Patterns of Genetic Inheritance: Dominant and Recessive Alleles, Disease, and Evolutionary Benefits - PDF

Patterns of Genetic Inheritance: Dominant and Recessive Alleles, Disease, and Evolutionary Benefits Heironymus Bosch, The Garden of Earthly Delights  Cholera has plagued humans for millennia https://wellcomecollectio...

Patterns of Genetic Inheritance: Dominant and Recessive Alleles, Disease, and Evolutionary Benefits Heironymus Bosch, The Garden of Earthly Delights  Cholera has plagued humans for millennia https://wellcomecollection.org/works/acv8r4bv Cholera is an infectious disease caused by the curved bacterium Vibrio cholerae A Periplasmic Polymer Curves Vibrio cholerae and Promotes Pathogenesis Bartlett, Thomas M. et al. Cell, Volume 168, Issue 1, 172 - 185.e15  Cholera produces a toxin that causes epithelial membranes to loose water Mechanism of Cholera Toxin Action: Vibrio cholerae produces a toxin called cholera toxin that disrupts the normal function of epithelial cells lining the intestines. The cholera toxin specifically targets and modifies the CFTR protein (Cystic Fibrosis Transmembrane Conductance Regulator), which plays a critical role in regulating chloride and water transport in cells. This water loss causes severe dehydration, leading to symptoms like muscle cramps, shock, and in extreme cases, death if rehydration treatment is not provided. What mutation might Cholera select for that would protect against death? Thiagarajah, Jay R. and Alan S. Verkman. “New drug targets for cholera therapy.” Trends in pharmacological sciences 26 4 (2005): 172-5.  Mutations in CFTR protect against Cholera There are over 2000 CFTR alleles described in humans! How many of you would like to have this mutation in Thiagarajah, Jay R. and Alan S. Verkman. “New drug targets for cholera your genome or your children’s genome? therapy.” Trends in pharmacological sciences 26 4 (2005): 172-5. Cystic fibrosis Elborn, J Stuart The Lancet, Volume 388, Issue 10059, 2519 - 2531  Mutations in CFTR also cause Cystic Fibrosis What is Cystic Fibrosis? Median Age at death for Patients Cystic fibrosis (CF) is a genetic disorder that affects With and Without Cystic Fibrosis the lungs and digestive system. It is caused by mutations in the CFTR gene. Mutant Alleles of the CFTR gene also cause thick, mucus to build up in various organs, especially the lungs. Clinical Features: Chronic respiratory infections, persistent coughing, difficulty breathing.  Allele fitness depends on the environment Allele fitness refers to how well an allele contributes to an organism's ability to survive and reproduce. The fitness of an allele is not fixed; it can vary depending on the environmental and selective pressures acting on the population. CFTR Mutations and Contextual Fitness: Mutations in the CFTR gene are considered harmful in modern, well-resourced environments due to the severe health issues they create. In regions affected by cholera, CFTR mutations provided a selective advantage due to partial protection against Cholera infection Rosemary G. Gillespie, et al., Adaptive Radiation, Encyclopedia of Biodiversity, Elsevier, 2001, Pages 25-44, https://doi.org/10.1016/B0-12-226865-2/00003-1.  Mapping Cystic Fibrosis using a family tree: Pedigree Analysis Squares = male Circles = female Bruno Heather Emory Camila Patrick Yazmeen Griffin Jocelyn Sydney Kirsten Devon Shaded symbols = affected by the disease (Cystic Fibrosis) Unshaded symbols = Hunter Gabby Josh unaffected (wild-type) This non-obvious pattern of inheritance raises many questions What explains this pattern of inheritance? How can we predict this outcome? What can be done to help the couples avoid the this fate for their children? How are traits transmitted from parents to offspring? How are traits transmitted from parents to offspring? Mendel discovered the basic principles of heredity by breeding garden peas in carefully planned experiments Advantages of using peas: Short generation time Large numbers of offspring Mating could be controlled; plants could be allowed to self-pollinate or could be cross- pollinated “That no generally applicable law of the formulation and development of hybrids has yet been successfully formulated can hardly astonish anyone who is acquainted with the extent of the task and who can appreciate the difficulties with which experiments of this kind have to contend.” -Gregor Mendel Mendel’s Experimental Approach In a typical