Medical Genetics 1

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Medical Genetics 1

• Prof Duncan Shaw
• http//www.abdn.ac.uk/gen155/djshome.html

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Major Groups of Clinical Disorders with a Genetic
Contribution

• Single gene defects
• Chromosomal abnormalities
• Congenital malformations
• Multifactorial diseases - most common causes of
  illness

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Autosomal recessive inheritance

• Cystic fibrosis (1/2000)
• Recessive mental retardation (1/2000)
• Congenital deafness (1/5000)

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Increased risk in autosomal recessive disease

• Consanguinity if parents are related
  (consanguinity) there is an increased risk that
  both parents carry the same recessive allele

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Ethnic associations with AR disease

• In particular populations, recessive allele
  frequency may have increased by selection in
  heterozygotes, or by genetic drift
• ?-Thalassaemia Cypriots, Greeks, Italians,
  Chinese, African-Americans
• Sickle Cell Disease Arabs, West Indians
• Tay-Sachs Disease Ashkenazi Jews (4 carriers)
• Severe Combined Immunodeficiency Syndrome Apache
  Native Americans
• Cystic Fibrosis Caucasians

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Finding the cystic fibrosis gene

• CF gene was found using positional cloning
• Linkage to markers on chromosome 7
• But that didnt get closer than several Mb
  still lots of genes
• To narrow the candidate region further, used
  linkage disequilibrium..

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Linkage and linkage disequilibrium

• Linkage is tested within families, LD by
  population study
• This marker is linked to the disease, but to
  different alleles (of the same marker gene) in
  each family

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How LD arises
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LD and haplotypes

• Haplotype the set of alleles carried by an
  individual chromosome
• With N bi-allelic markers, expect 2N possible
  haplotypes in population, because recombination
  creates all possible combinations of alleles
• If fewer than 2N haplotypes are observed, this is
  evidence for LD
• Previous example A1/A2 and CF/N gives 4
  haplotypes with recombination, or 3 with LD

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Testing for LD
c2 test for significance
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LD operates over short genetic distances
1
LD
0
-5000
-100 0 100
5000
Distance (kb) from disease gene
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Use of LD for gene mapping

• A gene can be mapped by linkage in families to
  within a few cM ( a few Mb in humans)
• If all or most cases of the disease are descended
  from a unique mutation, LD will be observed with
  markers about 100kb or less from the gene much
  closer than you can get using linkage alone
• In CF, about 70 of mutations are the same
  (DF508) and these show LD with markers very close
  to the CF gene this helped the gene to be
  identified

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Autosomal dominant inheritance

• An affected person usually has one affected
  parent
• Transmitted by either sex
• Child of an affected parent is at 50 risk of
  also being affected

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Autosomal Dominant Diseases

• Disease Frequency/1000 births
• Otosclerosis 3
• Familial hypercholesterolaemia 2
• Adult polycystic kidney disease 1
• Multiple exostoses 0.5
• Huntingtons disease 0.4

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Multiple exostoses
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The ear
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Comparisons between AD and AR

• Dominant
• Expressed in heterozygote
• Approx. 1/2 offspring affected
• Equal frequency and severity in each sex
• Paternal age effect on rate of new mutation
• Variable expressivity

• Recessive
• Expressed in homozygote
• Low risk to offspring
• Equal frequency and severity in each sex
• New mutations rare
• Constant expressivity in each family
• Importance of consanguinity

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Revision of linkage and Lod scores

• Affecteds have A marker allele from Dad,
  unaffecteds have B
• If random, would expect 5050 distribution
• Evidence for linkage?

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Revision of linkage and Lod scores (2)

• If marker and disease were unlinked, probability
  of this pedigree (1/2)4 1/16 0.0625
• If they are linked with RF 0.1 (10
  recombination), probability of pedigree (0.9)4
  0.66 and odds ratio (relative to no linkage)
  0.66/0.0625 10.56
• If they are linked with RF 0.0, probability of
  pedigree (1)4 1 and odds ratio (relative to
  no linkage) 1/0.0625 16
• To combine information from several families,
  take log10 of odds ( LOD score) and add them up
• LOD gt 3 good evidence for linkage LOD lt -2
  evidence against linkage -2 lt LOD lt 3 is
  inconclusive