Lesson

Where Does Elsie's Hair Color Come From? A "De-Simplified" Pedigree Lesson

Author(s): Solveig van Wersch1, Pamela Kalas*1

University of British Columbia

Editor: Lisa McDonnell

Published online:

Courses: GeneticsGenetics Introductory BiologyIntroductory Biology

Keywords: pedigree Multifactorial phenotypic variation penetrance expressivity quantitative variation

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Abstract

Resource Image

Pedigree analysis is part of most Genetics curricula, but the examples traditionally used in genetics courses present phenotypes as if they were entirely and inexorably defined by genotype. This does not reflect the current state of understanding in genetics, and can inadvertently reinforce the inaccurate belief that characteristics associated with any socially-defined group is governed by genes. In order for Genetics resources to better reflect present-day knowledge, instructors need teaching resources that acknowledge the multifactorial nature of phenotypic variation. Such resources are still scarce, particularly for pedigrees. This pedigree lesson, set up as a case study, allows students to “discover” the complexities of genotype-phenotype relationships using data from a published study. Students first become familiar with the specific single nucleotide polymorphism (SNP) in a single gene associated with the phenotype of interest (hair color), then contend with a series of increasingly challenging pedigrees, the last one seeming unsolvable. They then examine a figure from the research paper, showing the broad and overlapping ranges in hair color in each of the three relevant genotypic groups. This becomes the starting point for explaining the apparent inconsistencies in the most challenging pedigree, and for discussing the real-life complexities behind phenotypes and pedigree analysis. The lesson was well received by students, and their post-lesson assignments demonstrated a nuanced understanding of phenotype. Answers to exam assessment questions showed excellent pedigree analysis skills and a keen eye for the influence of environment on phenotypes.

Primary Image: An artist's rendition of phenotypic variation vs. pedigree simplicity. A pedigree chart is superimposed onto an image of the head, face and neck of a person with colorful hair. The colorful hair is reduced to black or white in areas where the pedigree is superimposed. Artwork by Jacelyn Shu, used with the artist’s permission.

Citation

van Wersch S, Kalas P. 2023. Where Does Elsie's Hair Color Come From? A "De-Simplified" Pedigree Lesson. CourseSource 10. https://doi.org/10.24918/cs.2023.48

Society Learning Goals

Genetics

Lesson Learning Goals

From the BioCore Guide:

  • Information Flow: Individuals transmit genetic information to their offspring; some alleles confer higher fitness than others. 
  • Information Flow: A genotype influences the range of possible phenotypes in an individual; the actual phenotype results from interactions between alleles and the environment.

Lesson Learning Objectives

Students who have successfully accomplished the learning goals will be able to:

  1. identify the mode of inheritance model that best fits a pedigree using a hypothesis-testing approach.
  2. integrate information deduced from multiple pedigrees to determine the relationship between two alleles (with respect to a given phenotype).
  3. interpret quantitative data showing the distributions of phenotypes across individuals with the same and different genotypes.
  4. explain how individuals with the same genotype (at a given locus) may have different phenotypes.
  5. propose plausible explanations for seemingly incompatible patterns of inheritance in a pedigree, and support them with empirical (including quantitative) and/or theoretical evidence.

Article Context

Introduction

Human pedigree analysis exercises provide engaging opportunities for students to develop and apply their understanding of transmission genetics, practice their analytical skills, and develop evidence-based arguments (1). However, these exercises also have shortcomings. Human pedigrees, particularly those used for teaching, depict individuals in a binary way (“affected” or “unaffected”), hiding the true range of variation in the trait of interest. In real life, almost all phenotypes encountered in pedigrees display variable expressivity (different levels of severity across individuals), requiring the establishment of criteria to classify an individual as “affected” vs. “unaffected,” but students are generally not made aware of this. Typical pedigree exercises also implicitly assume complete penetrance (that is, 100% of the individuals with the genotype have the phenotype of interest), and present genetic conditions as unambiguously dominant or recessive. This does not reflect what is observed in real life, where phenotypes are influenced by internal (e.g., cellular, molecular, physiological) and external environmental factors, as well as an individual’s genetic background.

Ample evidence indicates that variable expressivity and incomplete penetrance, which are manifestations of the multifactorial nature of most traits, are the rule rather than exceptions (e.g., 26). Yet Genetics textbooks, resources, and curricula hardly mention these phenomena, or environmental factors in general (7, 8). In line with this, we observed that of the 89 pedigrees, depicting 41 different conditions, presented in five major Genetics textbooks (913), only four (or 4.5%) illustrated incomplete penetrance, none included variable expressivity, and all 41 conditions were presented as strictly dominant or recessive. In contrast, OMIM (Online Mendelian Inheritance in Man) reveals that all 41 conditions display some level of multifactorial phenotypic variation (see Table 2 at end of manuscript).

We recognize the value of presenting challenging topics, such as human pedigree analysis, in the simplest possible way when first introducing them to novice learners. However, we believe students will benefit from witnessing the complexity of real-life phenotypic variation, as well as the inevitable subjectivity involved in categorizing individuals in discrete categories. By honoring the complexities of phenotypic variation, and de-emphasizing a strictly Mendelian view of Genetics (that is, “de-simplifying” Genetics) we can help learners develop a more accurate picture, and may also help them move away from overly deterministic perceptions of Genetics (14, 15). Such perceptions are problematic because of their biological inaccuracy and because they support the view that people belonging to a given socially defined group have a shared set of genes that distinguishes them from other groups in terms of their behaviors, abilities, and other characteristics (16, 17). Critically, multiple studies have demonstrated that this view plays a role in prejudice and discrimination (reviewed in 18).

