Mendelian Genetics Lecture Notes

LECTURE 2 Mendelian Genetics is Eukaryotic Genetics Inheritance has 2 separate components: 1. How do genes get passed from parents to offspring? 2. Given those genes in the offspring, what traits do we observe? Mendelian Gene = locus that occurs as multiple different alleles - Geneticist...

LECTURE 2 Mendelian Genetics is Eukaryotic Genetics Inheritance has 2 separate components: 1. How do genes get passed from parents to offspring? 2. Given those genes in the offspring, what traits do we observe? Mendelian Gene = locus that occurs as multiple different alleles - Geneticists study genetic variation Mendel’s Model - P Locus consists of 2 alleles: P and p - 3 Genotypes: PP, Pp, pp - Two phenotypes: purple and white Mendel inferred genetics from experimental data and studied pea plants 1. Used scissors to cut the stamens of plants, leaving only carpels, then transferred the stamens to other plants using a paintbrush 2. The sperm contained inside pollen grains stuck electrostatically to the paintbrush 3. Collected pea plants that had different phenotypes and then let them self-fertilize a. Round lines of pea plants always produced more round peas b. Wrinkled ones always made wrinkles c. Plants would breed true: offspring always look like the parents 4. Then he hybridized round and wrinkled peas = HYBRIDS a. Round made gametes for round, wrinkled for wrinkled b. Fertilization (syngamy: when 2 gametes come together to make new individuals) occurred = and only round peas were produced; roundedness was dominant c. F1 (only round) → F2 (both round and wrinkled) Mendelian ratios: 3:1 (¾ and ¼) ratio for all offspring - 75% F1 trait, 25% other parental trait Mendelian genes vary Locus: place in the genome where two alternate versions of the gene are found - Contains 2 alternates of a gene - Each sperm or egg gets one of those via coin toss (randomness) - The traits shown by each individual depend on the pair of gene copies inherited Phenotypes’ alleles need to be known for experimental procedures to be initiated The amount of enzyme can be nonlinearly related to the phenotype, and the nonlinearity results 1. Dominance: most typical situation, where one version of an allele is a dead version of the gene a. Gene → enzyme → branced starch → water retention → round pea b. Transposon-like insertion: r-allele stuck itself on the big R  c. A little bit of branched starch is enough to cause water retention and make a round pea - DOMINANT - a sigmoidal curve observed 2. Additivity: ordinary genetic variation is usually additive, with each additional allele adding a fixed amount a. Phenotype can be described as a baseline of the sum of the alleles b. Usually, for the alleles that alter phenotype only slightly c. Incomplete, partial dominance d. Over/under dominance: when heterozygotes have more or less dominance than the homozygotes Sickle cell anemia: the most common Mendelian disease - Single base mutation where GAG (Glu) → GTG (Val) at position 6, causing blood cells to be sickle-shaped and transport less oxygen than their original capacity - Homozygous recessive disease: Two recessive copies of the allele are needed for it to occur in a patient - Heterozygosity protects children against malaria infections, but they are not sick because one allele increases protection against malaria, but is not enough to make the patient have the symptoms of sickle cell disease Codominance: each allele has a separate, discernible phenotypic effect - Example: AB blood type LECTURE 3 Sex generates new genetic combinations Meiosis and fertilization generate enormous diversity very efficiently Crossing over: parts of the genes are exchanged, leading to many more segments of the genome to be segregated, creating more diversity Gametic sex 1. Isogamy: same-sized gametes 2. Anisogamy: different-sized gametes Hermaphrodites can be self-fertile or self-incompatible Haplodiploid sex determination - Males: haploid - Females: diploid - Nonreproductives: can be either Sex determination: some cue → developmental biology → sperm, eggs, both, neither - Cue: can be the temperature, presence of an individual, making one class of gametes, genes Sex chromosomes: 1. XY: XX females, XY males (XY = heterogametic, XX = homogametic) 2. ZW: ZW females, ZZ males 3. X0: XX females, X males 4. Z0: Z females, ZZ males  5. UV: U females, V males Chromosomal sex determination systems: chromosomes affect traits by chemistry, not essence 1. If there is a Y chromosome = male characteristics are observed 2. If there is no Y chromosome = female characteristics are observed 3. Transgenic mice: where XX females were developed into males with the addition of the SRY gene SRY locus: sex-determining region on the Y, eventually identified at a molecular level, which is a transcription factor. It initiates the developmental cascade of sex determination through the making of the SRY protein Spectra of sexual phenotype: 1. Chromosomes variation → gonadal sex → phenotypic sex spectrum 2. Intersex individuals: not phenotypically concordant with the spectrum a. Women who are XY who lack the receptor to recognize testosterone b. They exhibit female characteristics but internal testes due to he androgen receptor alleles c. They don’t menstruate Initial cues from the environment