Lecture Road Map
• Introduction of the course• Details of teaching tools
– Lectures – Group activities and – Seminars
• Evaluation Plan• Genetics introduction and clinical examples
• This course will deals with the Human as well as Medical genetics.
Genetic Course• The Aim of this course is to provide the student with a sound
understanding of normal and disease processes at the genetic level.
• This course will be comprised of different modalities of expressions such as Lectures, Seminars , Case base discussions and group activities.
• Each session will cover the general features of the normal and disease condition(s), and will focus on current understanding of the biochemical effects of normal conditions as well as biochemical defects (metabolic, structural or genetic) which underlie the disease state.
By the end of these sessions, the students should be able to
demonstrate the ability to discuss the normal and genetic
mechanisms that underlie several normal and disease processes.
Course Plan
Medical Genetics 2014.pdf
Chemistry, classification and characteristics of Purine and
Pyrimidine Bases
Chemistry, classification and characteristics of Nucleosides
and Nucleotides.
Classification, Function and occurrence of nucleotides in
human tissue and role of Nucleotides in the Human Body.
Role of Cyclic AMP and Cyclic GMP in the body.
Protein Synthesis
Lectures
Chromosome structure, classification and abnormalities
Genetic Variation and mutations
Genetic patterns of inheritance
Inborn errors of metabolism
Environmental and Genetic Interactions - Complex Patterns of Inheritance
Cancer genetics,
Breast and Ovarian Cancer and Inherited Predisposition
Genetic counseling, and ethical issues and decision making in medical
genetics.
Pharmacogenetics/Pharmacogenomics
Seminars
• Human genetics is the science of variation and heredity in humans
• Medical genetics deals with human genetic variation of significance in medical practice and research.
• Medical Genetics is concerned with how genes and heredity affect human health.
Genetics
Why Genetics is Necessary
Wilt Chamberlain,
a famous basketball player
(7 feet, 1 inch; 275 pounds)
Willie Shoemaker,
a famous horse racing jockey
(4 feet, 11 inches; barely 100 pounds).
Role of Genes in Human Disease• Most diseases / phenotypes result from the interaction between
genes and the environment
• Some diseases / phenotypes are primarily genetically determined– Achondroplasia
• Other diseases / phenotypes require genetic and environmental factors– Mental retardation in persons with PKU
• Some diseases / phenotypes result primarily from the environment or chance– Lead poisoning
100%Environmental
Struck by lightning
Infection
Weight
Cancer
Diabetes
Height
Sex, Down syndrome, achondroplasia
100% Genetic
Hair Colour
Genetics Review
T A C G C T T C C G G A T T C A A
Transcription
A U G C G A A G G C C U A A G U U
DNA
RNA
Translation
ABCDE ProteinAmino Acids
• Human body is made up of 75 trillion cells
• Every cells has a nucleus
• In the nucleus they contain Genes
• 99.9 % of genes are present in nucleus
• Few genes are present in Mitochondria
• Genes are small part of DNA
• DNA - is a nucleic acid that contains the genetic instructions specifying the
biological development of all cellular forms of life
• DNA is made up of Nucleotides
• Nucleotides is comprised of Sugar, Nitrogenous base and phosphate
Genetic Information• Gene – basic unit of genetic information. Genes determine the
inherited characters.
• Genome – the collection of genetic information.
• Chromosomes – storage units of genes.
• Human has 23 pairs of chromosomes
• These 46 chromosomes contain 6 billions individual characters of the genetic code.
• Genotype - the genetic constitution of the organism• Phenotype - the observable expression of genotype• Locus - a chromosomal location• Alleles - alternative forms of the same locus• Mutation - a change in the genetic material, usually
rare and pathological• Polymorphism - a change in the genetic material,
usually common and not necessarily pathological
Genetic Information
• Homozygote - an organism with two identical alleles• Heterozygote - an organism with two different alleles• Hemizygote - having only one copy of a gene
– Males are hemizygous for most genes on the sex chromosomes
• Dominant trait - a trait that shows in a heterozygote• Recessive trait - a trait that is hidden in a heterozygote• Cytogenetics: Study of chromosomes
Genetic Information
• Genomics: Study of genome, its organization and functions
• Population genetics: Genetic variation in human populations and factors that affect allele frequencies
• Clinical genetics: Application of genetics to diagnosis and patient care
• Genetic counseling: Risk information, psychological and educational support to patients and/or their families
Genetic Information
Human GenomeHuman diploid cells contain 46 chromosomes arranged in 23 pairs
• 2 sex chromosomes (X,Y):XY – in males.XX – in females.
• 22 pairs of chromosomes named autosomes.
