GeneticsGenetics

MeaningMeaning

The term Genetics was introduced by Bateson in 1906. It was derived from Greek word “Gene” which means ‘to become’ or ‘to grow into’.

Therefore, genetics is the science of coming into being.

WHAT IS GENETICS?????WHAT IS GENETICS?????

The branch of biology that deals with heredity, especially the mechanisms of hereditary transmission and the

variation of inherited

characteristics among

similar or related

organisms

“ Genetics is that branch of biological sciences which deals with the transmission of characteristics from parent to off spring.”

Terminology:Terminology:

What Is DNA?

DNA (deoxyribonucleic acid) carries the genetic information in the body’s cells.

DNA is made up of four similar chemicals (called bases and abbreviated A, T, C, and G) that are repeated over and over in pairs.

Adenosine, Thymine, Cytosine, Guanine

What Is a Gene?

A gene is a distinct portion of a cell’s DNA. Genes are coded instructions for making

everything the body needs, especially proteins. Human beings have about 25,000 genes.

Researchers have discovered what some of our genes do, and have found some that are associated with disorders (such as cystic fibrosis or Huntington’s disease). There are, though, many genes whose functions are still unknown.

GENEGENE

Gene hold the information to build and maintain their cells and pass genetic traits to off springs

ALLELEALLELE

 alleles are pairs or series of genes on a chromosome that determine the hereditary characteristics.. An example of an allele is the gene that determines hair color.

A dominant allele produces a dominant phenotype in individuals who have one copy of the allele, which can come from just one parent.

For a recessive allele to produce a recessive phenotype, the individual must have two copies, one from each parent.

An individual with one dominant and one recessive allele for a gene will have the dominant phenotype. They are generally considered “carriers” of the recessive allele: the recessive allele is there, but the recessive phenotype is not.

A phenotype (from Greek phainein, meaning "to show", and typos, meaning "type") is the composite of an organism's observable characteristics or traits, such as its morphology, development, biochemical or physiological properties, phenology, behavior, and products of behavior (such as a bird's nest).

Homozygous-an organism in which 2 copies of genes are identical i.e. have same alleles

Homozygous means you carry two genes that are the same for each trait. Example: BB for brown eyes. 

Heterozygous-an organism which has different alleles of the gene or Heterozygous means you carry two different genes for each trait Heterozygous-an organism which has different alleles of the gene

Example: Bb would also be brown eyes, though the small "b" would be the gene for blue eyes. It doesn't show up in the phenotype (outward appearance) because the gene for brown eyes is dominant. If someone had blue eyes they would be homozygous "bb".

Homozygous and HeterozygousHomozygous and Heterozygous

Here BB & bb is the homozygous and Bb is the heterozygous

What Are Chromosomes? Genes are packaged in bundles

called chromosomes. Humans have 23 pairs of

chromosomes (for a total of 46). Of those, 1 pair is the sex

chromosomes (determines whether you are male or female), and

the other 22 pairs are autosomal chromosomes (determine the rest of the body’s makeup).

Chromosomes:

Chromatin: made up of DNA, RNA & proteins that make up chromosome, Chromatin is located in the nucleus of a cell. During prophase of mitosis, chromatin fibers become coiled into chromosomes

Chromatids: one of the two identical parts of the chromosome.

Centromere: the point where two chromatids attach

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.

A series of codons in part of amRNA molecule. Each codon consists of three nucleotides, usually representing a single amino acid.

The nucleotides are abbreviated with the letters A, U, G and C. This is mRNA, which uses U (uracil). DNA uses T (thymine) instead.

Congenital Disease.Congenital Disease. Diseases which are present at birth.

Hereditary/Familial Disease.Hereditary/Familial Disease. Diseases which are derived from

one’s parents and transmitted in the gametes through the generations.

Not all congenital diseases are genetic( congenital Syphilis) and not all genetic diseases are congenital (Huntington disease).

Mutations.

Definition:Definition:

A permanent heritable change in a gene or chromosomal structure and are important in the causation of cancer and some congenital diseases.

