Lecture 17: Human Genetics. I. Types of Genetic Disorders. A. Single gene disorders
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1 Lecture 17: Human Genetics I. Types of Genetic Disorders A. Single gene disorders B. Multifactorial traits 1. Mutant alleles at several loci acting in concert C. Chromosomal abnormalities 1. Physical changes in chromosomal structure a. Deletion b. Inversion c. Translocation d. Insertion 2. Changes in chromosome number a. Trisomy b. Monosomy D. Mitochondrial inheritance 1. Mutations of mitochondrial DNA E. Diseases of unknown etiology II. Epidemiology A. Incidence 1. Single gene disorder a. 1% of the approximately 4 million annual live births in the United States b. Mendelian traits or diseases c. Examples i. Thalassemia ii. Tyrosinemia B. Mendelian traits (single gene disorders) 1. Categories a. Autosomal recessive inheritance i. Locus is on an autosomal chromosome and both alleles must be mutant alleles to express the phenotype b. Autosomal dominant inheritance i. Locus is on an autosomal chromosome and only one mutant allele is required for expression of the phenotype c. X-linked recessive inheritance i. Locus is on the X chromosome and both alleles must be mutant alleles to express the phenotype in females d. X-linked dominant inheritance i. Locus is on the X chromosome and only one mutant allele is required for expression of the phenotype in females e. Mitochondrial inheritance i. Locus is on the mitochondrial "chromosome"
2 C. Mendelian genetics 1. Mitosis (see Cell Biology Lecture) 2. Mutations can arise during DNA replication in mitosis a. Cause somatic diseases such as cancer 3. Fastest rate of growth occurs before birth a. Most genetic diseases are expressed at birth or during early development III. Inheritance of Mendelian Traits A. Symbols
3 B. Autosomal dominant inheritance 1. One mutant allele is all that is required for the expression of the phenotype a. Autosomal dominant disease should always be considered as being a heterozygote i. Disease is usually rare (1/10,000 individuals affected) ii. To produce a homozygote, two affected heterozygotes would have to mate (1/1,000,000) iii. Extremely rare instances where two affected individuals have mated iv. Mating of very closely related individuals is forbidden in our society. 2. Rare in nature 3. Males and females have an equally likely chance of inheriting the mutant allele 4. Normal siblings of affected individuals do not transmit the trait to their offspring 5. Defective product of the gene is usually a structural protein, not an enzyme 6. Sample pedigree a. Each affected individual has an affected parent b. No skipping of generations c. Males and females are equally likely to be affected d. 1/2 of the offspring of an affected individual are affected
4 E. Autosomal recessive inheritance 1. Most parents are normal 2. Hallmarks of autosomal recessive inheritance: a. Males and females are equally likely to be affected b. Recurrence risk to the unborn sibling of an affected individual is ¼ c. Trait is characteristically found in siblings, not parents of affected or the offspring of affected d. Parents of affected children may be related i. Consanguineous mating is involved e. Trait may appear as an isolated (sporadic) event
5 F. X-linked inheritance 1. Locus for a gene for a particular trait or disease lies on the X chromosome 2. X chromosome has no homologous chromosome in the male a. Male has an X and a Y chromosome 3. Inheritance pattern follows the pattern of segregation of the X and Y chromosomes in meiosis and fertilization a. Male child always gets X from one of mother b. Receives Y chromosome from father 3. X-linked genes are never passed from father to son 4. Female child always gets the father's X chromosome and one of the two X's of the mother a. Affected female must have an affected father 5. Males are always hemizygous for X linked traits a. Never heterozygoses or homozygotes b. Never carriers c. Single mutant allele will produce a mutant phenotype in the male d. Females must be either homozygous for the normal allele, heterozygous, or homozygous for the mutant allele 6. X-linked dominant a. Trait is never passed from father to son b. All daughters of an affected male and a normal female are affected i. All sons of an affected male and a normal female are normal c. Matings of affected females and normal males produce 1/2 the sons affected and 1/2 the daughters affected d. Males are usually more severely affected than females i. Trait may be lethal in males e. Females are more likely to be affected than males
6 7. X-linked recessive a. Never passed from father to son b. Males are much more likely to be affected than females c. All affected males in a family are related through their mothers d. Trait or disease is typically passed from an affected grandfather i. Through his carrier daughters to half of his grandsons. e. Examples i. Hemophilia ii. Duchenne muscular dystrophy
7 IV. Chromosomal inheritance A. Statistics /10,000 births a. 140 are 45, X i. Lack an X or a Y chromosome b. 110 have an extra chromosome 16 c. 20 have an extra chromosome 18 d. 40 have an extra chromosome 21 e. Rest have various different chromosomal abnormalities 2. Most will abort spontaneously a. Down s syndrome (extra chromosome 21) 3. 50/800 live a. 1 with an extra chromosome 18 b. 1 with a missing X or Y chromosome c. 10 with an extra chromosome 21 d. 15 with an extra X or Y chromosome e. 20 with abnormal chromosomal rearrangements of various sorts B. Types of chromosomal events 1. Autosomal abnormalities a. Mitotic non-disjunction (Mosaic) b. Meiotic non-disjunction i. Occur during gametogenesis ii. Most likely to affect oocytes iii. Chromosomes do not separate iv. Ploidy is disrupted 2. Robertsonian translocation a. Centromere break b. Piece of chromosome relocates to a non-homologous chromosome C. Sex chromosome abnormalities 1. Barr bodies 2. Turner syndrome a. Non-disjunction b. 45, X 3. Klinefelter syndrome a. Non-disjunction b. 47, XXY 4. XXX & XYY syndromes V. Multifactorial inheritance A. Polygenetic inheritance 1. Trait regresses to mean 2. Concordance
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