The Evolution of Genetic Science & Technology

1. The Evolution of Genetic Science & Technology Ciaran Morrison Centre for Chromosome Biology National University of Ireland Galway Downtown Galway, by Ronan Bree! http://www.chromosome.ie Genetic Discrimination- the case for a European-level legal response

2. Outline of presentation… Genetics – history and key concepts The genetic material – DNA and proteins Exploring the human genome Genetic testing and individualised genomics Future perspectives and the major scientific challenge Genetic Discrimination- the case for a European-level legal response

3. Genetics – history and key concepts… 1977 Phillip Sharp and Richard Roberts find that protein-coding genes are carried in segments 1860s Mendel’s work on peas allows the conclusion that traits are inherited through discrete units passed from one generation to the next 1940s Barbara McClintock describes mobile genetic elements in maize 1944 Oswald Avery shows in bacteria that nucleic acids are the ‘transforming principle’ 1870s Friedrich Miescher describes nucleic acids 2001 initial results from the Human Genome Project published 1909 The word ‘gene’ coined by Danish botanist Wilhelm Johannsen 1953 James Watson and Francis Crick publish the double helix model for DNA’s chemical structure 1910 Thomas Morgan’s work on fruitflies demonstrates that genes lie on chromosomes 1958 Crick proposes the ‘central dogma’ for biological information flow: that DNA makes RNA makes protein

4. Mendelian Genetics … TECHNIQUE EXPERIMENT Genetic Discrimination- the case for a European-level legal response

5. Mendelian Genetics – 3:1 ratios … Traits must come in discrete units – now called genes Genetic Discrimination- the case for a European-level legal response

6. 1st generation (grandparents) Mendelian Genetics in humans … Ff Ff ff Ff 1st generation (grandparents) Ww Ww ww ww 2nd generation (parents, aunts, and uncles) 2nd generation (parents, aunts, and uncles) Ff FF / ff ff Ff ff Ff Ww Ww ww ww Ww ww 3rd generation (two sisters) 3rd generation (two sisters) ff FF or WW ww Ff or Ww Many Mendelian traits – some cause disease e.g. cystic fibrosis Widow’s peak No widow’s peak Attached earlobe Free earlobe A dominant Mendelian trait A recessive Mendelian trait Genetic Discrimination- the case for a European-level legal response

7. Non-Mendelian inheritance… • Inheritance of traits (phenotypes) is often more complex than predicted by simple Mendelian genetics • Polygenic traits- those determined by more than one gene, vary in the population along a continuum • The sum of the effects of all the genes that contribute to the phenotype (e.g. height, skin colour) • Multifactorial traits - those that depend on the environment as well as the genotype • The sum of the effects of all the genes andthe environmental factors that contribute to the phenotype (e.g. height, skin colour) Genetic Discrimination- the case for a European-level legal response

8. DNA - The genetic material… Watson and Crick admiring their “tin and wire” model of DNA… Genetic Discrimination- the case for a European-level legal response

9. DNA - The genetic code… Genetic Discrimination- the case for a European-level legal response

10. DNA is packaged around proteins to form Chromosomes… From: Felsenfeld & Groudine (2003) Nature 242, 448 Genetic Discrimination- the case for a European-level legal response

11. The human genome- some numbers • 23 pairs of chromosomes (46 chromosome in diploid genome of just over 6 billion bp) plus small mitochrondrial DNA (15,000 bp – just 37 genes) • 20-23,000 proteins encoded (just 1.5% of total genome, but most of the rest of the genome is now known to be transcribed into RNA!) • Competition between public (Nature 15th Feb 2001, led by Jim Watson) and private teams (Science 16thFeb 2001, led by Craig Venter) led to completion of 90% of the genome. • Variation • Single Nucleotide Polymorphisms (SNPs) – one every 1,300 bp • Repetitive sequences are highly variable between individuals – basis of DNA fingerprinting & paternity testing • Copy number variations (CNVs) – typically ~100 (~3 Mb) between individuals • To date, ~2,850 genes (<100 prior to HGP!) underlying Mendelian diseases and ~1,100 genes involved in common polygenic disorders (Lander (2011) Nature470: 187-197). Genetic Discrimination- the case for a European-level legal response

12. A human genome …in every cell of the body! Dept. of Pathology, University of Washington Genetic Discrimination- the case for a European-level legal response

13. Mutations in CFTR (Cystic Fibrosis) Riordan et al. (1989) Science 245: 1066-1073; Rommens et al. (1989) Science 245: 1059-1065; Kerem et al. (1989) Science 245: 1073-1080; Kobler et al. (2006) Genet. Med. 8: 125-128 Genetic Discrimination- the case for a European-level legal response

