Download genetics, health and disease

GENETICS, HEALTH AND DISEASE
Our bodies are built from millions of cells, each of which contains the information for making and
maintaining a human body. The full set of information, our genome, consists of around 25,000 individual
genes that organise how our bodies grow and develop from a single fertilised egg. Genetics is the study
of this biological information, and of how it is passed on from one generation to another (inheritance).
Genes are not the only influence that affect human development and health: the environment interacts with
genetic make-up to determine, for example, lifespan and susceptibility to disease as well as many
behavioural characteristics. Only genetic information, however, is directly passed on from one generation
to the next.
The chemicals of life
Genetic information is stored inside each cell of
the body as deoxyribonucleic acid (DNA). The
essential functions of cells are performed by
proteins, which are also key components of
cellular structure. DNA has two primary
features: it is a code for directing the formation
of proteins, and it is also reproducible. The
special structure of DNA is essential for both
these functions. DNA has a long helical
"backbone" with nucleotide bases attached.
The chain pairing of these bases forms the
famous double-helix structure deduced by
Watson and Crick. There are four different
bases: adenine (A), cytosine (C), guanine (G) and thymine (T). Bases A and T bind together specifically and
reversibly, as do bases G and C.
Genes and chromosomes
A sequence of DNA that contains the information to code for a protein is called a gene. Every cell
contains a complete set of DNA instructions for making the human body; this is the genome. The human
genome contains 3 billion base pairs and around 25,000 genes representing 1-2% of the total genome. The
functions, if any, of most of the rest of the genome are not known. The protein-coding DNA of most genes
is not a continuous stretch but is interrupted by non-coding sequences called introns. Genes also contain
regulatory sequences that control whether and when that protein is made.
Within the cell, DNA is wound up very tightly and packaged with proteins to form chromosomes.
Corresponding chromosomes from different individuals of the same
species in general carry the same sets of genes in the same order. The
chromosomes always come in even numbers because they occur in
pairs whose members are very similar to each other; one member of
each pair is inherited from the mother and the other from the father,
with the result that every individual has two copies of each gene.
Humans have 23 pairs of similar (homologous) chromosomes. The two
sex chromosomes (X and Y) differ significantly from each other, but
the other (autosomal) chromosome pairs are nearly identical. Women
have two X chromosomes, whilst men have one X and one Y
chromosome. The set of chromosomes in a cell is known as the
karyotype. Special staining techniques can be used to visualise the
chromosomes; different chromosomes have characteristic sizes and
Set of chromosomes (karyotype) from
when stained show characteristic patterns of transverse bands.
a human male.
Gene expression
In order to make use of the information stored in its DNA, a cell needs to express that information - that is,
to produce the proteins encoded by the genes. Different types of cells (for example bone, liver and skin
cells) contain exactly the same DNA, but they have different functional characteristics because they have
expressed different sets of genes.
1
Mutation and variation
A mutation is an alteration in the normal sequence of a DNA
molecule, most commonly due to mistakes made by the cellular
machinery that copies DNA but also as a result of
environmental agents such as radiation or hazardous chemicals.
Most mutations are repaired by the cell, but if not they may
lead to loss or alteration of the function of the protein encoded
by the DNA. The nature and size of mutations vary. Small-scale
mutations change small numbers of bases, as few as a single base
(called a point mutation). Such mutations usually affect only a
single protein but can have drastic consequences. For example,
a change to a single base can lead to the formation of a nonMutations in reproductive cells are passed on
functional protein. Mutations outside the coding regions of
to all of the offspring's body cells.
genes can still affect protein production; for instance, they may
occur in regulatory regions, causing inappropriate gene
expression. Mutations in genes that encode DNA repair proteins may cause the cell to become errorprone, accumulating multiple mutations in its DNA. Large-scale mutations (also called chromosomal
rearrangements) often cause severe problems; for example, large deletions may completely remove one
or more genes, whilst large duplications may cause too much of
a protein to be produced, which can make cells grow wrongly.
Insertions and translocations, in which segments of DNA are
transferred from one chromosome to another, can change the
way genes are expressed.
Some genetic diseases are inherited from a parent or parents
who carry and pass on to their offspring a disease-associated
mutation. The parents may themselves have the disease, or they
may be unaffected but pass on a copy of the disease gene.
Cystic fibrosis is always inherited in this way. Other genetic
diseases may be caused by new mutations that occur in the
parental reproductive cells, such that although the parents do
not carry the disease mutation, their child does. An example of
a genetic disease that can arise in this way is type 1
neurofibromatosis.
