Population Genetics PDF

Population Genetics Karen Niederhoffer, BSc, MD, FRCPC, FCCMG Objectives (Where we’re going) By the end of this session students will be able to: 1) List the assumptions of the Hardy-Weinberg principle 2) Explain how violation of Hardy-Weinberg assumptions can impact al...

Population Genetics Karen Niederhoffer, BSc, MD, FRCPC, FCCMG Objectives (Where we’re going) By the end of this session students will be able to: 1) List the assumptions of the Hardy-Weinberg principle 2) Explain how violation of Hardy-Weinberg assumptions can impact allele frequency 3) Calculate genetic risk using Hardy-Weinberg equations 4) Describe how population genetics can be used to understand health issues like hypertension Outline (How we’ll get there) Population Genetics Hardy-Weinberg Principle A little math Tying it all together Images are reproduced and provided under the fair dealing exception in the Canadian Copyright Act. This document is available for your individual use; further distribution may infringe copyright. Background The theoretical Population Genetics The study of the distribution of the alleles/variation in genes in populations and the changes in the distribution of that variation Population Genetics Can be used to determine the health impact of variation and genetic risk at an individual level Allows us to examine the effects of events in the past and to evaluate current challenges, to identify predictors of disease and efficacy of treatments at the population level Hardy-Weinberg principle Hardy-Weinberg principle is the cornerstone of population genetics. It states that: allele and genotype frequencies in a population will remain constant from generation to generation in the absence of evolutionary influences. It can be expressed by the Hardy-Weinberg equations ` p+q=1 p2 +2pq + q2 = 1 How do we derive these equations?? For any particular gene there are different variations of a trait Each variation of the same trait is called an allele How do we derive these equations?? How do we derive these equations?? Let p represent Let q represent p q Therefore, for the entire population: + =1 How do we derive these equations?? Female alleles → A a Male alleles ↓ A AA Aa a Aa aa AA + Aa + aA + aa = 1 If A = p and a = q then… pp + pq + qp + qq = 1 OR… p2 +2pq + q2 = 1 How do we use these equations? Objective: Calculate genetic risk using Hardy-Weinberg equations How do we use these equations?? For trait X there are two alleles C and c. C is dominant to c. If you were able to determine that c was present in 70% of the population, what percent of the population has the C allele? Let p = C and q = c p + 0.7 = 1 Therefore p = 0.3 30% of the population has the C allele! How do we use these equations?? If there are 1000 people in our population, how many are expected to be carriers (Cc)? Since we know that carriers = 2pq And we just established that p = 0.3 and q = 0.7 The number of carriers = 2(0.3)(0.7) = 0.42 *1000 people = 420 people How do we use these equations?? But…we can only see phenotype (traits) …not genotype (alleles) Cystic fibrosis is a recessive condition. The birth prevalence of Cystic fibrosis is 1/2500 people. In the absence of a positive family history, what is the chance you are a carrier? How do we use these equations?? We want to figure out the carrier frequency, that is, the value of 2pq A person who has cystic fibrosis has two recessive alleles. This can be written as q2 We can’t quite calculate 2pq since we don’t know p However, maybe we can figure it out since we know that p= 1-q If q2 = 1/2500 Then q =1/50 = 0.02 Therefore, p = 0.98 And 2pq = 2(0.98)(0.02) = 0.039 ~ 1/25 Thus, where the prevalence of cystic fibrosis is 1/2500, the chance of a person being a carrier is 1/25 How do we use these equations?? John and Betty are carriers for cystic fibrosis. What is their chance of having an affected child? How do we use these equations?? What if we don’t know one individuals’ carrier status? John is known to be a carrier for cystic fibrosis. Betty has not had carrier testing. Prior to completing testing, what would you tell them is their chance to have an affected child? ? Calculating genetic risk What are we actually asking?? [chance dad is a carrier]*[chance dad will pass down the disease allele]*[chance mom is a carrier]*[chance mom will pass down the disease allele] How do we use these equations?? What if we don’t know one individuals’ carrier status? John is known to be a carrier for cystic fibrosis. Betty has not had carrier testing. Prior to completing testing, what would you tell them is their chance to have an affected child? ? How do we use these equations?? What if we don’t know either individuals’ carrier status? John has a brother with cystic fibrosis. Neither John or Betty have had carrier testing. Prior to completing testing, what would you tell them is their chance to have an affected child? Hardy-Weinberg Assumptions Objectives: List the assumptions of the Hardy-Weinberg principle Explain how violation of Hardy-Weinberg assumptions can impact allele frequency  Hardy-Weinberg principle Hardy-Weinberg principle is the cornerstone of population genetics. It states that: allele and genotype frequencies in a population will remain constant from generation to generation in the absence of evolutionary influences. It can be expressed by the Hardy-Weinberg equations ` p+q=1 Allele p2 +2pq + q2 = 1 Genotype/ Phenotype A population is said to be in Hardy-Weinberg equilibrium if alleles show a random distribution or remain the same from generation to generation.  