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2/16/2016 Recent DNA evidence Human genetics in the 21st century: Using bioinformatics to link genetics and traits Get a clue: CSI and the science of forensics (2016) Bioinformatics and Research Computing Whitehead Institute http://jura.wi.mit.edu/bio/ The New York Times DNA analysis of other “animals” 2 Linking genes and traits • To do this, we need to know something about Yeti: Extinct(?) polar bear Bigfoot: Cow Horse Wolf/coyote/dog Deer Sheep Raccoon Porcupine Human – Associations between genetic markers and physical traits – Gene function and regulation • Bioinformatics tries to address both topics 3 Jughead, May 1997 4 1 2/16/2016 150 years ago (1865) • Mendel presented his “Experiments on Plant Hybridization” Led to the particulate theory of inheritance George Bell Bioinformatics Bingbing Yuan Prat Thiru Yanmei Huang Inma Barrasa Tom DiCesare 6 Graphics Selected discoveries since Mendel • 1950s Linking genetics and traits using genomics • To do this, we need only – DNA is the genetic material – The structure of DNA • 1960s – Genome sequence (or a sample of it) for many individuals – The genetic code (DNA => protein) • 1970s – DNA sequencing – Selected trait(s) for the same individuals • 1990s‐2000s – Genome sequencing – [Some complex statistics] 7 8 2 2/16/2016 Sampling genome sequence Single nucleotide polymorphisms • Most of the genome is identical between individuals • Let’s concentrate only on the places that are the most different • SNPs (pronounced “snips”) because – Single: were looking at just one genome position – Nucleotide: DNA letter differs – Polymorphism: variation occurring commonly in a population (in at least 1% of individuals) Different locations in the genome Different individuals • SNPs can be in a gene or between genes 9 10 But humans (like peas) are diploid Nearby SNPs are associated • We have 2 genomes, with 2 copies of each chromosome • Each SNP can be • Nearby SNPs tend to stay together during meiosis • As a result, they tend to be genetically linked • One “tag SNP” can be used to represent a set of linked SNPs – Homozygous (ex: CC), or – Heterozygous (ex: TG) Genotype block “B” Different individuals Different individuals Genotype block “A” (linked SNPs) 11 12 3 2/16/2016 Genome‐wide association study (GWAS) Combining phenotype with genotype • Genotype: use all SNPs or a subset of tag SNPs • Phenotype: whatever trait(s) we want to study (as long as we think they at least partly genetic) Genotype block “B” Genotype block “A” Genotype block “B” Different individuals Different individuals Genotype block “A” • Compare every marker (SNP, tag SNP, etc.) to every trait • Is the trait associated (correlated) with any marker? 13 Interpreting GWAS 14 Exercise 1 • What does it mean that a trait is associated with a genetic marker? • Does the marker cause the trait? More research needed…. • Multiple markers can be associated with the same trait • Perform a small‐scale GWAS analysis Genotype block “B” Different individuals Genotype block “A” 15 16 4 2/16/2016 Resources for genotype‐phenotype interactions The GWAS catalog keeps growing As of 2014: Every point is an association with a trait or a disease http://www.ebi.ac.uk/fgpt/gwas/ 17 • Genotypes have been collected from large‐scale projects like – HapMap http://hapmap.ncbi.nlm.nih.gov – 1000 Genomes http://www.1000genomes.org • These projects include many populations (“ethnic groups”) • Sample HapMap data for SNP rs1834640 Fraction with this genotype Online Mendelian Inheritance in Man http://omim.org GWAS catalog http://www.genome.gov/gwastudies/ PheGenI http://www.ncbi.nlm.nih.gov/gap/phegeni/ ClinVar http://www.ncbi.nlm.nih.gov/clinvar/ SNPedia http://www.snpedia.com 18 Exploring genotype‐phenotype associations Taking ethnicity into account 100% 80% 60% 40% 20% 0% • • • • • • Detecting an association is only the first step. • One typically also wants to associate a trait with the choices of genotypes at that SNP. • SNPedia often reports these, such as for rs671 GG AG AA YRI JPT CHB Population CEU • What’s usual for one population may be very unusual for another population 19 20 5 2/16/2016 Interpreting associations Exercise 2 • An association means that the genotype of a marker (like a SNP) can help predict the presence of a trait, BUT – The SNP itself might have no effect – it may just be linked to another DNA element that has the effect – The effect may be very small – The association may be present only in certain individuals – The association may be one of many for this trait – it may only appear to be present (until other independent studies can verify it) • Link the genotype of your DNA sample to potential traits Note that this application of genetic association is not currently applied to forensics. • What experiment(s) could you design to verify that a SNP causes some effect? 21 22 Summary • One’s DNA can reveal hints about one’s – physical (and even mental) characteristics – medical and disease risks – family history => forensics => medicine => genealogy • A trait can be influenced by many genes (unlike Mendel’s pea traits) • In the future, how will scientists make this information even more useful? 23 6