or from genes can influence the trajectory along which an individual differentiates sexually - For a lot of organisms, the initial cue is chromosomal - Comes from the Y chromosome Autosomes: autosomal inheritance, where a gene resides in autosomal chromosomes Sex linkage: genetics of genes on sex chromosomes 1. Heterogametic: different kinds of sex chromosomes 2. Homogametic: same kind of sex chromosomes Sex linkage is about genes that are found on the sex chromosomes, not about sex-specific traits Sexual dimorphism: differences in the anatomy of the sexes (e.g., size) Sex-specific chromosomal usually carry only a few genes Y-linkage: genes for about 25 distinct proteins on the human Y chromosome 1. SRY proteins are required for sperm development, and components of the seminal fluid 2. Only one known Y-linked condition is not related to male fertility  a. Deafness in a particular Chinese family: Y-linked condition where the mutation that causes deafness that translocated to the Y gene but is usually found on autosomes X-linkage: more than a thousand genes on the X chromosome in humans, traits that aren’t related to sex are influenced by sex-linked genes 1. Each parent has 2 copies of each gene and contributes one, at random, to each offspring 2. Additional genes on the X chromosome are found 3. Hemizygous: only one allele from the mother (Xr) will mask “r”, and the phenotype will be as if they were homozygous Extranuclear inheritance: bits of DNA that are transmitted through cytoplasm and that aren’t part of the chromosome in the nucleus - All eukaryotes have a variety of organelles that contain DNA bits that arose through endosymbiosis in an ancestral eukaryote - Mitochondria arose originally from a free-living bacterium that entered into a symbiotic relationship with an ancestral eukaryotic cell - Chloroplasts, similar to this process - Apicoplasts: organelles inside unicellular parasites (like malaria) that retain part of the bacterial chromosome that was originally present in the endosymbiont Organelle genomes are transmitted exclusively from one parent - Mitochondrial: passed only along the maternal lineage - Y-chromosome: passed along paternal lineage - Exception: mussels have “double uniparental mitochondrial inheritance” where two kinds of mitochondria are present in every cell, one type is only transmitted by males, the other only by females Heteroplasmy: multiple mitochondrial genotypes within a single cell Independent segregation: alleles at multiple genes, 2 different loci behaving the same way, independent loci behave independently to affect unrelated traits - creation of diversity in reproduction - There can be more than two alleles at a locus Number of gamete types produced = (# of homologous chromosome pairs)^2 - 64 heterozygous chromosomes = 32 homologous pairs = 32^2 gametes produced Polyembryonic wasps: males are haploid, females are diploid, non-reproductively can be either, but haplo-diploid sex determination takes place in these species Pedigree analysis: Mendelian genetics in families can be analyzed through Pedigrees Mendelian traits: - 2 phenotypic classes - 1 locus - Dominance occurs - Most heritable traits do not exhibit these features - The usual contexts for Mendelian traits are rare disease, domesticated plants and animals, and experimental genetics in model organisms Alkaptonuria: the first Mendelian disease (urine → black when in contact with air) Huntington’s disease: autosomal dominant Consanguineous mating: mating between relatives (incest) - Prediction of the source of effect, mating can bring single alleles from ancestors to create affected offspring - More likely for recessive and rare alleles to come together and be present in both parents - Increases the likelihood of inherited recessive diseases being observed Working through Pedigree problems: 1. Write genotype:phenotype key 2. Mark unambiguous genotypes 3. Check for impossible genotypes 4. Reject impossibilities LECTURE 4 The 2 facets of genetics: 1. Understanding the facts of inheritance 2. A tool for revealing molecular biology The genetic screen: a tool for revealing molecular biology Mitosis makes genetically identical cells Homologous chromosomes act independently during mitosis Meiosis makes genetically unique cells 1. Cohesins hold the sister chromatids together 2. Spo11 cuts chromatids 3. The synaptonemal complex forms 4. The DNA Repair connects the cut-up chromatids and forms CHIASMA (the DNA connection holding the homologs together, visible by microscopy) 5. The newly joined DNA molecules now hold things together 6. Recombined homologs segregate at anaphase I: release of sister chromatid cohesin Linkage mapping: Use crossover frequency to position loci along a chromosome - Drosophila is used as a model for genetic experiments Not many common Mendelian traits in humans - The linkage between the genes for color-blindedness and hemophilia in men is an example of this Co-segregation of a trait and a site in the genome Molecular markers: alleles of DNA - A mutation leading to polymorphism within a population Polymorphism: any site in a genome that carries a mutation/genetic variation Single Nucleotide Polymorphism (SNP): variations in a single DNA base pair where different versions/mutations occur within populations - Important for