Genetics ppt

GeneticsGenetics

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

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

variation of inherited variation of inherited

characteristics amongcharacteristics among

similar or related similar or related

organismsorganisms

Terminology:Terminology:

Gene.Gene. Alleles- Dominant.Alleles- Dominant.

- Recessive.- Recessive. Nucleotides.Nucleotides. Codon.Codon. Genetic Code.Genetic Code.

GENEGENE

Biological unit of heredity.Biological unit of heredity.

Gene hold the information to build Gene hold the information to build and maintain their cells and pass and maintain their cells and pass genetic traits to offspringsgenetic traits to offsprings

In cells, a gene is portion ofIn cells, a gene is portion of

DNADNA

Gene (DNA)Gene (DNA)

RNA formationRNA formation

Protein formationProtein formation

Cell structure Cell enzymesCell structure Cell enzymes

cell functioncell function

ALLELEALLELE

Is one member of a pair or series of Is one member of a pair or series of different forms of a gene.different forms of a gene.

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

Heterozygous-an organism which Heterozygous-an organism which has different alleles of the genehas different alleles of the gene

Chromosomes: 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.

Congential Disease.Congential Disease.

Diseases which are present at Diseases which are present at birth.birth.

Hereditary/Familial Disease.Hereditary/Familial Disease.

Diseases which are derived Diseases which are derived from one’s parents and trasmitted in from one’s parents and trasmitted in the gametes through the generations.the gametes through the generations.

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

Mutations.

Definition:Definition:

Permanent changes in Permanent changes in the DNA. Those that affect germ the DNA. Those that affect germ cells are transmitted to the cells are transmitted to the progeny. Mutations in the progeny. Mutations in the somatic cells are not transferred somatic cells are not transferred to the progeny but are important to the progeny but are important in the causation of cancer and in the causation of cancer and some congenital diseases.some congenital diseases.

CAUSES OF MUTATIONSCAUSES OF MUTATIONS

Chemicals Chemicals Nitrous acidNitrous acid Alkylating agentsAlkylating agents 5- bromouracil5- bromouracil Antiviral drug iododeoxy uridineAntiviral drug iododeoxy uridine Benzpyrene in tobacco smokeBenzpyrene in tobacco smoke

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

virusvirus

Types Of Mutations.

• Point Mutation: Point Mutation: Substitution of a Substitution of a single nucleotide single nucleotide base by a different base by a different base. base.

• Categorized as:Categorized as:• TransitionTransition• transversion transversion MissenseMissense

MutationsMutations. .

NonsenseNonsense MutationsMutations. .

• Frameshift Frameshift Mutations: Mutations:

Insertion or Insertion or

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

Trinucleotide Trinucleotide Repeat Repeat Mutations: Mutations:

set of genetic set of genetic disorder caused disorder caused by trinucleotide by trinucleotide repeat in certain repeat in certain genes exceeding genes exceeding normal,stable normal,stable threshold e.g. threshold e.g. Fragile X Fragile X Syndrome.Syndrome.

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

Disorders.Disorders.

Disorders with Multifactorial or Disorders with Multifactorial or Polygenic inheritance.Polygenic inheritance.

Cytogenetic Disorders.Cytogenetic Disorders.

Disorders showing atypical patterns Disorders showing atypical patterns of inheritance.of inheritance.

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

Patterns Of Patterns Of Inheritance:Inheritance:Autosomal Dominant.Autosomal Dominant.

Autosomal Recessive.Autosomal Recessive.

X-Linked Recessive.X-Linked Recessive.

X-Linked Dominant.X-Linked Dominant.

Autosomal Autosomal Dominant Dominant Disorders.Disorders.

Manifested in Manifested in heterozygousheterozygous states. states.

Individuals with these diseases usually Individuals with these diseases usually have one affected parent .*have one affected parent .*

Variable to late onset.Variable to late onset.

These disorders usually involve non-These disorders usually involve non-enzymatic proteins; enzymatic proteins;

• Proteins involved in metabolic pathway Proteins involved in metabolic pathway regulation.regulation.

• Structural Proteins. Structural Proteins.

Inheritance Inheritance Pattern:Pattern:• Typical mating Typical mating pattern is a pattern is a heterozygous heterozygous affectedaffected individual individual with a with a homozygous homozygous unaffectedunaffected individual.individual.

