BCH I Patterns of Single Gene Inheritance Molecular and Biochemical Basis of Genetics Diseases PDF

Single-gene disorders Murad Odeh PhD Associate Professor Objectives Describe how genes are inherited, the types and extent of genetic variation seen in the human genome, and how these variations affect disease states and the diversity of normal variation. Obtain a family history and draw a...

Single-gene disorders Murad Odeh PhD Associate Professor Objectives Describe how genes are inherited, the types and extent of genetic variation seen in the human genome, and how these variations affect disease states and the diversity of normal variation. Obtain a family history and draw and interpret a pedigree. Perform pedigree analysis and identify the inheritance patterns Explain and identify non-Mendelian mechanisms: reduced penetrance, variable expressivity, uniparental disomy, epigenetics, mosaicism, genomic imprinting, and unstable repeat expansion. SINGLE GENE DISORDERS Single-Gene Inheritance (Mendelian Inheritance) Refers to genetic disorders or traits controlled by mutations in a single gene Follows inheritance patterns described by Gregor Mendel Characteristic Patterns of Transmission Each inheritance type has a specific pattern across generations Knowledge of family history and inheritance type aids in identifying carriers and understanding risk Mutation Variability: Even though a single gene primarily causes these diseases, several different mutations can result in the same disease but with varying degrees of severity and phenotype. Key Genetic Concepts: Penetrance: Likelihood that a gene mutation will result in disease expression. Expressivity: Variation in severity of disease symptoms among individuals with the same gene mutation. Genetic Testing: Methods like PCR and sequencing to confirm mutation presence and guide diagnosis. SINGLE GENE DISORDERS Individual mutant genes cause it. (monogenic) Present in one chromosome or both. Frequency as high as 1/500 Affect 0.2% of the population Incidence in live births is 0.36% Hospitalized children 6-8% Includes mitochondrial disorders PEDIGREE is a family tree that tracks traits or conditions through generations using these symbols and lines. Average % DNA Shared SINGLE GENE DISORDERS PATTERNS OF INHERITANCE AUTOSOMAL RECESSIVE Phenylketonuria Sickle cell anemia Cystic fibrosis Bardet-Biedl Syndrome Spondylothoracic Dysplasia AUTOSOMAL DOMINANT Neurofibromatosis type 1 Achondroplasia Familial hypercholesterolemia Marfan syndrome Huntington Disease X-LINKED Muscular dystrophy (XLR) Hemophilia A and B (XLR) Urea cycle disorders (XLR) Hypophosphatemic rickets (XLD) Incontinentia Pigmenti (XLD) Types of single-gene inheritance patterns, their characteristics, & examples of disorders Atypical Patterns of Inheritance Atypical Patterns of Inheritance Pseudo-autosomal inheritance Myotonic dystrophy 1.Myotonic dystrophy: A single gene disorder caused Dyschondrosteosis by mutations in the DMPK gene. Males are often more severely affected by 2.Dyschondrosteosis: A single gene disorder caused by dyschondrosteosis than females due to the X-linked inheritance pattern mutations in the SHOX gene. 3.Fragile X: A single gene disorder caused by mutations Genomic imprinting in the FMR1 gene. Fragile X 4.Prader-Willi syndrome: A single gene disorder Uniparental disomy caused by a lack of expression of paternal genes on Prader-Willi syndrome chromosome 15. Somatic mosaicism 5.Neurofibromatosis: A single gene disorder caused by Neurofibromatosis mutations in the NF1 or NF2 gene. Germline mosaicism 6.Osteogenesis imperfecta: A single gene disorder Osteogenesis imperfecta caused by mutations in the COL1A1 or COL1A2 gene. DMPK: Dystrophia Myotonic Protein Kinase gene SHOX: Short Stature Homeobox-Containing gene FMR1: Fragile X Mental Retardation 1 gene NF1: Neurofibromin 1 gene  Pseudo-Autosomal Regions (PARs) PAR1 Located at the distal ends of the short arms of the X and Y chromosomes Involved in pairing and recombination during meiosis PAR2 Located at the tips of the long arms of the X and Y chromosomes Smaller than PAR1 Undergoes recombination during meiosis Contains fewer genes compared to PAR1 Recombination in PARs Allows for exchange of genetic material between X and Y chromosomes Ensures proper segregation of chromosomes during meiosis Contributes to genetic diversity.  