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Medical Genetics-Mendelian Genetics Robert F. Waters, Ph.D. Preparation for Pathology Preparation for Immunology Preparation for Epidemiology Etc. Gametes Spermatogenesis Oogenesis Chromosomes (Karyotype) Classification of Chromosomes Centromeric Classification (Nuclear) Metacentric (mediocentric) • Center (nearly) Submetacentric (submediocentric) • Little off center • q-long arm • p-short arm Acrocentric • Centromere at the terminus Meiosis First meiotic division Meiosis Second meiotic division Human Spermatogenesis Human Oogenesis Intrauterine primary Oocyte First meiotic division Second meiotic division 12 to 50 years after start of meiosis Ova (secondary Oocyte) • Receives most of the cytoplasm Others become polar bodies Longer prophase in meiosis in females Higher probability of meiotic non-disjunction The Pedigree Propositus P1 (Parental) F1, F2, etc. (Filial) Phenylthiocarbamide (PTC) Taster vs. Non-taster Homozygous Heterozygous Complete dominance Punnett’s square Genotype and Phenotype Genotypic ratio and phenotypic ratio Autosomal Dominant Approximately 50% Males and Females affected Dentinogenesis imperfecta Pediatric opalescent brown color Wear down easily Dentinogenesis imperfecta Approximately 1:8000 Criteria for Autosomal Dominant Usually not fully expressed in heterozygous state Appears in every generation with no skipping Trait transmitted by affected person to half the offspring (average) Unaffected persons do not transmit the disease (not carriers) Occurrence and transmission of trait not influenced by sex (males ~ females) Autosomal Recessive Cystic Fibrosis Consanguinity and Recessive Inheritance Autosomal Recessive-Cont: Tay-Sachs Disease Ashkenazi Jews • Neuro-degenerative disorder High frequency in North America • Migrations Tyrosinemia Usually lethal Hepatic lethal Autosomal Recessive-Cont: Criteria Carrier identification, if possible Trait characteristically occurs in sibs, not in parents, immediate offspring, and most other close relatives About 1 in 4 ratio at birth to have trait Parents of affected child may be consanguineous (unknowingly) Males and females equally likely to be affected Multiple Alleles ABO blood type system Sex Linked Inheritance X-Linked May be X-linked Recessive May be X-linked Dominant When X-Linked gene in male (y) is considered hemizygous not heterozygous X-Linked Recessive Follow a well defined pattern Expressed always males and only in females that are homozygous Example (Hemophilia) Queen Victoria • Classical Hemophilia A (XR) • Deficiency in antihemophilic globulin • Clinical features • Severe arthritis’ • Internal joint hemorrhages • Difficulty in healing after cuts or abrasions X-Linked Recessive Normal Female Hemophiliac male OVA Xh y XH XH Xh XHy XH XH Xh XHy Daughters: 100% carriers (heterozygotes) Sons: 100% normal X-Linked Recessive Cont: Carrier Female Normal Male ova XH Xh XH XH XH XH Xh y XHy Xhy Daughters: 50% normal, 50% carriers Sons: 50% normal, 50% affected Criteria for X-Linked Recessive Inheritance Incidence of trait much higher in males Trait passed from affected man through all his daughters to half their sons Trait never passed directly from father to son X-Linked Dominant Inheritance Traits occur approximately twice as often in females Affected male transmits the trait to ALL of his daughters and to NONE of his sons X-Linked Dominant Cont: Example X-linked blood group system Xg Xg/Xg x Xga/y Male has Dom. Marker OVA Xg Xg Xga Xga/ Xg Xga/Xg y Xg/y Xg/y Daughters: Gen: Xga/ Xg Phen: Xg(a+) -- Like father Sons: Gen: Xg/y Phen: Xg(a-) –- like mother X-Linked Dominant Cont: Heterozygous female and Xg(a-)male Cross is Xga/ Xg x Xg/y Ova Xg y Xga Xg Xga/ Xg Xg/Xg Xga /y Xg/y Daughters:Xga/ Xg Xg/Xg – 50% receive dominant allele Sons: Xga /y Xg/y – 50% receive dominant allele Criteria for X-Linked Dominant Inheritance Affected males transmit trait to all of their daughters but to none of their sons Affected females who are heterozygous transmit the gene to half the sons and half the daughters In X-Linked dominant disorders, affected females are twice as common as affected males but will express the condition in a milder form (heterozygous) Penetrance Ability of any gene to be expressed When some individuals have the gene but fail to express it are said to have reduced penetrance Patients who have a gene and do not express it are said to have a nonpenetrant gene Expressivity The degree of expression of a penetrant gene Polymorphisms May be due to modifier genes E.g. oncorepressor genes repressing oncogenes Pleiotropy One gene, multiple effects Stem cells E.g. galactosemia Defect in galactose-1-phosphate uridyl transferase • Multiple effects • • • • Cirrhosis of liver Cataracts Galactosuria Mental retardation Reversed by galactose free diet Sex-Limited and SexInfluenced Genes Sex-Limited Trait Autosomally inherited trait expressed in one sex (e.g., male only) X-linked ruled out because may be transmitted by females Precocious puberty • Exhibit adolescent growth spurt around the age of four years Precocious Puberty Pedigree Autosomal dominant precocious puberty Sex-Limited Expression Testicular feminization XY males have testes but are also born with female external genitalia and raised as females (Some female secondary sexual characteristics at puberty) Autosomal Phenotypes with Unequal Male and Female Expression Hemochromatosis May be less expression in young females Menstrual cycle Iron storage disease Different from Thalassemias Treatments Latent Genes (Delayed Onset) Huntington’s Chorea Choreic movement Unpredictable, jerky, ballistic Mental deterioration Dominantly inherited Gene remains in population After reproductive age Variable onset Usually above 35