Rough draft.This research track is under review with Dr. Atit's lab. Content and sequence may still change.
The Baby Mateo Case
Genetics domainMedical Interventions (MI), with PBS overlapLesson 16 of 20Your seat: Population geneticist
Why Is CL/P More Common in Some Groups?
Discovery question
Why is lip and/or far more common in some human populations than in others?
💡 risk is built from many small-effect alleles plus environment crossing a threshold, and because frequencies and effects differ by ancestry, a risk variant found in one group may not transfer to another.
The plan
Prerequisite check
Before this page, you should know
- A is an animal studied to learn about a human process; mice and zebrafish are the workhorses for clefting.
- A is an animal with a chosen gene deliberately switched off, compared against a normal wild-type animal.
If not, review
Today's new idea is only
risk is built from many small-effect alleles plus environment crossing a threshold, and because frequencies and effects differ by ancestry, a risk variant found in one group may not transfer to another.
Learn first
What you will learn
Goal: Explain how , ancestry, , and a combine to make CL/P more common in some populations, and why a risk score built in one group transfers poorly to another.
Know by the end
- is how common a particular version of a gene is in a population; it differs by ancestry.
- An reports how many times more likely an outcome is per copy of a (1.0 means no effect).
- The polygenic model says many small risk factors add up, and the trait appears only once total liability crosses a cutoff.
- Replication means a real association should reappear in independent samples; the 8q24 (rs987525) signal is strong in Europeans but absent in Native-American-ancestry families, and rs642961 near IRF6 fails to replicate in African-ancestry samples.
- gnomAD reports broken down by ancestry, so you can read for yourself how the same variant is common in one group and rare in another.
Learn first
Model: Prevalence by ancestry, and a risk allele that changes strength by group
Researchers count how many babies per live births are born with an oral , and the numbers differ by ancestry. Globally, all oral clefts run about 1 in 700 live births. Asian populations are higher, as high as about 1 in 500; African populations are the lowest at about 1 in 2,500; and Native American or AI-AN communities are described as having among the highest incidence (no exact number is in the sources, so that is qualitative).
The strongest common risk variant for nonsyndromic CL/P is a SNP called rs987525, on 8q24 in a stretch of DNA with no -coding gene. Its measured effect changes by group: in Europeans the is about 2.57 for one copy and 6.05 for two copies (very strong), in southern Han Chinese it is not statistically significant, and in Native-American-ancestry Guatemalan families there is no evidence of association. A second risk variant, rs642961 near IRF6, is a clear in Europeans but repeatedly fails to replicate in African-ancestry Brazilian samples, where a different IRF6 SNP carries the signal. The rs642961 risk allele is also rarest in African populations (frequency about 0.11) and most common in Native Americans (about 0.27).
Do the work
Explore (work the model before reading on)
- In the prevalence model, which group has the highest prevalence and which has the lowest?
- How does the rs987525 effect in Europeans compare to its effect in Guatemalan families?
- For rs642961, the is rarest in African populations (0.11) and most common in Native Americans (0.27). How does that pattern line up with the prevalence pattern?
- If a SNP is a strong in Europeans but shows no evidence in another group, what does that tell you about using one population's risk variants to predict risk in a different population?
- Imagine a company builds a risk score by adding up European risk alleles, then sells it worldwide. Predict what happens when that score is used on a patient of a different ancestry, and explain why.
The plan
Guided notes
1
How cleft risk is built
Model start: risk is not one gene flipping on or off. It is built from many small pieces that add up.
- The fraction of people in a group who carry a given risk variant is its ____.
- Because frequencies differ by ____, the same variant can be common in one group and rare in another.
- The polygenic ____ ____ model says many small-effect alleles plus environment add up, and a appears only when total liability crosses a cutoff.
2
Why risk does not transfer between groups
- A real association should reappear in independent samples; this idea is called ____.
- When the 8q24 signal (strong in Europeans) does not replicate in Asian or Native-American-ancestry samples, that is evidence of ancestry-dependent genetic ____.
- matters too: mothers who smoke and whose fetus lacks active detoxifying enzymes have roughly ____-fold higher risk.
Explore
Reading the Research
What to read
Read the title and the abstract only, not the whole paper. Rahimov et al. 2008, AP-2alpha site in an IRF6 enhancer and cleft lip (Nat Genet)
Why this source matters
This is the published evidence behind today's idea: risk is built from many small-effect alleles plus environment crossing a threshold, and because frequencies and effects differ by ancestry, a risk variant found in one group may not transfer to another.
Words to unlock first
Reading moves
- Skim the title and abstract first to get the gist.
- Circle the one sentence that states the main claim.
- Box the evidence the authors give for that claim.
- Mark one sentence that confuses you, and move on.
Stop point
You do not need the methods or statistics yet. If a sentence is about lab technique or math you have not learned, mark it and skip it.
Your output
Write one claim-evidence sentence: what this source claims, and the one piece of evidence that backs it up.
Lab day
Using the database (what to capture)
Part of today's expected outcome is to actually open the tool below and write down the value it gives you. That captured value is the evidence you will use in your Claim, Evidence, Reasoning. Follow the steps, use the labeled screenshot so you do not get lost, and record each field.
gnomAD (Genome Aggregation Database)
Open the tool A reference catalog of DNA variation from many thousands of mostly healthy people. It tells you how common a variant is overall and within each ancestry group, plus how tolerant a gene is to being broken.
When you use this: Use this when you must decide whether a variant is harmful. A change that damages a but is essentially absent from healthy people is a red flag for disease; a change common in healthy people is almost certainly harmless. gnomAD is the healthy-population yardstick.
What the screen looks like
Step by step
- 1Open gnomad.broadinstitute.org and search the gene IRF6, or paste a specific variant.
