CHAPTER 2: GENOMIC SCIENCE AND GENOMIC
2.1. Using traditional genetic techniques, almost
2,000 genes for single-gene disorders had been identified by the
year 2000. More recent advances in genomic science (most notably
the completion of the human genome sequence) and genome technologies
have allowed identification of hundreds of genes that contribute
to inherited susceptibility to commoner, genetically complex diseases.
2.2. Because of the important role of genomic
science in this report, we explain in Boxes 1 and 2 below some
of the key concepts in genomic science and genomic medicine. A
glossary and list of acronyms is set out in Appendix 6
Key concepts in genomic science
Genetic information is encoded within an individual's DNA (deoxyribonucleic acid), long, spiral-shaped molecules formed into the famous double-helix structure. The strands of DNA are made up of hundreds of millions of units or 'letters' called nucleotides. Joined together, these letters contain the chemical code of instructions that directs the development and function of cells in the body, controlling biological processes such as the production of proteins.
Proteins are essential building blocks of cells and tissues and also control the biochemical reactions that are vital to life. Variations in DNA sequence can alter protein sequence and function, as well as the amount of protein that is produced. DNA sequence variations are therefore key to inter-individual differences in body form and function and therefore health and disease.
What is a genome?
An individual's entire DNA sequence is known as its "genome". The word "genome" is a synthesis of the words "gene" and "chromosome". About two per cent of the human genome is made up of genes, the functional units of DNA that contain the instructions to produce proteins. The rest of the genome may regulate where, when and in what quantity proteins are made (known as gene expression, to control when a gene is "switched on" to produce a protein, for example).
An individual's genome is encoded within structures known as chromosomes. Humans have 23 pairs of chromosomes which reside in the nucleus of almost every cell of the body. One of each pair of chromosomes is inherited from each parent and, in this way, variations in DNA sequence are passed from generation to generation.
Modern "genomic science" may be considered as the study and use of genomic information and technologies, coupled with other biological approaches and computational analyses, to advance our understanding and knowledge of genes and genome function.
Identification of the genes and DNA sequence variants that underlie inherited susceptibility to rare and common human diseases has been a major preoccupation of geneticists for the last 50 years and has led to fundamental advances in understanding of the molecular and cellular basis of these diseases.
Illustration of DNA and chromosomes within the cell nucleus
Courtesy of the National Human Genome Research Institute
Key concepts in genomic medicine
"Genomic medicine" can be defined as the use of genomic information and technologies to determine disease risk and predisposition, diagnosis and prognosis, and the selection and prioritisation of therapeutic options.
Pharmacogenetics and pharmacogenomics
"Pharmacogenetics" is the study of the way in which a particular gene or small number of genes affects drug metabolism or responsiveness. "Pharmacogenomics" is the study of the way in which genetic variation across the genome affects drug metabolism and responsiveness.
Stratified or personalised use of medicines
The stratified or personalised use of medicines employs laboratory tests, including pharmacogenetic or pharmacogenomic tests, to stratify a patient group according to their predicted responsiveness to a particular treatment. Stratified use of medicines helps to improve the effectiveness of treatments by targeting individuals who will respond well to particular treatment based, for example, on genetic tests, or by excluding individuals who are predicted to have an adverse reaction to treatments.
Advances in genome technologies
COSTS OF SEQUENCING
2.3. Development of highly automated methods
of DNA sequencing in the 1990s, compared with the labour intensive
methods used previously, greatly increased the capacity for scientists
to undertake DNA sequencing and paved the way for determining
the first complete sequence of the human genome. Since then, costs
have fallen significantly, capacity has continued to rise, and
several further human genomes have been sequenced. Oxford Nanopore
Technologies gave an indication of the extent of the cost reduction:
"The first [genome], mapped by the Human Genome project,
cost approximately $3 billion, the second $100 million and the
third, that of the DNA pioneer James Watson, $1.5million
It is estimated that the current cost of completing a human genome
is [now] in the range of several hundreds of thousands of dollars"
(pp 322-23). According to Applied Biosystems, getting the
price of sequencing a human genome "down to $1,000"
was "probably only onemaybe two, threeyears
away" (Q 662).
