Congenital and Genetic Disorders. Review of Genetic Control. Human Karyotype BIO 375. Pathophysiology

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1 Congenital and Genetic Disorders BIO 375 Pathophysiology Review of Genetic Control Genetic information for each cell is stored on chromosomes: Each body cell contains 2 sets (diploid) of chromosomes; one inherited from each parent 22 pairs of autosomes 1 pair of sex chromosomes (XX or XY) Karyotype is an arrangement of a cell s chromosomes based on size and shape Meiosis reduces the diploid number to haploid (1 set of autosomes + X or Y) Human Karyotype 1

2 Meiosis and Fertilization Meiosis reduced the 2n chromosome number or 46 down to n chromosome number of 23. Each ovum (egg) and sperm have 23 chromosomes All eggs have an X sex chromosome Sperm are either X or Y Fertilization of an egg by sperm reestablishes the diploid number of 46 and XX (female) or XY (male) sex determination. Chromosomes and Genes Each chromosome contains many genes which code for traits like hair color or metabolic enzymes. Genes are arranged in a linear fashion Humans have about 22,000 genes Each gene may exist in a population in alternative forms called alleles Some alleles code for faulty or disease causing genes 2

3 Some Terminology Dominant vs. recessive Genotype vs. phenotype Homozygous vs. heterozygous Codominance Incomplete dominance Multiple alleles Autosomal vs. sex linked inheritance Sex influenced vs. sex linked Polygenic (metric) traits More Terminology Penetrance Expressivity Carrier Age of onset Teratogenic agents Developmental disorders 3

4 DNA replication and Mutations DNA is copied from generation to generation by a process called semiconservative replication This is a highly accurate process Even so, occasionally, a copy error occurs resulting in a mutation Mutations can arise by other processes DNA code is transcribed to RNA and then translated into protein structures Gene Inheritance Genes control: Physical structures, e.g. collagen Metabolic processes, via enzymes Patterns of behavior, e.g. schizophrenia Both normal and disease causing genes are inherited in predictable patterns Genetic disorders may be: Single gene traits Multiple gene traits Due to chromosomal defects (number or structure) Examples of Gene Inheritance Autosomal single gene disorder: PTC taster or cystic fibrosis Sex linked single gene disorder Red-green colorblindness or hemophilia Multiple alleles ABO blood types Polygenic trait Intelligence or schizophrenia Age of onset Tay-Sachs disease Huntington s disease 4

5 Sex influenced trait Pattern baldness Baldness dominant in male heterozygote but recessive in female heterozygote Lyon Hypothesis (1961) Named after Mary Frances Lyon Suggested that dosage compensation in mammals is by inactivation of all but one X chromosome in cells with more than one X chromosome. Inactivation occurs at about day 16. The Barr body, visible in some female mammalian cells, is an inactivated X chromosome (Murray Barr 1949) Consequences of X-inactivation Multisomies are more tolerated in the X- chromosomes than autosomes Dosage compensation Variable expression in heterozygous females, e.g. hemophilia A 5

6 Chromosomal number defect Kleinfelter s Syndrome XXY 1/1,000 male births Turner s Syndrome Turner s Syndrome XO (1 in 10,000 female births) Monosomy of sex chromosomes; Almost normal in appearance until puberty Fail to menstruate; secondary sex characteristics fail to develop Shield chest; webbed neck; short stature Down s Syndrome Down s Syndrome Trisomy 21 (1 in 600 births) Epicanthal eye folds; hypotonia of skeletal muscles; small mouth with tongue protrusion common Atypical palm creases; pubic hair and beards sparse in males; heart malformations and low resistance to disease common Males infertile; some females fertile; low IQ scores 6

7 Chromosomal structure defect Cri du chat syndrome (cat cry syndrome) deletion of part of short arm of chromosome 5 Developmental Disorders May be due to exposure of embryo to negative environmental influences Radiation Alcohol (fetal alcohol syndrome) Cigarette smoking (low birth weight) Drugs Cocaine Abuse Maternal infections (e.g. Rubella) 7

8 Exposure in first two weeks usually results in death of embryo First two months most critical Time of rapid cell division Time of organogenesis There are different critical periods for different systems Developmental Disorders Diagnostic tools Pedigree analysis, e.g. in families where inherited disorders are present Screening for carriers, e.g. Tay-Sachs 8

9 Diagnostic tools Amniocentesis, e.g. chromosomal disorders and come gene defects Neonatal testing, e.g. phenylketonuria 9