Typical pedigree problems are quintessentially deterministic, so they have great potential for inadvertently strengthening essentialist beliefs and an inaccurate view of phenotypic variability in natural populations. There are some excellent pedigree lessons that expose students to traits with a range of expressivity (e.g., 19), but they do not explicitly address this aspect or the multifactorial nature of the traits they feature. Our goal with this lesson was to offer students an engaging de-simplified pedigree experience, while still providing them with opportunities to practice their fundamental pedigree analysis skills. We also hope to encourage other instructors to develop (and/or share) their own de-simplified pedigree resources.

Description of the Lesson Context: Hair Color Variation in Solomon Islands

The lesson is structured as an interrupted case study, a format that promotes critical thinking, engages participants, and helps instructors uncover students’ misconceptions or misunderstandings (20, 21). It is based on a famous genome-wide association study (GWAS) that identified a SNP associated with the striking blonde hair phenotype observed among Solomon Islanders (22). This SNP, apparently unique to populations from Oceania, consists of a C-to-T transition resulting in a missense mutation (arginine-to-cysteine, R93C) in TYRP1, encoding an essential enzyme in the eumelanin biosynthesis pathway (22).

This GWAS has several elements that lend themselves well to being incorporated into a pedigree analysis activity. First, hair color is a phenotype with which students have real-life experience. Second, the functional connection between the SNP and the blonde hair color is accessible and understandable for novice biology students. Finally, although the authors themselves discuss hair color in Solomon Islands as if it were a binary phenotype, they also report the results of quantitative measurements of hair pigmentation. These data clearly show that hair color exists on a spectrum, with a range of “blondness” and a range of “darkness,” and that there is overlap in the pigmentation ranges observed among homozygous most frequent variant (C/C), heterozygous (C/T) and homozygous R93C (T/T) individuals. This data set forms the crux of the lesson.

Intended Audience

We implemented this lesson in a cohort-based, first year science course at a large research university. The lesson is suitable for introductory biology and introductory genetics courses.

Required Learning Time

Students’ pre-class preparatory work should take no more than sixty minutes. The lesson itself takes one 80-minute class period, and the post-class assignment about fifteen minutes.

Prerequisite Student Knowledge

Students need to have a basic understanding of Mendelian genetics (monogenic crosses are sufficient), know the definition of a missense mutation, and realize that a single amino acid change in a protein has the potential to affect its structure and function. As in many biology courses, these topics were addressed in previous lessons, and for many students, also in high school. Students should also be comfortable working collaboratively in small groups, be able to read a “box-and-whiskers” graph, and be familiar with the symbols used in pedigrees. The pre-class assignment (Supporting File S1) includes videos covering all the fundamental elements of pedigree analysis needed for the lesson.

Prerequisite Teacher Knowledge

This article and the instructor key (Supporting File S2) include all necessary content-related and logistical information to implement this lesson. A brief summary of the GWAS design is also provided (Supporting File S3). Instructors should be comfortable with facilitating small group work, class discussions, and clicker questions. We recommend that instructors complete the preparatory work (that will be assigned to students) well in advance, so that if they have any questions that are not covered in the article or in the Instructor’s Notes, they will have time to investigate.

Scientific Teaching Themes

Active Learning

Students actively engage with the material for the majority of the lesson through small group and whole class discussions, clicker questions, and by answering the activity questions collaboratively (in class) and independently (pre- and post-class assignments). By and large, instructors are responsible for providing feedback and facilitating discussions rather than performing information transfer.

Assessment

The pre-class assignment (Supporting File S1) includes a short quiz that allows students to verify their comprehension of the preparatory materials. Assessment of students’ pedigree analysis skills occur informally, during the lesson, and formally on the final exam (Supporting File S4). Throughout the lesson, we assessed the accuracy of students’ answers to clicker and open-ended questions, as well as their contributions to discussion and responses to probing questions. On the final exam, we used marking keys to assess the accuracy of students’ answers to open-ended and multiple-choice problems. We also assessed students’ understanding of the complexities of genotype-phenotype relationships by examining the accuracy and depth of their assignment submissions.

The structure of the lesson offers several opportunities for informal self-evaluation. Students can compare their own ideas and answers to their peers’ during the group discussions, which also allows for informal peer-evaluation (students would often point out factual inaccuracies and reasoning errors to each other). Group discussions are followed by instructor-led debriefs, where instructors offer thorough feedback on the accuracy and completeness of a selection of answers, providing students some authoritative criteria to further self-evaluate their own work.

Inclusive Teaching

The lesson is highly structured, with several checkpoints that use clicker questions or instructor-led debriefs, and provide opportunities for students/groups to ask clarification questions before moving on. Such structured in-class activities benefit student learning in an equitable way (2325). The student handout (Supporting File S5) includes the questions and the case study story, organized into segments. The purpose of the story segments is not only to engage; these segments also provide some additional information and summarize essential points covered in the previous portion of the activity, such that all students/groups have this information on hand even if they have not taken notes during the check points. This minimizes the chance of losing students.

