The Evolution of Genetic Science & Technology

The Evolution of Genetic Science & Technology

Ciaran MorrisonCentre for Chromosome Biology

National University of Ireland Galway

Downtown Galway, by Ronan Bree!

http://www.chromosome.ieGenetic Discrimination- the case for a European-level legal response

Outline of presentation…

1. Genetics – history and key concepts

2. The genetic material – DNA and proteins

3. Exploring the human genome

4. Genetic testing and individualised genomics

5. Future perspectives and the major scientific challenge

Genetic Discrimination- the case for a European-level legal response

1953 James Watson and Francis Crick publish the double helix model for DNA’s chemical structure

1860s Mendel’s work on peas allows the conclusion that traits are inherited through discrete units passed from one generation to the next

1870s Friedrich Miescher describes nucleic acids

1910 Thomas Morgan’s work on fruitflies demonstrates that genes lie on chromosomes

1940s Barbara McClintock describes mobile genetic elements in maize

1958 Crick proposes the ‘central dogma’ for biological information flow: that DNA makes RNA makes protein

1909 The word ‘gene’ coined by Danish botanist Wilhelm Johannsen

1944 Oswald Avery shows in bacteria that nucleic acids are the ‘transforming principle’

1977 Phillip Sharp and Richard Roberts find that protein-coding genes are carried in segments

2001 initial results from the Human Genome Project published

Genetics – history and key concepts…

Mendelian Genetics …TECHNIQUE EXPERIMENT


Mendelian Genetics – 3:1 ratios …

Traits must comein discrete units – now called genes


Mendelian Genetics in humans …1st generation(grandparents)

2nd generation(parents, aunts,and uncles)

3rd generation(two sisters)

Widow’s peak No widow’s peakA dominant Mendelian trait

Ww ww

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Attached earlobe

1st generation(grandparents)

2nd generation(parents, aunts,and uncles)

3rd generation(two sisters)

Free earlobe

A recessive Mendelian trait

Ff Ff

Ff Ff Ff

ff Ff

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orFFFf

Many Mendeliantraits – some cause disease e.g. cystic fibrosis


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 o 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 genotypeo The sum of the effects of all the genes and the environmental

factors that contribute to the phenotype (e.g. height, skin colour)


DNA - The genetic material…Watson and Crick admiring their “tin and wire” model of DNA…


DNA - The genetic code…


DNA is packaged around proteins to form Chromosomes…

From: Felsenfeld & Groudine (2003) Nature 242, 448


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 16th Feb 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) Nature 470: 187-197).



…in every cell of the body!

Dept. of Pathology, University of Washington

A human genome


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 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…

1. Carrier screening for Mendelian diseases (e.g. cystic fibrosis)2. Pre-implantation diagnosis (IVF embryo screening)3. Prenatal diagnosis (e,g. Down’s syndrome)4. Genetic genealogy (paternal and maternal ancestry)5. 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

6. Patient diagnosis/prognosis (e.g. cancer)7. Forensic/identity testing (e,g. crime scenes, paternity/maternity

cases)8. Research tests (e.g. gene discovery, how genes work – data usually

not available to patients or their doctors)9. Pharmacogenomics – the influence of genetic differences (variation)

of drug responsesGenetic Discrimination- the case for a European-level legal response

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


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


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


DTC genetic testing…


James Watson’s genome…

From Olsen, M (2008) Dr. Watson’s base pairs. Nature 452. 819

• 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 SNPs relative 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!!!


The decreasing cost of sequencing…


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


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


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


The Evolution of Genetic Science & Technology

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