Genetic Basis of Human Disease and Implications for Germline Editing.

Slides:



Advertisements
Similar presentations
Mendelian Genetics.
Advertisements

Linkage and Genetic Mapping
Medical Genetics 1 Prof Duncan Shaw
Note that the genetic map is different for men and women Recombination frequency is higher in meiosis in women.
SNP Applications statwww.epfl.ch/davison/teaching/Microarrays/snp.ppt.
Mendelian Genetics K. Sathasivan Basic genetic terms. Mendel's laws of inheritance. Complexities of genetic expression. Mendelian genetics in Humans.
ANNOUNCEMENTS  Homework #2 is due on Monday in lecture.  Change to 1b. Do not calculate a  2 value. Just calculate the expected phenotypic ratios if.
Chapter 5 Heredity.
Genetic Analysis in Human Disease
November 17, 2007Georgia Tech / ORNL Bioinformatics Conference1 Opportunities at the NIH Peter Good, Ph.D. NHGRI November 17, th Georgia Tech / ORNL.
Patterns of Inheritance Chapter 14, 15 Mendelian Genetics and its Extensions.
Genetics SC Biology Standard B The students will be able to predict inherited traits by using the principles of Mendelian Genetics, summarize.
14.1 Human Chromosomes What makes us human? What makes us different from other animals such as a chimpanzee? About 1% of our DNA differs from a chimp.
Office hours Wednesday 3-4pm 304A Stanley Hall. Fig Association mapping (qualitative)
Human Genetics Introduction 1.
Dr. Almut Nebel Dept. of Human Genetics University of the Witwatersrand Johannesburg South Africa Significance of SNPs for human disease.
Genetics for Imagers: How Geneticists Model Quantitative Phenotypes
Introduction to Inheritance Sara Levene Registered Genetic Counsellor London IDEAS Genetic Knowledge Park.
Variation.
Common Disease Findings (case study on diabetes) GWAS Workshop Francis S. Collins, M.D., Ph.D. National Human Genome Research Institute May 1, 2007.
Autosomal dominant inheritance Risks to children where both parents are affected: the basics a tutorial to show how the genes segregate to give the typical.
Beginnings PART 2 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
GENETICS AND POLITICS Benedicte Callan Sid Richardson Fellow LBJ School, Center for Health and Social Policy LBJ School, CHASP 1.
1 Human Genetics Biology: Exploring Life Campbell, Williamson, Heyden Prentice Hall.
1 Modern Genetics Chapter 4. 2 Human Inheritance Some human traits are controlled by single genes with two alleles, and others by single genes with multiple.
Chapter 14 – The Human Genome
Chapter 12 Human Genetics.
Genetic Analysis in Human Disease. Learning Objectives Describe the differences between a linkage analysis and an association analysis Identify potentially.
Genes, Environment- Lifestyle, and Common Diseases Chapter 5.
PowerPoint Lecture Outlines to accompany
The medical relevance of genome variability Gabor T. Marth, D.Sc. Department of Biology, Boston College Medical Genomics Course – Debrecen,
Sample pedigree - cystic fibrosis female male affected individuals.
Mapping of complex traits Andy Willaert Center for Medical Genetics Ghent.
1 Genes, Environment- Lifestyle, and Common Diseases Chapter 5.
Whole genome association studies Introduction and practical Boulder, March 2009.
Genes, Environment, and Common Diseases Chapter 5 Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.
Genetic Disorders By: Tanner and Jack.
What’s the Difference? Genetic and Common Diseases.
QTL Studies- Past, Present and Future David Evans.
Genetic disorders can be due to any of the following factors: A. Monogenetic Disorders: Caused by a mutation in a single gene 1. Autosomal recessive alleles:
PEDIGREES (12.3) * a chart that shows how a trait and the genes that control it are inherited within a family. Symbols: female male mate/ marriage offspring.
Other Diseases & Disabilities
A genetic disorder is an illness caused by one or more abnormalities in the genome, especially a condition that is present from birth (congenital). Most.
Unit 2 – Pedigrees.
GENETICS Dr. Samar Saleh Assiss. Lecturer Mosul Medical College Pathology3 rd year.
WHAT IS THE IMPACT OF THE HUMAN GENOME PROJECT FOR DRUG DEVELOPMENT? Arman & Fin.
Diseases caused by abnormal chromosomes or by defective genes inherited from one or both parents.
Physician Assistants and Personalized Medicine Francis S. Collins, M.D., Ph.D. National Human Genome Research Institute PAEA Annual Meeting October 27,
Gene350 Animal Genetics Lecture 5 3 August Last Time Study chromosomes – The normal karyotypes of animals – Chromosomal abnormalities – Chromosomal.
1 Finding disease genes: A challenge for Medicine, Mathematics and Computer Science Andrew Collins, Professor of Genetic Epidemiology and Bioinformatics.
Brendan Burke and Kyle Steffen. Important New Tool in Genomic Medicine GWAS is used to estimate disease risk and test SNPs( the most common type of genetic.
variation and Hardy-Weinberg principle
Allele-Specific Copy Number in Tumors
Extending Mendelian Genetics
Heredity Chapter 11 Green Book.
Extensions on Mendelian Genetics
Two copies of each autosomal gene affect phenotype.
Chromosomes and inheritance.
Different mode and types of inheritance
Genetic Testing.
Beyond GWAS Erik Fransen.
Pedigrees BIO Predict offspring ratios based on a variety of inheritance patterns (including dominance, co-dominance, incomplete dominance, multiple.
MENDEL AND THE GENE IDEA OUTLINE
Recent Insights Into the Genetics of Inflammatory Bowel Disease
Class Notes #8: Genetic Disorders
Medical genomics BI420 Department of Biology, Boston College
Medical genomics BI420 Department of Biology, Boston College
Heredity Review Chapters
Introduction to Genetics
Chapter 10 assessment.
Presentation transcript:

Genetic Basis of Human Disease and Implications for Germline Editing

Human Diseases and Traits Rare, Mendelian Cystic fibrosis, Huntington Disease, Diastrophic Dysplasia … Common, polygenic Heart disease, Alzheimer’s Schizophrenia, Height, Obesity Intelligence?... Avoid all cases of severe genetic disease Eliminate disease alleles from population Eliminate disease risk ’Enhance’ human population What do we know about disease genes?

1. Principles for Mapping Disease Genes (1980s) A - C + A - C + A - C + A - C +

Mapping Disease Genes: Rare, Mendelian Linkage Mapping in Families Rare Inherited: Monogenic A - C + A - C + A - C + A - C + A - + C A/C Disease Gene

From Gene Mapping to Gene Discovery 1 Million bases

Cystic Fibrosis Gene ATGCAGAGGTCGCCTCTGGAAAAGGCCAGCGTTGTCTCCAAACTTTTTTTCAGCT GGACCAGACCAATTTTGAGGAAAGGATACAGACAGCGCCTGGAATTGTCAGACAT ATACCAAATCCCTTCTGTTGATTCTGCTGACAATCTATCTGAAAAATTGGAAAGAG AATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCTAAACTCATTAATGCCCTTCG GCGATGTTTTTTCTGGAGATTTATGTTCTATGGAATCTTTTTATATTTAGGGGAAGT CACCAAAGCAGTACAGCCTCTCTTACTGGGAAGAATCATAGCTTCCTATGACCCG GATAACAAGGAGGAACGCTCTATCGCGATTTATCTAGGCATAGGCTTATGCCTTC TCTTTATTGTGAGGACACTGCTCCTACACCCAGCCATTTTTGGCCTTCATCACATT GGAATGCAGATGAGAATAGCTATGTTTAGTTTGATTTATAAGAAGACTTTAAAGCT GTCAAGCCGTGTTCTAGATAAAATAAGTATTGGACAACTTGTTAGTCTCCTTTCCA ACAACCTGAACAAATTTGATGAAGGACTTGCATTGGCACATTTCGTGTGGATCGC TCCTTTGCAAGTGGCACTCCTCATGGGGCTAATCTGGGAGTTGTTACAGGCGTCT GCCTTCTGTGGACTTGGTTTCCTGATAGTCCTTGCCCTTTTTCAGGCTGGGCTAG GGAGAATGATGATGAAGTACAGAGATCAGAGAGCTGGGAAGATCAGTGAAAGAC TTGTGATTACCTCAGAAATGATTGAAAATATCCAATCTGTTAAGGCATACTGCTGG GAAGAAGCAATGGAAAAAATGATTGAAAACTTAAGACAAACAGAACTGAAACTGA CTCGGAAGGCAGCCTATGTGAGATACTTCAATAGCTCAGCCTTCTTCTTCTCAGG GTTCTTTGTGGTGTTTTTATCTGTGCTTCCCTATGCACTAATCAAAGGAATCATCC TCCGGAAAATATTCACCACCATCTCATTCTGCATTGTTCTGCGCATGGCGGTCAC TCGGCAATTTCCCTGGGCTGTACAAACATGGTATGACTCTCTTGGAGCAATAAAC AAAATACAGGATTTCTTACAAAAGCAAGAATATAAGACATTGGAATATAACTTAAC GACTACAGAAGTAGTGATGGAGAATGTAACAGCCTTCTGGGAGGAGGGATTTGG GGAATTATTTGAGAAAGCAAAACAAAACAATAACAATAGAAAAACTTCTAATGGTG ATGACAGCCTCTTCTTCAGTAATTTCTCACTTCTTGGTACTCCTGTCCTGAAAGAT ATTAATTTCAAGATAGAAAGAGGACAGTTGTTGGCGGTTGCTGGATCCACTGGAG CAGGCAAGACTTCACTTCTAATGGTGATTATGGGAGAACTGGAGCCTTCAGAGGG TAAAATTAAGCACAGTGGAAGAATTTCATTCTGTTCTCAGTTTTCCTGGATTATGC CTGGCACCATTAAAGAAAATATCATCTTTGGTGTTTCCTATGATGAATATAGATAC AGAAGCGTCATCAAAGCATGCCAACTAGAAGAGGACATCTCCAAGTTTGCAGAGA AAGACAATATAGTTCTTGGAGAAGGTGGAATCACACTGAGTGGAGGTCAACGAGC AAGAATTTCTTTAGCAAGAGCAGTATACAAAGATGCTGATTTGTATTTATTAGACTC TCCTTTTGGATACCTAGATGTTTTAACAGAAAAAGAAATATTTGAAAGCTGTGTCT GTAAACTGATGGCTAACAAAACTAGGATTTTGGTCACTTCTAAAATGGAACATTTA AAGAAAGCTGACAAAATATTAATTTTGCATGAAGGTAGCAGCTATTTTTATGGGAC ATTTTCAGAACTCCAAAATCTACAGCCAGACTTTAGCTCAAAACTCATGGGATGTG ATTCTTTCGACCAATTTAGTGCAGAAAGAAGAAATTCAATCCTAACTGAGACCTTA