The Personal Genome Navigating the DNA Marketplace Bryant McAllister, PhD Associate Professor of Biology University of Iowa bryant-mcallister@uiowa.edu The Triangle Club February 18, 2018

The Personal Genome Recreational Genetics – analyses of individual DNA sequence data to inform geographic ancestry, biological relationships and physical/behavioral traits through direct-to-consumer (DTC) genetic tests. Personalized Medicine – analyses of individual DNA sequence data to diagnose genetic causation of a medical condition and/or tailor medical treatment under guidance of a physician and supported by other medical services. Define Genome _ the entirety of DNA sequence information present in each of your cells, and shared among the cells of your body First Human Genome Sequence completed in 2003 – a reference for you, but different Recreation Genetics – use of your own, or family members, genetic data to inform geographic origins, biological relationships, physical/behavioral traits Different from Personalized Medicine – use of your genetic data to diagnose or treat diseases 1) How many are familiar with direct-to-consumer genetic tests? Show hands 2) Keep hands raised if you have done a test yourself, or manage the test of a family member 3) Keep hands raised if you have done multiple tests on yourself, or manage multiple tests

Introduced in November 2007 at $999 Introduced in November 2007 at $999. Price dropped to $299 in May 2012, and reduced again to $99 in December 2012.

DNA Interest Group Meetings: 4th Tuesday of each month, 6-7 pm Iowa City Public Library, Room A February 27 – Race & Ancestry March 27 – Why the Y Chromosome April 24 – National DNA Day May 23 – Pharmacogenetics

Personal Genome Learning Center Mission: foster knowledge of genetic and evolutionary principles through engagement with personal genomics Engage students in the application of genetic and evolutionary principles through the exploration of personal genome data. Involve students in public outreach events and workshops that support understanding of personal genome results and applications. Develop resources that support learning genetic and evolutionary principles relevant to understanding personal genome data.

Three of the major players in the direct-to-consumer genetic testing marketplace. Ask: How many have done a test by one of these three companies?

Genome-wide SNP Analysis: Major Testing Options 23andMe – Report revised in 2015. Includes Ancestry Estimates & DNA Matching ($99 list); Carrier Status & Trait Prediction reports also available ($199 list). AncestryDNA – Includes Ancestry Estimate and DNA Matching ($99 list). Integrated with Ancestry.com family tree for an extra subscription fee. MyHeritageDNA – Includes Ancestry Estimate and DNA Matching ($99 list). DNA matches on same platform as tree-building infrastructure. Family Tree DNA – Various tests available including Family Finder SNP test ($79 list).

Long standing interest in the science, technology and applications in “recreational genetics” A little over a year ago, I proposed to offer a first-year seminar course on personal genomics, including an opportunity for students to do a test on themselves, and then set out to learn what was offered by the different companies. First, parents given AncestryDNA tests Tested myself using the Geno2.0 kit from The Genographic Project; finding – I’m basically a brit with a bit of Native American mixed in.

Genome-wide snp analysis Now, I want to turn the attention to genetic test of your whole genome. If you have ever seen a news story with the title of, “genes associated with” or “genes identified that cause” its likely that this is a discovery enabled by the same or similar testing platform you can pay $99 to have your own genome analyzed. Chromosomes, DNA, and your unique genetic profile

DNA is the Cellular Recipe for Life A Genome is the entire set of DNA molecules present in a cell. Each DNA molecule contains a string of A=T pairs and G≡C pairs as a DNA sequence. Cells of an individual contain the same genome sequence, but different from any other individual. In the case of mitochondrial DNA, it about 16,000 pairs of A-T and G-C bases. Change in the bases of mtDNA through mutation, thus changes in DNA sequence is relatively slow, so your mtDNA sequence is likely the same as your mothers, and her mothers, but as you move back through the generations changes will have accumulated in your lineage compared to others in this room.

