Genetics

GENETICSLec 1

Dr.Shatha Th.Ahmed
Ninevah Medical College
Department of pathology

• Chromatid. One of the two identical parts of the chromosome

• Centromere. The point where the two chromatids touch.
• Short arm: p
Chromosomes consist of a DNA-protein complex

DNA replication

Hereditary disorders

Those disorders that are derived from parents & transmitted through generations. Therefore, they are called familial.
Congenital
Means born with, so congenital disorders are those disorders that are present at birth.
Not all genetic disorders are present during infancy.
Some of the congenital diseases have no any genetic defect (e.g. congenital syphilis).


Gene is a region of DNA that produces a functional RNA molecule.
Human genome have about 30,000 genes which can give rise to greater than 100,000 proteins .

Genetics is the study of single or a few genes and their phenotypic effects.

Genomics is the study of all the genes in the genome and their interactions.

Proteomics is the measurement of all proteins expressed in a cell or tissue.

Genes and Human Diseases

Human genetic disorders can be broadly classified into

1- Disorders related to mutations in single genes with large effects, these associated with highly penetrance meaning that the presence of the mutation is associated with the disease in a large proportion of individuals they usually follow the classic Mendelian pattern of inheritance (e.g., sickle cell anemia .

2- Chromosomal disorders.

These arise from structural or numerical alteration in the autosomes and sex chromosomes they are uncommon but associated with high penetrance.
About 50% of spontaneous abortions during early pregnancy are due to chromosomal abnormalities

3-Complex multigenic disorders.

More common than the previous two
They are caused by interactions between multiple variant forms of genes and environmental factors.
including atherosclerosis, diabetes mellitus, hypertension, and autoimmune diseases


MUTATIONS
Is defined as a perminant change in the DNA sequence of a gene.

Somatic cells Germ cells

cancers & inh inherited disease
congenital abnormalities

Mutation

Mutation
Types of mutation
1-Gene mutation (most common and clinicaly significant)
2-Chromosome mutation – structural changes within the chromosome – translocations, deletions, etc
3-Genome mutation – alteration in the number of chromosomes e.g trisomy ,monosomy.

Gene mutation could be1.Point mutation

Result from substitution of a single base in the DNA coding a portion of gene
- Missense– result in substitution of one amino acid for another in the coded protein
conservative – function of protein is not affected
- nonsense mutation :
a point mutation affecting the codon for glutamine (CAG) creates a stop codon (UAG) if U is substituted for C premature termination of β-globin gene translation( β thalassemia )
not conservative – function of protein altered



2.Frame-shift mutation
Which results from insertion or deletion of one or 2 base pairs that alters the reading frame of the DNA strand.
A change in 3 or more base pairs leads to missing of one or more amino acids.

3.Trinucleotide repeat mutation

Such type of mutation leads to amplification of a sequence of 3 nucleotides as in fragile X chromosome syndrome in which there is a 250 or more repeat of CGG. (normally up to 29) within a gene called familial mental retardation gene(FMR1)
• 4. Mutations within non-coding sequence
• Deleterious effects may also result from mutations that do not involing the exons. Point mutations involving these regulatory sequences may lead to total lack of transcription.





Phenotype means the clinical expression. Could be physiological (height, color) or pathological (DM, HT).

Pleiotropism is a single gene defect that may lead to many phenotypic effects as in sickle cell anemia.


Genetic heterogeneity means mutations at several gene-loci that lead to the same clinical disorder as in Phenylketonuria.
.


Mendelian disorders: Are due to single gene mutation of large effect.

About 80-85% of these mutations are familial, the remainder represent new mutations.

Although gene expression is usually described as dominant or recessive, in some cases, both of the alleles of a gene pair may be fully expressed in the heterozygote a condition called codominance. Histocompatibility and blood group antigens are good examples of such.

Autosomal Dominant Disorders

Manifested in the heterozygous state.

At least one parent is usually affected.

Males & females are affected & both can transmit the disorder.

When one parent is affected, half of their children have the chance of getting the condition.

In some cases the condition appears as a new mutation (i.e. both parents are not affected). Many such mutations occur in the germ cells of older fathers.

• The onset may be delayed in some cases like in Huntington disease.

• Some persons inherit the disorder but are phenotypically normal this phenomenon is called reduced penetrance.
• In others the mutant gene is expressed differently among individuals this is called variable expressivity.
• Non-enzyme proteins are affected usually:
• Proteins involved in regulation of metabolic pathways.
• Key structural proteins such as collagen & spectrin are commonly affected.


• Examples of Autosomal Dominant Diseases
(Mnemonic: Vo Familial Hypercholesterolemia Autosomal DOMINANT Hai)
von Willebrand disease,
familial polyposis coli,
familial hypercholesterolemia.
Adult polycystic kidney disease,
Dystrophia myotonica
Osteogenesis imperfecta,
Marfan disease,
Intermittent porphyria
Neurofibromatosis,
Achondroplasia,
Tuberous sclerosis
Huntington disease, Hereditary spherocytosis,