An introduction to Genome
Science & Technology
Noel Lowndes
Chair, Biochemistry &
Director, Centre for Chromosome Biology
NUI Galway
Downtown Galway, by Ronan Bree!
http://www.chromosome.ie
Genetic Discrimination, Galway '11
Outline of presentation…
1.  Genetics – history and key concepts
2.  The genetic/epigenetic material – DNA and proteins
3.  Genetic testing – phenotypes revealed!
4.  The human genome and its impact on society
5.  Future perspectives and the major scientific challenge
Genetic Discrimination, Galway '11
Genetics – history and key concepts…
Adapted from Pearson, H (2006) Nature 441, R17-R29
Mendelian Genetics …
TECHNIQUE
Genetic Discrimination, Galway '11
EXPERIMENT
Mendelian Genetics – 3:1 ratios …
Traits must come
in discrete units
– now called genes
Genetic Discrimination, Galway '11
Mendelian Genetics in humans …
1st generation
(grandparents)
Ww
ww
ww
Ww
1st generation
(grandparents)
2nd generation
(parents, aunts,
Ww ww ww Ww
and uncles)
3rd generation
(two sisters)
Ff
Ww ww
2nd generation
(parents, aunts,
FF/
Ff ff
and uncles)
WW ww
or
Ww
Ff
ff
ff
Ff
Ff
Ff
ff
ff
FF
or
Ff
3rd generation
(two sisters)
Widow’s peak
No widow’s peak
A dominant Mendelian trait
Many Mendelian
traits – some cause
disease e.g. cystic fibrosis
Genetic Discrimination, Galway '11
Attached earlobe
A recessive Mendelian trait
Free earlobe
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 genotype
o  The sum of the effects of all the genes and the environmental
factors that contribute to the phenotype (e.g. height, skin colour)
Genetic Discrimination, Galway '11
DNA - The genetic material…
Watson and Crick admiring their “tin and wire” model of DNA…
Genetic Discrimination, Galway '11
DNA - The genetic code…
Genetic Discrimination, Galway '11
DNA is packaged around proteins to
form Chromosomes…
From: Felsenfeld & Groudine (2003) Nature 242, 448
Genetic Discrimination, Galway '11
Chromosome replication and segregation…
Chromosomes
DNA molecules
Chromosome
duplication
Centromere
Sister
chromatids
Chromosome
segregation
Sister chromatids
Genetic Discrimination, Galway '11
Chromosome segregation – the movie…!
From Kevin Sullivan, Centre for Chromosome Biology, Galway
Genetic Discrimination, Galway '11
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.
2.
3.
4.
5.
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 2 mutations in hereditary breast
cancer
•  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 availalble to patients or their doctors)
9.  Pharmacogenomics – the influence of genetic differences (variation) of
drug responses
Genetic Discrimination, Galway '11
Procedure…
•  Currently 1000s of genetic tests available and growing all the
time
•  Informed consent required (for medical tests genetic counseling
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, Galway '11
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, Galway '11
So, results often require confirmation…!!
Genetic Discrimination, Galway '11
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 - opposed by scientific community
Genetic Discrimination, Galway '11
DTC genetic testing…
Genetic Discrimination, Galway '11
The human genome…
•  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 know 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) resulted in 90% of genome (currently
92.3% complete - http://www.strategicgenomics.com/Genome/index.htm)
•  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, Feb
2011)
•  Nevertheless, “the greatest impact of genomics has been the ability to
investigate biological phenomena in a comprehensive, unbiased, hypothesisfree manner”- Eric Lander 2011
Genetic Discrimination, Galway '11
James Watson’s genome…
From Olsen, M (2008) Dr. Watson’s base pairs.
Nature 452. 819
Genetic Discrimination, Galway '11
•  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!!!
Watson’s redaction…
•  Watson has removed information about the status of one of
his genes, APOE (linked to Alzheimer’s) from the database for
personal reasons!
•  Presumably, related to his mother suffering form Alzheimer’s and
he has a son who is bipolar
•  More recently removed 2 Mb around APOE as other linked
variants can be used to infer his APOE status.
Genetic Discrimination, Galway '11
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 hominids
•  A future landmark – 1 million genomes!!
Genetic Discrimination, Galway '11
The major problem…
•  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 personalized risk
prediction
Genetic Discrimination, Galway '11
A final note…
•  Genetic technologies will greatly benefit mankind but
will also be abused by some
•  Regulation is required but it should be fully cognisant
of the science
Genetic Discrimination, Galway '11