Students work through the handout questions in small groups, which leverages the diversity of knowledge, understanding, perspectives, and skills brought by the group members and provides opportunities for peer-teaching/peer-learning (26). Working in small groups also allows students to discuss in a more comfortable setting compared to sharing ideas with the entire class, promoting equity and offering the potential for students to feel included (27, 28). In our classes, students self-selected their groups, typically choosing to work with classmates who sat next to them.

The lesson includes different kinds of questions (analytical, factual, predictive, opinion-based) representing a variety of Bloom’s levels and knowledge types (29), and requiring different answer formats (written summary, graph interpretation, multiple choice, short answers, etc.). This promotes contributions from students with diverse skills, abilities, and levels of understanding. The materials can also easily be adapted for accessibility; for example, students can receive electronic versions of the handouts, allowing them to zoom into the figures for better or more comfortable viewing and/or apply “read aloud” software if needed.

Lesson Plan

This lesson first engages students with questions that generally address diversity among humans, and mechanisms whereby differences in DNA sequences (genotype) can influence phenotypes (Part I). Students then analyze a series of progressively more challenging pedigrees, culminating in a case where, unbeknownst to them, incomplete penetrance is at play (Part II). Finally, students examine some of the quantitative data from the original GWAS (22), which allows them to explain the seemingly “impossible” pattern of inheritance seen in the last pedigree (Part III).

The lesson (summarized in Table 1) is designed to be completed over one or two class sessions; in our case it took place over one 80-minute class period. It also includes some pre-class preparatory work (Supporting File S1), plus a read-through and first attempt at Part I of the case study/handout (Supporting File S5). Altogether, the preparatory work should take no more than 60 minutes.

Table 1. Lesson plan timeline. This plan assumes 80-minute lecture blocks, but the lesson can be easily adapted to 50-minute blocks.

Activity Description Estimated Time Notes
Preparation for Class
Instructor preparation Instructor reviews all the lesson materials and makes the relevant pieces accessible to students. Depends on level of familiarity To be made available to students, ideally 5–7 days before class: pre-class assignment (Supporting File S1) and Part I + Part II of the case/handout (Supporting File S5), which students should also bring to class.
Pre-class assignment Students read a brief article, watch three short instructional videos, and complete a quiz. At the discretion of the instructor, they may also be asked to give a first attempt at Part I. 30–35 minutes; up to 60 if a first attempt at Part I is included. Instructions, links to the article and videos, and quiz questions are available in Supporting File S1. Note that the article discusses blonde hair color as being a recessive trait, but this simplification will be challenged in Parts II and III of the lesson.
First look and attempt at Part I Students familiarize themselves with Parts I+II of the handout and attempt Questions 1–5. 15–25 minutes The lessons can be successfully conducted even if students do not attempt the questions at home, but expect it to take more time.
During Class
Part I, in small groups Students form groups of 3–4 and discuss their answers to Part I and try to come up with a consensus. 10 minutes Students work on/refer to their handout (Supporting File S5); instructor circulates among groups, asks prompting and probing questions, provides feedback and encouragement.
Part I, class discussion/ debrief Instructor leads a whole-class discussion/debrief on the answers to Part I. 10 minutes Instructor uses slide deck (Supporting File S6) to structure the discussion. Tips and suggestions are included in the instructor’s slides presenter notes and in the instructor’s key (Supporting File S2).
Part II, in small groups Students work on Part II in their groups and try to come up with a consensus. 10 minutes As for Part I, students work on their handout; instructor circulates. It is not expected that students solve the fourth pedigree (Elsie’s) at this point.
Part II, class discussion/ debrief Instructor leads a whole-class discussion/debrief on the answers to Part II. 15 minutes Same as for Part I. When getting to Question 8, the instructor lets students consider it for a few minutes before answering. No need for the class to come up with a definite answer at this point.
Part III, in small groups Instructor distributes Part III; students work on the questions in their groups. 15 minutes Same as for Parts I and II. It is helpful to invite students not to spend excessive time on Questions 9–11.
Part II, class discussion/ debrief Instructor leads a whole-class discussion/debrief on the answers to Part III. 20 minutes This is the most important place for discussion, and if tight on time, Questions 12–14 should be prioritized by leaving sufficient time for their discussion. If needed, Question 15 can also be part of the take-home assignment with Question 16.
After Class
Take-home assignment Students consider Question 16 (may discuss it with peers) and submit written responses. 20 minutes Give students sufficient time to develop well thought-out answers.
Instructor’s feedback Instructor reads the submissions and provides feedback (individual and/or class-wide). Depends on class size This is an excellent opportunity for the instructor to gauge students’ level of understanding and perspective on the relationships between genotypes and phenotypes. The instructor can provide the class with a summary of the most representative or interesting points made, with commentary.

During class time, the lesson should be divided between having the students develop and discuss answers to the case study questions (Supporting File S5) in small groups, and debriefing/reviewing the answers as a whole class. Therefore, instructors should be comfortable facilitating small group work and leading class discussions.

Pre-Class Preparation: Instructor

Instructors should start to prepare for the lesson at least one week ahead of time, as students will need some pre-class preparation, too. Preparation will include reviewing all the lesson materials, planning the logistical details (e.g., time allotted for the pre-class assignment, electronic or hard copy handouts, etc.), and preparing the necessary materials. These are:

  • The pre-class assignment (Supporting File S1), which includes two brief articles, three videos, and a short comprehension quiz. Students should have the opportunity to access these resources at least four to five days prior to the in-class portion of the lesson.