CACCGTTTCTCATTAGAAGGAGATGCTCCTGTCTCCTGGACAGAAACAAAAAAAC AATCTTTTAAACAGACTGGAGAGTTTGGGGAAAAAAGGAAGAATTCTATTCTCAAT CCAATCAACTCTATACGAAAATTTTCCATTGTGCAAAAGACTCCCTTACAAATGAA TGGCATCGAAGAGGATTCTGATGAGCCTTTAGAGAGAAGGCTGTCCTTAGTACCA GATTCTGAGCAGGGAGAGGCGATACTGCCTCGCATCAGCGTGATCAGCACTGGC CCCACGCTTCAGGCACGAAGGAGGCAGTCTGTCCTGAACCTGATGACACACTCA GTTAACCAAGGTCAGAACATTCACCGAAAGACAACAGCATCCACACGAAAAGTGT CACTGGCCCCTCAGGCAAACTTGACTGAACTGGATATATATTCAAAAAT TTTCCATTGTGCAAAAGACTCCCTTACAAATGAATGGCATCGAAGAGGATTCTGAT GAGCCTTTAGAGAGAAGGCTGTCCTTAGTACCAGATTCTGAGCAGGGAGAGGCG ATACTGCCTCGCATCAGCGTGATCAGCACTGGCCCCACGCTTCAGGCACGAAGG AGGCAGTCTGTCCTGAACCTGATGACACACTCAGTTAACCAAGGTCAGAACATTC ACCGAAAGACAACAGCATCCACACGAAAAGTGTCACTGGCCCCTCAGGCAAACTT GACTGAACTGGATATATATTCAAGAAGGTTATCTCAAGAAACTGGCTTGGAAATAA GTGAAGAAATTAACGAAGAAGACTTAAAGGAGTGCTTTTTTGATGATATGGAGAG CATACCAGCAGTGACTACATGGAACACATACCTTCGATATATTACTGTCCACAAGA GCTTAATTTTTGTGCTAATTTGGTGCTTAGTAATTTTTCTGGCAGAGGTGGCTGCT TCTTTGGTTGTGCTGTGGCTCCTTGGAAACACTCCTCTTCAAGACAAAGGGAATA GTACTCATAGTAGAAATAACAGCTATGCAGTGATTATCACCAGCACCAGTTCGTAT TATGTGTTTTACATTTACGTGGGAGTAGCCGACACTTTGCTTGCTATGGGATTCTT CAGAGGTCTACCACTGGTGCATACTCTAATCACAGTGTCGAAAATTTTACACCACA AAATGTTACATTCTGTTCTTCAAGCACCTATGTCAACCCTCAACACGTTGAAAGCA GGTGGGATTCTTAATAGATTCTCCAAAGATATAGCAATTTTGGATGACCTTCTGCC TCTTACCATATTTGACTTCATCCAGTTGTTATTAATTGTGATTGGAGCTATAGCAGT TGTCGCAGTTTTACAACCCTACATCTTTGTTGCAACAGTGCCAGTGATAGTGGCTT TTATTATGTTGAGAGCATATTTCCTCCAAACCTCACAGCAACTCAAACAACTGGAA TCTGAAGGCAGGAGTCCAATTTTCACTCATCTTGTTACAAGCTTAAAAGGACTATG GACACTTCGTGCCTTCGGACGGCAGCCTTACTTTGAAACTCTGTTCCACAAAGCT CTGAATTTACATACTGCCAACTGGTTCTTGTACCTGTCAACACTGCGCTGGTTCCA AATGAGAATAGAAATGATTTTTGTCATCTTCTTCATTGCTGTTACCTTCATTTCCAT TTTAACAACAGGAGAAGGAGAAGGAAGAGTTGGTATTATCCTGACTTTAGCCATG AATATCATGAGTACATTGCAGTGGGCTGTAAACTCCAGCATAGATGTGGATAGCT TGATGCGATCTGTGAGCCGAGTCTTTAAGTTCATTGACATGCCAACAGAAGGTAA ACCTACCAAGTCAACCAAACCATACAAGAATGGCCAACTCTCGAAAGTTATGATTA TTGAGAATTCACACGTGAAGAAAGATGACATCTGGCCCTCAGGGGGCCAAATGA CTGTCAAAGATCTCACAGCAAAATACACAGAAGGTGGAAATGCCATATTAGAGAA CATTTCCTTCTCAATAAGTCCTGGCCAGAGGGTGGGCCTCTTGGGAAGAACTGGA TCAGGGAAGAGTACTTTGTTATCAGCTTTTTTGAGACTACTGAACACTGAAGGAGA AATCCAGATCGATGGTGTGTCTTGGGATTCAATAACTTTGCAACAGTGGAGGAAA GCCTTTGGAGTGATACCACAGAAAGTATTTATTTTTTCTGGAACATTTAGAAAAAA CTTGGATCCCTATGAACAGTGGAGTGATCAAGAAATATGGAAAGTTGCAGATGAG GTTGGGCTCAGATCTGTGATAGAACAGTTTCCTGGGAAGCTTGACTTTGTCCTTG TGGATGGGGGCTGTGTCCTAAGCCATGGCCACAAGCAGTTGATGTGCTTGGCTA GATCTGTTCTCAGTAAGGCGAAGATCTTGCTGCTTGATGAACCCAGTGCTCATTT GGATCCAGTAACATACCAAATAATTAGAAGAACTCTAAAACAAGCATTTGCTGATT GCACAGTAATTCTCTGTGAACACAGGATAGAAGCAATGCTGGAATGCCAACAATT TTTGGTCATAGAAGAGAACAAAGTGCGGCAGTACGATTCCATCCAGAAACTGCTG AACGAGAGGAGCCTCTTCCGGCAAGCCATCAGCCCCTCCGACAGGGTGAAGCTC TTTCCCCACCGGAACTCAAGCAAGTGCAAGTCTAAGCCCCAGATTGCTGCTCTGA AAGAGGAGACAGAAGAAGAGGTGCAAGATACAAGGCTTTAG