experiment, Mendel mated two contrasting, true-breeding varieties, a process called hybridization The true-breeding parents are called the P generation The hybrid offspring of the P generation are called the F1 generation or F1 hybrids Mating F1 hybrids with other F1 hybrids through self- pollination or cross-pollination produces the F2 generation What do you think the flower color will be when crossing P purple flowered plants with P white flowered plants in the F1 and F2 generations? Flower color results from P cross F₁ Generation: The F₁ generation plants from this cross were all purple- flowered, indicating that the purple trait is dominant over white. Dominance is where one allele (purple) masks the expression of another allele (white) in hybrids. F₂ Generation: In the F₂ generation, he observed 705 purple-flowered plants and 224 white-flowered plants. This resulted in a ratio of approximately 3:1 (purple to white), a classic Mendelian ratio for a monohybrid cross involving a dominant and a recessive allele. What was the most important aspect of Mendel’s experimental design? Mendel’s Law of Segregation During gamete formation, the two alleles for each gene separate, or "segregate," so that each gamete receives only one allele for each gene. Explains how genetic diversity is maintained and how recessive traits can reappear in later generations after being "hidden" in hybrids. Provides a foundation for understanding genetic inheritance and paved the way for the study of dominant and recessive alleles. “Those traits that pass into hybrid association entirely or almost entirely unchanged, thus themselves representing the traits of the hybrid, are termed dominating and those that become latent in the association, recessive.” -Gregor Mendel Experiments on Plant Hybrids (1865) Mendel’s Law of Segregation Traits are determined by genes with each adult carrying two versions (alleles) of each gene. Gametes carry only one allele for each trait. Alleles are either dominant or recessive Alleles segregate into gametes in a ratio of 1:1 Gametes meeting are random, independent events Interphase Meiosis explains the Law of Segregation Sperm Pp P p P PP PP Eggs PP pp p P p This non-obvious pattern of inheritance raises many questions What explains this pattern of inheritance? How can we predict this outcome? What can be done to help the couples avoid the this fate for their children? How are traits transmitted from parents to offspring?  Is Cystic Fibrosis caused by a dominant or recessive allele? RR rr cc CC Cc Cc Cc Cc Cc Cc Cc Rr cc Applying the mendelian recessive model to CF: Cystic fibrosis is recessive because it skips generations. Rr or RR rr Unaffected parents, carriers (Cc), have affected children (cc), showing that CF can "skip" generations. Why do we not observe CF in a 3:1 ratio?  Inheritance is probabilistic, not deterministic Probabilistic Inheritance: Inheritance of genetic traits, for recessive, follows probabilistic rules rather than deterministic ones. When both parents are carriers of the CF mutation (genotype Cc), each child has a 25% chance of inheriting two mutated alleles (cc), which would result in CF. Probabilities apply to each pregnancy and do not guarantee that a specific number of children will have the disorder. Mendelian Ratios as Probabilities: Chance: 25% 50% 25% Punnett squares give you the expected outcomes Odds: 1:4 2:4 1:4 Expected Odds Ratio converges to the Real Odds Ratio after many (infinite) independent trials. ps://www.nhlbi.nih.gov/health/cystic-fibrosis/causes This non-obvious pattern of inheritance raises many questions What explains this pattern of inheritance? How can we predict this outcome? What can be done to help the couples avoid the this fate for their children? How are traits transmitted from parents to offspring? Why trait ratios vary in families A Coin Flip Analogy Just as each child of two CF carriers has a 25% chance of inheriting two recessive alleles, each coin flip has a 50% chance of landing heads or tails–exact outcome not guaranteed! If you flip a coin a 4 times, you might not get exactly 2 heads and 2 tails. You might get all heads, all tails, or a different mix—this variability is due to random chance. Small sample sizes lead to variability! Each outcome is unaffected by any other outcome before it or after it, because they are independent events The probability “resets” with each pregnancy So if this is random how can genetic testing help?  