DNA MICROARRAY TECHNOLOGIES
2.4. DNA microarray technologies also became
available in the 1990s, enabling simultaneous measurements of
hundreds of thousands of DNA molecules (and of the related RNA
(ribonucleic acid) molecules). Microarrays allow gene function
to be characterised on a genome scale, as opposed to earlier methods
that made measurements on an individual, gene-by-gene basis. They
also permit measurement of the extent to which every gene in the
genome is switched on or off in a microscopic tissue sample, allowing
construction of a "gene expression signature" or "expression
profile"; and they can be used to determine an individual's
DNA sequence at thousands or millions of specified locations in
the genome (thereby creating a "genome profile"). Microarrays
provide powerful ways to investigate the role of single or multiple
genes and DNA sequence variants in disease processes, both in
individuals and in populations.
2.5. Advances in genome technology have permitted
and driven extraordinary advances in genomic science. As will
be seen in this report, these advances are now permeating the
healthcare arena. This creates a significant new market for genome
technology companies, some of which are based in the UK, in diagnostics,
drug development and continuing scientific discovery. Because
of the leading role played by UK scientists in genomic science,
because of continuing charitable and Government funding of genomic
science, and because of the potential for genome-related clinical
trials and research in the National Health Service (NHS), the
UK is well placed to capitalise on this market.
Genetics of rare and common diseases
2.6. There are several thousand human genetic
disorders each of which is caused by an important DNA sequence
variationa mutationin a single gene. Examples are
Huntington's disease and cystic fibrosis. These disorders differ
in major ways from the much commoner, genetically complex diseases
that develop under the influence of multiple genes and the environment
such as diabetes, coronary heart disease and several types of
2.7. In Table 1 below we describe some of the
key differences between single-gene disorders and genetically
complex diseases. These differences are illustrated diagrammatically
in Figures 2 and 3.
Genetic differences between single-gene and genetically complex
|Frequency in the population||Generally less than 1 person in 1,000.
||Up to 1 person in 3.|
|Underlying cause||Disease caused by DNA mutation in single gene, though disease severity and age-of-onset varies according to the individual mutation and may be affected by the presence of other modifier genes.
||Disease susceptibility influenced by DNA sequence variation in multiple genes acting in concert with environmental factors (see Figure 3). Individual DNA sequence variations each contribute a small proportion of the overall risk of disease.
|Familial inheritance||Simple dominant, recessive, or sex-linked inheritance (see Figure 2).
||No simple mode of inheritance.|
|Familial risk||Possession of the disease gene confers a high and quantifiable risk to other family members.
||Possession of "low penetrance" susceptibility genes confers a small increase in risk to other family members.
|Success with gene identification before 2005
||Over 2,000 disease genes identified. Most disease genes not identified to date are exceptionally rare.
||Fewer than 20 disease genes identified.
|Success with gene identification since 2005
||Similar rate of gene identification prior to and since 2005.
||500 new disease genes localised and, in many instances, identified.
|Ante-natal diagnosis||Carried out in Clinical Genetics departments in conjunction with genetic counselling.
||Not applicable in genetically complex diseases, in which individual disease genes have a small effect on disease risk.
|Examples||Cystic fibrosis, Huntington's disease, haemophilia, sickle cell disease.
||Coronary heart disease, rheumatoid arthritis, common forms of diabetes and obesity.
Inheritance of single-gene (recessive) disorders
Courtesy of Kesson Magid, University College London
Genetic and environmental contributions to single-gene and
RISK OF DISEASE
2.8. The likelihood of developing a single-gene
disorder or a genetically complex disease can be expressed in
terms of "absolute risk" or "relative risk".
