Molecular Polymorphism: GNSA 510 Part 1
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Questions and Answers

What is a characteristic of copy number variations (CNVs)?

  • They are always balanced translocations.
  • They have no impact on gene function.
  • They always consist of inversions.
  • They can lead to disease via dosage sensitivity. (correct)

Which genetic mechanism is associated with CNVs?

  • Unequal crossing over. (correct)
  • Chromosomal breaks and rejoining.
  • Balanced translocations.
  • Gene regulation changes.

What condition is caused by a trinucleotide CAG repeat in the FMR-1 gene?

  • Hemophilia A.
  • Prader-Willi syndrome.
  • Cri-du-chat syndrome.
  • Fragile X Syndrome. (correct)

Which of the following is true regarding non-CNVs such as inversions and balanced translocations?

<p>They can affect gene function without causing dosage effects. (D)</p> Signup and view all the answers

What is a common cause of autism according to the genetic studies mentioned?

<p>Single gene Mendelian inheritance. (D)</p> Signup and view all the answers

What are insertions and deletions (INDELS) also known as?

<p>Deletion and insertion polymorphisms (B)</p> Signup and view all the answers

Why is Sanger Sequencing considered the gold standard for genome sequencing projects?

<p>It has proven accuracy and reliability in large resequencing projects. (B)</p> Signup and view all the answers

What capability does Mutation Surveyor provide in the detection of INDELS?

<p>It automates calls of heterozygous and homozygous INDELS. (B)</p> Signup and view all the answers

What conditions can be caused by indels?

<p>Tay-Sachs disease and various forms of cancer (A)</p> Signup and view all the answers

What accuracy does Mutation Surveyor achieve in detecting INDELS with specific sequencing conditions?

<p>Greater than 99% accuracy when using bi-directional sequences of greater than Plured 20 (B)</p> Signup and view all the answers

What describes a de novo deletion?

<p>A deletion that occurs spontaneously (B)</p> Signup and view all the answers

Which CNV type leads to an increase in gene expression?

<p>Duplication (D)</p> Signup and view all the answers

What can result from a genomic imbalance due to CNVs?

<p>Congenital anomalies (B)</p> Signup and view all the answers

Which of the following gene types are enriched in copy number variations?

<p>Brain development and immune system genes (D)</p> Signup and view all the answers

Which CNV type involves the exchange of segments between two different chromosomes?

<p>Translocation (B)</p> Signup and view all the answers

What is a likely consequence of an insertion in the genome?

<p>Altered gene expression (D)</p> Signup and view all the answers

What can an inversion in DNA lead to?

<p>Novel gene fusion (D)</p> Signup and view all the answers

Which statement about inherited duplications is correct?

<p>They are inherited from a parent. (D)</p> Signup and view all the answers

Which of the following methods is not used to identify indels?

<p>Polymerase Chain Reaction (D)</p> Signup and view all the answers

What are the two possible origins of copy number variations (CNVs)?

<p>Inherited and De novo (B)</p> Signup and view all the answers

Which type of CNV involves a segment of DNA being flipped within the genome?

<p>Inversion (C)</p> Signup and view all the answers

What describes the outcome of a deletion CNV?

<p>Complete gene loss (C)</p> Signup and view all the answers

Which of the following CNV types can potentially result in the production of novel fusion genes?

<p>Translocation (C)</p> Signup and view all the answers

What is a common source of CNVs during the production of germ cells?

<p>Non-allelic Homologous Recombination (D)</p> Signup and view all the answers

What does a duplication event in DNA typically lead to?

<p>Increased gene dosage leading to phenotypic changes (A)</p> Signup and view all the answers

Which of the following characteristics can a CNV NOT exhibit?

<p>Exclusively affecting non-coding regions (C)</p> Signup and view all the answers

What is the primary effect of INDELs that are not a multiple of 3 in coding regions?

<p>They can lead to frameshift mutations. (A)</p> Signup and view all the answers

Which INDEL class involves inserting random DNA sequences?

<p>INDELs containing random DNA sequences (A)</p> Signup and view all the answers

Which type of polymorphism originates from a single mutation effect?