Product Rule To determine the probability that independent events will happen, the general rule is to multiply the probabilities of the individual events. P(A∩B)=P(A)⋅P(B) Example 1: Rolling Dice Example 2: Mendelian Genetics Question: You roll two dice. What is the Question: If each parent has a 50% chance of probability of rolling a 4 on the first die and a passing on a specific allele (e.g. A or a) what is 5 on the second die? the probability of the offspring receiving the Solution: The outcome of the first die doesn’t AA genotype? affect the second (independent). The Solution: For each parent, the probability of probability of rolling a 4 on one die is 1/6 and passing on allele A is ½. The events are rolling a 5 on the other die is also 1/6. independents so: According to the product rule: P(offspring AA) = 1/2 x 1/2 = 1/4 P(4 and 5) = 1/6 x 1/6 = 1/36  Sum Rule To determine the probability of two or more mutually exclusive events add the respective probabilities together. P(A∪B)=P(A)+P(B) Example 1: Drawing a card Example 2: Chance of purple Question: Suppose you draw a single card Question: In a heterozygote cross of pea plants from a deck. What is the probability of with purple flowers, what is the probability of drawing either a heart or a club? having offspring with purple flowers? Solution: Solution: P(drawing a heart) = 13/52 P(RR) = ¼; P(Rr) = ¼; P(rR) = ¼; P(drawing a club) = 13/52 P(purple) = P(RR) + P(Rr) + P(rR) = ¼+ ¼+ ¼ = ¾ Since these are exclusive events: P(heart or club) = 13/52+13/52 = 26/52 = 1/2 This non-obvious pattern of inheritance raises many questions What explains this pattern of inheritance? How can we predict this outcome? What can be done to help the couples avoid the this fate for their children? How are traits transmitted from parents to offspring?  Genetic testing of the parents gives the probability of the outcome for their children Purpose of Genetic Testing: Genetic testing determines the carrier status of parents, which helps predict the Cc probability of their children inheriting CF. Savannah Scenario 1: If Savannah is not a carrier, Scenario 1: Savannah Scenario 2: Savannah the Punnett square shows that her children each have a 50% chance of being C C C c carriers (Cc) and a 50% chance of being unaffected (CC). There would be no C C chance of cystic fibrosis (cc) Scenario 2: If Savannah is also a carrier Devon Devon (Cc), then their children would have a 25% chance of having CF (cc), a 50% c c chance of being carriers (Cc), and a 25% chance of being unaffected (CC).  Counseling Based on Mendelian Genetics Suppose a couple both have a brother who Remember the coin flip died from the same recessive disease analogy: each child represents an independent event in the sense that its genotype is unaffected by the genotypes of older siblings ? How can a genetic counselor determine the risk that this couple will have a child with the disease?  Counseling Based on Mendelian Genetics is determined by the Rules of Probability If both members of the couple had a sibling with If both are carriers, there is a 1/4 the recessively inherited illness, both of their chance of having the recessive illness parents were carriers These probabilities all represent Thus each has a 2/3 chance of being a carrier independent events and so the themselves probability of all events happening is C c the product of their individual probabilities. The overall probability of them C CC Cc having a child with the illness is Cc x Cc -> 2/3 x 2/3 x 1/4 = 1/9 c Cc cc What if we want to predict the outcome of multiple traits? Inheritance outcomes for multiple traits Hypothesis for Independent Assortment: Each pair of alleles will segregate independently of other pairs during gamete formation, resulting in all possible combinations of alleles in the offspring. Hypothesis for Dependent Assortment: Each allele pair will be inherited together as a unit during gamete formation, resulting in fewer than all combinations of alleles in the offspring. Do the alleles for one trait assort into gametes dependently or independently of the alleles for a different trait?  Mendel’s experiment on multiple traits Experiment Hypothesis P Generation YYRR × yyrr Gametes YR yr F1 Generation YyRr (dihybrid) Do you think we will get a 3:1 phenotypic ratio or a 9:3:3:1?  