Genetics

GENETICSLecture. 2

By
Lecturer Dr. Zahraa Marwan
Mosul Medical College
Department of pathology

B. Defects of Single Genes with Large Effect (Unifactorial or Mendelian Disorders):

Introduction:
Mendelian disorders account for approximately 1% of all adult admissions to hospital and about 6-8% of all pediatric hospital admissions.
They represent the most common purely genetic abnormality as compared to other causes.
They are caused by a mutation in a single gene. A mutation is a disturbance in the sequence of the nucleotide arrangement in the DNA molecule, or it is simply a permanent change in the DNA.
Mutations may give rise to inherited disorders or may cause cancer or congenital malformation.

• Mendelian Disorders

• Mutations involving single genes follow one of three patterns of inheritance: autosomal dominant, autosomal recessive, or X-linked.
• • A single-gene mutation may lead to multiple phenotypic effects (pleiotropy), and conversely, mutations at several genetic loci may produce the same trait (genetic heterogeneity).
• It is now increasingly being recognized that even known “single-gene” diseases are influenced by inheritance at other genetic loci, which are called modifier genes.
• Phenotype means the clinical expression . Could be physiological (height, color) or pathological (DM, HT).
• A phenotype results from the expression of the genetic code (genotype), as well as the influence of environmental factors and the interactions between the two.


Mendelian Disorders
All mendelian disorders are the result of mutations in single genes that have large effects.

80% to 85% of these mutations are familial.

some autosomal mutations produce partial expression in the heterozygote and full expression in the homozygote. Example :Sickle cell anemia & sickle cell trait.

TRANSMISSION PATTERNS OF SINGLE-GENE DISORDERS:

Three patterns of inheritance:
Autosomal dominant, autosomal recessive, and X-linked.
1-Autosomal Dominant Disorders:
Autosomal dominant conditions are characterized by the following:
With every autosomal dominant disorder, some proportion of patients do not have affected parents because of new mutations involving either the egg or the sperm from which they were derived.
Clinical features can be modified by reduced penetrance and variable expressivity. Some persons inherit the disorder (the mutant gene) but are phenotypically normal this phenomenon is called reduced penetrance.

1-Autosomal Dominant Disorders:

• In contrast, the mutant gene is expressed differently among all individuals carry the mutant gene, this is called variable expressivity.
For example, manifestations of neurofibromatosis type 1 range from brownish spots on the skin to multiple skin tumors and skeletal deformities.
In many conditions, the age at onset is delayed: symptoms and signs do not appear until adulthood (as in Huntington disease).

• Non-enzyme proteins are affected usually in Autosomal dominant conditions :

• Proteins involved in regulation of complex metabolic pathways.
• Key structural proteins such as collagen & spectrin are commonly affected,

1-Autosomal Dominant Disorders:

AD disorders are manifested in the heterozygous states.

At least one parent is usually affected.

Males and females are affected equally and both can transmit the disorder.

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

2- Autosomal Recessive

Autosomal recessive traits make up the largest category of mendelian disorders.
Because autosomal recessive disorders result only when both alleles at a given gene locus are mutated, such disorders are characterized by the following features:
• The trait does not usually affect the parents of the affected individual, but siblings may show the disease.
(2) siblings have one chance in four of having the trait (i.e., the recurrence risk is 25% for each birth).
(3) if the mutant gene occurs with a low frequency in the population, there is a strong likelihood that the affected individual is the product of a consanguineous marriage.


In contrast to those of autosomal dominant diseases, the following features generally apply to most autosomal recessive disorders:
• Expression of the disorder tends to be more uniform than with dominant diseases
• Complete penetrance is common.
• Onset is frequently early in life
• New mutations may occur but are rarely detected.
• Many of the mutated genes encode enzymes.
• Autosomal recessive disorders include almost all inborn errors of metabolism.

3- X-Linked Disorders

• Absence of father-son transmission.
• All daughters of affected male are obligate carriers.
• Dominant and recessive apply only to the female, males are hemizygous.
• Nearly all X-linked disorders are recessive.
• The only X-linked dominant disorders are vitamin D-resistant rickets and Alport's syndrome (Hereditary glomerulonephritis with nerve deafness)


Features of X-linked disorders
• Females are carriers & males are affected.
• The carrier females transmit the disorder only to their sons which have the chance of 50% to be affected.
• The affected male cannot transmit the disease to sons, but all the daughters are carriers.

Heterozygous females rarely express the disease when there is

Random inactivation of the other X-chromosome.



Father is affected & mother is a carrier.





Female has one affected X-chromosome as in Turner syndrome.

MUTATION:

Is defined as a permanent change in the DNA.

Somatic cells Germ cells

cancers & inherited disease
congenital abnormalities

Mutation

Mutations:
• Types of mutations:
• 1-Chromosome mutation – structural changes within the chromosome – translocations, deletions, etc
• 2-Genome mutation – loss or gain of whole chromosomes: monosomy and trisomy
• 3- Gene mutation – alterations at the level of the gene


Gene mutation could be:1.Point mutation:
Results from the substitution of a single nucleotide base by a different base, resulting in the replacement of one amino acid by another in the protein product.
A point mutation that alters the meaning of the genetic code are called missense mutation.
If the substituted amino acid causes little change in the function of the protein, the mutation is called a “conservative” missense mutation.
On the other hand, a “non conservative” missense mutation replaces the normal amino acid with a very different one. (The change in the base will form a new code coding for a different amino acid in the protein changing its character and behavior resulting in disease, e.g. all cases of thalassemia, sickle cell disease, PKU, etc).

1.Point mutation:

certain point mutations may change an amino acid codon to a chain termination codon, or stop codon (a mutation occurs in one of the three codons). This mutation usually stops the signal (e.g. termination of gene transcription.
As in some forms of -thalassemia.

2.Frame-shift mutation

Which results from insertion or deletion of 1 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.

characterized by amplification of a sequence of three nucleotides.
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 within a gene called familial mental retardation 1 (FMR1). (normally up to 29).

Classification of Genetic disorders:

1. Classical Genetic Diseases:
a. Chromosomal (Cytogenetic) disorders.
b. Single gene (or unifactorial) disorders (Mendelian Disorders).
c. Multifactorial disorders.
2. Non-Classical Diseases "or the single gene disorders with atypical pattern of inheritance":
a. Diseases caused by mutations in mitochondrial genes.
b. Triplet repeat mutations.
c. Uniparental disomy.
d. Genomic imprinting.
e. Gonadal mosaism.

C. Multifactorial disorders (polygenic):

• Largest group among genetic disorders.
• Multifactorial (also called polygenic) inheritance is involved in many of the physiologic characteristics (e.g. weight, height, blood pressure, hair color, etc.).
• A multifactorial physiologic or pathologic trait may be defined as one governed by the additive effect of two or more genes of small effect but conditioned by environmental, non-genetic influences.


Features of multifactorial Inheritance (MFI):
In MFI, the risk of expressing the disease is conditioned by the number of mutant genes inherited. Also the greater the number of affected relatives, the higher the risk for other relatives.
The rate of recurrence is the same for all first- degree relatives of the affected individual between 2-7%.
The risk of recurrence of the phenotypic abnormality in the subsequent pregnancies rises to 9% after 2 affected siblings.

Features of multifactorial Inheritance (MFI):

Common phenotypic expressions governed by “multifactorial” inheritance
– Hair color
– Eye color
– Skin color
– Height
– Intelligence
-This form of inheritance is believed to underlie such common diseases, E.g. Hypertension, Diabetes, type II, gout, cleft lips, cleft palates and pyloric stenosis, congenital heart diseases, cancer.

Thank you