Differences in Sex-linked Pedigrees Patterns for Autosomal Dominant Compared to Autosomal Pedigrees Inheritance Sex-linked pedigrees show the inheritance of sex-linked Males and females are equally likely to have the trait. traits. There is male-to-male transmission. These traits tend to appear more frequently in Traits do not skip generations (generally). males than females. If the trait is displayed in offspring, at least one parent If a mother has the trait, all her sons should also have it. must show the trait. There is no male-to-male transmission of the trait. The son of a female carrier has a 50 percent chance of inheriting the trait. A compound heterozygote is a person who has two different mutated alleles for a particular gene, one from each parent, but each allele is a different mutation of the same gene. Here’s a simple explanation: Normally, we have two copies of each gene — one from our mother and one from our father. In a compound heterozygote, each copy of the gene has a different mutation (a change in the genetic code) that causes a disorder. Even though the mutations are different, they can still cause the same disease because both mutations affect the gene’s ability to work properly. Comparison of Regular Heterozygosity (Allelic Heterozygosity) and Compound Heterozygosity in Genetic Inheritance Allelic heterogeneity two different mutations within the same gene (same chromosome) causing the same disease. Loci heterogeneity mutations on two different genes (located on different chromosomes) also lead to the same disease. Phenylalanine hydroxylase (PAH) PAH converts phenylalanine to tyrosine. Individuals with PAH deficiency, as seen in PKU, have: Accumulation of phenylalanine in the blood and tissues. Various neurological symptoms & intellectual disabilities. Tyrosinase and Albinism Tyrosinase is involved in melanin production. Disorders related to tyrosinase include a lack of melanin production characterizes albinism. Homogentisic acid 1,2-dioxygenase This enzyme is involved in the degradation of tyrosine and phenylalanine. Mutations lead to alkaptonuria – Acid accumulation (Dark Urine, Dark connective tissues and joint problem). Branched-chain α-keto acid dehydrogenase and Maple Syrup Urine Disease (MSUD) Involved in the catabolism of branched-chain amino acids (leu, Ile, Val) Defects in this enzyme are associated with Maple Syrup Urine Disease (MSUD) – increased ketoacids Neurological symptoms, developmental delays Monoamine oxidase (MAO) and Neurotransmitter Metabolism breaks down neurotransmitters such as serotonin, dopamine, and norepinephrine in the brain. Deficiencies or inhibition can lead to alterations in neurotransmitter levels (psychiatric and neurological disorders) Molecular & Biochemical Basis of Genetic Diseases I & II Murad Odeh, PhD Associate Professor Objective Understanding diseases' genetic and biochemical basis is essential to predicting phenotypes and their transmission and designing treatment strategies. Diseases discussed Cystic fibrosis Sickle cell anemia Thalassemia Alpha Beta Hyperphenylnemia Familial hypercholesterolemia Muscular dystrophy Osteogenesis imperfecta Cystic Fibrosis (CF)  A modifier gene A gene that influences the expression or severity of a disease caused by a primary gene mutation. Does not directly cause the disease, but modifies its impact. In cystic fibrosis (CF), modifier genes affect: Severity of disease symptoms How intense the symptoms are. Age of onset When the symptoms first appear. Response to treatment How well the disease responds to medical interventions. Common Types of Mutations Causing Cystic Fibrosis Class I: Protein production mutations Class II: Protein processing mutations Class III: Gating mutations Influence of Modifier Genes on Cystic Fibrosis (CF) Phenotypes May modulate the phenotype by: Acting on the fundamental molecular level. Providing alternative chloride conductance Regulating splicing and expression of the CFTR gene. LCR enhances the expression of linked genes Phenylalanine is an essential amino acid. Relationship Between Apolipoproteins (Apo100 & ApoB-48) and Lipoproteins (LDL-C) in Lipid Metabolism and Cardiovascular Health Key Points: ApoB exists in both ApoB-100 (found in LDL) and ApoB-48 (found in chylomicrons). ✓ ApoB-100 is crucial for LDL-C transport and a marker