The differences between absolute and relative risk with respect
to single-gene disorders and genetically complex diseases are
described in Box 3.
Understanding risks for single-gene disorders and genetically
|"Absolute risk" is defined as the chance an individual has of developing a disease over a time-period. For example, a 65-year-old man has a one in 10 risk of developing dementia in the remainder of his lifetime. This can be represented as 10 per cent absolute risk.
In single-gene disorders, absolute risk for family members can be accurately predicted. For example, in the dominantly inherited Huntington's disease, the siblings and offspring of an affected individual have a 50 per cent absolute risk of developing the disease themselves.
In genetically complex diseases the effect of inheriting a particular susceptibility gene is often expressed as "relative risk", which is used to compare the risk in two different groups of people (see Figure 4).
For example, the absolute lifetime risk of developing a disease may be five in 100 in the general population, and the relative risk of the disease may be increased by 20 per cent in people who carry a particular genetic variant. The "relative risk" ascribed to this genetic variant is defined as 1.2, because the risk has risen from 1.0 ("normal" population risk) to 1.20 (increased risk for people carrying the genetic variant). In this population, this 20 per cent increase in relative risk represents an increase in absolute risk from five in 100 to six in 100. While a (relative) risk increase of 20 per cent sounds high, the absolute risk increase of one in 100 extra cases provides a more practical indication of risk to a member of that population.
Multiple Genes and Risks
Genetic predisposition to developing a complex disease
such as type 2 diabetes.
Genetic research associates DNA markers with the risk of developing
a complex disease. Testing for a number of markers builds an estimate
of individual risk. This risk is expressed relative to an average
individual of the same ethnicity and age.
Courtesy of Kesson Magid, University College London
2.9. "Penetrance" is the proportion
of individuals who carry a particular genetic variant who will
go on to develop the disease. The breast cancer genes BRCA1
and BRCA2 are examples of genes with "high penetrance"
because over 80 per cent of individuals who carry a mutation in
one of these genes will develop breast or ovarian cancer, or both,
in their lifetime. Genetic variants associated with common diseases
are mostly of "low penetrance", because the increased
risk of developing the disease that is conferred by carrying the
gene is relatively low.
Identification of susceptibility
genes for common diseases
2.10. The completion of the human genome sequence,
increasing knowledge of DNA sequence differences between individuals
and rapidly advancing technology for reading DNA sequences have
led to significant progress in identifying genes underlying common,
genetically complex diseases ("susceptibility genes").
By January 2009, more than 500 new susceptibility genes for these
diseases had been systematically mapped to the genome and, in
many cases, the underlying genes were identified. Professor Sir John
Bell, Chairman of the Office for Strategic Coordination of Health
Research (OSCHR), described the coming together of these developments
as "one of those inflection points that you get in medicine
every so often" which give rise to "very significant
opportunities to apply [a] methodology in a patient setting"
THE GENOME-WIDE ASSOCIATION STUDY (GWAS)
2.11. The method that has led to the discovery
of hundreds of new susceptibility genes for common diseases is
known as the genome-wide association study (GWAS). It allows the
entire genome to be scanned effectively for the genetic variants
that influence the development of disease. It is described more
fully in Box 4.
Discovery of susceptibility genes for common diseasesthe
|Genome-wide association studies (GWASs) compare populations that have a particular disease with control groups without the disease in order to identify genetic differences between the two groups. If particular genetic variants are found to be more frequent in people with a particular disease than the controls, these variants are said to be "associated" with the disease.|
Most of the letters of the genome, around 99.9 per cent, do not differ between individuals. However the small fraction that do differknown as DNA sequence variants or polymorphismsnot only explain inter-individual differences in body form and function, but serve as the molecular signposts in GWASs that indicate association between genes and the development of different diseases.