Cystic Fibrosis Gene ATGCAGAGGTCGCCTCTGGAAAAGGCCAGCGTTGTCTCCAAACTTTTTTTCAGCT GGACCAGACCAATTTTGAGGAAAGGATACAGACAGCGCCTGGAATTGTCAGACAT ATACCAAATCCCTTCTGTTGATTCTGCTGACAATCTATCTGAAAAATTGGAAAGAG AATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCTAAACTCATTAATGCCCTTCG GCGATGTTTTTTCTGGAGATTTATGTTCTATGGAATCTTTTTATATTTAGGGGAAGT CACCAAAGCAGTACAGCCTCTCTTACTGGGAAGAATCATAGCTTCCTATGACCCG GATAACAAGGAGGAACGCTCTATCGCGATTTATCTAGGCATAGGCTTATGCCTTC TCTTTATTGTGAGGACACTGCTCCTACACCCAGCCATTTTTGGCCTTCATCACATT GGAATGCAGATGAGAATAGCTATGTTTAGTTTGATTTATAAGAAGACTTTAAAGCT GTCAAGCCGTGTTCTAGATAAAATAAGTATTGGACAACTTGTTAGTCTCCTTTCCA ACAACCTGAACAAATTTGATGAAGGACTTGCATTGGCACATTTCGTGTGGATCGC TCCTTTGCAAGTGGCACTCCTCATGGGGCTAATCTGGGAGTTGTTACAGGCGTCT GCCTTCTGTGGACTTGGTTTCCTGATAGTCCTTGCCCTTTTTCAGGCTGGGCTAG GGAGAATGATGATGAAGTACAGAGATCAGAGAGCTGGGAAGATCAGTGAAAGAC TTGTGATTACCTCAGAAATGATTGAAAATATCCAATCTGTTAAGGCATACTGCTGG GAAGAAGCAATGGAAAAAATGATTGAAAACTTAAGACAAACAGAACTGAAACTGA CTCGGAAGGCAGCCTATGTGAGATACTTCAATAGCTCAGCCTTCTTCTTCTCAGG GTTCTTTGTGGTGTTTTTATCTGTGCTTCCCTATGCACTAATCAAAGGAATCATCC TCCGGAAAATATTCACCACCATCTCATTCTGCATTGTTCTGCGCATGGCGGTCAC TCGGCAATTTCCCTGGGCTGTACAAACATGGTATGACTCTCTTGGAGCAATAAAC AAAATACAGGATTTCTTACAAAAGCAAGAATATAAGACATTGGAATATAACTTAAC GACTACAGAAGTAGTGATGGAGAATGTAACAGCCTTCTGGGAGGAGGGATTTGG GGAATTATTTGAGAAAGCAAAACAAAACAATAACAATAGAAAAACTTCTAATGGTG ATGACAGCCTCTTCTTCAGTAATTTCTCACTTCTTGGTACTCCTGTCCTGAAAGAT ATTAATTTCAAGATAGAAAGAGGACAGTTGTTGGCGGTTGCTGGATCCACTGGAG CAGGCAAGACTTCACTTCTAATGGTGATTATGGGAGAACTGGAGCCTTCAGAGGG TAAAATTAAGCACAGTGGAAGAATTTCATTCTGTTCTCAGTTTTCCTGGATTATGC CTGGCACCATTAAAGAAAATATCATCTTTGGTGTTTCCTATGATGAATATAGATAC AGAAGCGTCATCAAAGCATGCCAACTAGAAGAGGACATCTCCAAGTTTGCAGAGA AAGACAATATAGTTCTTGGAGAAGGTGGAATCACACTGAGTGGAGGTCAACGAGC AAGAATTTCTTTAGCAAGAGCAGTATACAAAGATGCTGATTTGTATTTATTAGACTC TCCTTTTGGATACCTAGATGTTTTAACAGAAAAAGAAATATTTGAAAGCTGTGTCT GTAAACTGATGGCTAACAAAACTAGGATTTTGGTCACTTCTAAAATGGAACATTTA AAGAAAGCTGACAAAATATTAATTTTGCATGAAGGTAGCAGCTATTTTTATGGGAC ATTTTCAGAACTCCAAAATCTACAGCCAGACTTTAGCTCAAAACTCATGGGATGTG ATTCTTTCGACCAATTTAGTGCAGAAAGAAGAAATTCAATCCTAACTGAGACCTTA CACCGTTTCTCATTAGAAGGAGATGCTCCTGTCTCCTGGACAGAAACAAAAAAAC AATCTTTTAAACAGACTGGAGAGTTTGGGGAAAAAAGGAAGAATTCTATTCTCAAT CCAATCAACTCTATACGAAAATTTTCCATTGTGCAAAAGACTCCCTTACAAATGAA TGGCATCGAAGAGGATTCTGATGAGCCTTTAGAGAGAAGGCTGTCCTTAGTACCA GATTCTGAGCAGGGAGAGGCGATACTGCCTCGCATCAGCGTGATCAGCACTGGC CCCACGCTTCAGGCACGAAGGAGGCAGTCTGTCCTGAACCTGATGACACACTCA GTTAACCAAGGTCAGAACATTCACCGAAAGACAACAGCATCCACACGAAAAGTGT