  • A handout comprising Parts I and II of the case study (Supporting File S5, pages 1–4) accessible to the students a few days before the in-class portion of the lesson.

  • A handout consisting of Part III of the case study (Supporting File S5, pages 5 and 6) to distribute to students in class after completion of Part II. Ideally, if instructors choose to use paper format, this handout should be in color.

  • A paper copy of the instructor’s key (Supporting File S2) and a copy of the case study/student handout (Supporting File S5) for the instructor to keep on hand during the lesson.

  • The slide deck for the lesson (Supporting File S6), which instructors can use as is or customize to their own needs and preferences. For instance, some instructors may choose to integrate some of the notes and suggestions from the instructor’s key into the presenter notes, or show the slides depicting the study design (Supporting File S3).

The day before the in-class portion of the lesson, instructors check if students have completed the comprehension quiz and remind them to please come to class prepared.

Pre-Class Preparation: Students

Students read the assigned articles, watch the videos and complete the quiz. One article introduces the SNP and the phenotype on which the case study is based, while the other provides an overview of multifactorial traits. The two YouTube videos, which demonstrate how to conduct a (traditional) pedigree analysis, are complemented by the “Pedigree Unspoken Assumptions” clip, where two students discuss some of the major assumptions that we implicitly make when first analyzing pedigrees. At this point, students can complete the short comprehension quiz, and move on to reading Part I of the case study and attempting the questions associated with it. They can complete this task individually or collaboratively, as long as each one of them records their answers or, if they are unable to answer, their points of confusion. If instructors have the opportunity to do so, it may help to keep the case study handout (Supporting File S5, pages 1–4) “locked” and accessible only upon completion of the comprehension quiz.

Part I: In Class

Students should bring copies of Parts I and II of the case/handout to class; this could be either a digital version or a printed-out copy of the file (Supporting File S5, pages 1–4) made available by the instructor. However, if a paper format is used, we recommend instructors having extra copies on hand. Instructors should also have copies of Part III of the case/handout ready to be distributed when the time comes. At the start of class, the instructor provides quick and simple instructions (e.g., groups of three or four will work on Part I for a designated amount of time, those who are done ahead of time should go ahead to Part II, groups that have questions should raise their hands) so that the activity can get underway without delays. As students work collaboratively and discuss their answers to Part I of the case (Questions 1–5), the instructor should circulate among groups, check on them and provide quick feedback. The more feedback students receive in their small groups, the quicker the debrief will be. If multiple groups have demonstrated the same difficulty, or have the same question, instructors should ask for a moment of quiet and provide clarification to the whole class at once.

There are two main purposes to Part I. One is for students to think about both general and genetic differences within and between groups. This is relevant to understand the setup of a GWAS, but also important in order to realize that members of a natural population (including a human population) who belong to a specified group are going to be very genotypically diverse. The second purpose is to emphasize the mechanism whereby a small genotypic difference can have a highly visible influence on phenotype. Here, a single SNP in TYRP1 results in an amino acid substitution in the TYRP1 enzyme, potentially altering the protein’s structure and function (thus influencing a molecular/biochemical phenotype). This, in turn, would likely affect the production of eumelanin (a biochemical or metabolic phenotype), which would eventually influence hair color, the striking visible phenotype that we observe.

At the end of the designated time for small group discussions, the class reconvenes and “debriefs.” The instructor leads the class through a discussion/review of the answers using the slide presentation. On the slides, many of the questions are presented in a multiple-choice format so that students can vote and instructors can invite further contributions from supporters of each of the answers. The multiple-choice format also allows instructors to decide, based on the response distribution, whether a question needs to be discussed at all, or whether particular concepts need to be reviewed (then, or in future). The instructor’s key (Supporting File S2) offers extended answers and suggestions on feedback that instructors can provide.

One of the challenges of this lesson is time: students may want to discuss the questions further, may be curious about aspects that go beyond the objectives, or may struggle with specific elements. If time is tight, there are several ways in which instructors can address questions and clarify points that did not have a chance to be elaborated on in class, for example by offering dedicated office hours, or by inviting students to post their unanswered questions on the class discussion board (where both classmates and instructors or teaching assistants can address the questions).

Part II: In Class

The logistics for Part II is the same as for Part I: groups read Part II and work on Questions 6–8 for a designated amount of time, with the instructor circulating and providing clarification and feedback. Then the class reconvenes for a debrief to share answers. This segment focuses on pedigree analysis using increasingly challenging examples. The first pedigree is straightforward—the blonde hair phenotype perfectly fits an autosomal recessive mode of inheritance model. The next two examples are not particularly difficult to analyze, but they are ambiguous: they fit multiple mode of inheritance models, and require some quantitative thinking and judgment calls. Students also need to keep in mind that some of the lines of reasoning they may be using apply only to rare phenotypes, and blonde hair is not a rare phenotype in Solomon Islands. Finally, the fourth pedigree (Figure 1) is extremely challenging, and there is no expectation that students will be able to “solve it” at this point—in fact, some groups may not even get to it within the time allotted. This is entirely fine as long as during the “debrief” of Part II students realize that there is an apparent internal contradiction in this pedigree; resolving this apparent contradiction will be the focus of Part III. Instructors can also lengthen the time dedicated to this lesson (e.g., using part of an additional class period) to allow for any questions and discussions emerging from the challenging pedigree.