Throughout the late 1990s and early 2000s, catalogues of millions of variations in genome sequence between individuals were generated and maps of their distribution in the genome assembled. In the mid 2000s, technologies (such as microarrays) were developed to read hundreds of thousands to millions of changes in single letters of the genetic codeSingle Nucleotide Polymorphisms (SNPs)from an individual's genome in a single experiment, permitting the "genomic profiles" of large numbers of individuals to be constructed and analysed.
In 2006, the first GWASs were carried out. These expensive experiments required scanning of the entire genome and generation of genomic profiles in thousands of individuals. Statistical analysis of individual SNP frequencies in patients with different diseases and in controls was carried out to demonstrate an association between the possession of particular SNPs and susceptibility to particular diseases.
For example, the GWAS of the Wellcome Trust Case Control Consortium, published in June 2007, reported the localisation of 24 new susceptibility genes across a range of six common diseases: bipolar disorder, coronary heart disease, Crohn's disease, rheumatoid arthritis, and type 1 and type 2 diabetes.
Medical applications of genomic science
2.12. The National Institute for Health and Clinical
Excellence (NICE) gave us an indication of the current use and
potential value of genetic tests and other genomic technologies:
"Genetic tests for more than 1,200 diseases
have been developed, with more than 1,000 currently available
for clinical testing. Most are used for diagnosis of rare genetic
disorders, but a growing number have population-based applications,
including carrier identification, predictive testing for inherited
risk of common diseases, and pharmacogenetic testing for variation
in drug response. These tests and other anticipated applications
of genomic technologies for screening and prevention have the
potential for broad public health impact" (p 394).
PREDICTIVE DIAGNOSIS AND SINGLE-GENE DISORDERS
2.13. Identification of the disease gene in single-gene
disorders has had a number of beneficial consequences: it has
increased knowledge about disease development; it has enabled
precise molecular diagnosis; and, in a small number of cases,
given rise to new targeted therapies. Reliable prenatal diagnosis
is possible in single-gene disorders and is used to inform reproductive
decisions in the ante-natal clinic in families with a high risk
of severe genetic disorders. Predictive diagnosis in post-natal
life can be used to make lifestyle choices and to allow early
disease treatment at a pre-clinical stage.
PREDICTIVE DIAGNOSIS AND GENETICALLY COMPLEX DISEASES
2.14. Genetic susceptibility is only one of several
factors that can be used to predict common diseases. Other factors
include family history, environmental exposures (such as cigarette
smoking) and non-genetic tests such as blood cholesterol.
2.15. Data from GWASs have enabled the identification
of a large number of disease genes underlying common diseases.
But, whilst the new data are scientifically promising, their clinical
utility has yet to be demonstrated. Professor Sir John
Bell commented that "the suggestion that the data that come
out of the whole genome association data, with relatively small
but robust odds ratios, can be used to stratify patients in breast
cancer screening is an interesting idea but we will need to see
the data" (Q 432). The Wellcome Trust Sanger Institute
also sounded a note of caution: "for most common human diseases
only a small proportion of disease susceptibility has been explained
in terms of identified disease-causing [gene] variants" (p 329).
Consequently, identification of such variants is unlikely to lead
to a precise, individually-tailored diagnosis or measurement of
disease risk save in exceptional circumstances involving only
a small fraction of the population. Furthermore, gathering data
through the GWASs is still at an early stage and therefore, according
to the Academy of Medical Sciences (AMS), "the ability to
interpret genomic data accurately, and to use this information
to develop interventions to prevent or treat disease, still requires
a great deal of research effort" (p 464).
2.16. Potential benefits are, however, beginning
to emerge. For example, Professor Rory Collins, Director
of UK Biobank, told us:
"We may well find genetic variants that
produce only very small effects on risk, but what that could mean
is that we have identified a new pathway for disease. That pathway
could then open up the discovery of treatments that would act
on that pathway which could be of substantial benefit" (Q 499).
