Computational Personal Genomics: Making Sense of Complete Genomes

Readings

All students were required to respond to each paper (PDF).

SES #	TOPICS	READINGS
1	Human Variation: Challenges in human genomics, Variation, haplotypes, LD, Common and rare variant association	Lander. “Initial Impact of the Sequencing of the Human Genome.” Nature 470 (2011): 187–97. The 1000 Genomes Project Consortium. “A Global Reference for Human Genetic Variation.” Nature 526, no. 7571 (2015): 68–74.
2	Trait Association: Common and rare variant association, Mendelian vs. Complex, Basics of an association study, Phenotypes	Lander, Eric S., and Nicholas J. Schork. “Genetic Dissection of Complex Traits.” Science 265, no. 5181 (1994): 2037–48. Altshuler, et al. “Genetic Mapping in Human Disease.” Science 322, no. 5903 (2008): 881–8. Zuketal. “Searching for Missing Heritability: Designing Rare Variant Association Studies.” Proceedings of the National Academy of Sciences of the United States of America 111, no. 4 (2014): E455–64.
3	Personal Genomics and Ethics: Research studies: Consent, privacy, returning results, Medical applications: Testing, public health issues, obligations to relatives, privacy, Consumer options: Carrier testing, newborn testing, genetic testing, Gene editing: Benefits, ethical issues, where to draw the line	Overview Hudson. “Genomics, Health Care, and Society.” The New England Journal of Medicine, no. 365 (2011): 1033–41. Medicine Fulda, and Lykens. “Ethical Issues in Predictive Genetic Testing: A Public Health Perspective.” Journal of Medical Ethics 32, no. 3 (2006): 143–7. Prenatal / Newborns Almond. “Genetic Profiling of Newborns: Ethical and Social Issues.” Nature Reviews Genetics 7 (2006): 67–71. Henn. “Consumerism in Prenatal Diagnosis: A Challenge for Ethical Guidelines.” Journal of Medical Ethics 26, no. 6 (2000): 444–6. Yurkiewicz, et al. “Prenatal Whole-Genome Sequencing-Is the Quest to Know a Fetus’s Future Ethical?” The New England Journal of Medicine, no. 370 (2014): 195–7. Gene Editing Lanphier, et al. “Don’t Edit the Human Germ Line.” Nature 519, no. 7544 (2015).
4	Interpreting Coding (Rare) Variants: Rare variant detection from exome sequencing in family studies, Aggregate analyses (e.g. ExAC), Classifying function (PolyPhen), Overlapping constraint	Adzhubei, et al. “A Method and Server for Predicting Damaging Missense Mutations.” Nature Methods 7, no. 4 (2010): 248–9. Exome Aggregation Consortium. “Analysis of Protein-coding Genetic Variation in 60,706 Humans.” Nature 536, no. 7616 (2015): 285–91. Homsy, et al. “De Novo Mutations in Congenital Heart Disease with Neurodevelopmental and Other Congenital Anomalies.” Science 350, no. 6265 (2015): 1262–6. Flannick, et al. “Loss-of-function Mutations in SLC30A8 Protect Against Type 2 Diabetes.” Nature Genetics 46, no. 4 (2014): 357–63.
5	Interpreting Non-Coding (Common) Variants: Enriched cell types, Causal variants: Epigenomics, Comparative Genomics, Target genes: HiC, genetic links, activity links, Upstream regulators: Regulatory motifs, TF binding	Ward, and Kellis. “Interpreting Noncoding Genetic Variation in Complex Traits and Human Disease.” Nature Biotechnology 30 (2012): 1095–106. Kundaje, et al. “Integrative Analysis of 111 Reference Human Epigenomes.” Nature 518, no. 7539 (2015): 317–30. Claussnitzer, et al. “FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.” The New England Journal of Medicine 373 (2015): 895–907.
