Introduction to Medical Genetics

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Introduction to Medical Genetics
Dr John Loughlin
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Contact details

• Institute of Musculoskeletal Sciences
• john.loughlin_at_ndos.ox.ac.uk
• http//www.ndos.ox.ac.uk/ogg/

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Recommended reading list - textbooks

• Principles of Medical Genetics
• Gelehrter, Collins Ginsburg
• Lippincott, Williams Wilkins, ISBN 0683034456
• Or for a slightly more molecular read
• Human Molecular Genetics 3
• Strachan Read
• Garland Publishing, ISBN 0-8153-4182-2

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Journalsheavy going for beginners but Editorials
and News Views are manageable

• Nature Genetics
• http//www.nature.com/ng/index.html
• Nature Reviews Genetics
• http//www.nature.com/nrg/index.html
• Trends in Genetics
• http//www.trends.com/tig/default.htm

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7 lectures

• 1 Introduction
• 2 Chromosomes and chromosome abnormalities
• 3 Single gene disorders
• 4 Polygenic Disorders
• 5 Mutation and human disease
• 6 Genes in Populations
• 7 Mapping disease loci

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Glossary Definitions I

• Character - a structure, function, or attribute
  determined by a gene or group of genes
• i.e. the appearance of the seed coat in Mendels
  garden pea studies
• Trait - the alternate forms of the character
• i.e smooth or wrinkled peas

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Glossary Definitions II

• Phenotype - the physical description of the
  character in an individual organism
• i.e a green pea
• Genotype - the genetic constitution of the
  organism

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Glossary Definitions III

• Locus - a chromosomal location
• Alleles - alternative forms of the same locus
• Mutation - a change in the genetic material,
  usually rare and pathological
• Polymorphism - a change in the genetic material,
  usually common and not pathological

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Glossary and Definitions IV

• Homozygote - an organism with two identical
  alleles
• Heterozygote - an organism with two different
  alleles
• Hemizygote - having only one copy of a gene
• Males are hemizygous for most genes on the sex
  chromosomes

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Glossary and Definitions V

• Dominant trait - a trait that shows in a
  heterozygote
• Recessive trait - a trait that is hidden in a
  heterozygote

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A common misconception is that genes are dominant
or recessive

• However,
• it is the trait that is dominant or recessive,
  not the gene

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Standard pedigree symbols
Male, affected
Male, heterozygous for autosomal recessive trait
Female, unaffected
Female, heterozygous for Autosomal or X-linked
recessive trait
Male, deceased
Dizygotic (non-identical) twins
Mating
Monozygotic (identical) twins
Consanguineous mating
Spontaneous abortion or still birth
Pregnancy
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Role of Genes in Human Disease

• Most diseases / phenotypes result from the
  interaction between genes and the environment
• Some phenotypes are primarily genetically
  determined
• Achondroplasia
• Other phenotypes require genetic and
  environmental factors
• Mental retardation in persons with PKU
• Some phenotypes result primarily from the
  environment or chance
• Lead poisoning

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Struck by lightning
100 Environmental
Infection
Weight
Hair Colour
Cancer
Diabetes
Height
100 Genetic
Sex, Down syndrome, achondroplasia
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Medical genetics in the health service
A Medical Genetics Unit
Clinical Genetics Consultant
Molecular Genetics Lab
Cytogenetics Lab

• Clinical diagnosis
• Genetic counselling
• Risk assessment
• Prenatal presymptomatic diagnosis

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Major types of genetic disease

• Chromosomal disorders
• Lecture 2
• Single gene diseases
• Lecture 3
• Polygenic diseases
• Lecture 4

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Chromosomal disorders

• Addition or deletion of entire chromosomes or
  parts of chromosomes
• Typically more than 1 gene involved
• 1 of paediatric admissions and 2.5 of childhood
  deaths
• Classic example is trisomy 21 - Down syndrome

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Down Syndrome
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Single gene disorders

• Single mutant gene has a large effect on the
  patient
• Transmitted in a Mendelian fashion
• Autosomal dominant, autosomal recessive,
  X-linked, Y-linked
• Osteogenesis imperfecta - autosomal dominant
• Sickle cell anaemia - autosomal recessive
• Haemophilia - X-linked

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Neonatal fractures typical of osteogenesis
imperfecta, an autosomal dominant disease
caused by rare mutations in the type I collagen
genes COL1A1 and COL1A2
A famous carrier of haemophilia A, an X-linked
disease caused by mutation in the factor VIII
gene
Sickle cell anaemia, an autosomal
recessive disease caused by mutation in the
b-globin gene
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Autosomal dominant pedigree
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Polygenic diseases

• The most common yet still the least understood of
  human genetic diseases
• Result from an interaction of multiple genes,
  each with a minor effect
• The susceptibility alleles are common
• Type I and type II diabetes, autism,
  osteoarthritis

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Polygenic disease pedigree
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Identifying disease genes has been revolutionized
by the sequencing of the Human Genome
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The genome project

• A massive technical and computational project
  that was spread across the globe

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DNA Sequencing currently a fluorescent-based
technology
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The human sequence

• 3.3 billion base pairs
• Gene prediction as of Aug 2006 26,800

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February 2001 Human genome sequence published -
kind of
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The principal protagonists
Craig Venter Head of Celera Genomics
Francis Collins Head of the Human Genome Project
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A politically-mediated compromise
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The tale of a determined Brit
The Common Thread A Story of Science, Politics,
Ethics, and the Human Genome By John Sulston
and Georgina Ferry Joseph Henry Press ISBN
0-309-08409-1
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A racy read..
By James Shreeve. Knopf. ISBN 0-375-40629-8
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Accessing the sequence

• Public databases
• Freely available
• Continuously modified and updated

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Human sequence many others
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Searching for FRZB
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FRZB is located on chromosome 2
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FRZB transcript sequence
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Two common amino acid substitutions in FRZB
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Some other projects inspired by the genome
sequencing project

• Mapping all common DNA variants
• The HapMap project
• Elucidating their function, if any
• Mouse knock-out projects
• Diversity projects
• Regulatory elements

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Conclusions

• For a single gene disease identifying the causal
  mutation is now relatively straightforward
• Technological and analytical advances are also
  making polygenic diseases tractable
• Genetics is going to play an ever increasing role
  in medical diagnosis and in the development of
  improved treatment regimes

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The end Next weeks lecture Chromosome
abnormalities