1. W HAT D OES Y OUR G ENOME S AY A BOUT Y OU ? W HO S HOULD K NOW W HAT I T S AYS ? Spring 2016 W AKE B IOLOGY Original case reated by: Harvard Medical School Revisions by: AD Johnson, J Curran, Wake Forest University personal genetics education project

2. Our Genome is Our Personal, Unique DNA Information Affects appearance, behavior, health Half inherited from each parent, so: – We share traits with our parents – Siblings share traits – We pass traits to our children 2016: Even identical twins are unique!

3. MOST Traits & Variation Are Result Of Multiple Genes in Genome + Environment Example: This black female lab had THREE colors of puppies!

4. What Genes in Parents Produced These Colors? At least SEVEN genes control coat colors Each is different part of integrated “system”

5. One Locus, Called E Locus, Determines If Dogs (or Any Mammal) Makes Melanin At All Encodes receptor for melanocyte stimulating hormone (MSH) No receptor = no pigment How inherited, & WHY?

6. Which Dog Is LOW in Melanin?

7. The B Locus Controls Whether Dogs Make Black or Brown Melanin Melanin is brown until last step No last enzyme = brown With last enzyme = black

8. Here is a Gene-Environment Interaction

9. Body Temp Affects a Siamese’ Color Pattern One cat in show conditionand at home after retiring

10. A Temperature Sensitive Locus Controls When Siamese Cats Make ANY Melanins DOPA oxidase Body heat makes enzyme unfold –No first enzyme = pale Cool areas make working enzyme –With enzyme = dark Temp sensitive

11. What Is Genotype, Phenotype of Mother, Father That Produced These Puppies?

12. Pedigrees Trace Traits in Families Over Time

13. What Pattern Do You See?

14. Dominant Traits Appear Every Generation: One Copy of Mutated Allele is Enough Marfan sydrome: affects aorta, eyes, skeleton, lungs 1.All affected individuals have 1 affected parent. 2.About ½ of all children from an affected parent are affected. 3.Appears at different ages with differing severity

15. What Pattern Do You See?

16. These Are Recessive Inheritance Patterns: TWO Mutant Copies of Allele Needed Sickle cell anemia: recessive condition 1.Heterozygotes are “carriers.” 2.Unaffected parents can produce affected children. 3.About ¼ of children of 2 carriers are affected. 4.All children of affected individuals carry trait. 5.“Consanguinous” marriages increase risk

17. What Can We Deduce From This Pedigree? What Can We NOT Say? Maria Age 50 breast cancer MalcolmVanessa AngelaAshleyEmily Steven Chris Ages 22-37

18. What If We Cannot SEE Differences? Coat color, Marfan’s, SCA can be traced b/c responsible genes create visible changes Many disease genes: –Do not create visible “phenotype”, or –Appears too late for diagnosis, treatment How do we trace important genes we cannot see?

19. Which Celebrity’s Genetic Test Made News? 2013: double mastectomy at 37 –87% risk of breast cancer –Multiple family members died at young ages –50% risk ovarian cancer

20. “Reading” Our Genome: Genetic Marker Tests GQ #1: How do we know what to test for? GQ #2: What are the potential benefits, limits to genetic marker tests? GQ #3: What do we know as facts? What are we assuming? What more do we want to know?

21. Available Today! Our Entire Genome NIH Next-Gen Sequencing Goal : – “Complete” personal genomes – 6 Mbp sequenced for ~$1000 Why 6 Mbp? Why $1000

22. 6Mb Is What Makes Us Different! Human genomes are 99.8% identical. Total genetic variation is: 0.2% (1/500th) of genome, OR (3.2 x 10 9 bp × 0.002) ~ 6 million bp So WHY $1000?

23. “Reading” Our Genome: Whole Genome Sequencing GQ #4: What are potential risks & benefits of knowing entire genomes? GQ #5: Who should have access to the data? GQ #6: What information is/should be “public” vs. “private”? GQ #7: What decisions can be made based on those data?