<p>INDELs (B)</p> Signup and view all the answers

How can INDELs be utilized in forensic analysis?

<p>As genetic markers in studies of phylogenetic relationships (B)</p> Signup and view all the answers

What percentage of the variants on human chromosome 22 were identified as INDEL polymorphisms?

<p>13% (B)</p> Signup and view all the answers

For which regions can INDELs that are multiples of 3 altering transcriptional activity occur?

<p>Promoter regions (A)</p> Signup and view all the answers

What role do comprehensive variation maps serve compared to SNP maps alone?

<p>They enhance the identification of variants by integrating SNPs and INDELs. (C)</p> Signup and view all the answers

Which of the following statements regarding INDELs is incorrect?

<p>They have high mutation rates compared to SNPs. (C)</p> Signup and view all the answers

What is the primary hypothesis tested in relation to CNVs in autism spectrum disorder families?

<p>Identifying CNVs related to distant relatives could uncover novel ASD susceptibility genes. (C)</p> Signup and view all the answers

Which of the following best describes the significance of CNVs in genetic studies?

<p>They contribute to phenotypic heterogeneity and understanding genetic conditions. (B)</p> Signup and view all the answers

What is one of the key uses of mapping and identifying CNVs?

<p>To target chromosomal rearrangements causing developmental defects. (C)</p> Signup and view all the answers

Which technology is NOT mentioned as a method for identifying CNVs?

<p>SNP genotyping (A)</p> Signup and view all the answers

How does the size of CNVs compare to SNPs?

<p>CNVs are generally much larger, spanning from 100 bp to 3 Mb. (A)</p> Signup and view all the answers

What percentage of the reference genome is covered by CNVs compared to SNPs?

<p>CNVs cover 29.74% and SNPs cover less than 1%. (D)</p> Signup and view all the answers

Which of the following is NOT a type of CNV mentioned?

<p>Insertion (B)</p> Signup and view all the answers

What role do SNPs play in linkage disequilibrium?

<p>They help identify demographic events and candidate genes. (A)</p> Signup and view all the answers

Flashcards

What are INDELS?

Insertions and deletions (INDELS) are changes in the DNA sequence where genetic material is inserted or deleted.

How can INDELS cause disease?

INDELS can cause genetic diseases by disrupting the reading frame of the DNA sequence, leading to a premature stop codon and a non-functional protein.

What is Mutation Surveyor?

Mutation Surveyor is a software used to detect both homozygous and heterozygous INDELS in DNA sequencing data.

How does Mutation Surveyor work?

Mutation Surveyor uses a proprietary algorithm to align sequencing traces and identify differences, even in cases where a sequence is shifted by an INDEL.

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How does Sanger Sequencing compare to Next-Generation sequencing (NGS)?

Sanger sequencing, although often considered a gold standard, is being complemented by next-generation sequencing (NGS) techniques for large-scale DNA sequencing projects.

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INDELs

Changes in DNA sequence involving insertions or deletions of nucleotides.

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In-frame INDELs

INDELs that occur within coding regions of genes, where the number of nucleotides inserted or deleted is a multiple of three.

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Frameshift INDELs

INDELs that occur within coding regions of genes, where the number of nucleotides inserted or deleted is not a multiple of three.

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Non-coding INDELs

INDELs that occur in non-coding regions of genes, especially in the promoter regions, which might alter gene regulation.

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INDEL map

A map of common INDEL variations across the human genome.

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HapMap

A database of common genetic variations in the human genome, including both SNPs and INDELs.

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INDELs in evolution

INDELs are valuable tools for understanding human genetic diversity and evolution.

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INDELs in forensic analysis

INDELs can be used to identify individuals, especially in forensic investigations, and to study the relationships among different populations.

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Copy Number Variation (CNV)

Change in the number of copies of a DNA sequence.

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Deletion

A type of CNV where a segment of DNA is missing.

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Duplication

A type of CNV where a segment of DNA is duplicated.