Not all DNA alterations cause disease. Mutation provides the
basis for evolution: genetic alterations that increase
reproductive fitness (or at least do not decrease it) will tend to
persist and spread in a population. Over time, all species have
accumulated subtly different normal variants of a DNA
sequence that explain why individuals in these species are not
identical. This phenomenon is known as polymorphism.
Human DNA varies at about 1 base in every 300; only some of
this variation falls within genes (protein coding regions).
Alleles, genotype and phenotype
Different versions of the same gene at the same position on
corresponding chromosomes are known as alleles; because
Large-scale chromosomal mutations
every individual has two sets of chromosomes, there are two
alleles for every gene (one inherited from their mother and the
other from their father). Some alleles are identical in their
action but others produce quite different effects. For example, sickle-cell anaemia is caused by a variant
allele of a haemoglobin gene. If someone has two copies of the same allele then they are said to be
homozygous for that allele. If they have different alleles of that gene then they are heterozygous at that
genetic locus. An individual who is homozygous will show the characteristic associated with that form of
the gene. For example, a person with two copies of the ‘A’ allele encoding a particular blood protein has
type A blood. A person who has one copy of the A allele and one of the ‘O’ allele also has the A blood
2
type; in this case the A trait is said to be dominant over the O
trait and the O trait is said to be recessive. The set of alleles
that a particular person has is known as their genotype. The
AA
A
set of observable characteristics that they have is known as
their phenotype. The phenotype is the result of the
AO
A
interaction between the genotype and environmental factors;
OO
O
gene-environment interactions affect almost all human
characteristics, including susceptibility to disease. Sometimes the
environmental effects are small, for example eye colour is largely determined by the genotype. Other
characteristics of the phenotype, however, such as height and weight, depend more strongly on
environmental factors, although the genotype also
plays an important role.
Genotype
(alleles)
Phenotype
(blood group)
Genetics and disease
There are several thousand inherited diseases
known to be associated with mutations in single
genes. These diseases show simple patterns of
inheritance and are known as monogenic
(single-gene) or Mendelian disorders. Other
genetic diseases are caused by larger-scale
chromosomal alterations. Individually, genetic
diseases caused by chromosomal alterations or
single-gene mutations are rare, but collectively
Some genetic variations have no effect, but others can lead to
these disorders are relatively common, with a
disease or increased susceptibility to a disease.
combined birth prevalence of around 1-2%. In
addition, susceptibility to many common diseases of middle and later life is known to have a genetic
component. In these cases, the association between gene variants and disease is less clear-cut: more than
one gene may be involved and the genes interact in complex ways with each other and with environmental
and lifestyle factors to determine whether disease will develop. Recent advances in genetics and molecular
biology have begun to elucidate both the genetic mutations underlying many single-gene diseases, and some
of the genetic variants associated with susceptibility to some common diseases.
Monogenic diseases
For inherited monogenic diseases, if the
genotypes of parents with respect to a
disease-associated gene are known, then
the possible genotypes of their children
can be predicted. If the diseaseassociated allele is dominant, it prevails
over a normal allele, such that disease
will be present in all individuals with
either one or two copies of the disease
allele. The children of an affected parent
with one dominant allele and a normal
(a) Autosomal dominant disease
(b) Autosomal recessive disease
partner would therefore have a 50%
chance of inheriting a disease allele, and
Patterns of inheritance for single-gene disorders
hence of having the disease. Examples of
autosomal
dominant
disorders
include Huntingdon’s disease and neurofibromatosis. If, however, the disease-associated allele is recessive,
then the disease is only seen in individuals who do not have a normal allele. In these autosomal recessive
disorders such as cystic fibrosis and Tay-Sachs disease, affected individuals have two copies of a diseaseassociated allele; individuals with only one disease allele are healthy, but are carriers of the disease.
Haemophilia, Duchenne Muscular Dystrophy (DMD) and Fragile-X syndrome are examples of sex-linked
genetic disorders. This means that the gene associated with the disease is on one of the sex
chromsomes, almost invariably the X chromosome. Females have two X chromosomes, so a female with
one normal and one (recessive) haemophilia or DMD mutant allele will be a normal carrier. The sons of a
carrier mother and unaffected father have a 50% chance of carrying the mutant allele on their single X
chromosome, and therefore of being affected.
3
Numbers of people with some single-gene and chromosomal diseases.
Numbers are based on a typical health authority district with 3,000 births annually and a total population of 250,000; Non-recurrent genetic
diseases such as Down syndrome are not included.