studying genetic links and how the evolution of disease/transmission works Insertion/Deletion Polymorphism Indel  - Insertion: addition of a base pair(s) - Deletion: removal of a base pair(s) - Indel of a single base pair makes more of a change than 3 being changed, since the codon being coded might be changed and a different amino acid might be encoded within the genome, causing diseases or more variations within the population Short Tandem Repeats (STR): highly variable sequences in the genome that are unique for every individual, used as patterns for database searches and forensic science 1. Sample 2. PCR 3. Electrophoresis 4. CODIS profile (Combined DNA Index System) DNA polymerase III can have a high mutation rate due to the wrongly paired/flawed base pair sequences - For a single locus, the constant effect of each additional allele's additivity depends on the other allele at that locus - If double loci containing a suppressor allele (a dominant suppressor that wouldn’t allow a worm to roll, for example, showing epistasis) are not related to additivity Taxonomy of genetic variants: 1. SNPs: single nucleotide polymorphism (the simplest, most basic type of variation in populations where only a single base is changed) 2. Indels: insertions and deletions that could have neutral or detrimental effects depending on what/how many/which bases are inserted or deleted 3. STRs: short tandem repeats used for forensics due to high variability LECTURE 5 Morgan’s genetic notation: - “+” is used to represent wild type, the form typical in nature, genes are named for the mutant phenotype - Differentiated WT strands that carry Mendelian mutations are often generated via mutagenizing the wild type with chemicals or radiation Recombination frequency: (number of recombinant offspring)/(number of total offspring) - Distance between loci, measured with the unit cM = centiMorgans - 1% recombination frequency is one centiMorgan - If loci are farther apart, more room for crossovers and recombination is available; if closer, then less room is available and less recombination occurs If genetic maps are arranged differently, then very different predictions about phenotypes can be made: geneticists use genetic maps to experiment with the distances + different observations to find accurate representations for Epistasis Epistasis: genes are transmitted as described by Mendel, with complications due to linkage and extranuclear inheritance  - Transmission of phenotypes from one generation to the next requires a mapping of genotypes to phenotypes Phenotype = f(genotype) 1. Dominance: sigmoidal curve 2. Partial dominance: the Rr phenotype is intermediate between rr and RR 3. Additivity: linear graph Traits are often affected by variation at multiple genes 1. 1 locus = monogenic 2. 2 loci = digenic 3. Several loci = oligogenic 4. Lots of loci = polygenic Genetics is a function of the loci that vary - Variants influence phenotype - Genotype variation and phenotype are correlated Example: mouse color is affected by recessive mutations in the agouti and mc1r genes (autosomal and unlinked genes) - [(Mc1r / +) / (agouti / +)] / [(mc1r / +) / (agouti / +)] - Form two parental and two recombinant for each For a single locus: 1. Constant effect of each additional allele = additivity 2. The effect of an allele depends on the other allele at that locus = dominance For multiple loci 1. The effect of genotype at each locus is constant = additive 2. The effect of genotype at one locus depends on genotype at other loci = epistasis Epistasis: when the effect of one mutation depends on the genotype of another locus: - Example: one functional copy of either gene is sufficient for wild-type movement - Locus depends on genotype at other loci - Even though rol/rol is present, the fact that col-182N/col-182N is present makes the phenotype not roll Polygenic traits are affected by a large number of loci, and these traits have diverse distributions 1. Discrete: yes or no situation, no intermediate scenarios can happen (e.g., wrinkled or round pea shape) 2. Continuous: infinite number of increments/gradations (e.g., length, height, weight) 3. Meristic (counts): only integer values and no decimal or in-between values (e.g., number of scales on a fish) Ronald Fisher: developer of a mathematical model explaining how Mendelian inheritance of alleles can explain continuous variation, but was a eugenist and used it for destructive and unethical purposes/experiments Additivity and its effect on phenotype: 1. There is a fixed difference between the extreme phenotypes 2. As more loci are added, the phenotypes of each locus start to have a smaller effect  3. Extremes become rarer with more numbers of loci; the distribution of the phenotypes starts to take a normal-shaped distribution, with individuals having near-average phenotypes more frequently than diverse ones The Central Limit Theorem: the sum of a large number of random numbers follows a normal distribution 1. The basis model for polygenic traits 2. Polygenic traits are affected by large numbers of loci 3. Even in discrete traits, underlying genetics play a role a. The species that passes a certain threshold possesses certain traits b. Underlying genetics determine if the species will surpass a threshold Quantitative Trait Loci (QTL): a