Mendel observed independent assortment Result The Law of Independent Assortment: It states that each pair of alleles segregates independently of any other pair of alleles during gamete formation Implies that alleles are located on different chromosomes or far apart on the same chromosome (> 10 million base pairs) If alleles Dependently Assort the alleles are located close together on the same chromosome (linked) (< 10 million base pairs), this is very rare! What is the mechanism of independent assortment? Molecular basis of Independent Assortment Meiosis Overview: Meiosis is a specialized type of cell division that reduces the chromosome number by half, producing four haploid gametes from one diploid cell. Meiosis I (Reductional Division): Homologous chromosomes are separated, reducing the chromosome number from diploid to haploid. Random Orientation of Homologous Chromosomes at Metaphase I: Homologous chromosome pairs align randomly along the metaphase plate. Each pair's orientation is independent of others. Segregation During Anaphase I: Homologous chromosomes (and thus alleles) are pulled to opposite poles independently of other chromosome pairs. Random orientation of homologous chromosomes in Metaphase I causes independent assortment Metaphase I Independent Assortment: the assortment of alleles for one gene does not influence the assortment of alleles for another gene located on a different chromosome. Multiple Alleles and Genes: This mechanism applies to all chromosome pairs, so multiple genes (each with multiple alleles) are assorted independently. How many possible assortments are there of human chromosomes?  Calculating the number of possible combinations from independent assortment The number of possible combinations when chromosomes assort into gametes is 2n, where n is the haploid number of chromosomes Mendel’s peas have 14 diploid and n = 7 haploid 27 = 128 combinations Swamp Wallabies have 10 diploid and n = 5 haploid 25 = 32 combinations For humans, n = 23, there are Karyotype 223 = 8,388,608 combinations! from atlas Atlas Blue butterfly, n = 450, there are blue butterfly 2450 = 3x10135 combinations!!!! (Polyommatus atlantica) Toder R, et al (1997). "Comparative chromosome painting between two marsupials: origins of an XX/XY1Y The blue butterfly Polyommatus (Plebicula) atlanticus (Lepidoptera, Lycaenidae) holds the record of the highe 2 sex chromosome system".Mammalian Genome. 8 (6): 418–22. doi:10.1007/s003359900459 number of chromosomes in the non-polyploid eukaryotic organisms. Comp Cytogenet. 2015. doi: 10.3897/CompCytogen.v9i4.5760  Metaphase I randomization is not the only mechanism that leads to independent segregation Gene A, Allele 1 Gene A, Allele 2 Limitation of Metaphase I Gene B, Allele 1 Gene B, Allele 2 Randomization Alone: If independent assortment only depended on the random alignment of chromosomes, all genes on the same chromosome would always be inherited together. They would be "linked” We would find a significant fraction of crosses to show dependent assortment, but we do not… What is the other mechanism that leads to independent assortment?  Crossing Over ensures independence for genes on the same chromosome (mostly) Crossing over produces recombinant chromosomes, which combine DNA inherited from each parent Crossing over contributes to genetic variation by combining DNA from two parents into a single chromosome In humans, an average of one to three crossover events occur per chromosome When and Where does Crossing Over happen? Crossing Over happens in Prophase I of Meiosis When and Where It Happens: Crossing over occurs during Prophase I of Meiosis. Prophase I Nonsister Homologous chromosomes come together in of meiosis chromatids a process called synapsis held together Chiasma Formation: The chiasma (plural: during synapsis Pair of chiasmata) is the physical point where two non- homologs sister chromatids exchange genetic material. Chiasma Result of Crossing Over: Chromatids with new Synapsis and combinations of alleles are created, known as crossing over recombinant chromatids. Recombination separates linked genes and Centromere contributes to independent assortment, increasing the variety of genetic What TEMis the molecular mechanism combinations in offspring. of Crossing Over?  