GEN3051 Lecture 1: Human Genes and

Human Genetic Disorders

Aims for today are to revise/introduce important aspects of:

- Types and prevalence of genetic disorders in humans.
- Gene structure and expression.

Robert Bryson-Richardson
Room 309 Biology Building 17
robert.bryson-richardson@monash.edu
References: Nussbaum 7th ed Ch 3, pp. 25-36, Ch 7, Ch 8

Human Genetic Disorders

1. Single gene disorders

Human disorders can affect any aspect of physical or mental

properties.
Can be classified according to time of action:
- spontaneous miscarriage
- congenital (present at birth)
- childhood
- late onset
All result from combined action of genes and environment,
but can also be classified by relative contribution of the genetic
component:
1. Single gene
2. Chromosomal
3. Multifactorial

Any human gene can occur in mutant form.

Contains 22,219 data entries (as of 3 March, 2013)

20,891 autosomal
1,204 X-linked
59 Y-linked
65 mitochondrial
Of these entries, many are associated with a known
phenotype, others are only known from DNA sequence.
4043 description of phenotype and known mutation
Each gene has a unique six digit number
100000, 200000 - autosomal (pre May 1994)
300000 - X-linked
400000 - Y-linked
500000 - mitochondrial
600000 - autosomal (post May 1994)

Latest estimate from Human Genome Project is that there

are ~21,500 genes.
Mutants of many are very deleterious, strong selection
pressure against them, thus very rare.
For others mutations have milder consequences, but also
occur sporadically.
Catalogue of single gene disorders originated by Victor
McKusick, called
'Online Mendelian Inheritance in Man' (OMIM)
http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim
- Continuously updated catalogue of human genes and
genetic disorders. Phenotypic companion to HGP.

There are many single gene disorders but most are very
rare (< 1 in 10,000).
Total incidence among the newborn is ~1 in 100.
Specific single gene disorders may occur more frequently in
certain populations. For example:
- haemoglobin diseases up to 1 in 100 in Central and West
Africa
- cystic fibrosis up to 1 in 2,000 in Western Europe
Thought to be associated with heterozygote advantage (e.g.
malaria), or Founder effect.

Most disorders associated with single genes show recessive

inheritance.
- one working copy is as good as two (e.g. most enzyme
encoding genes).
- important to understand why this is.
But some show dominant inheritance (e.g. regulatory and
structural protein genes).
- important to revise why some mutations are dominant.
Distribution of
sickle cell allele
and malaria
in Africa

What are the three main molecular mechanisms by which a

mutant allele can be dominant to the wild type allele?

From Lewis R 2003

Human Genetics 5th ed
McGraw Hill

Cystic fibrosis: phenotype and genetic basis

Griffiths 9 Fig 6.2

From: Cummings 2006 Human Heredity 7

Turnpenny & Ellard 2005 EMG 12

Dominant mutant alleles

Most disorders associated with single genes show recessive
inheritance.
- one working copy is as good as two (e.g. most enzyme
encoding genes).
- important to understand why this is.

Much less common than recessive mutations. Three ways a

mutation can be dominant are:
1. Haploinsufficiency
Loss of function mutation. But 50% normal protein is not
enough for wild type phenotype. Not common.

But some show dominant inheritance (e.g. regulatory and

structural protein genes).
- important to revise why some mutations are dominant.

eg. Tailless mutation in mice

What are the three main molecular mechanisms by which a

mutant allele can be dominant to the wild type allele?

Loss of function mutation, protein made but non functional,

inhibits function of normal protein in heterozygotes. Often in
structural proteins which form dimers (or multimers).

2. Dominant-negative mutations.

eg. Kinky tail mutation in mice, Marfan Syndrome

3. Gain of function mutations

New function of the gene product, or protein always active,
or increased levels of expression, or inappropriate expression
eg. antennapedia mutation in Drosophila, Achondroplasia,
Huntington Disease

Hartwell Fig 7.27

2. Chromosomal disorders
Most chromosomal disorders are caused by aneuploidy.
- one chromosome present more or less than normal.
- occurs in at least 5% pregnancies.
- severity different for different chromosomes. Autosomal more severe than
sex chromosomal.
Among spontaneous miscarriages aneuploids are very frequent, 40-50%
up to the end of the first trimester.
- kinds differ from those seen in live births.

3. Multifactorial disorders
By far the most common disorders do not have a simple genetic
or chromosomal origin
- instead they have a part genetic, part environmental origin,
called multifactorial
The genetic component is usually polygenic (> 1 gene).

At birth, incidence is much lower (~1 in 200).

Chromosome aberrations also occur translocations, deletions,

duplications.
Eg. DiGeorge syndrome, deletion of 3Mb in 22q11.2 (Nussbaum Fig 6.9),
removes ~30 genes, 1 in 2000-4000 live births, has role in 5% congenital heart
defects.

