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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) - PowerPoint PPT Presentation
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Medical Genetics-Mendelian GeneticsRobert 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
Daughters: 100% carriers (heterozygotes)Sons: 100% normal
XH XH
Xh XH Xh XH Xh
y XHy XHy
X-Linked Recessive Cont: Carrier Female Normal Male ova
Daughters: 50% normal, 50% carriersSons: 50% normal, 50% affected
XH Xh
XH XH XH XH Xh
y XHy Xhy
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
Daughters: Gen: Xga/ Xg Phen: Xg(a+) -- Like fatherSons: Gen: Xg/y Phen: Xg(a-) –- like mother
Xg Xg
Xga Xga/ Xg Xga/Xg
y Xg/y Xg/y
X-Linked Dominant Cont: Heterozygous female and Xg(a-)male Cross is Xga/ Xg x Xg/y
Ova
Daughters:Xga/ Xg Xg/Xg – 50% receive dominant alleleSons: Xga /y Xg/y – 50% receive dominant allele
Xga Xg
Xg Xga/ Xg Xg/Xg
y Xga /y Xg/y
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 Sex-Influenced 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