The branch of biology that deals with heredity, especially the mechanisms of hereditary transmission and the
variation of inherited
similar or related
Biological unit of heredity.
Gene hold the information to build and maintain their cells and pass genetic traits to offsprings
In cells, a gene is portion of
Cell structure Cell enzymes
Is one member of a pair or series of different forms of a gene.
Homozygous-an organism in which 2 copies of genes are identical i.e. have same alleles
Heterozygous-an organism which has different alleles of the gene
Chromatin: DNA, RNA & proteins that make up chromosme
Chromatids: one of the two identical parts of the chromosome.
Centromere: the point where two chromatids attach
46 chromosomes. 22 pairs Autosomes and 1 pair Sex chromosomes.
NUCLEOTIDE : group of molecules that when linked together, form the building blocks of DNA and RNA; composed of phosphate group, the bases:adenosine,cytosine,guanine and thymine and a pentose sugar.In case of RNA,thymine base is replaced by uracil.
CODON : series of three adjacent bases in one polynucleotide chain of a DNA or RNA molecule which codes for a specific amino acid.
GENETIC CODE : the sequence of nucleotides in a DNA or RNA molecule that determines the amino acid sequence in the synthesis of proteins.
Diseases which are present at birth.
Diseases which are derived from one’s parents and trasmitted in the gametes through the generations.
Not all congenital diseases are genetic( congenital Syphilis) and not all genetic diseases are congenital (Huntington disease).
Permanent changes in the DNA. Those that affect germ cells are transmitted to the progeny. Mutations in the somatic cells are not transferred to the progeny but are important in the causation of cancer and some congenital diseases.
CAUSES OF MUTATIONS
Antiviral drug iododeoxy uridine
Benzpyrene in tobacco smoke
X – rays & ultraviolet light
Certain viruses such as bacterial virus
Types Of Mutations.
Point Mutation: Substitution of a single nucleotide base by a different base.
Missense Mutations .
Nonsense Mutations .
Insertion or deletion of one or two base pairs alters the reading frame of the DNA strand.
Trinucleotide Repeat Mutations:
set of genetic disorder caused by trinucleotide repeat in certain genes exceeding normal,stable threshold e.g. Fragile X Syndrome.
Classification Of Genetic Diseases:
Single Gene Defects/Mendelian Disorders.
Disorders with Multifactorial or Polygenic inheritance.
Disorders showing atypical patterns of inheritance.
Mendelian Disorders A genetic disease caused by a single mutation in the structure of DNA, which causes a single basic defect with pathologic consequences
Patterns Of Inheritance:
Autosomal Dominant Disorders.
Manifested in heterozygous states.
Individuals with these diseases usually have one affected parent .*
Variable to late onset.
These disorders usually involve non-enzymatic proteins;
Proteins involved in metabolic pathway regulation.
Typical mating pattern is a heterozygous affected individual with a homozygous unaffected individual.
Every child has one chance in two of having the disease
Both sexes are affected equally..
Structural Protein Defects:
Marfan’s Syndrome .
Mutation in the fibrillin gene.
Fibrillin important component of microfibrils in Elastin.
Tissues affected are Skeleton, Eyes and the CVS.
C/F include tall stature, long fingers, pigeon breast deformity, hyper-extensible joints,high arched palate, BL subluxation of lens, floppy Mitral valve, Aortic aneurysm and dissection, defects in skin,lungs.
Ehler-Danlos Syndrome(Cutis Hyperelastica):
Characterized by defects in collagen synthesis.
.Clinical Features include fragile, hyper-extensible skin, hyper-mobile joints, grotesque contortions, rupture of internal organs like the colon, cornea and large arteries, poor wound healing.
Defects in metabolic pathway proteins:
One of the most common mendelian disorders.
Mutation in the LDL receptor gene.
Hypercholesterolemia due to impaired LDL transport into cells.
Increased risk of atherosclerosis and coronary artery disease.
Increases Cholesterol leads to formation of Xanthomas.
Autosomal Recessive Disorders
Largest group of Medelian Disorders
Affected individuals usually have unaffected (carrier) parents.
Uniform, early age of onset.
These disorders usually involve Enzymatic Proteins.
Pattern Of Inheritance:
Typical mating pattern is two heterozygous unaffected (carrier) individuals.
The triat doesnot usually affect the parent, but siblings may show the disease
Siblings have one chance in four of being affecte
Both sexes affected equally.
Glycogen Storage Diseases. Category Disease Enzyme Hepatic Type. Von Gierke’s Disease type 1. Glucose-6-phosphotase. Myopathic Type. McArdle Syndrome. Muscle Phosphorylase. Miscellaneous Type. Pompe’s Disease type II Lysosomal Glucosidase.
X-Linked Recessive Disorders.
Most common X-linked disorders.
Usually expressed only in males.
Rarely, due to random X-inactivation, a female will express disease, called manifesting heterozygotes.
Pattern Of Inheritance:
Disease usually passed on from carrier mother.
Expressed in male offspring, females are carriers.
Skipped generations are commonly seen.
In this case, Recurrence risk is half of sons are affected, half of the daughters are carriers.
All the daughters are heterozygous carriers and all the sons are homozygous normal.
