequencing?

• Whole genome sequencing includes both coding and non-coding regions

• Whole genomes capture rare variants in non-coding regions, which can influence gene expression and disease.

• Exome sequencing only focuses on protein-coding genes, missing important regulatory elements

What type of research does the UK Biobank’s genome dataset primarily enable?

• The dataset is used to study links between genetic variants and disease.

Which major finding was made using the first 200,000 full genomes in the UK Biobank?

• Researchers discovered 29 rare genetic variants affecting height by as much as 7 cm, which were previously undetected.

Genome-Wide Association Studies (GWAS) previously relied on common single-letter DNA changes (variants), but full genome sequencing allows scientists to analyze ______________ variants, which can have stronger effects on traits.

Rare

TRUE /FALSE

The UK Biobank’s full genome data allows researchers to see structural variations such as missing, extra, or flipped DNA segments.

• True – Full genome sequencing allows detection of structural variations like missing, extra, or flipped DNA segments.

Amoebidium appalachense retained which DNA methyltransferases (DNMTs) that are typically lost in other unicellular holozoans?

DNMT1 and DNMT3

Unlike animal DNMT3, the DNMT3 enzyme in Amoebidium lacked which two protein domains?

ADD and PWWP

What type of viral DNA made up the majority of the hypermethylated regions in Amoebidium?

Giant viruses (Nucleocytoviricota)

The two major types of viral sequences found in the Amoebidium genome belonged to:

Giant viruses (GEVEs) and adintoviruses

The study found that giant viruses co-opted which eukaryotic chromatin-modifying enzyme?

• Lysine demethylase (KDM4)

Which methylation inhibitor was the only one to significantly reduce 5mC levels in Amoebidium?

• 5-azacytidine

Which viral genes remained silent even after methylation removal, suggesting additional layers of regulation?

Capsid proteins

What did comparisons of different isolates of Amoebidium reveal about viral insertions?

• They found that viral insertions were highly polymorphic, meaning different isolates had different viral DNA, suggesting ongoing viral integration and loss rather than a single historical endogenization event.

How does the presence of KDM4-like histone demethylases in endogenized giant virus sequences suggest a potential viral strategy for evading host defenses?

• KDM4 enzymes remove repressive histone marks (H3K9me3 and H3K36me3), which are associated with gene silencing.

• If a giant virus co-opted KDM4, it could potentially erase these silencing marks, allowing viral DNA to remain active in the host genome.

What patterns in gene body and transposon methylation in Amoebidium differ from those typically observed in vertebrates and plants?

• In Amoebidium, gene body methylation does not correlate with higher transcription, unlike in plants and vertebrates

• Transposon methylation is present, unlike in many invertebrates where transposons are often unmethylated.

What role does 5-methylcytosine (5mC) play in silencing viral insertions in Amoebidium, and how was this experimentally tested?

• 5mC acts as a silencing mechanism for viral insertions in Amoebidium, preventing their transcription.(tested by using 5-aza treatment )

• After 5mC was removed, hundreds of viral genes were reactivated, proving that methylation directly suppresses viral gene expression.

Explain how intein splicing efficiency affects the mode of DNA replication in Thermococcus kodakarensis.

• Higher splicing efficiency produces more mature RadA, favoring recombination-dependent replication (RDR).

• Lower efficiency reduces RadA levels, shifting replication toward origin-dependent replication (ODR).

Why does the deletion of the HEN domain lead to reduced RadA splicing efficiency?

• The HEN domain is crucial for intein splicing; its deletion impairs splicing efficiency, leading to lower levels of mature RadA.

How did temperature and single-stranded DNA (ssDNA) influence RadA intein splicing in the study?

• Higher temperatures and ssDNA improved intein splicing, suggesting environmental conditions regulate RadA function.

Describe the significance of the findings related to the mutant AL015 in terms of growth and DNA repair.

• AL015 had reduced RadA levels, slower growth, and increased sensitivity to DNA damage, demonstrating the essential role of RadA splicing.

Which of the following statements best describes the role of RadA in T. kodakarensis?

• It facilitates homologous recombination and recombination-dependent replication.

The HEN domain in RadA plays a crucial role in

Promoting intein mobility through DNA cleavage.

What was the primary method used to determine whether T. kodakarensis cells relied on RDR or ODR?

• Marker Frequency Analysis (MFA)

What was observed in the ΔoriΔcdc6 strain that confirmed the necessity of RDR in T. kodakarensis?

• Dependence on RadA-mediated replication despite reduced levels.

TRUE/FALSE

The study found that inteins might serve regulatory functions beyond their original role as mobile genetic elements.

TRUE : The study suggests inteins may have evolved regulatory roles.

TRUE/FALSE

High levels of RadA correlate with increased reliance on recombination-dependent replication (RDR).

True – Higher RadA levels promote RDR.

The ____________ domain within RadA allows for intein mobility by generating ____________, facilitating intein spreading within the genome.

HEN; double-stranded DNA breaks

The primary function of RadA in DNA replication is to mediate ____________ by forming nucleoprotein filaments on ____________.

homologous recombination; single-stranded DNA (ssDNA)

In Marker Frequency Analysis (MFA), a flat profile with no distinct peaks suggests that replication is occurring via ____________ rather than origin-dependent replication.

recombination-dependent replication (RDR)