Chapter 3 Genes in Pedigrees Mendelian Pedigree Patterns: - In humans over 10,000 Mendelian characters are known. - Dominance and recessiveness are properties of characters not genes. If a trait is expressed in a heterozygote for the genotype then the trait is a dominant character. Sickle cell anemia achondroplasia Type 1 Waardenburg - In experimental animals, semidominant is used if heterozygote is intermediate and dominant is used when homozygous and heterozygous are phenotypically similar.

- There are 5 basic Mendelian pedigree patters in humans Autosomal dominant Autosomal recessive X-linked recessive X-linked dominant Y-linked For X-linked traits (dominant or recessive) in females, X-inactivation causes some specific patterns. If the product of the gene is a circulating product (blood), then the female has an intermediate phenotype. If the gene product is localized, then the female shows patches of normal and abnormal tissues e.g. hypohidrotic ectodermal dysplasia (missing sweat glands and abnormal teeth and hair). X-inactivation confuses the distinction between dominant and recessive X-linked conditions.

- Locus heterogeneity occurs from defects in a complex pathway. E.g. autosomal recessive profound congenital hearing loss - Clinical heterogeneity occurs due to gene loci with multiple alleles. - difference in degree or severity of syndrome, e.g. Becker muscular dystrophy (mutations that partially inactivate the dystrophin gene product) and Duchenne muscular dystrophy (mutations that completely inactivate the dystrophin gene product). - difference could be qualitative e.g. inactivation of the androgen receptor gene causes 46, XY embryos to develop as females while a run of glutamine codons within the same gene cause a completely different disease, spinobulbar muscular atrophy or Kennedy disease

- Mitochondrial inheritance: mitochondrial genes cause a significant number of human genetic diseases because the mitochondrial genome is small but highly mutable. - High mutation rate is because mitochondrial DNA replication is more error-prone and the number of replication is much higher than nuclear DNA. - Mitochondrial genetic diseases have two features, matrilineal inheritance and frequent heteroplasmy.

Complications to the basic pedigree patterns: - Some recessive conditions can give a pseudo-dominant pedigree pattern (repeated marriages between “O” group with hetrozygotes). - Some dominant genes fail to express (nonpenetrance). Late-onset diseases (e.g. Huntington Disease) show age-related penetrance. - Some dominant diseases show variable expressivity (e.g. Waardenburg syndrome). - Anticipation is the tendency of some variable dominant conditions to become more severe in successive generations. This occurs in syndromes resulting from unstable expandable repeats such as Fragile-X, Huntington Disease and myotonic dystrophy. - Expression of a dominant imprinted gene depends on the parent from which it was inherited. - Male lethality complicates some X-linked dominant conditions. Absence of of the normal allele is lethal before birth. Affected males are not born. - New mutations can lead to mosaicism due to postzygotic or germinal (gonadal) mutations/ chromosome abnormalities.

- Molecular techniques such as PCR can reveal the presence of mosaicism - Chimeras are the result of fusing two zygotes into a single embryo (the reverse of twinning), or alternatively of limited colonization of one twin by cells from a nonidentical co-twin. - Using molecular techniques chimeras can be proved by too many parental alleles in one gene locus. E.g. intersex patients are 46,XY/46,XX

Factors affecting gene frequency in human populations: - In humans every gene locus is occupied with 2 alleles because we are diploid (2n). - For a locus with two alleles A1A2, then the populations is a mixture of three types of individuals A1A1, A1A2, and A2A2 . If the frequency of A1 = 0.5 and A2= 0.5 then the frequency of the three possible genotypes in the population would be: A1A1 = p2 A1A2 = 2pq A2A2 = q2 p2 + 2pq + q2 = 1.0 (Hardy-Weinberg distribution)