The Synaptonemal Complex and Chiasmata Formation During Crossing Over Sister Synaptonemal The Synaptonemal Complex aligns chromatids complex homologous chromosomes, allowing for interactions between non-sister chromatids. Each chromosome has two sister chromatids, which are copies connected by a centromere. During synapsis, the homologous chromosomes align, with the synaptonemal complex holding them together. Crossovers Once crossing over is complete, the Chiasmata synaptonemal complex disassembles, and the homologous chromosomes are held together at their chiasmata. This ensures Independent Assortment How can I use this knowledge to predict multi-gene, multi-allele crosses?  Independent Assortment explains the inheritance pattern of multiple disease traits Bb – Sickle Cell Disease Carrier Savannah Cc – Cystic Fibrosis Carrier CB Cb cB cb Savannah CB CCBB CCBb CcBB CcBb CcBB CcBb Relative # Percent Chance CB CCBB CCBb CcBB CcBb Devon CCBB = 2 CCBB = 12.5% CCBb = 2 CCBb = 12.5% cB CcBB CcBb ccBB ccBb CcBB = 4 CcBB = 25% CcBb = 4 CcBb = 25% ccBB = 2 ccBB = 12.5% cB CcBB CcBb ccBB ccBb ccBb = 2 ccBb = 12.5% Are there any exceptions to independent assortment?  Common human genetic diseases with Mendelian inheritance patterns Inheritance Gene Name(s) Disease Name Description Pattern A neurodegenerative disorder that affects muscle coordination and leads to HTT Huntington's Disease Dominant cognitive decline. A form of dwarfism characterized by short stature and disproportionately short FGFR3 Achondroplasia Dominant limbs. A connective tissue disorder affecting the heart, eyes, blood vessels, and FBN1 Marfan Syndrome Dominant skeleton. GLI3 Polydactyly Dominant Presence of extra fingers or toes. NF1 Neurofibromatosis Type 1 Dominant Causes tumors to form on nerve tissue. Adult-Onset Polycystic Kidney PKD1, PKD2 Dominant Characterized by the growth of numerous cysts in the kidneys. Disease CFTR Cystic Fibrosis Recessive Affects the respiratory and digestive systems due to thick mucus production. Causes red blood cells to assume a sickle shape, leading to various HBB Sickle-Cell Anemia Recessive complications. Leads to the buildup of phenylalanine, causing intellectual disability if PAH Phenylketonuria (PKU) Recessive untreated. HEXA Tay-Sachs Disease Recessive A fatal neurological disorder most common in infants. TYR, OCA2, TYRP1 Albinism Recessive Lack of pigment in the skin, hair, and eyes. HBA1, HBA2, HBB Thalassemia Recessive A blood disorder involving less hemoglobin and fewer red blood cells. GALT, GALK1, GALE Galactosemia Recessive Inability to process galactose leading to serious health issues. GJB2 Congenital Deafness Recessive Genetic forms of hearing loss present from birth.  Dominantly Inherited Disorders in Humans Dominant Alleles Overview: Dominant alleles express their traits even in the heterozygous state. Individuals with a single copy of the dominant allele (Dd) exhibit the disorder, while those with two recessive alleles (dd) do not. Achondroplasia: a form of dwarfism caused by a rare dominant allele. A mutation in the FGFR3 gene leads to abnormal bone growth resulting in shorter limb bones.  Dominance does not always mean common D d If both parents have achondroplasia the possible genotypes in their offspring are: 25% chance of DD (lethal), D DD Dd 50% chance of Dd (achondroplasia), 25% chance of dd (normal height). Dominance Does Not Mean Common: d Dd dd Achondroplasia is a rare condition in the general population, despite being dominant. Having two dominant alleles is lethal, thus DD parents do not exist, limiting population spread. DD – Embryonic Lethal Therefor, many cases are the result of spontaneous mutations rather than inheritance. Inheritance patterns are often more complex than predicted by simple Mendelian genetics The relationship between genotype and phenotype is rarely as simple as Mendel’s pea plant traits Many heritable traits are not determined by only 1 gene with 2 alleles Many heritable characters are not even well-modeled with the Mendelian framework of dominant and recessive However, the basic principles of segregation and independent assortment apply even to more complex patterns of inheritance Eye color follows a polygenic inheritance pattern, meaning it is influenced by multiple genes that each have a small additive effect on the final phenotype.  