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Medical Genetics 1

Medical Genetics 1. Prof Duncan Shaw http://www.abdn.ac.uk/~gen155/djshome.html. 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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Medical Genetics 1

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  1. Medical Genetics 1 Prof Duncan Shaw http://www.abdn.ac.uk/~gen155/djshome.html

  2. Major Groups of Clinical Disorders with a Genetic Contribution • Single gene defects • Chromosomal abnormalities • Congenital malformations • Multifactorial diseases - most common causes of illness

  3. Autosomal recessive inheritance • Cystic fibrosis (1/2000) • Recessive mental retardation (1/2000) • Congenital deafness (1/5000)

  4. 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

  5. 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

  6. Finding the cystic fibrosis gene • CF gene was found using positional cloning • Linkage to markers on chromosome 7 • But that didn’t get closer than several Mb – still lots of genes • To narrow the candidate region further, used linkage disequilibrium…..

  7. 1,2 1,2 1,2 1,2 1,1 1,1 2,2 1,1 2,2 2,2 1,1 2,2 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

  8. How LD arises

  9. 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

  10. Testing for LD c2 test for significance

  11. LD operates over short genetic distances 1 LD 0 -5000 -100 0 +100 +5000 Distance (kb) from disease gene

  12. 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

  13. 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

  14. Autosomal Dominant Diseases Disease: Frequency/1000 births: Otosclerosis 3 Familial hypercholesterolaemia 2 Adult polycystic kidney disease 1 Multiple exostoses 0.5 Huntington’s disease 0.4

  15. Multiple exostoses

  16. The ear

  17. 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 Comparisons between AD and AR

  18. Revision of linkage and Lod scores • Affecteds have A marker allele from Dad, unaffecteds have B • If random, would expect 50:50 distribution • Evidence for linkage?

  19. 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 > 3 good evidence for linkage; LOD < -2 evidence against linkage; -2 < LOD < 3 is inconclusive

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