of cardiovascular risk. ✓ ApoB-48 is involved in lipid absorption from the intestine to the liver, and elevated levels can indicate issues with fat metabolism. LDL-C carries cholesterol to cells, but excess levels can cause heart disease Summary of Cholesterol Transport and Apolipoproteins Cholesterol is transported in the bloodstream by lipoproteins: LDL, HDL, VLDL, and IDL. Each type has a unique role in cholesterol and triglyceride transport. Apolipoproteins (ApoB- 100 and ApoB-48) are critical for the structure and function of these lipoproteins, facilitating cholesterol metabolism and transport. Key Processes 1.Absorption: Dietary lipids form chylomicrons (ApoB-48) in the intestine. 2.Liver Role: Produces VLDL (ApoB-100), which loses triglycerides to become IDL and LDL. 3.Cellular Uptake: LDL delivers cholesterol to cells via LDL receptors. 4.Reverse Transport: HDL removes excess cholesterol, returning it to the liver. Clinical Implication: Managing LDL-C and ApoB-100 levels is vital for reducing cardiovascular risk. Genetic Mutations Leading to Clearance Impairment and Elevated Cholesterol Levels: LDL Receptor Mutations (LDLR): The LDL receptor removes low-density lipoprotein cholesterol (LDL-C) from the bloodstream. Mutations in the LDLR gene decrease the ability of cells to clear LDL-C, leading to elevated levels. Apolipoprotein B Mutations (APOB): Apolipoprotein B is a component of LDL particles. Mutations in the APOB gene affect the structure or function of apolipoprotein B, impairing LDL clearance and raising cholesterol levels. PCSK9 Mutations: PCSK9 regulates LDL receptor levels. Mutations in the PCSK9 gene increase LDL receptor degradation, reducing LDL clearance efficiency and higher LDL-C levels. not true muscle hypertrophy. It is fatty and connective tissue infiltration within the muscle, giving the appearance of enlarged or hypertrophied muscles. In a normal collagen molecule, there are two α1 chains and one α2 chain, forming a triple helix structure (2α1 + 1α2). OI Mutations: Disrupt the balance of α1 to α2 chains. Mutations in one or the other of these genes cause the body to make either abnormally formed collagen or too little collagen Pterin carbinolamine-4 α-dehydratase (PCD) This enzyme is involved in the biosynthesis of BH4. Mutations in PCD can lead to BH4 deficiency, affecting PAH activity and causing an increase in phenylalanine levels. Dihydropyridine reductase (DHPR) DHPR is essential for the recycling of BH4. Mutations in DHPR can also result in BH4 deficiency and impact PAH function. 6-pyruvate-tetrahydropterin synthase (PTPS) PTPS is another enzyme involved in BH4 biosynthesis. Mutations in PTPS can lead to BH4 deficiency, affecting the activity of PAH and causing elevated phenylalanine levels.  The effect M3 on the protein A. Arg to Ser The template strand (or noncoding strand or antisense B. Pro to Ser strand) codes for anticodons C. Ser to Arg The coding strand codes for codons D. Ser to Pro Clinical case Naseba is an 8-year-old living in a suburban Toronto, Canada community. Her parents immigrated from Pakistan when she was two years old. At age 3, she was in the 10th percentile for height and weight, pale, and had 5.8 g/dL hemoglobin. Molecular and Biochemical Complex Traits III, IV Murad Odeh, PhD Associate Professor Objectives Inheritance Single-gene inheritance (monogenic) Genetic modifier Environmental modifier Polygenic inheritance Multifactorial inheritance Complex trait Genetic Environmental Measures of inheritance Familial studies Adoption studies Twin studies Disease examples Vein thrombosis Cystic fibrosis Retinitis pigmentosa Diabetes 1 & 2 Hirschsprung disease Heritability Heritability is the proportion of variance in a particular trait, in a particular population, that is due to genetic factors, as opposed to environmental influences Definition: Heritability is a measure that helps us understand how much of the differences in a trait among individuals in a population are due to genetics rather than environmental factors. Interpretation: If a trait has high heritability, genetics play a significant role. Low heritability indicates that environmental influences have a more substantial impact on the trait. Purpose: It's a way to quantify the genetic contribution to variations in traits within a specific group of people. Genetic