locus that affects a quantitative trait Quantitative traits don’t show clean ratios in F2 generations, so a different mapping method is needed for display 1. Example: phenotypic differences in behavior, physiology, and neurochemistry between rats selected for tameness and for defensive aggression towards humans a. F1 generation showed extremes of tameness and aggression b. F2 generation showed intermediates and more diverse phenotype results 2. Example: wild-type benthic fish vs. WT/Eda transgene benthic a. Measured body angle b. Eda benthic fish have a significantly more marine-like body angle than wild-type Test statistic: evidence for a correlation between genotype and phenotype Pleiotropy: alleles at a single locus affect multiple traits Molecular genotyping: test for linkage at each position along the genome - Variation: an indicator that no one locus is going to be definitive for the traits (QTL) - Clear correlation: Use the test statistic to test what type of correlation is present Independent evolutionary events cause/force adaptations of species - Example: armored plates of lake fish are absent when they are in lakes, but when they are mixed into the seawater, armored plates occur - Genetic mapping explains this - Linkage group positions (cM), effects on locus, and phenotypes of armored plates presence relate to this genotype - Connection to behavior: when tested with the transgenic Eda gene, better schooling was observed - shows that the genetic variant affected two traits of armored plates and angling of the fish at once (multiple traits) LECTURE 6 Pseudogene: when a mutation in one gene reflects the activity of another gene, whether or not a gene depends on the environment Genes are physical objects, not raw information Anything that interacts with gene phenotypes Some cue → developmental biology → sperm, eggs, both, or neither - Cue: temperature, presence of an individual that makes one class of gametic genes  - Nongenetic disturbances that affect phenotypes are the basis of medicine Johannsen’s beans: random environmental variation 1. Showed a group of beans measured true 2. Passed many generations so that they were completely homozygous a. According to Mendelian principles, there should be no genetic variation 3. But when he planted them, he observed that some beans of a certain inbred line were big while some of them were small 4. Achieved a distribution of the phenotypes 5. Concluded that in the absence of genetic variation, environmental variation can cause phenotypic variation Normal distribution = central limit theorem - Very large amounts of environmental variations that are small can add up to bigger ranges of variation - Random environmental factors aren’t transmitted from generation to generation, but they contribute to the overall normal distribution of phenotypes Systeatic environmental variation: genetically identical beans planted in areas of different water amounts with no genetic variation but with environmental variation - SEV adds systematic phenotypic variation - SEV difference shifts to the mean, where they contribute to the phenotype - These systematic differences could be shared between offspring and parents - If there are systematic differences in phenotype due to shared environmental influence, then certain things will appear to be inherited similarly between parents and offspring - Human genetics: difficult to study because the way people grow up is environmentally correlated with the parents and offspring - Even if genetically identical, a systematic change in the environment could lead to a systematic phenotypic change - If lots of genotype experiences a systematic shift in their environment, then their phenotype is affected by the additive effect of the environment - The phenotype as a function of environment is a genotype’s “reaction norm.” - This means that the effect of the environment is different depending on the genotype Clausen, Keck, and Hiesey grew subspecies of a particular plant at a low elevation site in California and were able to control the systematic environmental variation, only focusing on genetic variation (COMMON GARDEN EXPERIMENT) - Found that plants native to that elevation grew better than the other subspecies - A change in environment can have a very different effect depending on genotype - Much of the time, there’s no single best genotype for all conditions, and different genotypes are adapted to different environments Common garden experiment: where species are grown in controlled and identical environments with no external variation, allows for the analysis of only genetic variation Genotype → phenotype: inheritance has two separate components:  1. How do genes get passed down from parents to offspring? 