CACTGGCCCCTCAGGCAAACTTGACTGAACTGGATATATATTCAAAAAT TTTCCATTGTGCAAAAGACTCCCTTACAAATGAATGGCATCGAAGAGGATTCTGAT GAGCCTTTAGAGAGAAGGCTGTCCTTAGTACCAGATTCTGAGCAGGGAGAGGCG ATACTGCCTCGCATCAGCGTGATCAGCACTGGCCCCACGCTTCAGGCACGAAGG AGGCAGTCTGTCCTGAACCTGATGACACACTCAGTTAACCAAGGTCAGAACATTC ACCGAAAGACAACAGCATCCACACGAAAAGTGTCACTGGCCCCTCAGGCAAACTT GACTGAACTGGATATATATTCAAGAAGGTTATCTCAAGAAACTGGCTTGGAAATAA GTGAAGAAATTAACGAAGAAGACTTAAAGGAGTGCTTTTTTGATGATATGGAGAG CATACCAGCAGTGACTACATGGAACACATACCTTCGATATATTACTGTCCACAAGA GCTTAATTTTTGTGCTAATTTGGTGCTTAGTAATTTTTCTGGCAGAGGTGGCTGCT TCTTTGGTTGTGCTGTGGCTCCTTGGAAACACTCCTCTTCAAGACAAAGGGAATA GTACTCATAGTAGAAATAACAGCTATGCAGTGATTATCACCAGCACCAGTTCGTAT TATGTGTTTTACATTTACGTGGGAGTAGCCGACACTTTGCTTGCTATGGGATTCTT CAGAGGTCTACCACTGGTGCATACTCTAATCACAGTGTCGAAAATTTTACACCACA AAATGTTACATTCTGTTCTTCAAGCACCTATGTCAACCCTCAACACGTTGAAAGCA GGTGGGATTCTTAATAGATTCTCCAAAGATATAGCAATTTTGGATGACCTTCTGCC TCTTACCATATTTGACTTCATCCAGTTGTTATTAATTGTGATTGGAGCTATAGCAGT TGTCGCAGTTTTACAACCCTACATCTTTGTTGCAACAGTGCCAGTGATAGTGGCTT TTATTATGTTGAGAGCATATTTCCTCCAAACCTCACAGCAACTCAAACAACTGGAA TCTGAAGGCAGGAGTCCAATTTTCACTCATCTTGTTACAAGCTTAAAAGGACTATG GACACTTCGTGCCTTCGGACGGCAGCCTTACTTTGAAACTCTGTTCCACAAAGCT CTGAATTTACATACTGCCAACTGGTTCTTGTACCTGTCAACACTGCGCTGGTTCCA AATGAGAATAGAAATGATTTTTGTCATCTTCTTCATTGCTGTTACCTTCATTTCCAT TTTAACAACAGGAGAAGGAGAAGGAAGAGTTGGTATTATCCTGACTTTAGCCATG AATATCATGAGTACATTGCAGTGGGCTGTAAACTCCAGCATAGATGTGGATAGCT TGATGCGATCTGTGAGCCGAGTCTTTAAGTTCATTGACATGCCAACAGAAGGTAA ACCTACCAAGTCAACCAAACCATACAAGAATGGCCAACTCTCGAAAGTTATGATTA TTGAGAATTCACACGTGAAGAAAGATGACATCTGGCCCTCAGGGGGCCAAATGA CTGTCAAAGATCTCACAGCAAAATACACAGAAGGTGGAAATGCCATATTAGAGAA CATTTCCTTCTCAATAAGTCCTGGCCAGAGGGTGGGCCTCTTGGGAAGAACTGGA TCAGGGAAGAGTACTTTGTTATCAGCTTTTTTGAGACTACTGAACACTGAAGGAGA AATCCAGATCGATGGTGTGTCTTGGGATTCAATAACTTTGCAACAGTGGAGGAAA GCCTTTGGAGTGATACCACAGAAAGTATTTATTTTTTCTGGAACATTTAGAAAAAA CTTGGATCCCTATGAACAGTGGAGTGATCAAGAAATATGGAAAGTTGCAGATGAG GTTGGGCTCAGATCTGTGATAGAACAGTTTCCTGGGAAGCTTGACTTTGTCCTTG TGGATGGGGGCTGTGTCCTAAGCCATGGCCACAAGCAGTTGATGTGCTTGGCTA GATCTGTTCTCAGTAAGGCGAAGATCTTGCTGCTTGATGAACCCAGTGCTCATTT GGATCCAGTAACATACCAAATAATTAGAAGAACTCTAAAACAAGCATTTGCTGATT GCACAGTAATTCTCTGTGAACACAGGATAGAAGCAATGCTGGAATGCCAACAATT TTTGGTCATAGAAGAGAACAAAGTGCGGCAGTACGATTCCATCCAGAAACTGCTG AACGAGAGGAGCCTCTTCCGGCAAGCCATCAGCCCCTCCGACAGGGTGAAGCTC TTTCCCCACCGGAACTCAAGCAAGTGCAAGTCTAAGCCCCAGATTGCTGCTCTGA AAGAGGAGACAGAAGAAGAGGTGCAAGATACAAGGCTTTAG AAGTTTGC A

