Genetics and internal medicine (1)

Genetics Course:Mastering Medical Genetics

Dr. Ahmed Elshebiny , MDDr. Ahmed Elshebiny , MDLecturer of Internal MedicineLecturer of Internal Medicine

Faculty of Medicine, Menoufyia UniversityFaculty of Medicine, Menoufyia University

Former Clinical Research FellowFormer Clinical Research Fellow,,Joslin Diabetes Center, Harvard UniversityJoslin Diabetes Center, Harvard University

Course includes1. Basic Principles of Medical Genetics 2. Genetic basis of disease: How diseases could be

inherited? 3. Medical Genetics in Clinical Practice : What is the

impact of genetics on the present and future of Medicine?

Let us start with this introductory video about genes

Medical Genetics Any application of genetic principles

to medical practice. “Genetics – study of individual genes

and their effects”

Outline

The Genetics course

Basics Diseases ApplicationsStructure & Facts

Functions

Inherited disorders

Gene Therapy

Cloning

Stem Cell

Genetic Testing

1. The Human Genome 2. DNA structure and packaging3. Mitochondrial DNA4. Chromosomal Morphology

5. Chromosome Replication6. Gene Expression7. Meiosis , Mitosis and Gametogenesis8. Epigenetics

9. Population Genetics10. Consanguinity11. Family medical History12. Inherited disorders13. Mendelian inheritance14. Non Mendelian inheritance15. Cytogenetic abnormalities

Structure & Facts of the Human Genome

Functions& Physiology

Clinical Genetics

2 -Genetic basis of disease1. Chromosomal abnormalities

2. Genetics of Metabolism

3. Genetics of Hemoglobinopathies

4. Genetics of Bleeding disorders

5. Genetics of Development

6. Cancer Genetics

3-Medical Genetics in Clinical Practice

Genetic testing Genetic screening Molecular diagnostics Genetic engineering Gene Therapy Stem cell therapy Cloning

Genetics Course (1):Mastering Medical Genetics

The Human Nuclear Genome Genome = all of the DNA in an organism or

cell Size of human genome: 3.4 billion base pairs Number of human genes: ~30,000 Genes vary in length and can cover thousands of

bases average size: ~3,000 bp Only about 2% of the human genome contains

coding genes Action of much of the genome is unknown

DNA Structure

DNA Structure

Epigenetics Epigenetics is the study of heritable changes

in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence, hence the name epi- (Greek: επί- over, above) -genetics.

These changes may remain through cell divisions for the remainder of the cell's life and may also last for multiple generations.

Chromosome Facts # of chromosomes per somatic cell: 22 pairs + 1 pair

sex-determining chromosomes = 46 # of chromosomes per gamete (egg/sperm): 23 One chromosome of each pair donated from each

parent’s egg or sperm Sex chromosomes: XY for males; XX for females Largest chromosome #1 = ~263 million base pairs

(bp) Smallest chromosome Y = ~59 million bp

Chromosomal morphology methods Chromosomal staning FISH

Chromosomal Banding

Chromosomes

Mitochondrial DNA

Circular Several copies No histones

Function of DNA

The Human genome functions

Gene Expression Transcription Translation

Meiosis , Mitosis and Gametogenesis Mitosis is the process by which a cell

separates its duplicated genome into two identical halves

Meiosis is the process that transforms one diploid into four haploid cells.

Where do your genes come from?

Genomic imprinting Most genes expressed equally from both alleles Small number of genes show differential expression

dependent on parent of origin (mainly on chromosomes 6,7,11,14,15)

‘Imprint’ is mediated by methylation transcriptional inactivation

Imprint persists through cell divisions in embryo Imprint removed at gametogenesis and then re-

established according to sex of transmitting parent

Population Genetics Is the study of distributions of genes in

populations Disease frequency Genotype frequencies from generation to

generation Genetic Polymorphisms

SNPs

Polymorphism Occurrence of 2 or more alleles at aspecific

genetic locus in frequencies greater than can be explained by mutations alone

Single nucleotide polymorphisms Restriction fragment length polymorphism

(RFLP) Variable number tandem repeat

polymorphism (VNTR)

Clinical genetics

Clinical genetics is the practice of clinical medicine with particular attention to hereditary disorders.

Inherited disorders Cytogenetic Single gene Polygenic Multifactorial

Clinical Genetics Genotype: An individual’s genetic makeup - forms of a

particular gene at a given locus

Phenotype: The observable expression of a genotype

Homozygous: Identical forms of a particular gene

Heterozygous: Different forms of a gene– CARRIER if one normal and one abnormal

Dominant: Condition phenotypically expressed in someone carrying one copy of a mutant gene

Recessive: Condition phenotypic ally expressed only in someone with two copies of the mutant gene

Autosomal dominance Vertical transmission

On average, 50% of offspring of affected parent will be affected

Unaffected individuals do not transmit trait

Males and females equally affected

Autosomal Dominant Conditions Marfan Syndrome Achondroplasia Familial (early-onset) Alzheimer

Disease Huntington Disease Familial Hypercholesterolemia Familial Breast Cancer (BRCA1 or

BRCA2 mutations)

Autosomal Recessive Inheritance Horizontal transmission; disease in siblings but usually not in earlier

generations (unaffected, carrier parents)

On average, 25% recurrence risk

Males and females equally affected

Increased consanguinity (relatedness) seen

Autosomal Recessive Conditions Sickle cell disease Cystic fibrosis Tay-Sachs disease Hemochromatosis Phenylketonuria Thalassemias

X-linked recessive inheritance Incidence of trait is much higher in males than

females No father-to-son transmission 100% of daughters of affected males are

(unaffected) carriers 50% of sons of carrier females are affected and

50% of daughters are carriers Trait may be transmitted through series of

carrier females

X-linked recessive conditions Haemophilia Duchenne and Becker muscular dystrophy Androgen insensitivity syndrome Hunter syndrome Glucose-6-phosphate-dehydrogenase

deficiency Bruton agammaglobulinaemia

Xplinked dominant Males and females affected, females usually less

severely affected than males 1 in 2 risk to children of affected female (M+F) All daughters of affected male affected but no male

to male transmission

X-linked dominant inheritance Males and females affected

Vitamin D resistant ricketsOTCDFragile X syndrome

Lethal in malesIncontinentia pigmentiRett syndromeXL chondrodysplasia

punctataGoltz syndrome

Mitochondrial inheritance Mitochondria are

exclusively maternally inherited

Males and females affected but only females will transmit to offspring

Risks to offspring of affected or carrier females are difficult to determine 0-100%

Family Medical Historyfamily medical history represents a “genomic

tool” that can capture the interactions of genetic susceptibility, shared environment and common behaviors in relation to disease risk.

References Merck manual : online textbook

E-medicine , online textbook , specialties,.

BRS series : Genetics 2010 Lecture notes : Genetics (2006) Kumar & Klark : Clinical Medicine 2009 Other Web Resources & books

Genetics Course (2):Mastering Medical Genetics