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Fragile X Syndrome

The FMR1 gene on the X chromosome has a trinucleotide repeat (CAG) and its copy number increases, leading to a decrease in the fragile X protein (FRP) expression, causing Fragile X Syndrome.

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Genome-wide Association Study(GWAS)

A large scale study of genetic variations across the whole genome to identify associations with traits or diseases.

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Translocation

Segments of DNA on two different chromosomes are exchanged. This can lead to altered gene regulation or the production of novel fusion genes, which can have phenotypic effects.

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Insertion

A segment of DNA is inserted into a different location in the genome. This can lead to alterations in gene expression or the creation of new genes, which can have phenotypic effects.

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Inversion

A segment of DNA is flipped, reversing the order of genes. This can lead to altered gene regulation or the production of novel fusion genes, which can have phenotypic effects.

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Non-allelic Homologous Recombination (NAHR)

A process that can lead to deletions or duplications in the genome during meiosis, or production of germ cells.

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Indel Detection Technologies

Techniques used to identify insertion and deletions, including next-generation sequencing (NGS) based methods, fluorescence in situ hybridization (FISH), and specialized software algorithms.

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De Novo Deletion

A deletion that arises spontaneously during development, not inherited from parents.

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Inherited Duplication

A duplication inherited from a parent.

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Dosage Sensitive Genes

Genes whose normal function depends on having the correct number of copies.

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De Novo CNV Formation

The process of acquiring new CNVs, often resulting in a condition not seen in parents.

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Genomic Imbalances

These occur when the number of genes in a region of the genome is altered, potentially causing developmental problems. These genes are usually dosage sensitive, so even small changes can affect their function.

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What are Copy Number Variants?

Copy Number Variants (CNVs) are variations in the number of copies of a DNA segment. They can be deletions, duplications, or complex rearrangements. They are a major source of genetic variation in humans, and can have a significant impact on health and disease.

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Why are CNVs important for understanding disease?

CNVs have been linked to many human diseases, including autism spectrum disorder (ASD). This is because CNVs can disrupt gene function, leading to developmental problems.

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How are CNVs identified?

CNVs can be identified using a variety of techniques, including array comparative genomic hybridization (aCGH), next-generation sequencing (NGS), quantitative polymerase chain reaction (q-PCR), and fluorescence in situ hybridization (FISH).

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What are Single Nucleotide Polymorphisms (SNPs)?

A Single Nucleotide Polymorphism (SNP) is a variation in a single nucleotide within a DNA sequence. They are the most common type of genetic variation in humans. SNPs can be used to identify genes associated with diseases.

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How do SNPs differ from CNVs?

Unlike CNVs, SNPs only involve a single base change. SNPs can impact the function of genes by changing the amino acid sequence of a protein, or by altering the regulation of gene expression.

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What is Linkage Disequilibrium (LD)?

Linkage Disequilibrium (LD) describes the non-random association of alleles at different loci. This means that some genetic markers are inherited together more often than expected by chance. Understanding LD is crucial for disease association studies, where researchers look for genetic variations associated with the development of a disease.

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What are Genome-wide Association Studies (GWAS)?

Genome-wide association studies (GWAS) aim to identify genetic variants that are associated with a specific trait, disease, or phenotype. They use a statistical method to analyze thousands or millions of SNPs across the entire genome to find associations with the disease or trait of interest.

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Why is Fine Mapping important?

Fine mapping is a method used in GWAS to narrow down the region of interest on a chromosome containing the causative genetic variant. It involves examining SNPs in a much smaller region within the initial association peak, providing greater resolution to pinpoint the specific variant.