Exceptions to Mendelian Inheritance Dependent Assortment Incomplete Dominance Codominance Epistasis Polygenic Inheritance https://en.wikipedia.org/wiki/Petunia  An example of Dependent Assortment Sickle Cell Disease Mutation Beta-Thalassemia Disease Mutation Dependent Assortment Due to Proximity: Mutations within the same gene they are physically linked by proximity The probability of Crossing Over between these two mutations is extremely low HBB gene length is ~1,600 bp and the Sickle Cell and Beta-Thalassemia mutations are Beta-Globin Gene (HBB) ~20-200 bp away from each other. The requirement for independence is a distance >1-10 million base pairs There are different degrees of dominance Complete dominance occurs when phenotypes of the heterozygote and dominant homozygote are identical All pea plant traits Dark hair, Widows peak Tongue rolling, curly hair Long eyelashes Incomplete dominance the phenotype of the F1 generation is somewhere in between the parental phenotypes In codominance, two dominant alleles affect the phenotype in separate, distinguishable ways Incomplete dominance in the Snap Dragon Incomplete Dominance: Neither allele completely masks the other; instead, they blend to produce a new phenotype. Parental (P) Generation: When a red-flowered plant (CᴿCᴿ) is crossed with a white-flowered plant (CʷCʷ), the F1 generation exhibits an intermediate phenotype. F1 Generation: All offspring (CᴿCʷ) in the F1 generation display a pink flower color. F2 Generation: When F1 plants (CᴿCʷ) are crossed, they produce offspring in a phenotypic ratio of: 1 Red (CᴿCᴿ) 2 Pink (CᴿCʷ) 1 White (CʷCʷ) This 1:2:1 ratio is characteristic of incomplete dominance and contrasts with Mendelian dominance, where dominant and recessive traits would typically appear in a 3:1 ratio.  The cystic fibrosis allele provides a heterozygote advantage to cholera infection C or c – Describes the genotype What will the pedigree look like if or – Describes the phenotype we color by cholera protection? cc CC Cc Cc Cc Cc Cc Cc Cc cc The phenotype is the disease of Cystic Fibrosis The phenotype is protection from Cholera What is the molecular basis of the heterozygote advantage?  The heterozygote advantage comes from dosage of the CFTR channel protein Experiment (from Gabriel et al., 1994) Test CFTR expression in mice with different genotypes: CFTR+/+, CFTR+/−, CFTR−/−. Western blot image shows CFTR protein levels for each genotype. CFTR+/− mice express an intermediate amount of CFTR protein. Mechanism of Heterozygote Advantage Heterozygotes have reduced CFTR protein levels compared to homozygous wild types but still enough to avoid cystic fibrosis symptoms. Reduced CFTR protein levels help prevent severe dehydration from cholera toxin- Do other recessive genetic diseases have a heterozygote advantage? induced water loss through CFTR channels. Gabriel, S. et al. (1994) Science DOI: 10.1126/science.7524148 Sickle Cell Disease is Recessive Sickle Cell Disease Heterozygote has protection from malaria What Sickle Cells actually look like Can you spot the sickle cells? What is the molecular mechanism of protection from malaria?  Molecular mechanism of sickle cell heterozygote allele protection from Malaria One Hypothesis - Enhanced Phagocytosis: Infected B/b or b/b cells are more likely to sickle and be recognized by the immune system. These cells are quickly cleared from the bloodstream by phagocytic cells, reducing the parasite load. https://en.wikipedia.org/wiki/Heterozygote_advantage Codominance There are three main alleles for the ABO blood group: IA, IB, and i. Each of these alleles can produce a specific surface carbohydrate on red blood cells or no carbohydrate at all IA allele: produces the A carbohydrate IB allele: produces the B carbohydrate i allele: doesn’t produce any carbohydrate Genotype IAIA or IAi: have the A phenotype because they have the A carbohydrate. Genotype IBIB or IBi : have the B phenotype, as they produce the B carbohydrate. Genotype IAIB: Codominance-both the A and B carbohydrates are present, resulting in the AB blood group. Genotype i: have the O blood group because no carbohydrate is produced. Codominance in chicken feathers Can you draw out the punnett square of a cross between a black (C BCB) and a white (CWCW) chicken? What is the probability that of getting chicken with speckled feathers?  