2.17. Furthermore, identification of a SNP or
set of SNPs (defined in Box 4 above), whilst not enabling individually-tailored
diagnosis, could contribute to the information needed to stratify
disease risk within the population, thereby enabling more accurate
targeting of treatments. This has important implications at the
population level as screening programmes will be able to identify
individuals at high risk of disease. For example, seven SNPs associated
with breast cancer, when taken together, "can identify women
who have quadruple the average risk in society of developing breast
These seven markers
can reliably identify
five per cent of women in our society that have more than a 20
per cent absolute risk of breast cancer," thus justifying
screening (Q 531). Similarly, "if you take eight sequence
discovered recently in eight places in the genome,
it allows us to identify the one per cent of males in our society
who have triple the risk of prostate cancer" (Q 531).
The Joint Committee on Medical Genetics (JCMG) provided a further
example in relation to colorectal cancer (p 552).
DIAGNOSING GENETIC SUBTYPES OF COMMON DISEASES
2.18. In a small proportion of casesand
in a minority of families with multiple cases of the same diseasea
disease develops not because of the predisposing effects of multiple
genes (combined with environmental factors) but because of a mutation
in a single gene ("single-gene subtypes"). Single-gene
subtypes occur in a wide range of conditions including diabetes,
Alzheimer's disease, Parkinson's disease, some cases of blindness
and several types of cancer. The proportion of single-gene subtype
cases varies markedly from disease to disease (less than five
per cent in Alzheimer's disease but as high as 50 per cent in
children diagnosed with diabetes under the age of six months).
Distinguishing between single-gene subtypes of common diseases
and their genetically complex form is important. The two categories
of the same disease may progress at different rates and may therefore
require different treatments. In addition, the risk to relatives
in single-gene forms of a disease is extremely highup to
50 per cent of siblings or offspring of an affected family member
may develop the diseaseso if a precise molecular diagnosis
is made in one family member, reliable prediction of disease risk
and appropriate treatment can be offered to other family members.
2.19. Identifying this distinction within common
diseases is having a profound effect on patient care. According
to Professor Steve O'Rahilly, Professor of Clinical
Biochemistry and Medicine at Cambridge, "what genetics is
doing increasingly is actually helping us to subdivide [common
diseases] into separate entities, some of which may end up having
specific therapies". He gave the example of diabetes: "a
very large number of people who had diabetes in the first few
months of life had a particular mutation. All of those individuals,
even after 30 years, could be taken off insulin and put onto a
tablet and they became insulin-free, having been a slave to this
injectable drug for many, many years. It caused dramatic changes
in their health benefits" (Q 182). The range of diseases
in which single-gene subtypes are now recognised is such that
genetic diagnosis is increasingly used within the NHS for these
PREDICTIVE GENETIC TESTS SOLD DIRECT TO THE CONSUMER
2.20. Although the clinical utility of the disease
association data from GWASs remains to be demonstrated, an increasing
number of private companies in different parts of the world, including
the UK, offer individual genetic tests or entire genomic profiles
for sale directly to consumers. These tests, known as "direct
to consumer tests" (DCTs), are mainly marketed and sold over
the Internet. We return to this issue in more detail in Chapter
GENOMIC TOOLS FOR MANAGING COMMON DISEASE
2.21. Whereas it may take some years to ascertain
the utility of DNA sequence variation in predictive testing for
common diseases, genomic tools are already being used in established
diseases to make more precise molecular diagnoses. This is leading
to new disease classifications and opportunities for more "personalised"
2.22. Cancer genetics is generally seen as leading
the field. For example, Professor Sir John Bell told
us that DNA microarray measurements of gene expression in tumour
tissue are already generating data that can "separate women
with breast cancer into high and low risks groups in a way that
you cannot do with other technologies. It may allow some women
who would have been exposed to chemotherapy to be able to avoid
chemotherapy, and other women with bad prognosis disease who would
not have been treated aggressively to be treated aggressively"
(Q 432). Professor Sir Bruce Ponder, Director of
Cancer Research UK Cambridge Research Institute, told us of trials
which, it was hoped, would identify "with sufficient precision"
those with "bad tumours who need the extra therapy"
and those who have not. If a trial currently being conducted in
Europe was positive, "it will be in routine practice within
the next two or three years" (Q 534).
