Medical Genetics 1 Prof Duncan Shaw

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

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

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 DegreeExample% alleles shared 1stSiblings, parent/child50 2ndUncle/niece, grandparent/child 25 3rd1 st cousins12.5

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

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…..

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 1,2 1,1 1,1 2,2 1,1 1,2 2,2 2,2 1,1 2,2

How LD arises

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

Testing for LD Marker A (shows LD with disease) Marker B (no LD, but could be linked) Allele 1Allele 2Allele 1Allele 2 Patients Controls test for significance

LD operates over short genetic distances LD 0 1 Distance (kb) from disease gene

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 ( F508) and these show LD with markers very close to the CF gene – this helped the gene to be identified

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

Autosomal Dominant Diseases Disease:Frequency/1000 births: Otosclerosis3 Familial hypercholesterolaemia2 Adult polycystic kidney disease1 Multiple exostoses0.5 Huntingtons disease0.4

Multiple exostoses

The ear

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

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?

Revision of linkage and Lod scores (2) If marker and disease were unlinked, probability of this pedigree: (1/2) 4 = 1/16 = 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/ = If they are linked with RF = 0.0, probability of pedigree: (1) 4 = 1 and odds ratio (relative to no linkage) = 1/ = 16 To combine information from several families, take log 10 of odds ( = LOD score) and add them up LOD > 3 good evidence for linkage; LOD < -2 evidence against linkage; -2 < LOD < 3 is inconclusive