GENETICS an Introduction

SDK

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