Assumptions Hardy-Weinberg makes 5 BIG assumptions: ✓Random mating ✓No mutation ✓No selection ✓Large populations ✓No migration If these assumptions are adhered to, the relative frequency of individuals who carry any particular allele at a locus will remain constant in a population. Violation of assumptions - Non-random mating H-W Assumption: everyone contributes their alleles equally Violation: some individuals contribute their alleles more than others in a given population. Therefore their alleles will be overrepresented in the next generation Violation of assumptions – New mutation H-W assumption: alleles remain constant in a population, just the combinations change Violation: sometimes a new mutation occurs which can introduce new alleles or proportion of alleles into the population. Violation of assumptions – Selection H-W assumption: all alleles have equal fitness Violation: traits are more or less advantageous relative to each other and therefore individuals who have the more advantageous allele are more likely to survive/reproduce and contribute their allele to the population whereas those with less advantageous alleles are less likely to survive/reproduce Violation of assumptions – Genetic drift H-W assumption: alleles in one generation are equivalent to the proportion seen in subsequent generations Violation: genetic drift can occur when a large population undergoes an event that results in a new population that may not be representative of the original population. Examples include bottleneck effect and founder effect. Violation of assumptions – Migration H-W assumption: no alleles enter or leave population Violation: people moving in and out of population introduce or take out alleles from the population, changing the relative frequencies So what’s the point? If our population deviates from our idealized calculation, then we know an evolutionary force is at work What does knowledge of population genetics mean practically? The good and the bad Population Screening and Testing – the good Conditions can occur in any population, however often more common in specific ethnic groups Allows health care providers to identify populations at risk Can guide increase level of suspicion for a specific diagnosis Founder effect  Selective advantage The heterozygous advantage – the heterozygous genotype has a higher overall fitness compared to the homozygous dominant or recessive genotype Examples: Malaria and Sickle Cell Cystic fibrosis and cholera Piel et al., 2010. Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis Population Screening and Testing – the bad Impacts our interpretation of a “negative” test Grody et al., 2001. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening How does this tie into Hypertension (or other complex traits)?? Objective Describe how population genetics can be used to understand health issues like hypertension Thank you to Dr. Sherry Taylor Monogenic vs Polygenic Traits Monogenic vs Polygenic Traits Fig 1 - Heat map and extended pedigree showing the conceptual relationship among de novo mutations leading to disease (red), recent mutations with moderate effects arising within a clan (yellow and green), and older common variants with small effects segregating in the population (blue). An individual’s genetic disease risk emerges from the collection of variants he or she has inherited from both parental lineages of distant ancestors (typically common and of individually small effect), more recent ancestors (rare, but potentially larger effect), and de Cell. 2011 Sep 30;147(1):32-43. novo mutations. Clan genomics and the complex architecture of human disease. Lupski JR, Belmont JW, Boerwinkle E, Gibbs RA. Modes of Natural Selection at the Genome Level Katherine J Siddle, Lluis Quintana-Murci The Red Queen's long race: human adaptation to pathogen pressure Current Opinion in Genetics & Development, Volume 29, 2014, 31–38 http://dx.doi.org/10.1016/j.gde.2014.07.004 THEME OF THE WEEK: HYPERTENSION! (Don’t Panic!) Hypertension, aside from a few inherited forms is the classic polygenic disorder Large number of loci with VERY small effects on blood pressure Large influence of lifestyle on genetic traits. Lifestyle interventions can have a large impact on biology. The larger these peaks, the more lifestyle, environmental and phenotypic traits link with and influence the effect of that locus SNPs identified through GWAS as being associated with blood pressure explain approximately 27% of the 30– 50% estimated heritability of the blood pressure phenotype. Effect sizes are small 0.5 to 1mm Hg. Padmanabhan S, Dominiczak AF. Genomics of hypertension: the road to precision medicine. Nat Rev Cardiol. 2021 Apr;18(4):235-250. doi: 10.1038/s41569-020-00466-4. Epub 2020 Nov 20. *See notes for this slide for the description PMID: 33219353. Take home messages I guess Square One was right…you do need at least a little math H-W is a model to understand populations, but in reality assumptions are really unlikely to be met and therefore used more theoretically or to calculate “ideal” state questions And I actually use this in the clinic! Traits are often polygenic and therefore much more messy https://www.youtube.com/watch?v=WhFKPaRnTdQ