Chimpanzee contain 24 pairs of chromosomes Cow contain 30 pairs of chromosomes Chicken contain 39 pairs of chromosomes Bnana contain 11 pairs of chromosomes
Who determines the male or female Gender
• Is the mother• Is the father• Or is it by chance from any of the two
50% Girls50% Boys
Genotypes Phenotypes
• At each locus (location of a gene/marker on the chromosome) there are 2 genes. These constitute the individual’s genotype at the locus.
• The expression of a genotype is termed a phenotype. For example, hair color, weight, or the presence or absence of a disease.
• dis·ease (dĭ-zēz') • A pathological condition of a part, organ, or system of an
organism resulting from various causes, such as infection, genetic defect, or environmental stress, and characterized by an identifiable group of signs or symptoms.
• Lack of ease; trouble.
• DISEASES are seen as an abnormality in structure , function of CELLS → ORGANS → SYSTEMS ; generated by biochemical mechanisms.
What is a Disease
To examines and identifies the molecules involved in specific diseases. Theses molecules and process are DNA , replication, transcription translation and protein synthesis
All classes of biomolecules found in cells are affected in :
Structure,
Function, or
Amount in one or another disease .
Diseases can be caused by deficiency or excess of certain biomolecules .
Biochemical alterations that cause disease may occur slowly Or rapidly.
Many diseases are determined genetically.
What is Genetic level alterations
Genetic BasisOf Diseases
Changes an Enzyme
Changes an Enzyme inhibitor
Changes a receptor
Change a transport or carrier protein
Changes in Hemostasis
Changes in structuralProteins
Growth regulation
Changes an EnzymePhenylalanine hydroxylase Splice site mutation leading to reduced amount of PA hydroxylase Causing phenylketonuria
Changes an Enzyme inhibitor1-AntitrypsinMissense mutation that impair secretion of 1-Antitrypsin from liver to serum causing Emphysema and Liver disease
Changes a receptorLow density lipoprotein receptorDeletion or point mutation that reduce synthesis, Or transport to the cell surface of LDL receptors or binding to low density lipoprotein Causing Familial hypercholesterolemia
Change a transport or carrier protein1. HaemoglobinMutations in splice sites (commonest) leading to Reduced -globin.causing -Thalassemia. In -Thalassemia the -globin gene is usually deleted.
2.Cystic fibrosis transmembrane conductance Regulator. Deletions or point mutation causingCystic fibrosis.
Changes in HemostasisFactor VIII deletions, insertions, nonsense mutation reduce synthesis or abnormal factor VIIICausing Hemophilia A.
Growth regulatione.g.Rb tumor-suppressor gene causing Retinoblastoma etc
Changes in structural Proteins1. Collagen, Deletions Or point mutation that Produce reduced amount Of normal collagen or Normal amounts of mutant Collagen. Causing Osteogenesis imperfecta
2. Cell Membrane Fibrillin Missense mutations causing Marfan syndromeOr deletion of dystrophin gene Causing Duchene muscular Dystrophy
Molecules and Disease
MOLECULE Property affected
DISEASE BASIC CAUSE
DNA Structure/function
Sickle cell anemia Mutation
RNA Structure/function
Certain types of Thalasemia
Mutation (leading to splicing defects)
Protein Structure/function
Sickle cell anemia Mutation (Val replaces Glu at position 6 of β-chain
of HbS)
Lipid Amount ↑ Tay Sach’s disease Mutation (Resulting in defective enzyme-hexosaminidase A)
Glycogen Amount ↑ McArdle’s disease Mutation (Resulting in defective enzyme- muscle glycogen
phosphorylase)
GAG Amount ↑ Hurler syndrome Mutation resulting in defective Iduronidase
Electrolyte (Cl-) Amount ↑(in sweat)
Cystic fibrosis Mutation (Resulting in defective chloride transport)
Water Amount ↓ Cholera Infection (toxin of Vibrio cholerae
causes loss of water and electrolytes)
• Biochemical alterations that cause disease may occur rapidly or slowly– Cyanide (inhibits cytochrome oxidase) kills within a few
minutes– Massive loss of water and electrolytes (e.g., cholera) can
threaten life within hours– May take years for buildup of biomolecule to affect organ
function (e.g., mild cases of Niemann-Pick disease may slowly accumulate sphingomyelin in liver and spleen))
Rate of Biochemical Alterations
Deficiency or Excess of Biomolecules• Diseases can be caused by deficiency or excess of
certain biomolecules– deficiency of vitamin D results in rickets, excess
results in potentially serious hypercalcemia– Nutritional deficiencies
• primary cause - poor diet• secondary causes - inadequate absorption, increased
requirement, inadequate utilization, increased excretion
• Genes are associated with the development of diseases.