Condition
New cases
No. living
per year in
patients in
district
district
1/3,000
1/8,000
1.0
0.4
18
8
14
6
162
50
1/1.000
3.0
55
43
330
1/500
6.0
394
355
2360
1/12,000
1/2,500
0.25
1.2
19
69
12
30
70
280
1/100,000
0.03
1.3
0.8
10
1/5,000
1.6
36
32
220
1/30,000
0.1
8
5
230
1/2,000
1/10,000
1/54,000
1.5
0.3
0.06
25
23
2
20
20
1.7
50
46
4
1/10,000
0.3
3
2
46
1/13,000
1/27,000
1/250
0.2
0.1
18
9
15
6
36
18
Birth
frequency
No. unrelated families
No. relatives at > 1 in 10 risk of
being affected or carriers
Autosomal dominant disorders
Huntington's chorea
Familial polyposis coli
Adult polycystic disease
of kidneys
Familial
hypercholesterolemia
Tuberous sclerosis
Neurofibromatosis
Von-Hippel Lindau
disease
Retinitis pigmentosa
Bilateral
retinoblastoma
Myotonic dystrophy
1/7,000
Autosomal recessive disorders
Cystic fibrosis
Adrenal hyperplasia
Friedreich's ataxia
Spinal muscular
atrophy
Phenylketonuria
Usher's syndrome
Sickle cell disease in
Afro-Caribbeans
Thalassaemia
in Cypriots
in Indians
in Pakistanis
1/140
1/1,000
1/300
Estimates: actual figures depend on ethnic characteristics of the population and uptake of screening and offer
of prenatal diagnosis
X-linked recessive disease
Duchenne/Becker
muscular dystrophy
Haemophilia A and B
X-linked retinitis
pigmentosa
Other X-linked eye
disorders
Fragile-X syndrome
Other forms of X-L
mental disorders
1/9,000
0.3
8
7
78
1/20,000
0.15
11
7
66
1/7,000
0.43
23
14
70
1/7,000
0.43
23
14
70
1/4,000
0.75
52
49
360
1/4,000
0.75
52
49
360
Unbalanced
translocations
1/2,000
1.5
16
16
60
TOTAL
1/144
20.8
987
Chromosomal disorders
730
5056
Notes
Birth frequency: many of these birth frequencies are changing, and those listed here refer to the most recent figures. For example, the birth
frequency of Duchenne muscular dystrophy has fallen from 1 in 6,000 to 1 in 9,000 as a result of genetic counselling. The birth frequency of
thalassaemia in Cypriots has fallen to 0, as a result of antenatal screening, prenatal diagnosis and the offer of selective termination of pregnancy.
Data taken from: Royal College of Physicians of London. Purchasers’ guidelines to genetic services in the NHS. An aid to assessing the genetic
services required by the resident population of an average health district. London Royal College of Physicians, 1991.
4
Chromosomal disorders
Large-scale chromosomal alterations often arise due to errors during
cell division during the formation of reproductive cells. Aneuploidy (the
presence of an abnormal number of chromosomes) usually prevents
normal embryonic development and often causes spontaneous abortion.
Perhaps the best-known example of non-fatal aneuploidy is Down
syndrome, which is caused by the presence of an additional copy of
chromosome 21 (trisomy 21). Specific disorders are also associated
with structural alterations of chromosomes. Cri du chat syndrome is
caused by a deletion on chromosome 5. Disease may also result from
duplication of chromosomal regions; Fragile-X Syndrome is caused by
the presence of an abnormal number of sequence repeats (several
hundred) in a region of the X chromosome.
Trisomy 21 karyotype
Single-gene subsets of common diseases
Although most common diseases result from the combined effects of multiple genes interacting with
environmental factors, there are sometimes families in which several family members are affected by the
same disease, often at an early age, suggesting the existence of a single mutation that confers a high risk of
disease. In these single-gene subsets of common disease, such as familial hypercholesterolaemia, genotype
can be used with a fairly high degree of certainty to predict the development of disease (in this instance,
cardiovascular disease). In general, single-gene subsets of common diseases account for a maximum of 510% of the total burden of each disease.
Cancer
Cancer is often described as a ‘genetic disease’, in the
sense that it is caused by genetic alterations. It occurs
when the DNA instructions in a cell are damaged or
altered in such as way that the cell escapes the normal
mechanisms that should control its behaviour. Such
cells may multiply unchecked to form tumours and
acquire the ability to migrate to, lodge and grow in distant sites of the body (metastasis). The genetic
alternations that lead to cancerous behaviour are somatic mutations, however. That is, they occur in the
somatic cells of the body rather than the sperm or egg cells so they are not passed on to the next
generation. However there are some inherited mutations (that is, mutations that are present in all the cells
of the body including the sex cells) that predispose people who carry them to developing cancer in a
particular tissue or organ. The BRCA1 and BRCA2 mutations associated with a high risk of breast cancer fall
into this category.