CAUSES OF MUTATIONSCAUSES OF MUTATIONS

Chemicals Nitrous acid Alkylating agents 5- bromouracil Antiviral drug iododeoxy uridine Benzpyrene in tobacco smoke

X – rays & ultraviolet light Certain viruses such as bacterial virus

Types Of Mutations.

1.1. Point MutationPoint Mutation

2.2. DeletionDeletion3.3. Frameshift MutationsFrameshift Mutations4.4. Trinucleotide Repeat MutationsTrinucleotide Repeat Mutations

1. Point Mutation:1. Point Mutation:

Substitution of a single nucleotide base by a different base.

Sickle cell anaemia is the result of a point mutation in codon 6 of the b-globin gene resulting  in the substitution of amino acid glutamic acid by valine .  

b-globin is a major component of  adult haemoglobin (HbA). The single amino-acid substitution results in a type of haemoglobin termed HbS, which has different properties from the normal HbA.  Under conditions of low oxygen tension, or in an atmosphere containing a low oxygen level, the following changes occur:

(1)The haemoglobin agglutinates to form insoluble rod-shaped polymers;

(2)Red blood cells become distorted and sickle-shaped ;

(3)The sickle-shaped cells rupture easily causing haemolytic anaemia;

(4)The sickle shaped cells tend to block capillaries interfering with the blood flow to various organs.

2. 2. Deletion Mutations: Deletion Mutations:

Insertion or deletion of one or more base pairs alters the reading frame of the DNA strand.

Deletion of one codon causing Cystic Fibrosis.

Deletion of 6 codons in the b-globin gene resulting in a variant haemoglobin

3. 3. Frame shift mutations Frame shift mutations involve a deletion or insertion

of one or two base pairs within a coding sequence of a gene. 

 As the coding message is read in triplets codons and deletions the reading frame of mRNA is altered resulting in a non-sense sequence of amino acids.  

 An example occurs in the b-globin gene in which one nucleotide of codon 39 is deleted . The following reading frame is completely altered and continues until a stop codon is  encountered.  

Duchenne muscular dystrophy are caused by frame shift mutations in the dystrophin gene.

DeletionDeletion

InsertionInsertion

Tay-Sachs disease is a rare inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord

3. 3. Trinucleotide Repeat Trinucleotide Repeat Mutations: Mutations:

Trinucleotides are triplets of nucleotides that are repeated in tandem many times over. The number of repeats varies in different individuals.  

An example of trinucleotide repeats is - - - CAG CAG CAG CAG CAG - - - -, and is designated as (CAG)n where n is the number of repeats in the particular individual. 

A form of A form of mutationmutation characterized by a stretch of three  characterized by a stretch of three nucleotidesnucleotides ( (codoncodon) repeated in multiple times in the ) repeated in multiple times in the DNA sequence.DNA sequence. e.g. Fragile X Syndrome(developmental problems including learning disabilities and cognitive impairment. )

Classification Of Genetic Classification Of Genetic Diseases:Diseases: Single Gene Defects/Mendelian Disorders.

Disorders with Multifactorial or Polygenic inheritance.

Cytogenetic Disorders.

Disorders showing atypical patterns of inheritance.

Single gene disorders/ Single gene disorders/ Mendelian DisordersMendelian Disorders

A genetic disease caused by a single mutation in the structure of DNA, which causes a single basic defect with pathologic consequences

According to the Patterns Of According to the Patterns Of Inheritance, single gene disorders Inheritance, single gene disorders are:are:

Autosomal Dominant Disorder.

Autosomal Recessive Disorder.

X-Linked Recessive Disorder.

X-Linked Dominant Disorder.

Autosomal Autosomal Dominant Dominant Disorders.Disorders.

The pedigree on the right illustrates the transmission of an autosomal dominant trait.

Affected males and females have an equal probability of passing on the trait to offspring.

Affected individual's have one normal copy of the gene and one mutant copy of the gene, thus each offspring has a 50% chance on inheriting the mutant allele.

As shown in this pedigree, approximately half of the children of affected parents inherit the condition and half do not.