6	Bayesian Fine-Mapping and Multi-dimensional GWAS: Fine-mapping (Posterior probabilities). Bayesian models for computational fine-mapping, Multi-dimensional GWAS (Multi-Phenotype, Multi-ancestry, Multi-variant)	Pickrell. “Joint Analysis of Functional Genomic Data and Genome-wide Association Studies of 18 Human Traits.” Cell 94, no. 4 (2014): 559–73. Kichaev, et al. “Integrating Functional Data to Prioritize Causal Variants in Statistical Fine-Mapping Studies.” PLOS Genetics (2014).
7	Intermediate Phenotypes and QTLs: eQTLs, meQTLs, and other molecular traits, Allelic activity, Causality and mediation analysis, Mendelian randomization analysis	The GTEx Consortium. “The Genotype-Tissue Expression (GTEx) Pilot Analysis: Multitissue Gene Regulation in Humans.” Science 348, no. 6235 (2015): 648–60. Baran, et al. “The Landscape of Genomic Imprinting Across Diverse Adult Human Tissues.” Genome Resource 25 (2015): 927–36. Liu, Aryee, et al. “Epigenome-wide Association Data Implicate DNA Methylation as an Intermediary of Genetic Risk in Rheumatoid Arthritis.” Nature Biotechnology 31 (2013): 142–7.
8	Heritability and Phenotype Prediction: Missing heritability, heritability estimation, heritability partitioning, Polygenic risk scores, Predicting intermediate phenotypes	Golan, et al. “Measuring Missing Heritability: Inferring the Contribution of Common Variants.” Proceedings of the National Academy of Sciences of the United States of America 111, no. 49 (2014): 5272–81. Gusev, et al. “Partitioning Heritability of Regulatory and Cell-type-specific Variants Across 11 Common Diseases.” The American Journal of Human Genetics 95, no. 5 (2014): 535–52. Gamazon, et al. “A Gene-based Association Method for Mapping Traits Using Reference Transcriptome Data.” Nature Genetics 47 (2015): 1091–8.
9	Human Ancestry and Population Genetics: Coalescent theory. Recent Selection, Sweeps, Selection Pressures, Population Stratification. Admixture Mapping, Ancestral genome sequencing and analysis	Novembre, et al. “Genes Mirror Geography Within Europe.” Nature 456 (2008): 98–101. Sabeti, et al. “Positive Natural Selection in the Human Lineage.” Science 312, no. 5780 (2006): 1614–20. Sankararaman, et al. “The Genomic Landscape of Neanderthal Ancestry in Present-day Humans.” Nature 507, no. 7492 (2014): 354–7.
10	Cancer Genomics and Single-Cell Genomics: Genetic alterations: Somatic mutations, mutational signatures, rearrangements, Epigenetic alterations: Methylation, miRNAs, reprogramming, origin, Convergence at the regulatory region, gene, pathway, cellular level. Guiding convergence with physical, genetic, and activity networks	Cancer Genome Atlas. “Comprehensive Molecular Portraits of Human Breast Tumours.” Nature 490, no. 7418 (2012): 61–70. Lawrence, et al. “Mutational Heterogeneity in Cancer and the Search for New Cancer-associated Genes.” Nature 499, no. 7457 (2013): 214–8. Patel, et al. “Single-cell RNA-seq Highlights Intratumoral Heterogeneity in Primary Glioblastoma.” Science 344, no. 6190 (2014): 1396–401.
11	Experimental Manipulations: Genome editing and CRISPR, Experiment multiplexing, Screening and selection	Gaj, et al. “ZFN, TALEN, and CRISPR / Cas-based Methods for Genome Engineering.” Trends Biotechnology 31, no. 7 (2013): 397–405. Melnikov, et al. “Systematic Dissection and Optimization of Inducible Enhancers in Human Cells Using a Massively Parallel Reporter Assay.” Nature Biotechnology 30, no. 3 (2012): 271–7. Koike-Yusa, et al. “Genome-wide Reces-sive Genetic Screening in Mammalian Cells With a Lentiviral CRISPR-guide RNA Library.” Nature Biotechnology 32, no. 3 (2014): 267–73.
12	Final presentations	n/a