‘Big data’ analysis reveals function

Linkage Mapping without Families Rare Inherited: Monogenic Homozygosity Mapping: Inbred individuals ACA - GGC Denser Genetic Map Ancestral Segment (LD) Mapping: Isolated Populations ACA - GGC Even Denser Genetic Map! Mapping Disease Genes: Rare, Mendelian

Association mapping in populations Common Inherited: Polygenic Ancestral segments (LD): isolated populations Finland Ancestral segments (LD): general populations Denser genetic map ! Mapping Disease Genes: Common Diseases

Common Variant Association Studies Rare Variant Association Studies Need: Catalog of all common variants (~1%) local haplotype structure Technology to genotype huge sample collections for millions of SNPs Gene 1 Cases Controls Need: Technology to sequence huge sample collections for full exome or genome Mapping Disease Genes: Common Diseases

2. Mapping the Human Genome ( ) From Principles to Practice

Human Genome Project ( ) Genetic map:Genetic landmarks to trace inheritance Physical map: DNA fragments covering the chromosomes Sequence: DNA sequence (3 billion bases) Gene List: Identification of all genes Information freely available without restriction

Draft: (90%) June 2000Announced Feb 15, 2001Published Finished (99.3%) Apr 25, 2003Completed Oct 2004 Published

Correlation structure Septin2-like genes RAD50IL13IL4 IL5IRF1 OCTN2OCTN1RIL P4HA2 CSF2IL3 LACS2 SNPs = 50 kb CAh14bATTh14cIL4m2GAh18aCAh15a IRF1p1 CAh17aD5S1984CSF2p10 GGACAACC AATTCGTG TTACG CCCAA CGGAGACGA GACTGGTCG CGCAGACGA CGCGCCCGGAT TTGCCCCGGCT CTGCTATAACC CTGCCCCAACC CCAGC CAACC GCGCT CCACC CCGAT CTGAC ATACT CCCTGCTTACGGTGCAGTGGCACGTATT*CA CATCACTCCCCAGACTGTGATGTTAGTATCT TCCCATCCATCATGGTCGAATGCGTACATTA CCCCGCTTACGGTGCAGTGGCACGTATATCA CGTTTAG TAATTGG TGTT*GA TGATTAG ACAACA GTGACG GCGGTG ACGGTG GTTCTGA TGTGCGG TG*GTAA TAAG TATCA CGGCG Million Genotyping 10s Common variants , million —1 at a time >10 million Catalog of all common genetic variation in humans