The Human Genome Chromosomes: 23 pairs of linear DNA molecules inherited from both parents; 22 pairs of autosomes, and a single pair of sex chromosomes Gametes (egg or sperm) contain only 1 member of each pair

The Human Genome Chromosomes: 23 pairs of linear DNA molecules inherited from both parents; 22 pairs of autosomes, and a single pair of sex chromosomes Gametes (egg or sperm) contain only 1 member of each pair

Single Nucleotide Polymorphism SNP Analysis Single Nucleotide Polymorphism My mum’s hair colour is grey. My mom’s hair color is gray.

Single Nucleotide Polymorphism SNP Analysis Single Nucleotide Polymorphism My mom’s hair color is gray. My mom’s hair color was gray.

Genome-Wide SNP Analysis Each company uses a common testing technology that assesses about 600,000 different known variable sites (SNPs) in the DNA of your genome (including mtDNA in some cases). Most of the same sites are used in the tests of different companies.

Genome-Wide SNP Analysis # rsid chromosome position genotype rs12564807 1 734462 AA rs3131972 1 752721 AG rs148828841 1 760998 CC rs12124819 1 776546 AA rs115093905 1 787173 GG rs11240777 1 798959 AG rs7538305 1 824398 AC rs4475691 1 846808 CT rs7537756 1 854250 AG rs13302982 1 861808 GG rs55678698 1 864490 CC rs1110052 1 873558 TT rs147226614 1 878697 GG i6052728 1 878697 GG i6019302 1 881843 GG rs2272756 1 882033 GG

Ancestry composition Now, I want to turn the attention to genetic test of your whole genome. If you have ever seen a news story with the title of, “genes associated with” or “genes identified that cause” its likely that this is a discovery enabled by the same or similar testing platform you can pay $99 to have your own genome analyzed. Predicting the geographic origins of your ancestors

Prediction of Ancestry Composition G Given an individual with this genotype, what geographic areas is the person likely from? http://popgen.uchicago.edu/ggv/

These two tests are the most different in the sites analyzed These two tests are the most different in the sites analyzed. Results here are from the same person.

Uni-Parental Inheritance Maternal Transmission of mtDNA Paternal Transmission of the Y chromosome I’ll return to mtDNA haplogroups later in the talk. I’ve had my own mtDNA sequenced, and frankly it’s not that interesting or informative. I do hope, however, you have an appreciation of how the analysis of the mtDNA sequence can be used to identify relationships between you and others, and that the relationships identified through analysis of mtDNA only represent a single line of ancestry; mom to mom to mom. Now I want to turn to another single line of ancestry, the paternal line. Early successes in the analysis of mtDNA to determine relationships in humans were immediately complemented with analyses of the Y chromosome, which traces paternal lineages. Although, analysis of the Y chromosome is only applicable to males, it is broadly used in recreational genetics.

Uni-Parental Haplogroups Both 23andMe and Genographic Project predict haplogroup for mtDNA and Y chrom (for males) using SNPs on these DNAs

Y Chromosome Tree

DNA Relatives Revealing common ancestry through DNA matching Now, I want to turn the attention to genetic test of your whole genome. If you have ever seen a news story with the title of, “genes associated with” or “genes identified that cause” its likely that this is a discovery enabled by the same or similar testing platform you can pay $99 to have your own genome analyzed. Revealing common ancestry through DNA matching

Segment Matching Between Relatives identical segment Focusing on a single pair of chromosomes, this diagram illustrates the reduction in the length of a chromosome region inherited from a single ancestor. Exchange between pairs of chromosomes, which can occur each generation, reduces the size of regions inherited from ancestors. The 1st cousins in this diagram each inherited regions of this chromosome from their common grandfather. The brackets encompass an identical segment shared between the cousins in the overlapping region. Exchange between chromosome pairs gradually reduces the size of regions inherited from ancestors; however, segregation can result in the loss of identity with ancestors. At the 2nd cousin level of this diagram, the grandfather’s chromosome region is transmitted in the lineage on the left, whereas it is lost in the lineage on the right. Segregation produces a 50:50 chance of retention and loss of ancestral chromosome regions each generation. These processes occur independently across each of the 22 pairs of autosomes. Considering all 22 pairs of autosomes and the amount of exchange within these pairs, full 1st cousins with two common grandparents are expected to share 41 identical segments, on average. The expected number of identical segments shared between full 2nd cousins drops considerably to only 15.