After discussing each Part II question with the whole class, instructors should ensure that students are confident and comfortable with the answers agreed upon before moving on to the next. While a purpose of the lesson is to demonstrate the complexity of the relationship between phenotypes and genotypes, students should also be encouraged to propose a variety of simpler conclusions when they do not conflict with the data. Moving too quickly, or not approving of reasonable ideas and answers, can result in students’ confusion or uncertainty when answering future pedigree questions, or a sense that “there are no answers.” Because some of the pedigrees fit multiple mode of inheritance models, students may also want to know how they would be expected to answer in such a case on an exam question. Letting students know whether their proposed answers would be acceptable and get full credit on a test can be very helpful to those who wonder whether their knowledge and reasoning are sound. Many of the questions build upon those which come before, and taking the time to explore different topics (e.g., the effect of environment on phenotype) brought up by students earlier in the lesson will prime the class for the more complex questions at the end, improving their understanding. The instructor’s notes (Supporting File S2) include ideas for topics to bring into the conversations and prompts to encourage helpful lines of thought.

Part III

This is the crucial portion of the lesson, which distinguishes it from “traditional” pedigree exercises. The instructor distributes Part III of the case/handout (Supporting File S5, pages 5 and 6) and implements the same logistics as for the first two parts. Instructors should be aware that, as the content of this segment is inherently more challenging, groups require more support, prompting, and feedback while they work on the questions. In addition, the questions used for the debrief/discussion portion of Part III are open-ended, identical to the versions on students’ handouts, requiring that at least a few groups volunteer their answers for the whole-class discussion (this has not been a problem in our experience, quite the opposite).

In this part, students read and interpret a data figure from the original GWAS article (22), guided by Questions 10–13. This figure summarizes the distribution of hair color phenotypes across participants with each of the three TYRP1 genotypes of interest (C/C, C/T, and T/T), and students can observe how the hair color ranges of the three groups overlap, indicating that, although the T/T genotype is associated with blonde hair, there are some T/T individuals with darker hair than their counterparts with C/C and C/T genotypes, and vice versa. This finding provides evidence that students/groups can use to resolve the apparent contradiction in the fourth pedigree (revisited in Question 14). The range of phenotypic variation within each genotypic group also gives a glimpse of the complexity that is often disregarded when representing traits as binary models.

Post-Class: Students

Students complete Question 16 (Part III) as a homework assignment and submit it within one week. They are welcome to do some research on the topic, and to discuss the question with classmates and/or with the instructor, but their response needs to be individual and in their own words. From the students’ perspective, the purpose of the assignment is to take a moment to reflect on the lesson and think about how the principle that they “discovered” in the context of one phenotype may or may not apply to others.

Post-Class: Instructor

The post-class assignment allows instructors to assess how well students understand that phenotypes have complex, multifactorial bases, and do not solely depend on genotypes. If the lesson is successful, student answers should reflect the idea that while some traits may superficially display Mendelian inheritance patterns, most involve multiple genetic and environmental factors. In addition, as students justify their claims/explain their reasoning, instructors may identify misconceptions or logical flaws. It is essential that instructors provide feedback on the students’ post-class assignment either individually or to the class as a whole, for example by commenting on frequent and particularly relevant points that transpired from the assignment.

Teaching Discussion

The lesson was implemented two years in a row in the first semester of a first-year, cohort-based science program (composed of 72 students the first year and 70 the second), at the end of a module on Genetics. Both years, the lesson took place during a week characterized by a particularly heavy workload. The first year, there was no quiz associated with the pre-class preparatory readings and videos. Despite being generally highly motivated and hard-working, most students neglected the assigned pre-class activities and came to lecture unprepared. The instructor successfully mitigated this issue by modifying the timeline presented in Table 1 and giving students a little more time than planned to complete Parts I and II of the case study (Supporting File S5). While they were engaged with Part I, the instructor also explicitly encouraged students to think more deeply about the study design, about the factors that may influence hair color, and about genetic variation. Through informal prodding and probing, she ensured that students were able to make up for their lack of preparation and successfully analyze the Part II pedigrees. This early time investment left students better prepared to tackle the challenging questions of Part III, which they were then able to complete more quickly than anticipated.

For the second implementation, we added the comprehension quiz to the required pre-class activities. The instructor also asked that students read through and attempt the questions in Part I of the case/handout before class, and reminded them of the importance of taking these preparatory activities seriously. This time, students were well-prepared and the lesson went very smoothly, allowing the instructor to follow the planned timeline (Table 1). Contrary to our concerns, we also found that students who participated in the first implementation did not share materials or information about the lesson with those who were part of the second.

Students’ Reactions

Both years, students reacted enthusiastically. The level of engagement was very high for all elements of the lesson: there was a great deal of animated discussion within all the groups during the small-group discussion segments, and many different students, from different groups, contributed to the whole-class discussion/debriefing phases by answering questions, asking questions, or adding onto other classmates’ ideas. Rich, free-flowing discussions emerged during the whole-class/debriefing segments, where students also shared questions and ideas on the nature of science and of scientific data, often making connections to course material seen a month or so earlier. Even without the instructor’s prompting, there were very few moments of silence, and students’ engagement was such that the discussions went overtime.