2. Given those genes in the offspring, what traits do we observe? Mendelian trait: monogenic, dominant, discrete Environmental differences cause phenotypic differences even if the genotype is the same - Example: Johannsen’s beans’ weight according to the amount of rain Genotype-Environment Interactions The Linear Model: phenotype = average + genotype + systematic environment + gen- environment interaction + specific environment - These are all statistical effects: the average differences among groups of individuals in a population - y = intercept + (allele * allele dosage) + random # of normal distribution - y = a + bx + epsilon - Regression: line minimizing the squared deviations around those deviations later has one variation, which is what’s left over after we account for the average (RESIDUAL) - Residual: a way to partition the total phenotype variation into independent components that are part due to genetic variation and part due to environmental variation (FISHER) Variance: average squared deviation from the mean - Var (y) = [(sum of y-y)^2] / # of y - Showed that you can extract values by different transformations of the slope Heritability: the proportion of total phenotypic variance due to genetic variance - Ranges from 0 to 1 - Heritability = Vg/Vp = Vg / (Vg + Ve) - Environmental variance (Ve): phenotypic variance among genetically identical individuals - Genetic variance (Vg): variance among genotypes - Vg + Ve = Vp (phenotypic variance) - Total phenotypic variance: average squared deviation from the mean phenotype (this only works if genotype and environment are NOT correlated) Broad-sense heritability: used in experimental genetics, mainly, where we measure environmental variation clearly: a large number of identical individuals Narrow-sense heritability: only concerned with the fraction of genetic effects that will be transmitted to offspring in a way that makes a predictable relationship between the parents and the offspring  - Additive locus: equal contribution - Dominant locus: regression doesn’t go through the means - Narrow-sense: only concerned about the additive aspect Broad: best for genetic prediction - evidence that the trait is affected by genetic variation Narrow: best for genetic predictions about offspring phenotypes Galton: eugenics and determinism - Determinism: the idea that our traits are determined by genes and therefore are fixed and invariant and beyond our control (nature over nurture) - The US was the center of the eugenics movement - American eugenicists advocated sterilization LECTURE 7 Weismann’s mice experiment hypothesized that germline transmission explains hereditary and inherited mutations - Sometimes, mutations will be inherited - No mutations were inherited in 5 generations of mice - The data are consistent with the hypothesis Null hypothesis: a simple model that makes explicit, quantitative predictions, assigning probabilities to all outcomes The p-value: the probability of observing a result as different from our expectation as the one we actually observed, if the null hypothesis is true - NOT the probability that the hypothesis is true or false - It is already assumed to be true - Is the probability of data, GIVEN THE HYPOTHESIS - How far from the expected results (hypothesis) is the observed result? - Measure distance in terms of a standardized difference from the expected counts: the chi-square test statistic Chi-square test: difference between the observations and expectations, measures distance in terms of standardized difference from the expected counts - If the null hypothesis is true, the values for X^2 come from a probability distribution, the shape of the chi-squared distribution depends on the number of independent classes of observation (degrees of freedom) - Degrees of freedom: (# of variables - 1) Example: if the p-value is 0.239, data this far from the null hypothesis would occur 23.9% of the time if the null hypothesis were true Test for goodness of fit: 1. How far from the expected results are the observed results? 2. What is the probability of being so far from the expectation if the null hypothesis is true? LECTURE 8 Populations are diverse Mutations create diversity - Sometimes, mutations occur because radiation damages DNA in a way that it gets repaired with the introduction of a new mutation at a site 1. Radiation released from a reactor (e.g., Chernobyl) 2. UV radiation (sunlight) 3. Caused by chemical mechanisms (smoking) In Rockman Lab’s study (Tintori et al.), no evidence for an association between radiation level and mutation rate was found, P = 0.187 - 0.187 > 0.05 = results are not statistically significant) - Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident Biomedical research has been funded by the US Government We can describe populations with frequencies - Divide the recorded value by the total number of variables to arrive at the frequency value Allele frequency: (2*number of individuals with that genotype) / (2*total number of individuals) Random mating: randomly sample a sperm, and randomly sample an egg - Multiple probabilities of the independent events 1. pAA = p^2 2. pAT = 2pq 3. pTT = q^2 Hardy-Weinberg Equilibrium (HWE): After 1 generation of random mating, genotype frequencies reach a stable equilibrium defined by the allele frequencies - Random and non-alphabetical letter arrangement of the acronym HWE = random mating equilibrium of genotype frequencies Equilibrium is different under constant non-random mating 1. Self-fertilization 2. Inbreeding 3. Assortative mating 4. Population structure Things affecting allele frequencies to change: 1. Changes to the pattern of random or non-random mating 2. Mutation 3. Selection: natural or artificial selection, where alleles that increase the rate of population reproduction are factored and they tend to increase in frequency while the weaker alleles