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The Genetics of Complex Traits: What Are the Implications for Education? Michael J. Dougherty Director of Education, ASHG [email protected] NCHPEG Meeting, September 23, 2009 How are U.S. students doing in science and math? TIMSS, 2008 General trend in U.S. science achievement from fourth to twelfth grade is downward. “. . . there is actually a steady decline, not a sudden drop, in performance as students progress through school . . .” American Institutes for Research, 2007 How does genetics education fare in America? TABLE 1 NAEP test results in 2000 for science reveal a deficit in student understanding of core genetics concepts (O’Sullivan et al. 2003) Theme Classification Theory of evolution Reproduction Evolutionary relationships Darwin’s theory of evolution Genes* Mutation* Interpreting genetic material* Genetic disease* Recombinant DNA usage* Grade Students with complete/essential answers (%) Students with partial answer (%) Students with unsatisfactory answer (%) 8 8 12 12 12 12 12 12 12 12 23 53 61 25 51 21 2 1 5 8 16 NA NA NA NA 45 33 1 31 27 58 45 39 70 47 30 58 83 56 58 Percentages may not total to 100 due to rounding and student omission (i.e., no answer was given). *These questions are in the molecular and human genetics category. Prevalence of misconceptions by genetics topic 500 essays chosen at random (20% of total submitted); systematically reviewed for misconceptions. From Shaw, et al, Genetics 178: 1157, 2008. 55.6% had one misconception 20.2% had two or more Percent Percent of Misconceptions in Sample by Topic 25 20 15 14 17.2 12.8 12.8 10 5 0 Patterns of Inheritance Deterministic Nature of Genes Genetic Technology Nature of Genes & Genetic Materials Topic 8.4 8.2 7 Genetic Basis of Disease Genetics Research Reproductive Technology What does recent research indicate about single-gene disorders and what do we teach? Phenylketonuria (PKU) Mutations in phenylalanine hydroxylase gene (PAH) can cause phenylketonuria. Autosomal recessive. -Phenotypically there are at least four clinical phenotypes: classic PKU, moderate, mild, mild hyperphenylalaninemia Israeli study, n=180, Bercovich et al, J. Hum. Genet., 2008 - Only 63% of metabolic phenotypes could be predicted from exonic mutations. - Phenotypic inconsistencies existed when PAH had more than one mutation. Ataxia telangiectasia Autosomal recessive; ATM; rare neurodegenerative disorder (Smirnov and Cheung, Am J Hum Genet, 2008) Recessive expression Carriers resemble noncarriers. Dominant expression Carriers resemble AT patients. i.e., ATM genotype is associated with the differential expression of other genes. Why is this complexity important? May help explain why: - ATM mutations are susceptibility alleles for breast cancer. - Carriers have increased risk of heart disease (pleiotropy or polygeny?). - Heterozygous ATM mice have increased risk of cancer and metabolic syndrome. How common is this variation in “monogenic trait” phenotype likely to be? CF- carriers have increased risk of asthma; 1500 mutations; variable symptom severity. Gaucher- tremendous symptom variation in patients; carriers have increased risk of parkinsonism. FFI and CJD- (autosomal dominant) second-site mutations in PRNP were thought to be determinative of phenotype; however, variation in pathology and clinical manifestation implicate other factors. Do we teach single-gene traits and disorders in all their complexity? What is the most common tool used to teach genetics? From http://anthro.palomar.edu/mendel/mendel_2.htm Should this be the first and most common heuristic we use with our students? “If everyone on both sides of your family is tall, you are going to be tall. If half are tall and half are short, you have a 50/50 chance of being either tall or short. You also have the possibility of ending up somewhere in the middle.” If monogenic disease shows such complexity, how should we think about hypertension, diabetes, weight? Consider the difference in phenotype distribution between single-gene and complex traits. What causes such a distribution? Genes + Environment Are such traits common? Establishing population references for blood glucose and lipids (Bismenya, et al Afr Health Sci. 2006 December; 6(4): 247–253) Study: 183 university students Blood samples analyzed Results: Near-Gaussian distributions for glucose, total cholesterol, HDL, and LDL What do these results suggest about the underlying genetics and how can we study such traits? Genome-wide association study (or GWAS) Compare phenotypic “cases” to “controls” by comparing genetic differences at many different loci called SNPs. - Essentially a hypothesis generation technique made possible by highthroughput sequencing technology and massive computing power. Principle of a DNA microarray (from Carr et al, Comp. Biochem. Physiol., 2008) http://www.mun.ca/biology/scarr/DNA_Chips.html What are SNPs? Single-nucleotide polymorphisms GWA study of height (Weedon et al, Nature Genetics, 2008) Red dots represent SNPs with P < 5 x 10-7 in stage 1 and 2 analysis. What important educational messages are emerging from GWA studies? In Weedon study: - GWAS and genotyping on 30,000 individuals led to 20 variants associated with height. -Together, the 20 SNPs explain 3% of height variation. 