Epistasis In epistasis, expression of a gene at one locus alters the phenotypic expression of a gene at a second locus For example, in Labrador retrievers and many other mammals, coat color depends on two genes One gene determines the pigment color (with alleles B for black and b for brown) The other gene (with alleles E for color and e for no color) determines whether the pigment will be deposited in the hair How crosses work in epistasis Crossing two dogs with the genotypes BbEe×BbEe Black Labradors (with genotypes BBEE, BbEE, BBEe, or BbEe): have at least one dominant B allele and one dominant E allele Brown Labradors (with genotypes bbEE or bbEe): have two recessive b alleles and at least one dominant E allele Yellow Labradors (with genotypes BBee, Bbee, or bbee): have two recessive e alleles, which block the deposition of any pigment, resulting in a yellow coat regardless of the B gene alleles. The resulting phenotypic ratio is 9 black : 3 brown : 4 yellow. This 9:3:4 ratio is a classic example of recessive epistasis, where the ee genotype masks the expression of the B gene.  Polygenic inheritance Definition: Polygenic inheritance refers to the Height – Influenced by many genes, each with a inheritance of traits that are influenced by multiple small effect, along with nutrition and other genes, often spread across different chromosomes. environmental factors. Eye Color – Determined by multiple genes, Additive Effect: In polygenic traits, each gene resulting in a range of shades and hues. contributes a small, additive effect to the phenotype. Weight – Affected by genetic factors, metabolism, Continuous Variation: Traits with polygenic and lifestyle (diet, activity). inheritance typically display continuous variation, Intelligence – Influenced by numerous genes and resulting in a range of phenotypes (e.g., height, skin environmental factors. color). Blood Pressure – Controlled by various genetic loci Quantitative Traits: Polygenic traits are also known as and lifestyle factors. quantitative traits because they can often be Body Mass Index (BMI) – Shaped by genes related measured along a continuum. to metabolism and fat distribution. Cholesterol Levels – Determined by genes Environment Interaction: Polygenic traits are often regulating cholesterol production and processing. influenced by environmental factors, making them Diabetes Susceptibility – Multiple genes impact multifactorial (e.g., nutrition impacts height). insulin regulation and glucose metabolism.  A model for polygenic inheritance of skin color Melanin Production: Skin color is primarily determined by melanin, a pigment produced by melanocytes in the skin. Key Genes in Melanin Synthesis: MC1R (Melanocortin 1 Receptor): Influences the switch between eumelanin and pheomelanin production. TYR (Tyrosinase): Essential enzyme that catalyzes the first steps of melanin synthesis. SLC24A5: Affect melanin concentration in melanocytes, linked to lighter pigmentation. Polygenic Inheritance: Skin color is determined by multiple genes working together, each with small effects that contribute to a spectrum of pigmentation. Environmental Influence: Sun exposure increases melanin production (tanning), providing protection against UV damage.  Polygenic, epistatic interactions with CFTR gene Normal Airways CFTR protein functions as a chloride and bicarbonate ion transporter, maintaining pH. ATP12A protein functions as a proton pump, exporting hydrogen ions. With functional CFTR, chloride and bicarbonate ions balance the pH. CFTR function is defective, so chloride and bicarbonate ions cannot be export, leading to an acidic mucous layer. The acidic pH causes the mucus to become thick and sticky, increasing the risk of infections ATP12A is epistatic to CFTR: the proton pump continues to transport hydrogen ions, further acidifying the mucous due to the lack of CFTR- mediated bicarbonate export. ATP12A Proton Pump as an Emerging Therapeutic Target in Cystic. Biomolecules. 2023 Sep 27;13(10):1455. doi: 10.3390/biom13101455  CFTR ATP12A cross example ATP12A acts as a modifier gene that impacts the CT Ct cT ct severity of symptoms in individuals with CFTR mutations, rather than determining whether or not CT CCTT CCTt CcTT CcTt the disease occurs. 1. CFTR Gene: 1. C = Normal CFTR allele. Ct CCBt CCtt CcTt Cctt 2. c = Mutated CFTR allele. 2. ATP12A Modifier Gene: 1. T = High-risk ATP12A allele that increases cT CcTT CcTt ccTT ccTt acidity in the airway surface liquid (ASL), worsening CF symptoms. normal 2. t = Normal ATP12A allele that does not ct CcTt Cctt ccTt cctt exacerbate CF symptoms. CF In individuals with CF (cc), the presence of the TT or Tt genotypes will exacerbate symptoms, while tt No CF results in milder symptoms. Severe CF Cystic Fibrosis Modifier Genes Royal Pedigree of Hemophilia Transmission This non-obvious pattern of inheritance raises many questions What explains this pattern of inheritance? How can we predict this outcome? What can be done to help the couples avoid the this fate for their children? How are traits transmitted from parents to offspring? How can we cure genetic diseases? Towards a cure to for Cystic Fibrosis CFTR: New insights into structure and function and implications for modulation by small molecules https://doi.org/10.1016/j.jcf.2019.10.021  However, a substantial number of patients, such as those with class I mutations, including pre- mature termination codons (PTCs) and other variants where CFTR protein is not produced, are not amenable to modulator therapies.  