Relatedness of Children of Identical Twins: Comparison with Cousins Born to Non- Identical Twin Parents: Genetically, the children of identical twins would share a higher percentage of their genetic material compared to cousins born to non-identical twin parents. Similarity to Half-Siblings: The genetic relatedness would be like half-siblings but not identical because they still inherit genes from different parents. Legal and Social Considerations: Children of identical twins are legally and socially considered cousins. They would have a more significant genetic relatedness than cousins born to non-identical twin parents. Effect of Oral Combined Oral Contraceptive (COC) Use on Venous Thromboembolism (VTE) Risk: Risk Increase: COC use can increase the risk for VTE, including deep venous thrombosis (DVT) and pulmonary embolism (PE), compared with non-use. Mechanism of Action: Estrogen Influence on Gene Transcription: Estrogen, like many lipophilic hormones, affects the gene transcription of various proteins. Increase in Clotting Factors: Estrogen increase the production of clotting factors, such as factor II (prothrombin), factor VII, factor X, and fibrinogen, while also reducing the production of antithrombin III, a natural anticoagulant. This imbalance makes the blood more prone to clot formation. Relationship to Dose: Higher doses of estrogen appear to confer a greater risk of venous thrombus formation. Tunnel vision Environmental factors such as light exposure, diet, general health, and toxins can influence the severity and progression of RP. Protective measures, like UV filtering lenses, antioxidant-rich diets, and careful management of overall health, may help slow the disease progression in some individuals. Percentage of Genetic Similarities % of Genetic Similarities 1.Full siblings: Approximately 50% genetic similarity 2.Half-siblings (same mother): Approximately 25% genetic similarity 3.Half-siblings (same father): Approximately 25% genetic similarity 4.Cousins: Approximately 12.5% genetic similarity (assuming their parents are siblings) 5.Cousins from identical twin mothers & fathers: Between 25% and 50% genetic similarity (estimation; higher than regular cousins due to identical twin parentage) 6.Niece/nephew to aunt/uncle: Approximately 25% genetic similarity 7.Grandchild to grandparent: Approximately 25% genetic similarity 8.Parent to child: Approximately 50% genetic similarity 9.Identical twins: 100% genetic similarity 10.Fraternal twins: Approximately 50% genetic similarity (like regular siblings) 11.Aunt/uncle to niece/nephew: Approximately 25% genetic similarity 12.Second cousins: Approximately 3.125% genetic similarity (assuming their parents are cousins) (heritability) represents the proportion of variation in a trait that can be attributed to genetic factors in a population. End of Questions  What is heritability and How Is It Measured? Heritability is the proportion of phenotypic variation due to genetic variations among individuals in a population. Heritability is estimated by comparing individual phenotypic variation among related individuals in a population, by examining the association between individual phenotype and genotype data For example, as heritability ratio applies to individuals within populations, it cannot be used to predict genetic differences between races or other populations from phenotypic differences, whether they share the same environment or not If the relative risk To study Relative Risk is greater than 1, heritability, Ione then the event is would use more likely to Adoption Studies occur. If the relative risk is less than 1, then the event is less likely to occur Heritability is the proportion of variance in a particular trait, in a particular population, that is due to genetic factors, as opposed to environmental influences or stochastic variation. That’s just a general definition to give you a feel for it. Actually we need to be more rigorous than that. There are two definitions of heritability. A common simplification in all sorts of genetic studies and models is to assume that all alleles and all genotypes act independently of each other – this is called an ‘additive model.’ So for instance, if one allele of a particular SNP gives you a 1 cm increase in height, then being homozygous for that SNP should give you a 2 cm increase in height. Clearly, this model doesn’t allow for dominant or recessive effects, even though we know these abound. It also doesn’t allow for gene-gene interactions, where maybe that SNP only gives you a 1 cm increase in height if paired with another SNP. For these reasons, the additive model is a huge simplification, but a useful one. Now for the two definitions of heritability: ‘narrow sense heritability’ (h2) is defined as the proportion of trait variance that is due to additive genetic factors ‘broad sense heritability’ (H2) is defined as the proportion of trait variance that is due to all genetic factors including dominance and gene-gene interactions. Both kinds of heritability are incredibly tricky to estimate and to interpret. In terms of estimation, a big problem is that people who share parts of their genome tend to share parts of their environment too. One simple way you might think to estimate heritability is to plot children’s traits against the average of their parents, as shown in this example from Visscher 2008: In the example above, the slope is taken to be the heritability. The problem with this is that parent and child share a lot else besides half their genome. One approach to calculating heritability which largely avoids the confounding of genotype with shared environment is to compare the phenotypic concordance of monozygotic (MZ, identical) twins versus dizygotic (DZ, fraternal) twins. Both types of twins are expected to share virtually all environmental factors, including while in the womb, which is why this is a better study design than just comparing MZ twins to siblings. Comparing MZ to DZ twins lets you isolate the contribution of that marginal half shared genome to phenotypic concordance. Visscher 2008, citing Deary 2006 (ft), discusses the example of IQ, where MZ twins have concordance of.86 and DZ twins have concordance of.60. ”Concordance” in these studies seems to refer to a Pearson’s correlation or similar, so something like an r or ρ. (Why r and not slope, like in parent-offspring regression? See this post for further discussion). At first glance it is not clear how to convert these numbers –.86 and.60 – into an estimate of heritability. After all, both of these figures include both genetic and environmental factors. The key observation is that sharing a marginal half genome with your twin explains an additional.86-.60 = 26%, so in theory, sharing a full genome explains 2*26% = 52%. This is called Falconer’s formula: A limitation of heritability estimates derived from twin studies is the potential for unmeasured gene by environment interactions to contribute to phenotypic variance In other words, a heritability estimate cannot be used to determine the causes of differences between populations, nor can it be used to determine the extent to which an individual's phenotype is determined by genes versus environment. Monozygotic (MZ) Twins: Definition: Monozygotic twins, commonly known as identical twins, originate from a single fertilized egg (zygote) that splits into two embryos. Genetic Relatedness: MZ twins share 100% of their genetic material. They have nearly identical genetic makeup, as they come from the same fertilized egg. Concordance Rates: Comparing traits or conditions between MZ twins helps researchers assess the genetic contribution. If MZ twins show higher concordance rates (similarity in traits) compared to DZ twins, it suggests a genetic influence. Dizygotic (DZ) Twins: Definition: Dizygotic twins, also known as fraternal twins, result from the simultaneous fertilization of two separate eggs by two different sperm. Genetic Relatedness: DZ twins share, on average, 50% of their segregating genes, just like non-twin siblings born in separate pregnancies. Concordance Rates: Comparing traits between DZ twins provides information about the genetic and environmental factors influencing those traits. Lower concordance rates in DZ twins, compared to MZ twins, may suggest a genetic component. A limitation of heritability estimates derived from twin studies is the potential for unmeasured gene by environment interactions to contribute to phenotypic variance a heritability estimate cannot be used to determine the causes of differences between populations determine the extent to which an individual's phenotype is determined by genes versus environment.