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LabPerspective_Mod6
| Question | Answer |
|---|---|
| linkage analysis | Family based. Following inheritance of diseases among family members (using pedigrees) and test for consistent, repeated coinheritance of disease with a particular genomic region or even a specific variant when a family disease is passed on in a family. |
| genome-wide association analysis | Uses entire hist. of a pop to look for in/decreased frequency of a particular allele/set of alleles in a cohort of affected individuals compared to the control set of unaffected individs from the same pop. (useful for complex and multifactorial disease). |
| What is the basic definition of a genetic disease? | A genetic disease arises when an alteration in the DNA of an essential gene changes the amount or function of its product (mRNA, protein, or regulatory RNA) |
| genome-wide sequencing analysis | Direct genome wide sequencing of affected individuals and their parents/family members of specific population. Useful for rare Mendelian disorders when linkage analysis is not possible due to limited families or the mutation is a genetic lethal. |
| What percent carrier status constitutes a polymorphic locus? | An allele carried by 1% or more of the population. |
| Greek letter used to notate recombination frequency | Theta. 0=no recombination (linked); 0.5=independent assortment (unlinked). Recombination fraction of 1% translates to 1 centimorgan (cM); theta=0.01 |
| Linkage disequilibrium | Non-random association of alleles at different loci, meaning certain genetic variants are inherited together more often than expected by chance. |
| Which approach to discovering genes implicated in disease is family-based? | Linkage analysis |
| Which approach takes advantage of an entire population's history to find allele frequency differences in affected vs. control individuals? | Genome-wide association analysis |
| For what type of disorders is genome-wide sequencing particularly useful when linkage analysis is not possible? | Rare mendelian disorders or genetic lethals |
| What is a significant challenge in analyzing the billions of bases resulting from genome-wide sequencing? | Need for a robust filtering strategy. |
| What has been the enormous impact of linkage, association, and genome-wide sequencing on disease understanding? | Understanding pathogenesis and pathophysiology |
| Genome-wide association analysis is particularly useful for what type of diseases? | Complex and multifactorial disease |
| By what factor has next-generation sequencing reduced the cost of DNA sequencing from the original Human Genome Project? | Millionfold |
| What type of disorder, often resulting from new mutations, makes linkage analysis difficult due to a lack of sufficient families? | Genetic lethal disorders |
| What does a recombination frequency (θ) of 0.5 indicate? | Independent assortment |
| A LOD score greater than what value typically indicates strong evidence for linkage? | 3 |
| What concept describes the non-random association of alleles at different loci? | Linkage Disequilibrium |
| Which type of DNA variant is a common cause of disease, often resulting from deletions or mutations that reduce protein activity? | Loss of function |
| The Hb Kempsey variant, which locks hemoglobin in a high oxygen affinity state, is an example of what type of pathogenic variant effect? | Gain of function |
| Sickle cell disease is caused by a single amino acid substitution in β-globin, categorized as which type of pathogenic variant effect? | Novel Property. Missense pathogenic variant (gain of abnormal function / structural alteration). |
| What is the primary cause of α-thalassemia? | Deletions or mutations in α-globin genes. |
| Hereditary persistence of fetal hemoglobin (HPFH) is often due to what type of variant? | Regulatory mutations leading to ectopic or heterochronic expression. |
| What is the main characteristic of thalassemias? | Imbalance in globin chain synthesis |
| Which genetic modifier can influence the severity of hemoglobin disorders by affecting Hb F levels? | BCL11A. Transcription repressor BCL11A, which governs the switch from fetal to adult hemoglobin during development, is the target of the first FDA-approved CRISPR/Cas9 gene-editing therapy in humans |