2.23. In the same field, the level of expression
of the HER2 protein in the tumour is recommended by NICE as a
guide to treatment with the drug Herceptin.
In the diagnosis and treatment of leukaemia, according to the
Royal College of Pathologists,
it is already a requirement that
information about genomic changes in the tumour must be available
before the drug can be given. Data from one haematopathology laboratory
indicate close to a threefold increase in the use of these techniques
in the last two years. It is inevitable genomic analysis will
soon be a standard requirement for many much more common tumours"
2.24. Some of these tests are carried out by
simple techniques, others require more sophisticated sequence-based
or microarray-based techniques. In screening for cervical cancer,
present tests with Pap smears produce data whose "sensitivity
is about 50 per cent so you identify the problem about 50 per
cent of the time. By using genetic tools to look for papilloma
you might be able to eliminate the Pap smear altogether,
which would be a significant benefit, but you also get up to a
sensitivity which is nearer 90 per cent" (Q 432).
2.25. The use of genomic tools is not limited
to cancer management. In the treatment of HIV, viral sequencing
can guide the way medications are applied; in tracking the spread
of infectious diseases, viral sequencing can precisely categorise
strains of virus, such as swine flu virus. Genetic testing is
used to screen patients for likely hypersensitivity reactions
to the drug Abacavir, used in the treatment of HIV infection.
A commercial test for predicting foetal abnormalities such as
Down's syndrome, based on sequencing foetal DNA found in very
small quantities in the maternal bloodstream, is now being launched
in the United States, thereby avoiding the need for the traditional
amniocentesis test which carries a small risk of foetal mortality.
2.26. The potential for such genomic tests is
increasing. For example, cancer-causing changes in DNA sequence
have been detected in tumour cells, and microarray studies have
found structural changes in the tumour cell genome (such as gene
duplication and deletion), some of which correlate with drug responsiveness.
These advances are likely to lead to new tests for classification
of tumours which will, in turn, guide treatment.
2.27. Professor Sir John Bell thought
that applications of genomic technology which can be applied in
the clinical setting "are likely to happen in a very short
timeframe, particularly as the incentive to do it is enormous".
He suggested that "certainly within five years" there
was going to be a lot of activity with regard to the application
of genomic technologies to common disease (Q 424).
THE STRATIFIED USE OF MEDICINES AND PHARMACOGENOMICS
2.28. "Pharmacogenomics" is the study
of the way in which genetic variation across the genome affects
drug metabolism and responsiveness. It can be used to develop
tests to classify or stratify patient groups according to their
response to a treatment (see Box 2). Pharmacogenomic tests are
therefore one of a number of tests that can be used to personalise
a patient's treatment.
2.29. Professor Munir Pirmohamed, the UK's
first Professor of Pharmacogenetics, commented that although
the term "personalised medicines" was now commonly used,
as a physician, he had always carried out some personalisation
of medicines"I will try to personalise it depending
on what their background characteristics are, what other drugs
they are on and so on" (Q 719). This "personalised
prescribing" is indicative of a new range of genetic tests
that can be used to identify better drug treatments for individual
patients. Dr Annette Doherty of Pfizer said that "the
effect of pharmacogenomics and targeted medicines is being felt
in every aspect of research and development within the pharma
industry" (Q 719).