Part 2 Glossary Dominant Allele: An allele that expresses its trait even when only one copy is present in the genotype (e.g., purple flower color in peas). Recessive Allele: An allele that only expresses its trait when two copies are present in the genotype (e.g., white flower color in peas). Genotype: The genetic makeup of an individual, represented by alleles (e.g., AA, Aa, or aa). Homozygous: Having two identical alleles for a particular gene (e.g., AA or aa). Heterozygous: Having two different alleles for a particular gene (e.g., Aa). Mendel’s Law of Segregation: During gamete formation, the two alleles for each gene separate, so each gamete receives only one allele. Mendel’s Law of Independent Assortment: Alleles of different genes assort independently during gamete formation, provided the genes are on different chromosomes or far apart on the same chromosome. Monohybrid Cross: A genetic cross that examines the inheritance of a single trait. Dihybrid Cross: A genetic cross examining the inheritance of two traits simultaneously. Punnett Square: A chart used to predict the genetic outcomes of a cross by showing possible allele combinations. Incomplete Dominance: A genetic situation where the heterozygote shows a phenotype that is intermediate between the two homozygous phenotypes (e.g., pink flowers from red and white parents). Codominance: A genetic scenario where both alleles in a heterozygote are fully expressed, leading to a phenotype that shows both traits (e.g., AB blood type). Polygenic Inheritance: The inheritance pattern of a trait controlled by multiple genes, often resulting in continuous variation (e.g., height, skin color). Epistasis: Interaction between genes where one gene masks or modifies the expression of another gene (e.g., coat color in Labrador retrievers). Pedigree Analysis: A family tree diagram showing inheritance patterns of traits through generations. Carrier: An individual who has one recessive allele for a trait or disorder but does not express it due to the presence of a dominant allele. Genetic Testing: Analysis of DNA to detect specific genes or alleles, often used to assess disease risk. CFTR: A gene associated with cystic fibrosis; certain mutations provide partial protection against cholera. Heterozygote Advantage: A situation where heterozygous individuals have a fitness advantage in certain environments (e.g., sickle cell trait providing resistance to malaria). Crossing Over: A process during meiosis where homologous chromosomes exchange segments, increasing genetic diversity. Synapsis: Pairing of homologous chromosomes during meiosis, allowing for crossing over. Chiasma: The point where two chromatids exchange genetic material during crossing over. Allele Fitness: The contribution of an allele to an organism's reproductive success and survival in a specific environment. Allele fitness can vary depending on environmental factors and selective pressures. Selective Advantage: A genetic advantage that improves an organism's chances of survival and reproduction, often leading to an increased frequen cy of the advantageous allele in the population (e.g., CFTR mutation providing cholera resistance). Hybridization: The process of mating two different varieties or species to produce a hybrid. Mendel used hybridization in his pea plant ex periments by crossing true-breeding plants with contrasting traits. Independent Events: Events that do not influence each other’s outcomes. In genetics, each offspring’s genotype is an independent event, unaffec ted by the genotypes of its siblings. Recombinant Chromosomes: Chromosomes that result from crossing over during meiosis, containing a new combination of alleles from both parents, incre asing genetic diversity. Spontaneous Mutations: Random changes in DNA sequence that occur naturally without external influence, contributing to genetic variation.