Observations About the Lesson’s Effectiveness

In-Class Observations

Students’ answers to clicker questions, the responses that the small groups shared with the class, as well as the questions that they asked offered the first opportunity to assess the lesson’s effectiveness. Based on these indicators, by the end of the lesson, students accomplished the goals described in the Learning Objectives. With the benefit of peer discussions and the instructors’ careful feedback, students were able to successfully answer all the questions posed in the lesson.

Performance on Relevant Final Exam Questions

We were initially slightly concerned that the lesson may cause undue “confusion” on how to tackle a pedigree problem, but students’ performance on their final exams suggests this was not the case. The first year that we implemented the lesson, the final exam had students identify and justify the mode of inheritance model that best fit a pedigree using a hypothesis-testing approach (Learning Objective 1). Their performance (average score 83%; N = 75) was in line with that obtained the previous year, when pedigrees were taught in a “traditional” way (average score 78%; N = 79). In the second implementation of this lesson, we used the synpolydactyly questions (Supporting File S4) on the final exam and, again, students (N = 78) performed well (average of 84% on part A, which addresses Learning Objectives 1 and 2, and 76% on part B, which targets Learning Objectives 4 and 5). Notably, already in part A, a few students started considering a multifactorial mode of inheritance and the potential for incomplete penetrance, given the unlikelihood of multiple independent carriers of a rare allele “marrying into” the families depicted. This shows definite awareness of the complex nature of phenotypic variation.

Student Responses to Assignment Question (Question 16)

An analysis of students’ assignment responses (Question 16 in Supporting File S5) gave us a qualitative indication of their understanding of genotype-phenotype relationships (broadly speaking, Learning Goal 3). A total of 61 students (out of a class of 75) submitted their assignment in the first implementation of the lesson, and 72 students (out of 78) did so in the second, with only two responses demonstrating confusion about the concepts of genotype and phenotype. In both years, different students interpreted the question in slightly different ways. Some saw the case of hair color in Solomon Islands as an example where a large portion of the phenotypic variation is due to variation at a single locus, while others considered it a general illustration of multifactorial inheritance. Yet others focused on the large role of environmental factors. Regardless, all but three responses across the two implementations reflected complex and nuanced conceptions of the relationships between genotype and phenotype. Two major themes emerged from the students’ responses:

(i) Variation in different phenotypes involves different proportions of genetic and environmental contributions, different numbers of genes, and different environmental factors (n = 47 and n = 45 responses, or 77% and 62%, respectively, Year 1 and Year 2).

In some respects, this goes beyond the learning objectives, as students not only explained how phenotypic variation is often multifactorial, but also how the number of contributing factors (genetic and environmental) and the magnitude of their influences varies across phenotypes. Height was typically described as a phenotype that is likely to be influenced by a multitude of factors, each one making a small contribution. Several students contrasted height with the case of hair color seen in the lesson, where a single SNP is correlated with a very large proportion of phenotypic variation. Multiple students also brought up additional phenotypes that they either researched in the literature or have personal experience with.

Additionally, 27 and 48 students (47% and 67%, respectively) explicitly stated that phenotypic variation is generally complex and multifactorial. Many of these students also included examples detailing how individuals with identical genotypes may develop different phenotypes, or how someone may never develop the phenotype usually associated with their genotype, due to environmental factors.

(ii) But certain phenotypes are likely influenced by a single or a few genes (n = 21 and n = 30, or 34% and 41%).

Most of the students who included a discussion of ABO blood types in their assignment treated them almost as a special case of phenotypic variation that, unlike height, hair color, or other examples that they supplied, is likely unaffected by environmental factors and only influenced by a very small number of genes, with phenotypes directly correlated to genotypes. Students tended to associate this model to phenotypes that they described as “discrete,” “simple,” “cellular,” “unchanging,” “specific,” or “fundamental.”

Suggestions for Adaptations, Improvements, and Extensions

Improvements

Both times, the lesson took place within an enriched first-year science program, where students are used to engaging in “discovery” activities and challenging problems without necessarily having all the required information to arrive at a definite answer. To successfully implement the lesson in a wide variety of biology courses, we suggest drawing students’ attention to the complexity of phenotypic variation in the context of pedigrees ahead of the lesson, even just by emphasizing the importance of the assigned Nature Education pre-class article (30).

The lesson can be improved by including an assessment that directly tests students’ achievement of most or all the Learning Objectives in an individual, exam-like, but low-stakes setting (e.g., by using one of the questions offered in Supporting File S4). This would allow instructors to evaluate the success of the lesson and spot students’ points of confusions (which could then be targeted for clarification), while students would benefit from the opportunity to rigorously practice their skills and knowledge without the stress or anxiety potentially encountered in an exam. Alternatively, instructors can expand the post-class assignment (currently Question 16) by asking students to describe what they have learned and whether there was anything in the lesson that surprised them. This would allow instructors to get a sense for what the students got out of the lesson and also benefit the students, who would have to engage their metacognitive skills to reflect on, and verbalize, their learning.