14. Genetic testing… • The analysis of DNA and chromosomes (genotypes), as well as proteins, sugars, fats, metabolites or (molecular phenotypes) or external appearance, in order to detect mutations, including chromosome abnormalities, for… • Carrier screening for Mendelian diseases (e.g. cystic fibrosis) • Pre-implantation diagnosis (IVF embryo screening) • Prenatal diagnosis (e,g. Down’s syndrome) • Genetic genealogy (paternal and maternal ancestry) • Pre-symptomatic testing for adult-onset disorders • Cancer predisposition – e.g. BRCA1 and BRCA2 mutations in hereditary breast cancer predisposition • Alzheimer’s disease • Huntington’s disease • Patient diagnosis/prognosis (e.g. cancer) • Forensic/identity testing (e,g. crime scenes, paternity/maternity cases) • Research tests (e.g. gene discovery, how genes work – data usually not available to patients or their doctors) • Pharmacogenomics– the influence of genetic differences (variation) of drug responses Genetic Discrimination- the case for a European-level legal response

15. Procedure… • Currently 1000s of genetic tests available and growing all the time • Informed consent required (for medical tests, genetic counselling also required) • Performed on biological samples (blood, buccal smear, hair, skin, amniotic fluid, semen) • Sometimes difficult to interpret and the type of test, family and personal history should be considered Genetic Discrimination- the case for a European-level legal response

16. Results… • Positive test - can confirm risk of developing a disease, carrier status, diagnosis/prognosis, biological parents, identity, ancestry • False positives possible • Negative test - can demonstrate lack of gene variant linked to disease, non-carrier status, lack of genetic relationship. • False negatives possible. • Also, cannot yet test for all possible genetic alternations • Uninformative or ambiguous test – cannot confirm or rule out disease risk, diagnosis/prognosis or genetic relationship • Sometimes can’t distinguish between natural variation in DNA variants linked to disease and variants (termed polymorphisms) that have no impact on health Genetic Discrimination- the case for a European-level legal response

17. Direct-to-Consumer (DTC) genetic testing… • Genetic tests accessible directly to the consumer – for medical testing bypass requirement for a health care professional • Available for medical conditions (e.g. BRCA1/2 mutations, cystic fibrosis) • Benefits: • Consumer accessibility • Promotion of proactive healthcare • Privacy of genetic information • Problems: • Lack of regulation - exaggerated and inaccurate advertising • Lack of professional guidance - misinterpretation of results • Controversial – generally opposed by scientific community Genetic Discrimination- the case for a European-level legal response

18. DTC genetic testing… Genetic Discrimination- the case for a European-level legal response

19. James Watson’s genome… • 1st genome sequenced by a next generation sequencing method (in 2 months!) • $1,000,000 (1/100th the cost of traditional methods) • 3,300,000 SNPsrelative to HGP reference genome (82% previously known) • Most SNPs presumed to be neutral, however, 11,000 (85% of those previously known) altered proteins • ~23 CNVs ranging from 26 kb to 1.6 Mb (9 gains, 14 losses) • 1 region of homozygous loss! • Sequence typical for human genetic variation • Currently, extremely difficult to extract medically relevant inferences from individual genomes • Couldn’t even make a rough prediction of Watson’s height from his genome sequence!!! From Olsen, M (2008) Dr. Watson’s base pairs. Nature 452. 819 Genetic Discrimination- the case for a European-level legal response

20. The decreasing cost of sequencing… Genetic Discrimination- the case for a European-level legal response

21. Genomics – future perspectives… • The thousand genomes project – essentially MOST human genetic variation (>1% across the genome and >0.1% in genes) will be identified • Sequencing costs per human genome falling very dramatically (due to come down to $1,000 soon, eventually even $100!!) • Whole genome sequencing will be used in medicine • Diagnostic evaluation of children with major intellectual disability, autism, birth defect and developmental delays of unknown cause! • Sequencing the genomes of patients will be used to assess their suitability for specific drugs, e.g. identifying hypersensitive individuals (Pharmacogenetics) • Comparing patient’s genomes with that of their parents will identify newly arising mutations! • Couples may sequence their genomes before having children! • Cancer genomes will be sequenced to identify best treatment regimes • Reconstruction of some of the salient features of human history • Structure of ancestral human population in Africa • Population dispersals throughout the world • Gene flow with archaic/ extinct hominids Genetic Discrimination- the case for a European-level legal response

22. The major challenge… • Genome sequences (all the functional elements) are just the vocabulary, which is not much use without the grammar (the rules that govern how the functional elements are integrated together to create an individual) • The primary goal of human genomics is to improve the treatment of disease through understanding the underlying molecular pathways • A secondary goal is to provide patients with personalised risk prediction Genetic Discrimination- the case for a European-level legal response

23. A final note… • Genetic technologies have huge potential to benefit mankind but can be abused • Regulation is required but it needs to be fully informed by the science Genetic Discrimination- the case for a European-level legal response