• Such as – Single gene disorders– Chromosomal disorders– Mitochondrial disorders– Multi-factorial disorders .
Genetic Association of Diseases
Characterized by genetic mutations of single genes. More than 6000 single gene disorders are known. These gene disorders are inherited in recognizable patterns e.g.:
Autosomal dominant - clinically evident if one chromosome affected (heterozygote). e.g., Familial hypercholesterolemia & Huntington's disease
Autosomal recessive - both chromosomes must be affected (homozygous)e.g., Sickle cell anemia & PKU
X-linked - mutation present on X chromosome• females may be either heterozygous or homozygous for affected gene• males affected if they inherit mutant gene• e.g., Duchenne muscular dystrophy DMD
Single Gene Disorders
• Excess or loss of chromosomes, deletion of part of a chromosome, or translocation– e.g., Trisomy 21 (Down syndrome)
• Recognized by analysis of karyotype (chromosomal pattern) of individual (if alterations are large enough to be visualized)
• Translocations important in activating oncogenes– e.g., Philadelphia chromosome - bcr/abl)
Chromosomal Disorders
Klinefelter Syndrome
47 XXY or XXY syndrome Has Extra X chromosome It occurs in every 500 to 1000 births (in the USA).
Since the condition is relatively mild, many cases are not diagnosed till puberty.The gynaecomastia confers an increased risk of breast cancer
Turner Syndrome (45, X)
Absence of an entire sex (X) chromosome Obviously, only in females - a result of
nondisjunction of the X-chromosomes during meiosis.
The ovaries are rudimentary Stature is small. About 30 percent of females with Turner syndrome have extra folds of skin on the neck (webbed neck)
MITOCHONDRIAL DISORDERS
• Caused by mutations in non-chromosomal DNA of mitochondria. e.g. :
• Leber’s hereditary optic neuropathy [LHON]
• Moyclonus epilepsy with ragged red fibers [MERRF]
• Mitochondrial encephalopathy with lactic acidosis and stroke like episodes [MELAS] .
multifactorial Disorders COMPLEX OR POLYGENIC DISORDERS :
• Interplay of number of genes and environmental factors Pattern of inheritance does not conform to classic Mendelian genetic principles Combination of environmental & genetic mutations involved in this group. e.g. :
• Cardiovascular diseases
• Hypertension
• Diabetes
• Cancer [susceptibility genes for breast cancer found on chromosomes 6,11,13,14,15,17 & 22] .
Definition : replacement or change of a nucleotide base with another, in one or both strands, or addition or deletion of a base pair in a DNA molecule .
Hb A β chain Glu6 to Hb (S) β chain Val 6
Mutations
Inborn error of Metabolism
• Group of genetic disorder, in which a specific enzyme is affected,
producing a metabolic block, that may have pathological
consequences
• It is results from a mutation in a structural gene that may affect
structure of the encoded protein (an enzyme) an inborn
error of metabolism may result .
• Phenylketonuria Mutant enzyme is phenylalanine hydroxylase Synthesize less tyrosine , have ↑ plasma levels of Phe and
other metabolites of Phe ( e.g. phenylpyruvate) ↑ excretion of phenylpyruvate and other metabolites in
urine
Inborn error of Metabolism
Knowing exact cause of disease at molecular level –better
understanding of etiopathogenesis of disease process.
Correction at level of missing biochemical end product e.g.
thyroxine administration
Correction at level of excess substrate e.g. low Phe diet in PKU
Replacement of a defective enzyme e.g. Gaucher disease.
Advantages of Knowing Genetics
Replacement of defective protein e.g. Factor VIII in
hemophilia
Increasing the action of less active mutant enzyme by giving
more cofactor or co enzyme e.g. Vit. B12 for methylmalonic
aciduria
Gene therapy – an ongoing area of research which would is
expected to offer the final solution to genetic diseases.
Advantages of Knowing Genetics
Gene Therapy
Gene therapy is a technique used for correcting defective genes responsible for disease development
Gene therapy is permissible in humans at present for somatic cells only.
Major problem is complexity and efficacy
• Types of gene therapy :
Replacement : Mutant gene removed and replaced with a normal gene
Correction : Mutated area of affected gene would be corrected and
remainder left unchanged
Augmentation : introduction of foreign genetic material into a cell to
compensate for defective product of mutant gene “ only gene therapy
currently available today's”.
Gene Therapy
Genetics
I might be turning into my mother.
After all,I have her straight nose
and her broad bonesher stubbornness to
hold on to the truths you knowand the lies you don't.
I might be turning into my father.
After all,I have his brown eyes
and his quick mindhis readiness to
leave things behind and let the roadunfold like twine.
Thank You