Post on 14-Apr-2017
Learning Objectives• Familiar with the different branches of genetics• Able to recollect and understand the basic concepts
in genetics like penentrance, pleiotropy etc.• Able to explain the basis of classification of genetic
disorders• Able to list the single gene disorders• Able to explain the principles of Mendelian law of
inheritance• Able to explain/discuss the biochemical/molecular
basis of single gene disorders
CytogeneticsIt deals with the study of chromosomes
and of sex chromatin Developmental genetics Genetic control of physiological
processes in the initial prenatal period of 12 weeks
• Biochemical genetics Proteins make a structural
protein/enzyme that control various metabolic processes in the body thereby influencing growth and differentiation
Mutations in DNA --- VARIANT protein synthesis --- phenotypic effect
1. Gene mutations leading to inborn errors of metabolism
2. Haemoglobinopathies3. Polymorphisms revealed by an altered
response to drugs Immunogenetics It deals with the genetic basis of the
immunological phenomenon in an organism
Cancer genetics
Population genetics
It deals with the study of genes in population.
It also tells us about distribution of genes and how genotypes are maintained or changed in population.
Pleiotropy
• Phenomenon in which a single gene mutation leads to many phenotypic effects is called pleiotropism
• Eg: Marfan’s syndrome• Single gene mutation in gene fibrillin affects
connective tissue component of skeleton, eye and CVS leading to dislocated lens, mitral valve prolapse
Genetic heterogeneity
• Phenomenon in which mutations at different genetic loci produce same result is called genetic heterogeneity
• Eg: Retinitis pigmentosa
Penentrance
• Phenotypic expression of an inherited mutant gene / percentage carriers of the gene that express the trait is called penentrance
• When some individuals inherit the mutant gene but are phenotypically normal (person may have the abnormal gene but never expressed the disease) trait is of reduced penentrance
Variable expressivity
• If a trait is seen in all individuals carrying the mutant gene but express the disease with different severity it is called variable expressivity
• Eg: neurofibromatosis
Type of mutations (based on the extent of damage)
Genome mutation: (whole chromosome) loss or gain of whole chromosome giving rise to
monosomy or trisomy
Chromosome mutation: (visible chromosome change)Rearrangement of genetic material giving rise to visible
changes in the chromosome– Gene mutation: (may, and often, result in a single
base error)
GENETIC DISORDERS
Single gene mutations, following classical Mendelian inheritance patterns
Multifactorial inheritance Chromosomal disorders Structural /numerical abnormalities in
autosomes and sex chromosomes
Multifactorial inheritance
Diseases involved by both genetics as well as environmental influences
Caused by interaction between multiple variant forms of genes and environmental factors
No single susceptible gene is individually sufficient for inducing the disease
Eg: Cleft lip or palate Congenital heart disease, Coronary heart disease Hypertension, Type II DM
SINGLE-GENE DISORDERS These disorders are the result of mutation of a
single gene of large effect
Mutation refers to PERMANENT change in DNA muatations that affect germ cells - transmitted to progeny - give rise to inherited disorders mutations in somatic
cells - not transmitted to progeny - give rise to cancers and congenital malformations
GENE MUTATIONS• Point mutation• Substitution of a single nucleotide base by
a different base• Val ----- Glutamic acid• Frame shift mutation • Insertion / deletion of one or two base
pairs in the DNA sequence Eg: Cystic fibrosis of pancreas
Tri-nucleotide REPEATSAmplification of a sequence of three
nucleotidese.g., CGG repeats many times in fragile X
syndromeMutations involving single genes typically
follow one of three patterns of inheritance: Autosomal dominant Autosomal recessive and Sex-linked recessive ( X- chromosome )
AUTOSOMAL DOMINANT
• Disease is in HETEROZYGOTES• NEITHER parent may have the disease (NEW mut.)• REDUCED PENETRANCE (env?, other genes?)• VARIABLE EXPRESSIVITY (env?, other genes?)• May have a DELAYED ONSET• Usually result in a REDUCED PRODUCTION or
INACTIVE protein
Autosomal Dominant• Manifested in the heterozygous state• Atleast one parent of an index case is usually
affected• Both males and females affected, both can
transmit the disease• New mutations can occur – neither siblings are
affected nor they have affected parents• Incomplete penentrance• Variable expressivity• Delayed onset
Examples
Huntington disease Neurofibromatosis Polycystic kidney Hereditary spherocytosis Von willebrand disease Marfan syndrome EHLERS-DANLOS syndromes(some) Familial hypercholesterolemia
• Clinical features can be modified by variations in penentrance and expressivity
• Eg: Neurofibromatosis type 1 brownish spots on the skin to multiple skin
tumors and skeletal deformities
Autosomal recessive disorders
• Most common type of Mendelian disorder• Parents may not show the disease, but siblings
may• Siblings have one chance in four of having
trait• Expression of defect more uniform than in AD• Complete penentrance is common• Early onset in life
Examples PhenylKetonUria Galactosemia Lysosomal storage diseases Wilson disease Hemochromatosis Glycogen storage diseases Sickle cell anemia Thalassemias EHLERS-DANLOS (some) Alkaptonuria
Heredity in hemophilia
Normal women Affected male
Gametes
Children
Parents
Trait-carrying Normal Trait-carrying NormalGirl boy girl boy
Heredity in hemophilia
Gametes
Children
Parents
Normal Normal Trait-carrying Affected girl boy girl boy
Examples
Duchenne muscular dystrophy Hemophilia , A and B G6pd deficiency Wiskott-aldrich syndrome Diabetes insipidus Lesch-nyhan syndrome Fragile-x syndrome
Biochemical and molecular basis of Single-gene (Mendelian) disorders
1. Enzyme defects and their consequences
2. defects in membrane receptors and transport systems
3. alteration in the structure, function or quantity of non-enzyme proteins
4. Mutations involving unusual reaction to drugs
Enzyme defects and their consequences• Mutations result in the synthesis of an enzyme
with reduced activity / reduced amount of normal enzyme
• Metabolic block• A) accumalation of substrate eg: accumalation of substrates in the lysosomes
due to deficiency of degradative enzymes – lysosomal storage diseases
• an enzyme defect leading to decreased amount of end product
• Eg: albinism def. of tyrosinase leads to reduced synthesis
of melanin from tyrosine
Defects in the receptors and transport systems
• Eg: reduced synthesis/function of LDL receptor leads to defective transport of LDL into cells --- excessive cholesterol synthesis --- familial hypercholesterolemia
• Cystic fibrosis --- transport system for chloride ions is defective in sweat glands, lungs and pancreas
Alteration in structure, function / quantity of non-enzyme proteins
• Thalassemia – reduced amount of alpha/beta chains
• Defective structural proteins – collagen, spectrin / dystrophin
• Osteogenesis imperfecta, hereditory spherocytosis and muscular dystrophies
Genetically determined adverse reaction to drugs
• Eg: G6PD Hemolytic anemia on taking antimalarial drug
Primaquine
MCQ’s1. Albinism results from deficiency of A) CatalaseB) TyrosinaseC) Xanthine oxidaseD) Pyruvate kinase2. Most striking example of disease due to
point mutation E) Sickle cell anemiaF) Down’s syndrome