24. Three Main Types of Genetic Tests Clinical tests –Mandatory: State of NC’s newborn screen –Diagnostic: Natera: Panorama Test, Horizon Screen Pathway Genomics: Carrier DNA Insight Federal identity tests Direct to consumer tests

25. Elective DNA Testing Genographic Project 23 and Me Ancestry DNA Family Tree DNA Full Genomes Determigene Sure Genomics All currently active companies Different: – Tests – End goals of testing – Levels of supporting evidence – Data sharing plans

26. Summarizing a Genetic Test Service What are they testing? Why are they testing it? What is the rationale? What is the evidence supporting their testing? Is this a “reasonable” testing tool? Who has access to the data collected? Have there been problems with their tests?

27. Groups Will Report Back on One Company Have 5 minutes at start of class to organize ~5 minute presentation: – What is group testing? – Why are they testing it? What is the rationale? – What is the evidence supporting their testing? – Is this a reasonable test? – Who has access to the data collected? 2-5 minutes for follow-up questions

28. Individual Homework: Follow-Up Summary 1.As a class, what were our major findings? (Limit to max. of 5) 2.What questions did we leave unanswered, or open for future discussion? 3.What are the greatest risks, benefits of genetic and genomic testing? What EVIDENCE are you basing your position on?

29. Individual Homework: Debrief and Wrap-Up 4.What were our learning goals for this ENTIRE topic? 5.Which activities helped us get to those goals? 6.Anything we should not do again? 7.What else would have been useful?

30. Genetic Tests: Comparison Example State of NC’s newborn screening program Mandatory clinical test for all newborns Starting Links: – http://www.babysfirsttest.org/newborn- screening/states/north-carolina http://www.babysfirsttest.org/newborn- screening/states/north-carolina – http://www.ncdhhs.gov/dph/wch/families/newborn metabolic.htm http://www.ncdhhs.gov/dph/wch/families/newborn metabolic.htm

31. Genetic Tests: Comparison Example Natera Inc., Panorama Test Prenatal clinical test through physicians only Starting Links: – http://www.panoramatest.com/en/expecting-mother http://www.panoramatest.com/en/expecting-mother – http://www.panoramatest.com/healthcare-provider http://www.panoramatest.com/healthcare-provider

32. T ESTING C OMPANIES TO E VALUATE Companies are numbered in order they will be presented. Which group evaluates the company was assigned at random.

33. Genetic Tests: Class Example #1 National Geographic Foundation’s Genographic Project Direct to consumer test / research Starting Links: – https://genographic.nationalgeographic.com https://genographic.nationalgeographic.com – http://education.nationalgeographic.com/education/gen ographic-project-educator-discount/?ar_a=1 http://education.nationalgeographic.com/education/gen ographic-project-educator-discount/?ar_a=1 Group 2

34. Genetic Tests: Class Example #2 23 and Me, Inc., Direct to consumer tests Ancestry screening and health markers Starting Links: – https://www.23andme.com https://www.23andme.com – https://www.23andme.com/research/ https://www.23andme.com/research/ Group 6

35. Genetic Tests: Class Example #3 Ancestry DNA Direct to consumers Personal DNA marker testing Starting Links: – http://dna.ancestry.com/ http://dna.ancestry.com/ – http://dna.ancestry.com/legal/informedConsent http://dna.ancestry.com/legal/informedConsent Group 4

36. Genetic Tests: Class Example #4 Family Tree DNA Direct to consumers DNA analysis for lineage tracing Starting Links: – https://www.familytreedna.com/ https://www.familytreedna.com/ – https://www.familytreedna.com/learn/ https://www.familytreedna.com/learn/ Group 1

37. Genetic Tests: Class Example #5 Full Genomes Corp. Direct to consumer test Full genome sequencing Starting Links: – https://www.fullgenomes.com https://www.fullgenomes.com – https://www.fullgenomes.com/purchases/11/ https://www.fullgenomes.com/purchases/11/ Group 7

38. Genetic Tests: Class Example #6 Determigene Direct to consumer Multiple DNA tests Starting Links: – http://www.determigene.com/ http://www.determigene.com/ – http://www.determigene.com/products_services.asp http://www.determigene.com/products_services.asp Group 5

39. Genetic Tests: Class Example #7 Sure Genomics, Inc. Direct to consumers Full genomic DNA sequences Starting Links: – http://www.suregenomics.com/ http://www.suregenomics.com/ – http://www.suregenomics.com/about-us/ http://www.suregenomics.com/about-us/ Group 3