2.30. Although the Wellcome Trust suggested that
"the impact of genomics on drug development pipelines has
not been as profound as many had predicted" (p 75),
the Human Genetics Commission (HGC) regarded pharmacogenetics
as the area from which new developments were "most likely
to come into clinical practice
within the short term"
(Q 288). The Royal College of Pathologists indicated that
they would welcome this. They anticipated that DNA and RNA-based
diagnostic approaches will "guide more appropriate treatment
and avoid ineffective treatment, and will identify some patients
who do not need treatment. [They] will be an absolute requirement
before the administration of many new treatments, especially new
anti-cancer drugs; [and] will increasingly allow the prior prediction
of severe adverse [drug] reactions" (pp 107-8).
2.31. The Bioindustry Association referred to
the increasing numbers of drugs for which genetic tests may guide
treatment or prevent side effects (p 481). In the United
States, pharmacogenomic information is contained in about 10 per
cent of labels for drugs being currently approved by the Food
and Drug Administration (FDA).
The FDA had been "very proactive in encouraging the submission
of [drug side effects] data under a voluntary scheme which takes
account of the fact that much of the science is at the exploratory
stage at present" (p 478). According to the pharmaceutical
company AstraZeneca, the FDA's activities had placed the United
States "at the forefront in progressing [pharmacogenetic]
research towards translation into medical practice" (p 478).
Bioinformatics and genomic medicine
2.32. "Bioinformatics" may be defined
as a discipline which uses computers and computational expertise
to analyse, visualise, catalogue and interpret biological information
in the context of the genome sequences of humans and other species.
2.33. As we highlighted in our 2001 report on
Human Genetic Databases,
there has been a dramatic increase in our capacity to collect
genetic and genomic data in recent years. Genomic tests in a clinical
setting and genomic experiments for basic biology generate quantities
of data for which manual analysis is unthinkable. Indeed, for
many genomic experiments, even the most advanced computers may
struggle to undertake necessary tasks.
2.34. According to the Wellcome Trust Sanger
Institute, "our ability to understand basic human biology
has been transformed via the high throughput data production platforms
resulted in the rapid advancement of
genomic research and in major breakthroughs in our understanding
of the biology behind human health and diseases" (p 328).
2.35. Meeting the information technology (IT)
requirements of genomic medicine is therefore critical. Professor Dame
Janet Thornton, Director of the European Bioinformatics Institute,
described its importance in this way: "genomic medicine is
very exciting and does have enormous potential
For us the
informatics challenges that this poses are enormous. It is clear
that it will be the biomedical informatics that will allow translation
from knowledge and research into medical practice, delivered through
in the clinics, in the hospitals and ultimately
for the GPs" (Q 695).
2.36. Within the NHS, Dr Elles, Director
of Molecular Genetics at the National Genetics Reference Laboratory,
described the challenge of interpreting DNA-based clinical results,
telling us that:
"[an] immediate need
us day in and day out, is increasingly that we find variants in
the DNA sequence of patients and we are not always sure what that
variant means so it is the task of the laboratory scientist to
try and interpret that by comparing whether for example that variant
has been seen in another laboratory in the UK. That search may
need to go much further afield and ask where in the world has
that variant been seen; is it associated with the condition; can
we produce a sensible clinical report for that patient" (Q 264).
We consider bioinformatics in more detail in Chapter 5.
The role of epigenetics in disease
2.37. "Epigenetics" refers to changes
in phenotype (appearance) or gene expression caused by mechanisms
other than changes in the underlying DNA sequence. Epigenetics
is a scientific discipline that has run in parallel with genetics,
and the two have recently converged because of their shared use
of genome technologies and the desire to link genetic and epigenetic
changes to traits such as disease susceptibility. The molecular
basis of epigenetic changes is a modification of DNA or a modification
of the packaging proteins known collectively as chromatin. Since
these changes are not encoded in the genome sequence (unlike mutations),
they are not generally passed down from generation to generation.
2.38. A fundamental feature of the epigenetic
characteristics of an individual is that they can be modified
by environmental factors such as the intrauterine environment,
nutrition, stresses, tobacco and alcohol. Professor Sir John
Bell commented on how the new sequencing tools were providing
a "fantastic window" on epigenetic modifications and
that maps would soon appear of epigenetic modifications in the
development of different types of common diseases (Q 440).