New DNA sequencing technology: Can discover all rare variants in individuals ~2,000,000-fold decrease in cost over decade Moore’s Law Sequencing Cost per million bases

3. Mapping Disease Genes ( ) Mendelian Inheritance in Man

Family-based linkage mapping Biolo Common Mendelian disease genes 1990 (pre HGP) ~ ~ ~4000

Family-based linkage mapping Biolo Common Common Disease Largely fails: < 10 genes found Exceptions instructive: APOE – Alzheimer’s NOD2 – Crohn’s CFH – Macular degeneration HLA – immune disorders Different than Mendelian disease Common variants with odds ratios of 2-5 Mendelian Disease Common Disease

Common Variant Association Studies (CVAS) – aka GWAS Rare Variant Association Studies (RVAS) Need: Catalog of all common variants (~1%) local haplotype structure Technology to genotype huge sample collections for millions of SNPs Gene 1 Cases Controls Need: Technology to sequence huge sample collections for full exome or genome Population-based mapping of common disease

KCNJ PPARg 2001 IBD5 NOD CTLA PTPN22 CD25 IRF5 PCSK9 CFH 2007 NOS1AP IFIH1 PCSK9 CFB/C2 LOC q24 IL23R TCF7L2 Genetic variants affecting human diseases Cholesterol Obesity Myocardial infarction QT interval Atrial Fibrilliation Type 2 Diabetes Prostate cancer Breast cancer Colon cancer Height Uric Acid Age Related Macular Degeneration Crohns Disease Type 1 Diabetes Systemic Lupus Erythematosus Asthma Restless leg syndrome Gallstone disease Multiple sclerosis Rheumatoid arthritis Glaucoma Celiac Disease FGFR2 TNRC9 MAP3K1 LSP1 8q24 CDKN2B/A 8q24 (n=6) ATG16L1 5p13 10q21 IRGM NKX2-3 IL12B 3p21 1q24 PTPN2 TCF2 CDKN2B/A IGF2BP2 CDKAL1 HHEX SLC30A8 TBL2 TRIB1 KCTD10 ANGLPT3 GRIN3A MEIS1 LBXCOR1 BTBD9 C3 8q24 ORMDL3 4q25 TCF2 GCKR FTO C12orf30 ERBB3 KIAA0350 CD226 16p13 PTPN2 SH2B3 ITGAM BLK HMGA2 GDF5-UQCC HMPG CRAC1 JAZF1 CDC123 ADAMTS9 THADA WSF1 LOXL1 GLUT9 L7R TRAF1/C5 STAT4 4q27 ABCG8 MLXIPL GALNT2 PSRC1 NCAN

Schizophrenia Mark Daly Steven McCarroll Beth Stevens

Schizophrenia 6,000 people 0 genes!

Schizophrenia 20,000 people 5 genes

Schizophrenia 50,000 people 62 genes

Schizophrenia 110,000 people 108 genes !

Schizophrenia 110,000 people 108 genes ! Calcium channels Glutamate signaling

Strongest gene effect is on Chromosome 6 Gene region involved in Immune system (p< )

Schizophrenia gene identified: C4

Synaptic pruning in normal development and schizophrenia Allison Bialas Matt Baum Birth Child Adult Extensive pruning in adolescence and early adulthood (time of schizophrenia onset) Schizophrenia patient Control Schizophrenia patient Loss of synapses in brains from schizophrenic patient

Schizophrenia: A disease of excess synaptic pruning? Allison Bialas Matt Baum Idea: Can schizophrenia be treated or prevented by affecting synaptic pruning?

4. Implications for Germline Editing

Human Diseases and Traits Rare, Mendelian Cystic fibrosis, Huntington Disease, … Common, polygenic Heart disease, Alzheimer’s Schizophrenia, Height, Obesity Intelligence?... Avoid all cases of severe genetic disease Eliminate disease alleles from pop’n Decrease disease risk ‘Enhance’ human population

Rare Mendelian Disease: Dominant D+D+ ++ D+D+D+D+ Heterozygous parent Half of offspring affected Half of offspring unaffected Can use pre-implantation diagnostics (PGD) PGD+germline editing adds relatively little *

Rare Mendelian Disease: Dominant D+D+ ++ D+D+D+D+ Heterozygous parent Half of offspring affected Half of offspring unaffected Can use pre-implantation diagnostics (PGD) PGD+germline editing adds relatively little DD ++ D+D+D+D+D+D+D+D+ Homozygous parent All offspring affected Germline editing would be useful Homozygotes are extremely rare For Huntington’s disease, only dozens of cases found worldwide