DISORDERS WITH MULTIFACTORIAL (POLYGENIC)INHERITANCE
Involved in many physiologic characteristics of humans e.g. height, weight, hair color
Defined as one governed by additive effect of two or more genes of small effect but conditioned by environmental, non genetic influences
The disorder becomes manifested only when a certain number of effector genes, as well as conditioning environmental influences are involved
Rate of recurrence is 2 to 7%
COMMON DISEASES ASSOCIATED:
Cleft lip and palate
Congenital heart disease
Neural tube defects
Coronary artery disease
Cytogenetic Disorders .
Basic tool of cytogeneticist
Karyotype is a photographic representation in which chromosomes are arranged in order of decreasing length
Giemsa stain (G banding) technique—each chromosome can be seen to possess a distinctive pattern of alternating light and dark bands of variable widths
Shorthand of Cytogenetics:
Short arm denoted as p, long arm denoted q .
Each arm divided into numbered regions from the centromere onwards.
Each region numerically arranged into bands .
For e.g., 5p24 would denote chromosome 5, short arm, region 2 and band 4.
Cytogenetic disorders may result from structural or numeric abnormalities of chromosomes
It may affect autosomes or sex chromosomes
Normal Chromosomal number is 46. (2 n =46). This is called euploid state. (Exact multiple of haploid number).
Polyploidy : posession of more than two sets of homologous chromosomes. Chromosomal numbers like 3n or 4n. (Incompatible with life); generally results in spontaneous abortion
Aneuploidy : Any Chromosomal number that is not an exact multiple of haploid number . E.g 47 or 45.
Most common cause is nondisjunction of either a pair of homologous chromosomes during meiosis I or failure of sister chromatids to separate during meiosis II.
The resultant gamete will have either one less chromosome or one extra chromosome.
Fertilization of such gamete will result in zygote being either trisomic ( 2 n +1 ) or monosomic ( 2 n -1 ).
Monosomy in autosomes is incompatible with life. Trisomy of certain autosomes and monosomy of sex chromosomes is compatible with life.
The presence of two or more types of cell populations in the same individual.
Postzygotic mitotic nondisjunction will result in one trisomic and one monosomic daughter cell.
The descendants of these cells will produce a mosaic.
Usually result from chromosomal breakage, resulting in loss or rearrangement of genetic material.
Patterns of breakage:
Transfer of a part of one chromosome to another chromosome
Translocations are indicated by t
Balanced reciprocal translocation is not harmful to the carrier, however during gametogenesis, abnormal gametes are formed, resulting in abnormal zygotes
Centric fusion type or robertsonian translocation:
The breaks occur close to the centromere, affecting the short arms of both choromosomes
Transfer of the chromosome leads to one very large and one extremely small chromosome
The short fragments are lost, and the carrier has 45 chromosomes
Such loss is compatible with survival
However, during gametogenesis difficulties arise
Result when one arm of a chromosome is lost and the remaining arm is duplicated, resulting in a chromosome consisting of two short arms only or of two long arms.
Loss of a portion of chromosome
This can be terminal (close to the end of the chromosome on the long arm or the short arm), or it can be interstitial (within the long arm or the short arm).
A ring chromosome is a variant of deletion.It occurs when break occurs at both the ends of chromosome with fusion of the damaged ends.
Occur when there are two breaks within a single chromosome with inverted reincorporation of the segment.
Since there is no loss or gain of chromosomal material, inversion carriers are normal.
An inversion is paracentric if the inverted segment is on the long arm or the short arm .
The inversion is pericentric if breaks occur on both the short arm and the long arm .
General Features of Cytogenetic Disorders:
Associated with absence, excess, or abnormal rearrangements of chromosomes.
Loss of genetic material produces more severe defects than does gain.
Abormalities of sex chromosomes generally tolerated better than those of autosomes.
Sex chromosomal abnormalities are usually subtle and are not detected at birth.
Most cases are due to de novo changes (i.e. parents are normal and recurrence in siblings is low).
Cytogenetic Disorders involving Autosomes .
Trisomy 21/Down’s Syndrome:
Most common chromosomal disorder.
Down syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 21 st chromosome
Trisomy 21 is caused by a meiotic nondisjunction event.
With nondisjunction, a gamete ( i.e. , a sperm or egg cell) is produced with an extra copy of chromosome 21; the gamete thus has 24 chromosomes
When combined with a normal gamete from the other parent, the embyo now has 47 chromosomes, with three copies of chromosome 21.
About 4% of cases are due to Robertsonian translocations.
Maternal age has a strong influence
Karyotype for trisomy Down syndrome. Notice the three copies of chromosome 21
Other Trisomy Syndromes:
Trisomy 18 :Edwards Syndrome.
Trisomy 13 :Patau Syndrome.
Cytogenetic Disorders involving Sex Chromosomes.
Extreme karyotypic variations seen frequently with Sex Chromosomes, with females having 4-5 extra X Chromosomes.
Males with two to three Y chromosomes have also been identified.
Defined as Male Hypogonadism, develops when there are at least two X chromosomes and one or more Y chromosomes.
Usual karyotype is 47,XXY. The extra X may be maternal or paternal.
Results from nondisjunction of sex chromosome during meiosis.
Risk factors include advanced maternal age and a history of exposure to radiation in either parent.
Increase in body length between soles and pubis.
Reduced facial, body and pubic hair. Gynecomastia.
Mild mental retardation.
Primary hypogonadism in phenotypic females.
Results from partial or complete monosomy of the X chromosome.
Most common cause is absence of one X chromosome.
Less commonly, mosaicism, or deletions on the short arm of the X chromosome.