2.39. Although the science of epigenetics is
progressing very rapidly, it appears that it will be several years
before epigenetic science will impact significantly on healthcare
in the NHS due to the lack of understanding about the cause and
effect of epigenetic changes on disease prevalence, and lack of
specific therapies that target epigenetic processes. For this
reason, we do not consider epigenetics further in this report.
The importance of biobanks and
population cohorts for advancing genomic science
2.40. In recent years, two large national epidemiological
cohort collections have been established in the UK: Generation
Scotland and UK Biobank. These large cohort studies have the potential
to contribute significantly to our understanding of the complex
interplay of genetic and environmental factors that lead to the
development of common diseases (p 11). Professor Andrew
Morris, Chairman of the Generation Scotland Scientific Committee,
suggested that the setting up of these collections demonstrated
a recognition "that we need very, very large studies to be
able to have the power and the certainty to tease out the modest
clinical impact that many of these genetic variants have
We are looking at very small effects in large populations, hence
the numbers are so important" (Q 485).
2.41. UK Biobank plans to recruit a sample group
of 500,000 people by 2010. The project is collecting biological
samples, and also lifestyle and environmental information, and
will make samples available to researchers, subject to certain
conditions, to conduct genetic studies. Generation Scotland differs
from UK Biobank in being family-based rather than population-based.
Generation Scotland will recruit 50,000 subjects from families.
The family structure is believed to give additional information
over a population cohort of equivalent size due to the ability
to trace disease prevalence through families, therefore strengthening
the genetic associations with disease.
2.42. A further cohort project, launched in January
2008, is the 1,000 Genomes Project. This project, in which the
Wellcome Trust Sanger Institute is a major partner, will use new
sequencing technology to sequence the entire genomes of 1,000
individuals to identify very rare variants, found at frequencies
of less than one per cent. This will allow a much more detailed
view of human genetic variation than was previously available.
Dr Francis Collins, former Director of the National Human
Genome Research Institute, said that the 1,000 Genomes Project
was expected "to increase the sensitivity of disease discovery
efforts across the genome five-fold and within gene regions at
This will change the way we carry out studies
of genetic disease".
2.43. It is expected that diverse databases,
such as the 1,000 Genomes Project, will ultimately be combined
with the UK Biobank lifestyle and environment data. At present,
UK Biobank is not linked to death records or hospital episode
statistics in the UK.
2.44. Genomic science has built rapidly on the
achievements of the human genome project, bringing new-found understanding
of the genetic basis of common diseases, and other advances that
have already started to be used in healthcare. The use of genetic
and genomic tests has become established in the management of
diseases such as leukaemia and HIV, in predicting individual responsiveness
and side effects to certain drugs, and in diagnosing genetic subtypes
of common diseases such as diabetes, sudden cardiac death and
blindness. These developments have enormous further potential
in improving and rationalising management of a broad range of
diseases, and in advancing strategies for disease prevention and
public health. In the chapters that follow, we consider how such
developments in genomic medicine can be brought more widely into
2.45. We are also aware of developments in related
areas, such as gene therapy and stem cell therapies, and other
technologies such as proteomics and metabonomics that have the
potential to impact on clinical practice, either now or in the
future. However, these areas are beyond the scope of this inquiry.
1 Seshadrietal et al, Neurology, 1997,
Wellcome Trust Case Control Consortium, "Genome-wide association
study of 14,000 cases of seven common diseases and 3,000 shared
controls", Nature, vol. 447, 7 June 2007, pp 661-78. Back
Professor Finbarr Cotter, Barts and the London School of Medicine. Back
House of Lords Science and Technology Committee, 4th Report, Session
2000-01, Human Genetic Databases: challenges and opportunities
(HL Paper 57). Back