Rare Mendelian Disease: Recessive m+m+ m+m+ mmm+m++m+m++ Heterozygous unaffected parents One-quarter of offspring affected To avoid affected offspring: Can use pre-implantation diagnostics (PGD) PGD+germline editing adds relatively little

Rare Mendelian Disease: Recessive m+m+ m+m+ mmm+m++m+m++ Heterozygous unaffected parents One-quarter of offspring affected To avoid affected offspring: Can use pre-implantation diagnostics (PGD) PGD+germline editing adds relatively little To avoid most cases of devastating genetic diseases, the most important intervention would be ensuring access to genetic testing so carrier couples know they are at risk To eliminate disease alleles from population, we’d all need to use IVF – since we all carry multiple disease genes in heterozygous state

Rare Mendelian Disease: Recessive m+m+ m+m+ mmm+m++m+m++ Heterozygous unaffected parents One-quarter of offspring affected To avoid affected offspring: Preimplantation diagnostics available (PGD) PGD+germline editing adds relatively little m+m+ m+m+ mmm+m++m+m++ Homozygous parents All offspring affected Germline editing would be useful Very rare, unless brought together by disease E.g.: Deaf parents with mutations in same gene

Human Diseases and Traits Rare, Mendelian Cystic fibrosis, Huntington Disease, … Common, polygenic Heart disease, Alzheimer’s Schizophrenia, Height, Obesity Intelligence?... Avoid all cases of severe genetic disease Eliminate disease alleles from pop’n Decrease disease risk ‘Enhance’ human population

Common, Polygenic Disease Genetic variants have modest effects Handful: 3-5-fold 99+%: <1.2-fold Why? Selection keeps strong alleles at low frequency Disease processes are buffered

Common, Polygenic Disease Genetic variants have modest effects Handful: 3-5-fold 99+%:<1.2-fold Why? Selection keeps strong alleles at low frequency Disease processes are buffered Schizophrenia Population 1% risk C4 gene 1.1% risk Polygenic risk score Top 100 loci (statistically significant) Top decile: ~3% risk Top 10,000 loci (only a fraction significant)Top decile: ~10% risk

Common, Polygenic Disease Is there a free lunch? Genetic variants have ‘pleiotropic’ effects and environmental interactions Inflammatory bowel disease Lower risk of:Higher risk of: FUT2NorovirusCrohn's & Type 1 diabetes IFIH1 Type 1 diabetes Crohn's disease RNF186 Ulcerative colitis Chronic kidney disease Viral infection Lower risk of:Higher risk of: CCR5HIV West Nile (13x higher risk for fatal cases)

Common, Polygenic Disease: Germline editing Avoid deleterious variants? Most have very small effects Those with large effects usually rare: treat like Mendelian Bestow protective variants with large effects? Very few examples overall Moreover, want common (to assess impact in homozygotes) ideally, with no downsides (undesired pleiotropic effects)

Common, Polygenic Disease: Germline editing Avoid deleterious variants? Most have very small effects Those with large effects usually rare: treat like Mendelian Bestow protective variants with large effects? Very few examples overall Moreover, want common (to assess impact in homozygotes) ideally, with no downsides (undesired pleiotropic effects) Best candidates: ApoE2, 3 vs. ApoE4 (3%) Higher Alzheimer’s risk PCSK9 null(<2%) Lower LDL levels, heart attack risk

Common, Polygenic Disease: Germline editing Avoid deleterious variants? Most have very small effects Those with large effects usually rare: treat like Mendelian Bestow protective variants with large effects? Currently, very few such examples Moreover, want common (to assess impact in homozygotes) ideally, with no downsides (undesired pleiotropic effects) Best candidates: ApoE2, 3 vs. ApoE4 (3%) Higher Alzheimer’s risk PCSK9 null(<2%) Lower LDL levels, heart attack risk Still, we have incomplete knowledge about pleiotropic effects If alleles are so good, why aren’t they at higher frequency?

Summary and Conclusion Rare, Mendelian diseases Vast majority of cases can be addressed by IVF and PGD Some cases of compelling need, although rare If we wish to avoid devastating genetic diseases, most important intervention is ensuring couples have access to genetic testing to know they are at risk Common, Polygenic diseases Thousands of genes being identified — revealing disease processes, pointing to therapeutic hypotheses For vast majority of variants, impact on risk is small Currently, at most a few plausible variants for editing Conclusion Genetic basis of human disease is complex We still have a lot to learn Before making permanent changes to the human gene pool, we should use great caution

Breakout Sessions List of Breakout Sessions is in your program The same five sessions will be held on Tues and Wed Room sizes vary—equilibrate Staff (green badges) will be outside auditorium to direct you to rooms Breakout sessions will end at 7pm Reception to follow in Great Hall