at least one common variant at all SNPs in this segment Matching of SNPs # rsid chromosome position Tester Match rs12564807 1 734462 AA GG rs3131972 1 752721 GG AG rs148828841 1 760998 CC CC rs12124819 1 776546 AA AA rs115093905 1 787173 GG GG rs11240777 1 798959 GG AG rs7538305 1 824398 AA AC rs4475691 1 846808 TT CT rs7537756 1 854250 GG AG rs13302982 1 861808 GG GG rs55678698 1 864490 CC CT rs1110052 1 873558 GG TT rs147226614 1 878697 GG GG i6052728 1 878697 GG GG i6019302 1 881843 GG GG rs2272756 1 882033 AA GG Half-Identical: at least one common variant at all SNPs in this segment

Genetics for Genealogy Results vary dramatically based on individual ancestry and database composition – test the oldest generation. American Colonial Ancestry 19th Century German Migrants to Texas Two females, both born about 1940

Genetics for Genealogy Results vary dramatically based on individual ancestry and database composition – test the oldest generation. American Colonial Ancestry & 1/8 19th Century Irish Migrants 19th Century German Migrants Their children, both born in late 1960’s

Genetics for Genealogy Results vary dramatically based on individual ancestry and database composition – test the oldest generation. Endogamy increases the background level of relatedness among individuals. Lists of DNA matches contain two types of errors: The genetic identity shared with the relative was not inherited from your most common ancestor(s), but rather a more distant ancestor. Relatives descended from a known common ancestor(s) do not appear in the list of DNA relatives. DNA relatives may be connected through multiple pathways of common ancestry.

Family Testing Strategy Test my (and my mother’s) mtDNA; and my dad’s mtDNA Currently conducting a test on distant cousin that should share my Y chromosome Also, testing the Y from a cousin of my mothers to examine my maternal grandfathers patriline ~50% identical

Genetics for Genealogy: Major Testing Options AncestryDNA ($99 list) – Fully integrated with active Ancestry.com tree with powerful features; no ability to directly examine matching DNA segment(s) MyHeritageDNA ($99 list) – Detailed information on genetic basis of DNA matches; DNA matches exist on site for building family trees (accepts raw data from 23andMe or AncestryDNA) Family Finder Test at Family Tree DNA ($79 list) – Broad set of features to examine DNA matches; website navigation challenging and database relatively small (accepts raw data from 23andMe or AncestryDNA) 23andMe ($199 or $99) – Good for broad set of interpretations, entertainment, & validating relationships; most users are private and not motivated by genealogy

Traits Now, I want to turn the attention to genetic test of your whole genome. If you have ever seen a news story with the title of, “genes associated with” or “genes identified that cause” its likely that this is a discovery enabled by the same or similar testing platform you can pay $99 to have your own genome analyzed. Inference of personal characteristics influenced by your genetic profile

Considerations Now, I want to turn the attention to genetic test of your whole genome. If you have ever seen a news story with the title of, “genes associated with” or “genes identified that cause” its likely that this is a discovery enabled by the same or similar testing platform you can pay $99 to have your own genome analyzed.

informed decisions about whether to use such services.” “There is also a continuing need for educational initiatives that will allow consumers to understand what test results will mean for them in order to make informed decisions about whether to use such services.”

Questions About DNA Tests What outcome(s) do you want in the test results? What does the DNA test assay? What interpretations are delivered in the results? How would you use these results? What is the cost, and how does it compare with competitors? Are there additional fees associated with access or use of test results? Are other customers satisfied with the service? Are the terms of service acceptable to you?

Potential Consequences of the Results from a Personal Genetic Test Surprising findings about family relationships New relatives discovered by genetic matching Discovery of genetic relationship between your parents Different relationship than expected with other tested family members Surprising prediction of ancestry composition Individuals contain a genetic mixture representative of their ancestry through human history Surprising discovery of genetic susceptibility to disease You and/or your children may have an increased chance of developing an incurable genetic disease