From Turnpenny and Ellard 12 Figure 15.1

3.1 Congenital abnormalities

Incidence of congenital abnormalities among newborn is high
heart and vessels
central nervous system
gastrointestinal tract
limb
urogenital system

10 per 1,000
10 per 1,000
4 per 1,000
2 per 1,000
4 per 1,000

Examples neural tube defects such as spina bifida (as high as 1% in some
countries), cleft lip and cleft palate
Most congenital abnormalities of genetic origin have a multifactorial basis
Percent of cases
Cause
Genetic
- Chromosomal
6%
- Single gene
7.5%
- Multifactorial
20-30%
Environmental
5-10%
Unknown
~50%

Nussbaum Fig 8.8

3.1 Congenital abnormalities

Incidence of congenital abnormalities among newborn is high
heart and vessels
central nervous system
gastrointestinal tract
limb
urogenital system

10 per 1,000
10 per 1,000
4 per 1,000
2 per 1,000
4 per 1,000

Examples neural tube defects such as spina bifida (as high as 1% in some
countries), cleft lip and cleft palate
Most congenital abnormalities of genetic origin have a multifactorial basis
Cause
Percent of cases
Genetic
- Chromosomal
6%
- Single gene
7.5%
- Multifactorial
20-30%
Environmental
5-10%
Unknown
~50%

These diseases cause morbidity and premature mortality in

~60% individuals during their lifetime (Nussbaum Table 8.1).
- Thus have a high impact in medicine.
How can we study the genetic basis of such multifactorial
disorders? (RB lectures)
- Population studies, family studies, twin studies, adoption
studies, polymorphism associations, etc.
In some cases both the genetic and environmental components
are known:
eg. type 1 diabetes, venous thrombosis
But for most complex disorders we dont understand the
underlying mechanisms of the gene-gene and gene-environment
interactions.

3.2 Late onset disorders

Incidence of later acquired disorders with some genetic
basis is relatively high
Disorder

Incidence

cancers
diabetes mellitus
insulin dependent (Type I)
late onset (Type II)
single gene
schizophrenia
bipolar affective disorder
autism
epilepsy
multiple sclerosis
Parkinson disease
asthma

~25%
up to 10%
<1%
<10%
<0.01%
1%
0.5-1%
up to 0.1%
~3%
~1%
~1%
4%

inflammatory bowel disease

1-2%

etc.

Summary of genetic disorders

May occur prenatally, at birth, during childhood or in adulthood
May be caused by:
- a defective single gene
- a chromosomal abnormality
- both polygenic and environmental factors (multifactorial)
Single gene disorders are of many types but most are very rare (total = ~1 in
100 among newborns)
Chromosomal disorders are of few types and arise sporadically (total = ~1 in
200 among newborns)
Multifactorial disorders are very common:
- 20-30% of congenital abnormalities
- contribute to many late onset disorders
Multifactorial disorders are the most important in medical genetics, but
genetic basis is difficult to determine

Gene organisation
Molecular definition of a gene:
Sequence of DNA that is required for the production of a
functional product either a polypeptide or a functional
RNA molecule.
A gene includes more than just the coding sequence, also
adjacent sequences required for proper expression i.e.
production of mRNA in correct amount, at correct place, and
at correct time.
To control their expression genes are organised into functional
groups of base sequence:

Fig 3.4

promoter, terminator, regulatory sequences, coding sequence

(start and stop codons). Nussbaum Fig 3.4

Fig 3.5
Fig 3.4

www.ncbi.nlm.nih.gov/genome/guide/human/index

Human globin gene

sequence

Fig 3.7

The language of molecular and cellular genetics:

Fig 3.2

References

Clone

Primers

cDNA

Probe

Cumming, M. Human Heredity: Principles and Issues 7th Edition,

Brooks Cole

Hybridisation

Quantitative PCR

Insert

Restriction Enzyme

Griffiths, A.J.F., Wessler, S.R., Lewontin R.C., Caroll, S.B. Introduction

to Genetic Analysis 9th Edition, W.H. Freeman

Library

Plasmid

Ligation

Vector

Microarray

RNA in situ hybridisation

Northern blot

Immuno-histochemistry

Oligonucleotide

Western blot

Hartwell L., Hood, L., Goldberg, M.,L., Reynolds, A., E., Silver, L., M.,
Veres, R. Genetics: From Genes to Genomes 2nd Edition, McGraw Hill
Lewis, R. Human Genetics, 5th Edition, McGraw Hill
Nussbaum, R.L., McInnes, R.R. and Willard, H.F. Genetics In
Medicine Thompson and Thompson, 7th Edition Saunders Elsevier,
2007
Turnpenny, P., Ellard, S. Emerys Elements of Medical Genetics 12th
Edition, Churchill Livingstone, Elsevier

Polymerase Chain Reaction