Possible Adaptations and Extensions

The lesson took place in-person during an 80-minute lecture block, but it can be adapted to fit into one and a half 50-minute slots. In this case, we suggest trying to conclude the whole-class discussion/debrief of Part II in the initial class period, and have a brief recap at the start of the next class period before proceeding with Part III. If class time is an issue, or if instructors want to maximize the class time spent on discussion rather than having students spend valuable minutes reading and comprehending the questions, we recommend having students attempt to answer the questions in Part I and Part II of the handout (Supporting File S5) before coming to class, as part of their pre-class preparation. Instructors can then start lecture with a whole-class discussion/debrief of Parts I and II, which should take about 15 minutes, before distributing Part III and continuing the lesson as described in Table 1. This may be appropriate for a setting where students are more experienced and already very familiar with “traditional” pedigree analysis. Alternatively, tutorial (i.e., recitation or discussion sessions), if applicable, can offer an excellent opportunity for students to complete, and receive feedback on, Parts I and II of the handout. This would also afford students more individual attention, and have their uncertainties clarified in an often more comfortable environment than a large lecture. Students would then be perfectly ready to tackle Part III in lecture. Finally, instructors can shorten Part I further by omitting Question 4 (which is not critical for the rest of the activity).

As with most active lessons, implementation in larger classes (e.g., 200 or more students) will require some extra considerations. Ideally, a minimum of one teaching assistant or analogous personnel per 60 or so students would join the instructor in circulating among the groups and offering feedback during the group activities, and would help with providing feedback for the post-class assignment. Instructors may also need to extend the time dedicated to debriefing, as in a larger class there will be more groups wanting to share their answers, and more students may have questions.

The lesson can also be easily adapted to a synchronous or asynchronous online format, where students receive electronic copies of the lesson handouts. In a synchronous, videoconference format, the small group work can take place in “breakout rooms” with group members sharing screens and the instructor circulating among the rooms and bringing the class back together for the whole-class discussion/debrief. In an asynchronous context, groups could submit their answers for Part I, receive feedback (which could include a request to review and resubmit), and be asked to discuss the feedback with their group (e.g., on a discussion board) before receiving access to Part II. The same would happen with Parts II and III.

We realize that in some curricula, pedigree analysis may be covered before some or all of the students have become familiar with transcription, translation, mutations, and how exactly a SNP may influence a physical phenotype. This should not deter instructors from taking advantage of our lesson: the Stanford Medicine News article assigned as pre-class preparation (31) provides enough context at a very accessible level, and it is entirely possible to skip Questions 4 and 5 without compromising the main focus of the lesson. On the other hand, courses that include a discussion of GWAS could take advantage of the example presented here (Supporting File S3) so that students would already be familiar with the context (if the pedigree lesson has already occurred) or as a way to lead into the lesson, so that students would start with a solid understanding of the study design.

As an extension, the general structure of our lesson can be applied to any phenotype for which there are data showing variable expressivity, incomplete penetrance, or any other phenomenon highlighting the complexity of phenotypic variation. Students can also be invited into the lesson development process, as has happened at our institution where a collaboration between students and instructors produced a de-simplified pedigree lesson on hemophilia A (M. Moussavi, R. Goel, A. Jackman, N. Alibhai, L. Norman, J. E. Klenz, P. Kalas, in preparation). However, de-simplifying pedigrees does not need to be cumbersome. Instructors could run their regular lessons on pedigree analysis and supplement them with some data and/or discussions addressing the real-life, complex, multifactorial nature of the phenotypes in question. After analyzing a pedigree for red-green colorblindness, students could go on OMIM, enter “red-green colorblindness,” and report back on what they found, followed by a discussion. Or, along with a straightforward pedigree featuring Charcot-Marie-Tooth disease, students could read a first-person account on the variable expressivity and incomplete penetrance of this condition (32). Our hope is that colleagues far and wide will be motivated to develop and share de-simplified pedigree lessons that honor the complexity of many interesting phenotypes. The genetic conditions and information listed in Table 2 offer a potential starting point.

Table 2. Ten hereditary conditions frequently represented in textbook pedigrees. Pedigrees found in textbooks as part of examples, problem sets, or answers to problem sets traditionally present the relevant hereditary condition in simplified and unrealistic ways. This document summarizes how ten genetic conditions are presented in the section(s) dedicated to human pedigree analysis across five major genetics textbooks (913), and contrasts this with more accurate descriptions of their modes of inheritance and phenotypic variation found in the literature and on databases.

Condition Traditional Presentation Additional Information for a More Accurate Description
Achondroplasia Autosomal dominant; binary (affected or unaffected)

Variable expressivity: A recent review (33) reports variation in severity for craniofacial phenotype, in the foramen magnum, and in height. The author describes the overall level of variable expressivity for achondroplasia “only modest.”

Incomplete dominance/superdominance: Homozygosity for the mutant allele is associated with a more severe phenotype than that observed in heterozygotes, with also some distinct features (OMIM 100800).

Albinism Autosomal recessive; binary (affected or unaffected)

Genetic heterogeneity: Mutations at different loci (e.g., OCA2, MC1R, TYR, TYRP1, GPR143, MITF, SLC24A5) result in different kinds of albinism (OMIM 203200, 606952, 203290, 203100, 300650, 103500). Different modes of inheritance exist for albinism, including autosomal recessive, X-linked recessive, and autosomal dominant, depending on the locus in question. Different mutations at a given relevant locus can result in different types of albinism.

Variable expressivity: A spectrum of pigmentation levels is observed among individuals with the same type of albinism (34), including between siblings (35).

Incomplete dominance: A degree of incomplete dominance is reported for OCA2 albinism (36).