Individuals with these diseases usually have one affected parent .*

Autosomal Dominant Conditions: •  Huntington Disease •  Acondroplasia (short-limbed dwarfism) •  polycystic kidney disease

Inheritance Pattern:Inheritance Pattern:

• Typical mating pattern is Typical mating pattern is a a heterozygous heterozygous affectedaffected individualindividual with a with a homozygous homozygous unaffectedunaffected individual. individual.

• Both sexes are Both sexes are affected equally..affected equally..

Disorders:Disorders:

Marfan’s Syndrome:Marfan’s Syndrome:

genetic disorder that affects the body's connective tissue. 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.

What is Fibrillin? Marfan syndrome is caused by changes in fibrillin

genes. Fibrillin is a glycoprotein, which is essential for the formation of elastic fibers or microfibrils that provide strength and flexibility to connective tissue.

Connective tissue holds the body together and helps control the growth and repair of tissues and organs.

Fibrillin normally is abundant in the connective tissue found in the aorta, in the ligaments that hold the eye's lenses in place, in the bones and the lungs.

How is Fibrillin related to Marfan syndrome? Marfan syndrome is caused by changes (mutations)

in one member of the pair of fibrillin genes. As a result, the body produces fibrillin that does not work and connective tissue that is not as strong as it should be.

The growth and development of the body are affected, particularly in the connective tissues of the aorta, eye and skin.

It causes overgrowth of the long bones of the body, resulting in tall height, long arms and legs, and a weakened structural support in blood vessels, heart valves, cartilage and ligaments.

Ehler-Danlos Syndrome(Cutis Ehler-Danlos Syndrome(Cutis Hyperelastica):Hyperelastica):

Characterized by defects in collagen synthesis/connective tissue.

Clinical Features include fragile, hyper-extensible skin, hyper-mobile joints, rupture of internal organs like the colon, cornea and large arteries, poor wound healing.

Autosomal Autosomal Recessive Recessive DisordersDisorders

 Recessive conditions are clinically manifest only when an individual has two copies of the mutant allele.

When just one copy of the mutant allele is present, an individual is a carrier of the mutation, but does not develop the condition.

Females and males are affected equally by traits transmitted by autosomal recessive inheritance.

When two carriers mate, each child has a 25% chance of being homozygous wild-type (unaffected); a 25% chance of being homozygous mutant (affected); or a 50% chance of being heterozygous (unaffected carrier).

Affected individuals are indicated by solid black symbols and unaffected carriers are indicated by the half black symbols.

Autosomal recessive diseases: •  Cystic fibrosis •  Tay-Sachs •  hemochromatosis •  phenylketonuria (PKU)

Pattern Of Inheritance:Pattern Of Inheritance:

Typical mating pattern is two heterozygous unaffected (carrier) individuals.

The trait doesnot usually affect the parent, but siblings may show the disease

Siblings have one chance in four of being affected

Both sexes affected equally.

Disorders:Disorders:

X-Linked X-Linked Recessive Recessive Disorders.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.

An unaffected woman carries one copy of a gene mutation for an X-linked recessive disorder. She has an affected son, an unaffected daughter who carries one copy of the mutation, and two unaffected children who do not have the mutation.

Pattern Of Pattern Of Inheritance: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.

Recurrence risk: All the daughters are heterozygous carriers and all the sons are homozygous normal.there is no father to son transmission, but there is father to daughter and mother to daughter and son transmission. If a man is affected with an X-linked recessive condition, all his daughter will inherit one copy of the mutant allele from him.

Disorders:Disorders:

X-linked DominantX-linked DominantDisorderDisorder

Because the gene is located on the X chromosome, there is no transmission from father to son, but there can be transmission from father to daughter (all daughters of an affected male will be affected since the father has only one X chromosome to transmit).

Children of an affected woman have a 50% chance of inheriting the X chromosome with the mutant allele.

X-linked dominant disorders are clinically manifest when only one copy of the mutant allele is present.

X-linked Dominant Disorders •  some forms of retinitis pigmentosa •  Chondrodysplasia Punctata •  hypophosphatemic rickets 

DISORDERS WITH DISORDERS WITH MULTIFACTORIAL MULTIFACTORIAL

(POLYGENIC)INHERITANCE(POLYGENIC)INHERITANCE

Multifactorial inheritance, also called complex or polygenic inheritance.