- 2Read the global (how often the change appears across all people).
- 3Open the populations breakdown to see the frequency by ancestry, and check the gene constraint scores (is tolerated?).
Capture these fields
- Variant or gene searched: IRF6 R84C (or the gene IRF6)
- Global allele frequency: 0 (absent), or a very small number like 0.00001
- Frequency by ancestry: Differs by group; for example rs642961 is ~0.11 in African and ~0.27 in Native American samples
- Gene constraint (LOEUF / pLI): IRF6 is constrained: a low LOEUF / high pLI means broken copies are not tolerated
How to read it: A damaging variant that is absent or extremely rare in gnomAD's healthy population is consistent with being pathogenic; a variant that is common in healthy people is evidence it is benign. A constrained gene (low LOEUF, high pLI) means losing a working copy tends to cause disease, so loss-of-function changes there deserve extra weight. Because frequencies differ by ancestry, always read the per-population numbers, not just the global one.
Lost? How to read gnomAD (constraint and frequency)Where this fits
Tested on (Ohio WebXam)
Genetics of Disease · 072130
PLTW lesson
MI · Genetics domain · Genetics and population health; risk factors
WebXam domain
Bio-Molecular Technology
Evidence to produce
A research consortium hands you a draft polygenic risk score for CL/P built entirely from European data and asks you to sign off for global clinical use. In three to four sentences, give your recommendation and cite at least two pieces of evidence (for example the 8q24 non-replication in Guatemalan families and the rs642961 non-replication in African-ancestry samples), then say what data you would need before the score could be trusted in a new population.
Lab / skill
Medical Interventions (MI) · AP Biology
Explore
Vetted readings for this lesson
- Rahimov et al. 2008, AP-2alpha site in an IRF6 enhancer and cleft lip (Nat Genet)
- Beaty et al. 2010, GWAS of CL/P, MAFB and ABCA4 (Nat Genet)
- Birnbaum et al. 2009, 8q24 susceptibility locus for nonsyndromic cleft lip (Nat Genet)
- Bezerra et al. 2019, IRF6 polymorphisms in Brazilian nonsyndromic CL/P (Braz J Otorhinolaryngol)
- gnomAD (Broad Institute): allele frequency by ancestry, search variant rs642961
The plan
Track your progress today
Check these off as you work through the lesson, then submit. This tells Mr. Mendoza how you're doing so he can help the class. It does not replace turning in your producible.
Use the code Mr. Mendoza gave you, not your name. Saved on this device.
Check off as you finish
- Read the Model and answered the Explore questions.
- Filled in the guided notes in my own words.
- Defined the new vocabulary with an example.
- Opened gnomAD (Genome Aggregation Database) and recorded the value it gave me.
- Built the producible: A research consortium hands you a draft polygenic risk score for CL/P built entirely from European data and asks you to sign off for global clinical use. In three to four sentences, give your recommendation and cite at least two pieces of evidence (for example the 8q24 non-replication in Guatemalan families and the rs642961 non-replication in African-ancestry samples), then say what data you would need before the score could be trusted in a new population.
- Wrote my Claim, Evidence, and Reasoning exit ticket.
Pick your period and code first.
Check yourself
Exit ticket (Claim, Evidence, Reasoning)
- Claim: A polygenic risk score for CL/P built in one population may not work in another.
- Evidence: rs987525 has an near ____ in Europeans but shows no evidence in Guatemalan families, and rs642961 fails to replicate in ____-ancestry samples.
- Reasoning: Because and effect differ by ancestry, a score built in one group is ____ in another.
How this is graded (rubric)
For: A research consortium hands you a draft polygenic risk score for CL/P built entirely from European data and asks you to sign off for global clinical use. In three to four sentences, give your recommendation and cite at least two pieces of evidence (for example the 8q24 non-replication in Guatemalan families and the rs642961 non-replication in African-ancestry samples), then say what data you would need before the score could be trusted in a new population.
| Criterion | Proficient | Developing | Beginning |
|---|---|---|---|
| Complete | Every required part of the artifact is present and filled in. | Most parts are present, but one is missing or left blank. | Several parts are missing. |
| Accurate | The science and data are correct and match the evidence. | Mostly correct, with a small factual slip. | Key science or data is wrong. |
| Scientific reasoning (CER) | States a claim, backs it with specific evidence, and explains the reasoning. | Has a claim and evidence, but the reasoning is thin or missing. | Gives an answer with no evidence or reasoning. |
| Professional communication | Clear, organized, and labeled the way a clinician or scientist would write it. | Readable but disorganized or missing labels. | Hard to follow. |
| Submitted | Turned in the right way (Schoology for routine work) and confirmed. | Turned in, but in the wrong place or unconfirmed. | Not turned in. |
How the model answer scores against this rubric
- CompleteProficient: Nothing is left blank: the model fills every part of "A research consortium hands you a draft polygenic risk score for CL/P built entirely from European data and asks you to sign off for global clinical use. In three to four sentences, give your recommendation and cite at least two pieces of evidence (for example the 8q24 non-replication in Guatemalan families and the rs642961 non-replication in African-ancestry samples), then say what data you would need before the score could be trusted in a new population.".
- AccurateProficient: Every number and claim matches the case evidence.
- Scientific reasoning (CER)Proficient: It names a claim, cites the specific evidence, and explains the reasoning, not just the answer.
- Professional communicationProficient: It is organized and labeled like a real chart note.
- SubmittedProficient: It would be turned in on Schoology and confirmed.
Explore
Where this leads: careers
Population Geneticist Genetic Epidemiologist
What's next: We found why CL/P differs across whole populations, but population averages are not a family. Mateo's parents now ask the practical question: if they have another child, what is the chance that child also has a ? That family is what we chase next.