1. Segregation and patterns of human inheritance n Material covered in this lecture is partly review; however we will cover exceptions to standard patterns of inheritance more completely than is usually done in an introductory course. n It is assumed that each student is familiar with the terminology on pp. 51-52 and with the analysis of pedigrees, Figs. 5-1 (p. 52), 5- 2 (p. 53) and handouts.

2. Dominance vs Recessiveness n Refers to phenotype –however, common to use in reference to allele –can be ambiguous! HbS (recessive sickle cell anemia, co-dominant expression of globin, dominant malaria resistance) n Incomplete dominance –phenotype of homozygote more severe than that of heterozygote n Codominance –both phenotypes expressed

3. Dominant phenotypes - why isn’t one good copy of a gene enough? n Haploinsufficiency n Dominant negative effects n Gain of function mutations n Inherited susceptibility: inheritance of one mutant allele with subsequent loss of heterozygosity as a somatic mutation

4. Autosomal recessive inheritance n Autosomal recessive phenotype typically see in sibship of proband but not in parents or offspring or other relative n Males and females equally affected n Parents of affected individual often consanguineous n Recurrence risk for each sib of proband = 1 in 4 (25%)

5. Autosomal dominant inheritance n Phenotype usually appears in each generation (except when new mutation or incompletely penetrant) n Any child of affected parent has 50% chance of inheriting the trait n Phenotypically normal individuals do not normally transmit the trait n Males and females equally affected and equally likely to transmit n Many cases due to new mutation

6. X-linked recessive inheritance n Incidence of trait higher in males than in females n Heterozygous females usually unaffected but may manifest with variable severity due to XCI n Responsible allele passed from male to all daughters and from heterozygous female to 50% of her sons n A significant number of cases are due to new mutation

7. X-linked dominant inheritance n Affected males with normal mates have no affected sons and no normal daughters n Both male and female offspring of female carriers have a 50% chance of inheriting the trait n For rare phenotypes, affected females are more common than affected males (fetal loss of affected males)

8. Complications leading to hard- to-interpret pedigrees n Contiguous gene syndromes n Locus heterogeneity n Allelic heterogeneity n Penetrance and expressivity n Pleiotropy n Germ-line mosaicism n Imprinting effects n Age of onset