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