Penetrance and expressivity
In many (but not all) single-gene
diseases, a person with a specific
Variable penetrance – only some individuals
Ovals represent individuals
genotype is virtually certain to
with the mutation develop the disease
with the disease gene:
develop the associated disease
(phenotype), though its symptoms,
Unaffected
age of onset and severity may vary.
The likelihood that a person
Mildly affected
Variable expressivity – individuals with the
carrying
a
disease-associated
mutation show different disease severity
genotype will develop the disease is
Moderately affected
known as the penetrance of the
Severely affected
phenotype. Huntington's disease is
virtually 100% penetrant. The
Variable penetrance and expressivity–
BRCA1 gene mutations associated
only some individuals with the mutation
develop the disease; disease severity varies.
with breast and ovarian cancer are
highly
penetrant,
but
not
completely so; estimates of the lifetime penetrance of these mutations vary from about 60-85%. Most of
the genetic variants associated with susceptibility to multifactorial disease are thought to be common in the
population (so they are generally described as polymorphisms rather than mutations), but of low
5
penetrance. Variations in penetrance are caused by the modifying effects of other genes and/or by
environmental factors. Expressivity is another important concept in genetic disease, and refers to the
degree to which a phenotype is expressed – individuals affected by a disease with variable expressivity will
show different symptoms and disease severity.
The human genome project
Over the last 15 years, scientists across the world have worked out the complete
sequence of the 3 billion nucleotides in human DNA. The aim now is to find all the
genes and to work out what they do. This research is producing an enormous
amount of information: high-powered computers and software are needed to store
and analyse it. What the scientists have so far is a sort of ‘average’ sequence based
on DNA from a small number of people. Now they are looking at larger numbers of
people from different human populations and are trying to find the points in the
sequence where humans vary from one another.
Genetic testing
A genetic test is a test to detect the presence or absence of, or alteration in, a particular
gene, chromosome or gene product, in relation to a genetic disorder. This may involve
DNA sequencing to identify disease-associated mutations, or examination of chromosomes
(cytogenetic analysis). For example, cytogenetic analysis is used to identify trisomy 21 for
diagnosis of Down’s Syndrome. Genetic testing may also include physical examinations or
biochemical tests for specific proteins or markers that indicate the presence of abnormal
genes. In the case of phenylketonuria, for example, the genetic test is based on the
detection of elevated concentrations of the amino acid phenylalanine in a blood sample.
Diagnostic genetic testing
The aim of diagnostic genetic testing is to establish the presence of a specific genetic disease, often in
infants or young children, and ideally so that appropriate treatment may be undertaken. For example, in an
infant with wasted muscles and difficulty in walking, symptoms consistent with muscular dystrophy but
which might also have another cause, a genetic test could be used to provide a definitive diagnosis.
Antenatal diagnostic testing requires fetal cells to be obtained by chorionic villus sampling or amniocentesis.
The purpose of antenatal testing is to provide the parents with information that they may choose to act on,
for example, by preparing for the birth of a disabled child, or by electing to terminate the pregnancy. A
couple who have previously given birth to a child with a recessive single-gene disorder may elect to
undergo antenatal diagnostic testing in subsequent pregnancies. For some couples in this situation,
termination of an affected pregnancy is unacceptable but they wish to avoid giving birth to another affected
child. In some cases, the option of pre-implantation genetic diagnosis may be available. This procedure
involves the creation of embryos by in vitro fertilisation and the removal of 1-2 cells from each embryo that
are tested for the disease-causing genotype. Embryos that are unaffected by the genetic disease are used to
establish a pregnancy.
Carrier testing
Couples or individuals who know that a genetic disease runs in their family, or is prevalent in the
population to which they belong, may wish to know their risk of passing on the disease to their children. In
populations originating from some Mediterranean areas, for example, the single-gene autosomal recessive
disease beta-thalassemia is relatively common. Couples may elect to undergo genetic testing to determine
whether they are carriers of the disease-causing allele. Other examples of diseases for which carrier testing
is sometimes used are cystic fibrosis (most common in Caucasian populations), sickle-cell anaemia (mostly
in people of African origin), thalassaemia (populations from Asia and the Mediterranean) and Tay-Sachs
disease (in Ashkenazic Jews).