•Every child has one Every child has one chance in two of chance in two of having the diseasehaving the disease

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

Disorders:Disorders:

Structural Protein Defects:Structural Protein Defects:

Marfan’s SyndromeMarfan’s Syndrome..

Ehler-Danlos Syndrome.Ehler-Danlos Syndrome.

Marfan’s Marfan’s Syndrome:Syndrome: Mutation in the fibrillin Mutation in the fibrillin gene.gene.

Fibrillin important Fibrillin important component of microfibrils in component of microfibrils in Elastin.Elastin.

Tissues affected are Tissues affected are Skeleton, Eyes and the CVS.Skeleton, Eyes and the CVS.

C/F include tall stature, C/F include tall stature, long fingers, pigeon breast long fingers, pigeon breast deformity, hyper-extensible deformity, hyper-extensible joints,high arched palate, BL joints,high arched palate, BL subluxation of lens, floppy subluxation of lens, floppy Mitral valve, Aortic Mitral valve, Aortic aneurysm and dissection, aneurysm and dissection, defects in skin,lungs.defects in skin,lungs.

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

Characterized by defects in collagen Characterized by defects in collagen synthesis.synthesis.

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

Defects in metabolic pathway Defects in metabolic pathway proteins:proteins: Familial Hypercholesterolemia:Familial Hypercholesterolemia:• One of the most common mendelian disorders. One of the most common mendelian disorders.

• Mutation in the LDL receptor gene.Mutation in the LDL receptor gene.

• Hypercholesterolemia due to impaired LDL Hypercholesterolemia due to impaired LDL transport into cells.transport into cells.

• Increased risk of atherosclerosis and coronary Increased risk of atherosclerosis and coronary artery disease.artery disease.

• Increases Cholesterol leads to formation of Increases Cholesterol leads to formation of Xanthomas.Xanthomas.

Autosomal Autosomal Recessive Recessive DisordersDisorders

Largest group of Medelian DisordersLargest group of Medelian Disorders

Affected individuals usually have Affected individuals usually have unaffected (carrier) parents.unaffected (carrier) parents.

Uniform, early age of onset.Uniform, early age of onset.

These disorders usually involve These disorders usually involve Enzymatic Proteins.Enzymatic Proteins.

Pattern Of Pattern Of Inheritance:Inheritance:

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

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

Siblings have one chance in Siblings have one chance in four of being affectefour of being affecte

Both sexes affected equally.Both sexes affected equally.

Disorders:Disorders:

Glycogen Storage Glycogen Storage Diseases.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 X-Linked Recessive Recessive Disorders.Disorders.

Most common X-linked disorders.Most common X-linked disorders.

Usually expressed only in males.Usually expressed only in males.

Rarely, due to random X-inactivation, a Rarely, due to random X-inactivation, a female will express disease, called female will express disease, called manifesting heterozygotes.manifesting heterozygotes.

Pattern Of Pattern Of Inheritance:Inheritance:

• Disease usually passed on Disease usually passed on from carrier mother. from carrier mother.

• Expressed in male Expressed in male offspring, females are offspring, females are carriers.carriers.

• Skipped generations are Skipped generations are commonly seen.commonly seen.

• In this case, Recurrence In this case, Recurrence risk is half of sons are risk is half of sons are affected, half of the affected, half of the daughters are carriers.daughters are carriers.

• Recurrence Recurrence risk:risk:• All the All the daughters are daughters are heterozygous heterozygous carriers and all carriers and all the sons are the sons are homozygous homozygous normal.normal.

Disorders:Disorders:

DISORDERS WITH DISORDERS WITH MULTIFACTORIAL MULTIFACTORIAL

(POLYGENIC)INHERITA(POLYGENIC)INHERITANCENCE Involved in many physiologic Involved in many physiologic

characteristics of humans e.g. characteristics of humans e.g. height, weight, hair colorheight, weight, hair color

Defined as one governed by additive Defined as one governed by additive effect of two or more genes of small effect of two or more genes of small effect but conditioned by effect but conditioned by environmental, non genetic environmental, non genetic influencesinfluences

The disorder becomes manifested The disorder becomes manifested only when a certain number of only when a certain number of effector genes, as well as effector genes, as well as conditioning environmental conditioning environmental influences are involvedinfluences are involved

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

COMMON DISEASES ASSOCIATED:COMMON DISEASES ASSOCIATED: 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.