Cystic fibrosis Autosomal recessive; binary (affected or unaffected)

Incomplete penetrance: Cystic fibrosis (CF) is genetically heterogeneous and some mutations are associated with incomplete penetrance (e.g., 37, 38).

Variable expressivity: Numerous symptoms; variability in symptoms presence and severity (OMIM 219700); reports of patients not diagnosed until middle age or later (39). There is a relationship between severity of lung function phenotypes of people with CF and their genotype at the MBL2 locus, as well as ABO blood type genotype (40, 41).

Incomplete dominance: The prevalence of 57 out of 59 CF-related symptoms is significantly higher in CF carriers (heterozygotes) than in matched non-carriers (homozygous wild-type) (6).

Hemophilia A X-linked recessive; binary (affected or unaffected)

Variable expressivity: Great variation in severity; clinically heterogeneous; level of F8 clotting factor in plasma varies from <0.01 to 0.4 IU/mL, with 0.5 to 1.5 IU/mL being considered “normal range” (OMIM 306700; 42).

Incomplete dominance: Carriers (heterozygotes) often have reduced F8 (~25% of cases <0.4 IU/mL) and bleed more frequently compared to non-carriers (43).

Huntington’s disease Autosomal dominant (affected or unaffected)

Incomplete penetrance: Associated with specific allele variants (OMIM 143100; 44, 45).

Variable expressivity: Variation in the presence, severity, and progression of various symptoms, and age of onset (45).

Incomplete dominance: No. Two studies reported no differences in phenotype between heterozygotes and homozygotes for the mutant alleles (46, 47).

Marfan’s syndrome Autosomal dominant, binary (affected or unaffected)

Incomplete penetrance: Present for at least some typical symptoms (3, 48).

Variable expressivity: Great clinical variability and highly variable expressivity (OMIM 154700).

PKU Autosomal recessive; binary (affected or unaffected); phenotype greatly mitigated by low-phenylalanine diet

Incomplete penetrance: Restriction of dietary phenylalanine greatly reduces penetrance (OMIM 261600; 3).

Variable expressivity: Variability in clinical severity upon exposure to dietary phenylalanine, and variability in the tolerance of dietary phenylalanine (OMIM 261600).

Incomplete dominance: Increased levels of plasma phenylalanine in PKU carriers (heterozygotes) compared to non-carriers upon administration of aspartame (49).

Polydactyly Autosomal dominant; binary (affected or unaffected); incompletely penetrant

Genetic heterogeneity: There are multiple types of polydactyly, most of which are highly genetically heterogeneous, including a dozen loci (OMIM 174200, 174400, 174500, 174700).

Incomplete penetrance: Different levels of (incomplete) penetrance in different types of polydactyly (OMIM 174200, 174400, 174500, 174700).

Variable expressivity: Reported for all types of polydactyly (50).

Incomplete dominance: Not reported (superdominance associated with some loci variants in mouse). However, different modes of inheritance, not restricted to Mendelian inheritance are reported for different types of polydactyly and, in some cases, for different alleles of a locus within a type (5052).

PTC taste sensitivity Autosomal dominant; binary (affected or unaffected)

Variable expressivity: Quantitative, continuous trait where a range of sensitivity levels exist and an arbitrary threshold separates “tasters” from “non-tasters” (5355). Numerous reported cases of people whose sensitivity level differed at different times, including changes between “taster” and “non-taster” (56).

Incomplete dominance: An extensive inheritance study (54) found that a multifactorial model with a major incompletely dominant locus best explained the patterns observed. Another study (53) proposes a two-loci model that explains cases where two “non-taster” parents produce “taster” children.

Tay-Sachs disease Autosomal recessive; binary (affected or unaffected)

Variable expressivity: Variability in clinical severity, progression, and symptoms (OMIM 272800).

Incomplete dominance: Not reported; carriers have a partial deficiency in the HexA enzyme, but no disease symptoms (OMIM 272800).

Supporting Materials

  • S1. Elsie’s hair – Pre-class assignment

  • S2. Elsie’s hair – Instructor key and notes

  • S3. Elsie’s hair – Study design

  • S4. Elsie’s hair – Sample assessment

  • S5. Elsie’s hair – Student handout

  • S6. Elsie’s hair – Questions presentation

Acknowledgments

The authors wish to thank the two cohorts of students who enthusiastically participated in the lesson, and C Goedhart for constructive feedback on the manuscript. PK is particularly indebted to KM Schmid and colleagues, whose workshop at SABER West 2021 inspired the development of this lesson. With gratitude, the authors acknowledge that UBC’s Point Grey campus, where the lesson was implemented, is located on the unceded, ancestral, and traditional territory of the hən̓q̓əmin̓əm̓ speaking ʷməθkʷəy̓əm (Musqueam).

All activities reported on in this article are considered QA/QI activities under the Canadian Tri Council Policy Statement (TCPS) on Ethical Conduct for Research Involving Humans. According to Article 2.5 of TCPS2, Canadian policy framework governing research ethics, QA/QI activities do not require institutional research ethics review.

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Authors

Author(s): Solveig van Wersch1, Pamela Kalas*1

University of British Columbia

About the Authors

*Correspondence to: Pamela Kalas; UBC Department of Zoology; 6270 University Boulevard; Vancouver, BC; V6T 1Z4; Canada; kalas@zoology.ubc.ca

Competing Interests

None of the authors have a financial, personal, or professional conflict of interest related to this work.

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