Multifactorial inheritance disorders are caused by a combination of environmental factors and mutations in multiple genes(genetic factor). For example, different genes that influence breast cancer

susceptibility have been found on chromosomes 6, 11, 13, 14, 15, 17, and 22. Some common chronic diseases are multifactorial disorders.

Rate of recurrence is 2 to 7%Rate of recurrence is 2 to 7%

COMMON DISEASES ASSOCIATED with DISORDERS WITH COMMON DISEASES ASSOCIATED with DISORDERS WITH MULTIFACTORIAL INHERITANCEMULTIFACTORIAL INHERITANCE

Diabetes mellitusDiabetes mellitus HypertensionHypertension GoutGout Cleft lip and palateCleft lip and palate SchizophreniaSchizophrenia Bipolar disorderBipolar disorder Congenital heart diseaseCongenital heart disease Skeletal abnormalitiesSkeletal abnormalities Neural tube defectsNeural tube defects Coronary artery diseaseCoronary artery disease

Cytogenetic Disorders.

Cytogenetic disorders may result from structural or numeric abnormalities of chromosomes

It may affect autosomes or sex chromosomes

Numeric Abnormalities: Normal Chromosomal number is 46. (2n=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.

Aneuploidy:

Most common cause is nondisjunction (attach)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 ( 2n+1 ) or monosomic ( 2n-1 ).

Monosomy in autosomes is incompatible with life.

Trisomy of certain autosomes and monosomy of sex chromosomes is compatible with life.

Mosaicism: A person or a tissue that contains two or more

types of genetically different cells.

Mosaicism is caused by an error in cell division very early in the development of the unborn baby.

Examples of mosaicism include: Mosaic Down Syndrome Mosaic Klinefelter Syndrome Mosaic Turner Syndrome

Structural Abnormalities: Usually result from chromosomal

breakage, resulting in loss or rearrangement of genetic material.

Patterns of breakage: • Translocation.• Isochromosomes.• Deletion.• Inversions.• Ring Chromosomes.

TRANSLOCATIONTRANSLOCATION when a part of one chromosome is transferred

to another chromosome Translocations are indicated by t E.g. 46,XX,t(2;5)(q31;p14) There are two type of translocation.

1. In a reciprocal translocation,

segment from two different

chromosomes have been

exchanged

2. 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

These occur with chromosomes 13, 14, 15, 21, and 22

Such loss is compatible with survival

ISOCHROMOSOMESISOCHROMOSOMES 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.

DELETIONDELETION 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.

INVERSIONS A portion of the chromosome has broken off ,

turned upside down and reattached, therefore genetic material is inverted.

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 .

Ring Chromosome

A portion of a chromosome has broken off and formed a circle or ring . This can happen with or without loss of genetic material.

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).

Defn of de novo change: An alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell (egg or sperm) of one of the parents or in the fertilized egg itself.

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 21st chromosome

Trisomy 21 is caused by a meiotic nondisjunction (attach) 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 2 to 3 Y chromosomes have also been identified.

Klinefelter’s Syndrome:

Defined as Male Hypogonadism (doesnot

produce enough testosterone), 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.

A A karyotypekaryotype (Greek karyon = kernel, seed or nucleus) is  (Greek karyon = kernel, seed or nucleus) is the number and appearance of chromosomes in the the number and appearance of chromosomes in the nucleus of a eukaryotic cell. nucleus of a eukaryotic cell. 

Results from nondisjunction of sex chromosome during meiosis.

Risk factors include advanced maternal age and a history of exposure to radiation in either parent.

Clinical Manifestations:

Increase in body length between soles and pubis.

Reduced facial, body and pubic hair. Gynecomastia.

Testicular atrophy. Infertility. Mild mental retardation.

Turner Syndrome:

Primary hypogonadism in females

Results from partial or complete monosomy of the X chromosome.

Most common cause is absence of one X chromosome.

Less commonly, mosaicism(addition no. of

chromosome), or deletions on the short arm of the X chromosome.

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