Newborn screening
In the UK, blood samples from newborn babies are routinely screened to detect rare genetic diseases for
which early intervention can avert serious health problems or death. Phenylketonuria (PKU), a metabolic
disease that causes severe mental retardation if undetected but which can be prevented by a special low
6
phenylalanine diet, has been screened for since 1969. National newborn screening programmes for cystic
fibrosis and sickle-cell disease are being introduced. There is no cure for cystic fibrosis but early diagnosis
and treatment is thought to benefit the health of affected children. Screening for sickle-cell anaemia allows
early diagnosis and prophylactic treatment with antibiotics and vaccines to prevent infection.
Predictive genetic testing
Predictive genetic testing (also known as pre-symptomatic testing) is
the use of genetic testing to predict whether an individual will develop a
genetic disease. It can only be used where the disease-associated mutation
is known and is highly penetrant, for example in Huntington’s disease. As
this is a late-onset disease, a person with a parent affected by the disease
will not know whether he or she has inherited it until he or she reaches
middle age. However, DNA testing will reveal whether the mutation is
present, changing that person’s individual risk from 50% to either 100% or
zero. Ideally, predictive genetic testing is used in association with
prophylactic treatment for individuals who test positive. However, Huntington's disease is untreatable and
fatal, so careful counselling is essential for any person from an affected family who is contemplating
undergoing genetic testing.
Testing for genetic susceptibility
As genetic research advances, genetic variants are being identified that appear to be associated with
increased or decreased risk of particular diseases. An example is the APOE4 allele of the gene encoding a
blood protein called APOE, which is associated with an increased risk of Alzheimer’s disease. However, the
presence of an E4 allele is neither necessary nor sufficient for a person to develop Alzheimer’s, so a genetic
test for this allele, although technically straightforward, has limited predictive value. The clinical usefulness
of such as test is also low, as there is currently no effective treatment or prophylaxis for the disease. In the
future genetic susceptibility testing may find a place in mainstream clinical medicine, probably as part of an
overall risk assessment that would include environmental and lifestyle factors. Any genetic tests used as
part of such as assessment would need careful evaluation of their accuracy and clinical usefulness.
A new era for medicine?
Genetic scientists hope that once we know more about how the genetic programme
works, both in healthy cells and as a disease develops, we may have new ideas about
how diseases can be treated or prevented. Research on the human genome may lead
to a new approach to medicine, where individual genetic factors can be taken into
account when working out a person’s risk of disease and, if they become unwell,
deciding on treatment tailored to that individual. For example, it is known that individuals can respond in
very different ways to the same medicine: in one person it may work well, in another it may have no effect,
while another again may experience a serious side-effect. Some of this variation in response to medicines is
genetic. Research in pharmacogenetics seeks to identify important gene variants for each drug, with a
view to developing pharmacogenetic tests for use before prescription of drugs; testing which genetic
variants a person has could tell doctors what drug and what dose would be best for that individual.
Genetics and society
Some of these developments in medicine are still a long way off –
probably several decades – but it is not too early to start thinking
about the impact they may have on our lives. Everyone in society
needs to be involved in this debate. Many possible dangers have been
suggested, such as discrimination against people with a particular
genetic make-up, or attempts to produce ‘designer babies’. In
debating these issues, we must always keep in mind that although
genes play an important part in determining ‘who we are’, they are
by no means the whole story. We must avoid both unrealistic
expectations from advances in genetics, and unrealistic fears.
7
Further information (on-line resources)
•
Public Health Genetics Unit – news and information about advances
in genetics and their impact on public health and the prevention of
disease. Information resource page provides information about the
genetic basis of selected diseases.
http://www.phgu.org.uk
•
National Human Genome Research Institute – information about genetics, inherited disease
research and the future of health and genetics research.
http://www.genome.gov/Health/
•
Wellcome Trust Sanger Institute ‘Your Genome’ site - information about genome science.
http://www.yourgenome.org
•
DNA from the beginning - animated tutorial from the DNA Learning Centre in Cold Spring
Harbor.
http://www.dnaftb.org/dnaftb/index.html
•
Medicine and the new genetics – medical genetics information from the US Department of Energy
human genome website, including gene testing and genetic counselling.
http://www.ornl.gov/TechResources/Human_Genome/medicine/medicine.html
•
GeneTests medical genetics information resource – includes GeneReviews, genetic disease
profiles.
http://www.geneclinics.org
•
Genes and Disease - collection of articles that discuss genes and associated
diseases from the US National Center for Biotechnology Information.
http://www.ncbi.nlm.nih.gov/disease/
Image credits
U.S. Department of Energy Human Genome Program, http://www.ornl.gov/hgmis
NIH Publication No. 97-3905, Understanding Gene Testing http://www.accessexcellence.org/AE/AEPC/NIH/
Cambridge Genetics Knowledge Park
Document produced by Alison Stewart & Philippa Brice,
Cambridge Genetics Knowledge Park.
8