slowly get reduced in number (NON RANDOM) 4. Genetic drift: leads to the most rapid loss of variation through RANDOM events, certain alleles are completely wiped out due to events that happen by chance, reducing overall allele frequencies due to the survival of particular, RANDOM alleles Frequencies change due to random sampling, and bigger samples experience smaller frequency changes - Genetic drift will lead to the most rapid loss of variation in the population with the smallest size - If there are fewer individuals, then a single change affects frequencies more because your denominator of individuals when you’re dividing to solve for frequency is now a smaller value, therefore a bigger change in frequency if the population is smaller - Random sampling causes changes in frequencies Genetic drift results in the loss of variation: - Genetic drift is a RANDOM PROCESS where a RANDOM event causes the genetic pool to be affected significantly - It is driven by chance, and no single allele is favored over another - These fluctuations can cause certain alleles to be randomly eliminated, resulting in a decrease of variation and loss of certain alleles, which causes less genetic diversity Individuals have related ancestors, and their ancestors occur more than once in the pedigree Probability distribution: the area under all the bars in a graph Bottleneck effect: When population sizes are significantly reduced in a short period of time, this can happen easily in large populations if something sudden happens that only a few of the alleles are sampled from one generation to the next - Characterize species that face pressure from humans - The surviving population only reproduces within itself, causing little genetic variation and diversity - Reduction in allele frequencies and genetic diversity within the population Founder Effect: If a population founds a new population/land by sending out a small number of migrants, this reduces genetic diversity - New populations founded by successive migration events that involve relatively small numbers of individuals breed within themselves, favoring only a small number of alleles - This reduced diversity in the genetic pool and reduced allele frequencies - Human populations experienced the Founder Effect LECTURE 9 We’re barely related to most of our relatives We inherit no DNA from most of our ancestors Genetic mapping in populations is done by: 1. Linkage mapping in experimentally tractable organisms 2. Linkage mapping in Pedigrees 3. Association mapping in populations Test for an association with phenotype - Null hypothesis: SNP genotype is unrelated to phenotype, allele effect = 0 - If P=0.2, since 0.2 > 0.05, the data isn’t statistically significant, and we cannot reject the null hypothesis - So, the data are not improbable if the null hypothesis is true  - This does not mean that the null hypothesis has a 20% chance of being true Linkage Disequilibrium: the non-independence of loci in real populations - If we know the genotype at one position, we can predict it at another location with great accuracy - When a correlation between genotype and phenotype is observed, we don’t know if that is due to the locus that we have measured that is causing the phenotype - Genotypes at nearby loci tend to be correlated - Linkage disequilibrium makes each observed locus informative about nearby, unobserved loci - Region 1 is NOT independent, therefore exhibits LINKAGE DISEQUILIBRIUM Genome-wide Association Studies (GWAS): each point is one genotyped SNP, each spike includes SNPs that are in linkage disequilibrium with one another and with the causal variant - Manhattan plot: each point represents one variant that’s been genotyped, and it’s plotted according to its position on the x-axis - X-axis: position in the genome - Y-axis: -log(p-value) - Thresholds for significance in GWAS: typically a threshold of 0.05 divided by the number of tests - With one million markers, that is a threshold of p = 5*10^-8, or (-log(p)) = 7.3  - Answer: partial dominance - because if it was overdominance, the middle point would be the peak. GWAS point to molecular causes of trait variation (how strongly each SNP in linkage disequilibrium with the most significant SNPs are: 1. Associated loci have very small effects 2. Linkage disequilibrium makes it difficult to know causal variants a. CRISPR can’t be applied to polygenic traits 3. Most heritability is due to huge numbers of variants with effects too small to detect in GWAS 4. Most variants that affect phenotypes are noncoding regulatory variants that act by influencing mRNA levels Polygenic score: allele effect * allele dose across all associated loci - (genotype at locus 1 * effect of locus 1)+(genotype at locus 2 * effect of locus 2)... - The sum of allelic effect cikkected frim GWAS analysis allows to predict how phenotypic traits will occur in individuals - Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations - Allelic effects are estimated from specific populatons - Populations have slightly different allele frequencies at many loci - Populations have Genotype-Environment Correlations Genotype doesn’t cause phenotype, no causal variance but little population variation that creates illusion of false correlation is due to difference in phenotype due to environmental conditions