KARYOTYPINGKARYOTYPING Basic tool of cytogeneticistBasic tool of cytogeneticist

Karyotype is a photographic Karyotype is a photographic representation in which chromosomes are representation in which chromosomes are arranged in order of decreasing lengtharranged in order of decreasing length

Giemsa stain (G banding) technique—Giemsa stain (G banding) technique—each chromosome can be seen to possess each chromosome can be seen to possess a distinctive pattern of alternating light a distinctive pattern of alternating light and dark bands of variable widthsand 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

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 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: 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.

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

Transfer of a part of one chromosome Transfer of a part of one chromosome to another chromosometo another chromosome

Translocations are indicated by tTranslocations are indicated by t E.g. 46,XX,t(2;5)(q31;p14)E.g. 46,XX,t(2;5)(q31;p14) Balanced reciprocal translocation is Balanced reciprocal translocation is

not harmful to the carrier, however not harmful to the carrier, however during gametogenesis, abnormal during gametogenesis, abnormal gametes are formed, resulting in gametes are formed, resulting in abnormal zygotesabnormal zygotes

Centric fusion type or robertsonian Centric fusion type or robertsonian translocation:translocation:

The breaks occur close to the The breaks occur close to the centromere, affecting the short arms of centromere, affecting the short arms of both choromosomesboth choromosomes

Transfer of the chromosome leads to Transfer of the chromosome leads to one very large and one extremely small one very large and one extremely small chromosomechromosome

The short fragments are lost, and the The short fragments are lost, and the carrier has 45 chromosomescarrier has 45 chromosomes

Such loss is compatible with survivalSuch loss is compatible with survival However, during gametogenesis However, during gametogenesis

difficulties arisedifficulties arise

ISOCHROMOSOMESISOCHROMOSOMES Result when one arm of a chromosome is lost and Result when one arm of a chromosome is lost and

the remaining arm is duplicated, resulting in a the remaining arm is duplicated, resulting in a chromosome consisting of two short arms only or chromosome consisting of two short arms only or of two long arms.of two long arms.

DELETIONDELETION Loss of a portion of chromosomeLoss of a portion of chromosome This can be terminal (close to the end of the This can be terminal (close to the end of the

chromosome on the long arm or the short arm), chromosome on the long arm or the short arm), or it can be or it can be interstitialinterstitial (within the long arm or (within the long arm or the short arm). the short arm).

A ring chromosome is a variant of deletion.It A ring chromosome is a variant of deletion.It occurs when break occurs at both the ends of occurs when break occurs at both the ends of chromosome with fusion of the damaged ends.chromosome with fusion of the damaged ends.

INVERSIONSINVERSIONS Occur when there are two breaks within a Occur when there are two breaks within a

single chromosome with inverted single chromosome with inverted reincorporation of the segment.reincorporation of the segment.

Since there is no loss or gain of chromosomal Since there is no loss or gain of chromosomal material, inversion carriers are normal.material, inversion carriers are normal.

An inversion is An inversion is paracentricparacentric if the inverted if the inverted segment is on the long arm or the short segment is on the long arm or the short arm .arm .

The inversion is The inversion is pericentricpericentric if breaks occur if breaks occur on both the short arm and the long arm .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 Down syndrome is a chromosomal abnormality characterized by the abnormality characterized by the presence of an extra copy of genetic presence of an extra copy of genetic material on the 21material on the 21stst chromosome chromosome

Trisomy 21 is caused by a meiotic Trisomy 21 is caused by a meiotic nondisjunction event.nondisjunction event.

With nondisjunction, a gamete (With nondisjunction, a gamete (i.e.i.e., a , a sperm or egg cell) is produced with sperm or egg cell) is produced with an extra copy of chromosome 21; the an extra copy of chromosome 21; the gamete thus has 24 chromosomesgamete thus has 24 chromosomes

When combined with a normal When combined with a normal gamete from the other parent, the gamete from the other parent, the embyo now has 47 chromosomes, embyo now has 47 chromosomes, with three copies of chromosome 21.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.

Klinefelter’s Syndrome:

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.

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 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.

DIAGNOSIS OF GENETIC DISEASEDIAGNOSIS OF GENETIC DISEASE

Conventional Cytogenetic AnalysisConventional Cytogenetic Analysis FISH FISH Molecular AnalysisMolecular Analysis