6% 6% ≤ 17 “tall” alleles 6% ≤ 17 “tall” alleles 5 cm ≥ 27 “tall” alleles 6% ≥ 27 “tall” alleles As of mid-2008, there were a total of 54 “validated” SNP variants for height (Visscher). Implicated genes: signaling, ECM, cancer. What effect would learning through these examples have on students’ understanding of patterns of inheritance and the nature of genes? How might genetics principles related to complex traits contribute to a more informed public and better health care? Genetic variation and common disease (Adeyemo and Rotimi, Public Health Genomics, 2009): Used GWAS to investigate loci showing strong and consistent association with several common diseases. - Studied 11 populations; estimated allele freq. using HapMap data Conclusions: a) wide variation in allele frequencies across populations, up to 40-fold b) FST, a measure of population differentiation due to drift, varied widely for the susceptibility loci: 0.12- HapMap autosomal avg. (0 would mean no genetic substructure, random mating, etc) 0.019 - .201 for type 2 diabetes 0.022 - .520 for prostate cancer Health risk estimated from any “of these risk alleles is likely to show wide variation across populations simply as a function of its frequency, and this risk difference may be amplified by gene-gene and geneenvironment interactions.” How are the results of GWAS likely to be most useful? If we focus on genetics alone, can we explain continuous distributions? Will students understand this message? The environment is, of course, crucial to complex trait expression, as it is for single-gene disorders. Some genotypes may “predispose” to certain conditions only in the presence of environmental triggers. Genetic polymorphism affecting severe depression. [Data from A. Caspi, et al. 2003. Science 274: 1527.] Note: A recent meta-analysis by Risch, et al. (JAMA, 2009, 301(23): 2462-71) supports a link between stress and depression but found no link between serotonin transporter genotype, alone or in combination with stress. Environmental influence on phenotype: Do we teach it? Classic experiments After 100 generations of inbreeding, mice continue to show metabolic variability (Storrs and Williams, PNAS, 1968). The variability in growth of plant clones at different elevations (Clausen, Keck, and Hiesey, 1940s and 1950s) High school curriculum Five out of six leading high school texts lack a sound discussion of incomplete penetrance (and most fail to distinguish it from variable expressivity), let alone genetic and environmental modifiers contributing to it (e.g., the influence of pregnancy and smoking on carriers of BRCA1/2). - Also, missing from a majority: “gene-environment interactions and the potential influence of these interactions on disease” (from L. Doyle, 2009) An alternative genetics education paradigm: Inverting the curriculum Many phenotypes related to health and disease vary continuously. Such traits often have multifactorial causation; multiple genes and environmental interactions are critical. Additive models of gene action help explain continuous variation, but predicting phenotypes from genotypes is difficult. Some phenotypes are strongly influenced by single genes, and mendelian segregation allows more precise prediction of phenotypes from genotypes. Simplified Conceptual Flow for an Inverted Genetics Curriculum 1. 2. 3. Many traits show continuous variation (e.g., height, weight, forearm length, extroversion, etc). Such traits (quantitative/complex traits) can be inherited and are strongly influenced by the environment. The level of a quantitative trait can be understood in terms of “contributing factors” that offspring receive from parents. a. many contributing factors (in an additive model) lead to greater manifestation of a trait; b. fewer factors lead to less manifestation; and c. most combinations lead to an intermediate level of manifestation. Concepts 4-8 are part of a traditional genetics unit: 4. 5. 6. 7. 8. 9. Contributing factors that offspring receive from parents are called genes and are carried on the chromosomes passed from parents to children; Genes exist in different forms called alleles; Alleles are passed from generation to generation through the processes of meiosis and fertilization; The movement of chromosomes (and the alleles they carry) during meiosis and fertilization lead to characteristic patterns of inheritance; Following the inheritance of one gene (one pair of alleles) or two genes (two different pairs of alleles) reveals the patterns of inheritance first identified by Mendel: a. monohybrid crosses result in a 3:1 phenotypic ratio and reveal segregation of alleles; and b. dihybrid crosses result in a 9:3:3:1 phenotypic ratio and reveal independent assortment of genes. The genes and alleles contributing to complex traits segregate and assort according to the same patterns identified by Mendel except that: a. in complex traits, many genes and alleles contribute to one trait rather than each gene contributing to a separate single-gene trait (e.g., as in dihybrid crosses); and b. when only one gene or allele primarily determines a trait (e.g., smooth pea texture vs. wrinkled), the resulting trait shows a rare pattern of variation (i.e., discrete, not continuous). More env influence Less env influence Trauma Height, weight, CVD CF, HD, AT Language spoken ------Cancer------ Schizophrenia Increasing genetic influence A Continuum of Genetic Influence