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A. Introduction:

1. Genetics is one of the foundations of modern Biology

2. There are problems unique to the study of human genetics
    - practical, experimental obstacles
    - bioethical considerationsHuman Genetics and the understanding of human diseases
    - single gene disorders
    - polygenic (multifactorial) diseases
    - diseases resulting from somatic mutations
    -nuclear vs mitochondrial mutations

3. Human Genetics can be applied
    - an intellectual activity with important practical implications
    - genetic counseling and preventive medicine; ..... - prospects for gene therapy
    - positive and negative eugenics: any concerns for the future? what is our past experience?

4. For a general discussion of Genetics and Public Issues the following Web Sites are a good start:

NATIONAL CENTER FOR GENOME RESOURCES
THE HUMAN GENOME PROJECT
HOWARD HUGHES MEDICAL INSTITUTE
INFORMATION FOR GENETIC PROFESSIONALS

B. Review of Mendelian Genetics

1. Basic concepts
     - germ cells and somatic cells; haploidy, diploidy, aneuploidy
     - chromosomes, chromatids, sister chromatids
     - genes and alleles
     - genotype and phenotype
     - recessive, dominant, co-dominant alleles
     - homozygous, heterozygous, hemizygous
     - epistasis, reduced penetrance, variable expressivity
     - polygenic traits
these terms will not be reviewed at length, but should be familiar from basic undergraduate Genetics courses;

1. Mendel's Law of Segregation 2. Mendel's Law of Independent Assortment

2. Resources and Review

a) see U of Arizona , a review of basic Mendelian genetics for those preferring to look at monitors instead of books
b) a good site for looking up terminology is: Genetics Glossary
c) interesting historical information for those who have the leisure: Historical Papers

C. Genes and Proteins. Inborn Errors of Metabolism

1. Examples of inborn errors of metabolism

- alkaptonuria: defect in homogentisic acid oxidase
- phenylketonuria: defect in phenylalanine hydroxylase
- albinism: tyrosinase deficiency causing defect in melanin synthesis
- Lesch-Nyhan syndrome: HPRT as a salvage enzyme in purine metabolism:
- Tay-Sachs disease: hexosaminidase A deficiency (Ganglioside GM2 metabolism)
- Gaucher disease: glucocerebrosidase deficiency (lysosome)
- Zellweger syndrome: defective peroxisome biosynthesis
- Maple syrup urine disease: defective branched chain keto-acid dehydrogenase
- McArdle's disease: glycogen metabolism
- galactosemias: galactose-1-phosphate uridyl transferase deficiency- hundreds more could be cited here (see Ref. #3 below)

2. One of the most important sources of information is the following:

OMIM
Online Mendelian Inheritance in Man

see also GENE TESTS for Genetics Clinics, Counseling and Testing,
and Counseling (another good site for looking up various genetic diseases)

3. Pedigree Construction and Analysis

a) standard symbols used in Human Genetics

- affected vs. unaffected individuals
- heterozygous carriers; screening for carriers;
- monozygotic twins
- cosanguineous matings
- still born/spontaneous abortion
- in utero of unknown phenotype

b) genetic counseling

- interpretation: dominant vs recessive traits; sex-linked traits
- autosomal dominant, autosomal recessive,
- X-linked traits
- criteria for determination from pedigrees (numerous examples)

4. Prenatal diagnosis

- amniotic fluid sampling
- chorionic villi sampling
- cytogenetic analysis
- enzyme assays
- restriction analysis and Southern blots
- PCR analysis of defined genomic regions

5. Gene therapy - Potential and problems

- vectors and target cells
- expression levels and regulation
- long term stability; potential use of stem cells
- somatic vs germ cells as targets
- risks
......................STAY TUNED.........

Selected References
- McKusick, V.A. MENDELIAN INHERITANCE IN MAN. Catalog of autosomal dominant, autosomal recessive, and X-linked phenotypes. The Johns Hopkins University Press; Baltimore, 7th edition, 1986. This is the last edition to appear on paper. All of this information is accessible as a data base accessible through the Internet. There were 3907 entries in 1986 and the number approaches >>5000 by now.

OMIM
Online Mendelian Inheritance in Man

- Stanbury, J.B., Wyngaarden, J.B., Fredickson (Consulting Editors) C.R. Scriver, A.L. Beaudet, W.S. Sly, D. Valle The Metabolic Basis of Inherited Disease; McGraw Hill Book Company, New York. The 6th edition (1990s ) has over 2000 pages of fine print. The latest edition (Nov. 2000) comes in several volumes, and it is also available as a CD ROM. $495.- from amazon.com