| In which regions are hemoglobin disorders particularly prevalent? | Regions with prevalent malaria |
| What public health approach has successfully reduced the birth rates of newborns affected by thalassemia? | Carrier screening programs |
| Genome-wide sequencing is particularly useful for identifying what type of genetic disorder? | Rare Mendelian disorders |
| What is the range for the recombination frequency (θ)? | 0 to 0.5 |
| What does D in Linkage Disequilibrium (LD) measure? | The deviation from expected haplotype frequencies |
| Recombination | exchange of genetic material between homologous chromosomes during meiosis; the frequency (θ) ranges from 0 to 0.5. |
| Linkage | occurs when loci close together on a chromosome are inherited together more often than expected by chance. |
| Linkage Disequilibrium (LD) | means alleles at different loci are associated more often than expected—usually because they are physically close or inherited together through generations. |
| Linkage Equilibrium | means independent assortment (alleles segregate randomly). |
| What is LOD (logarithm of odds) and what is it used for? | quantifies evidence for linkage. Used in gene-mapping studies and historic linkage analyses that led to discoveries such as the CFTR and HBB genes. |
| What does LOD ≥ 3 mean? | genes are linked (~1000 : 1 odds) |
| What is Hardy–Weinberg Equilibrium (HWE) used for? | describes genotype frequencies in ideal populations and underlies carrier-frequency estimation for AR conditions. |
| Locus heterogeneity | Variants in different genes → same phenotype (e.g., retinitis pigmentosa). |
| Allelic heterogeneity | Different variants within one gene → same phenotype (e.g., CF caused by > 2000 different CFTR mutations). |
| Loss of function (LOF) | A reduced or absent protein (e.g., β-thalassemia). |
| Gain of function (GOF) | A new or toxic effect (e.g., Huntington CAG repeat expansion). |
| What is dominant negative effect? | An abnormal protein interferes with a normal one (e.g., osteogenesis imperfecta). |
| What is Haploinsufficiency | 50 % protein level insufficient (e.g., PAX6 → aniridia; TBX5 → Holt-Oram). |
| Recombination Frequency (θ) | 0 → perfect linkage; 0.5 → independent assortment. 1 cM ≈ 1 % recombination. |
| Haplotype | Block of alleles inherited together on one chromosome. |
| Polymorphism | DNA variant ≥ 1 % frequency in population (SNP, indel, microsatellite). |
| Penetrance | Probability a carrier of a genotype shows the phenotype. |
| Variable Expressivity | Range of symptom severity in individuals with the same genotype. |
| Describe Hemoglobin Structure & Genes | Each Hb molecule = 4 subunits (2 α + 2 β). α globin genes (HBA1, HBA2) on chromosome 16 (4 total); β globin gene (HBB) on chromosome 11 (2 total). |
| Adult Hb Composition | HbA (α₂β₂) 96–98 %, HbA₂ (α₂δ₂) 2–3.5 %, HbF (α₂γ₂) < 1 %. |
| Describe Developmental Switching | HbF dominant in fetus → gradual transition to HbA by ~6 months post-birth. |
| What can a CBC tell you in regards to Hemoglobinopathy? | It screens for microcytosis aka small blood cells (low MCV/MCH). |
| What can iron studies tell you about Hemoglobinopathy? | It can rule out iron deficiency. |
| What is Hemoglobin electrophoresis (HPLC) used for? | quantifies Hb fractions and detects variants. Note that an α-thalassemia silent carrier or trait may have normal electrophoresis. |
| how do you determine α/β gene deletions or point mutations. | DNA testing |
| What chromosome and gene(s) for α-Thalassemia? | Chr 16; HBA1/HBA2 |
| What chromosome and gene(s) for β-Thalassemia? | Chr 11; HBB |
| What region is α-thal/Constant Spring most prevalent? | SE Asia |
| What region is β-Thalassemia most prevalent? | Mediterranean |
| What region is sickle cell most prevalent? | Africa |
| What is Hydroxyurea mechanism? | induces HbF →leading to less sickling. |
| Describe phenotype for (α-Thalassemia) given this genotype: αα/–– (cis) or −α/−α (trans) | Trait / Minor Mild microcytosis ± anemia |
| Describe phenotype for (α-Thalassemia) given this genotype: αα/−α | Silent carrier Asymptomatic; normal labs. |
| Describe phenotype for (α-Thalassemia) given this genotype: ––/−α | Hb H disease Moderate anemia; HbH (β₄) band on electrophoresis. |
| Describe phenotype for (α-Thalassemia) given this genotype: ––/−- | Hydrops fetalis (Hb Bart’s) Severe anemia; often fatal in utero. |
Created by:
hannahstevens