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Study Notes

Molecular Polymorphism: Pharmaco-Toxicogenomic GNSA 510 (Part 1)

  • SNPs are variations in DNA sequences
  • SNPs display abundance, classification (SNP type, alleles, CNVs/Indels), distributions (genomic position, intra/inter-population)
  • LD (linkage disequilibrium) and haplotypes are relevant concepts
  • Paper analysis of SNPs involves application technology, detection techniques (genotyping), and inherited disease implications

INDELS

  • INDELs (insertions or deletions) can change the nucleotide sequence count
  • Coding regions with INDELs can affect the length of an INDEL, potentially causing frameshift mutations or premature termination codons
  • Non-coding regions with INDELs can affect transcriptional activity
  • The length of an INDEL is often a multiple of 3 in non-coding regions

Chromosome 22 and INDEL Polymorphisms

  • Early studies focused on variations on chromosome 22
  • 13% of variants on chromosome 22 were INDEL polymorphisms

Five Major INDEL Classes

  • Insertions or deletions of simple base pairs
  • Monomeric base pair expansions
  • Multi-base pair expansions (e.g., 2-15 bp repeat units)
  • Transposon insertions
  • INDELs with random DNA sequences (ranging from 2 to 9,989 bp)

Importance of INDELS

  • Alter human phenotypes and cause diseases
  • Used in forensic analysis
  • Used as genetic markers in natural populations (especially in phylogenetic studies)
  • These polymorphisms originate from single mutations and have low mutation rate advantages over STRs

Mapping INDELS

  • Useful to integrate human INDEL variation maps into HapMap
  • A complete description of variation in haplotype blocks would help identify specific variations
  • Comprehensive maps (including both SNPs and INDELs) are more effective than SNP maps for identifying variants

Identification of INDELS

  • Identification uses short or long reading sequencing, aCGH/exome sequencing, and GWAS

Detection of Insertions and Deletions (INDELS)

  • INDELS can lead to significant genetic diseases (e.g., Tay-Sachs disease, Alzheimer's, other cancer forms)
  • Mutation Surveyor software is used to detect both homo/heterozygous INDELS
  • This software compares sample mobility to a reference trace and realigns sequences for better accuracy (greater than 99% accuracy for sequences of 20+ bp)

Definition of CNVs

  • CNVs (copy number variations) are changes in the number of copies of a DNA segment
  • CNVs have diverse origins (inherited or de novo)
  • CNVs show quantitative variation and can be located in target regions (e.g., single genes, dozens of genes, or no genes)

CNV Types

  • Duplication
  • Deletion
  • Translocation
  • Insertion
  • Inversion

Sources of CNVs

  • Non-allelic homologous recombination (NAHR) is a primary source
  • NAHR during meiosis leads to deletions or duplications in germ cells
  • The presence of segmental duplications supports the NAHR theory

Deletion and Duplication

  • De novo deletion vs. inherited duplication
  • CNVs shown in family diagrams

Clinical Impact of CNVs

  • Gene dosage-sensitive genes
  • Genomic imbalance-related congenital anomalies

Genes Involved in Copy Number Variation

  • Genes involved in brain development and activity, immune system functions, and cell division are often spared, suggesting that other functions that have evolved rapidly in humans tend to be enriched in CNVs

Mapping and Identifying CNVs

  • Used for identifying genes that cause common diseases/deficiencies
  • Contribute to more accurate and complete human genome references
  • Exclude variations in unaffected individuals to target chromosomal rearrangements

CNV vs. SNP

  • CNVs are larger changes in DNA segments than SNPs (single nucleotide polymorphisms)
  • CNVs affect a larger portion of the genome than SNPs
  • CNV numbers total 38,406 in a given database (for comparison, SNPs total 14,708,752)

SNP Distribution

  • SNPs are useful to examine linkage disequilibrium, recombination rates, and association with complex traits
  • SNPs can help map complex traits, aid in fine mapping, and highlight demographic events that shaped population variation
  • SNPs can identify candidate genes and inform study selection

CNVs that Cause Disease

  • Fragile X Syndrome's trinucleotide repeat causes a decreased quantity of fragile X protein (FRP) causing the syndrome.

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Molecular Polymorphism: Pharmaco-Toxicogenomic GNSA 510 (Part I) PDF

Description

Explore the world of molecular polymorphism in this quiz based on GNSA 510. Learn about SNPs, INDELs, and their implications in pharmacogenomics and toxicogenomics. Delve into crucial concepts like linkage disequilibrium, haplotypes, and chromosome 22 variations.

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