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Introduction to Genetics-contd
Dr.Sahithyaa Assistant professor
Dept. of Community Medicine
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Contents
• Blood groups & Diseases.
• Multifactorial causation and Role of genetic predisposition in common disorder.
• Genomic projects.
• Preventive and social measures.
• Diagnostic and screening services.
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Blood groups & Diseases
• At present 14 blood group systems have been discovered in man (ABO and Rh blood groups).
• Blood groups are determined by genes.
• Gene O is recessive with no antigens while A and B are co-dominant
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Genotypes & phenotypes in ABO systems
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Rhesus system
• The Rhesus system depends upon three genes (C, D and E) and their alleles (c, d and e).
• In India, 93% are Rhesus positive while it is 85% among western Nations.
• The importance of the rhesus system is Erythroblastosis foetalis.
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Blood group & Disease
• Haemolytic tendencies , Duodenal and gastric ulcer common in O.
• Stomach cancer, thrombosis , Ca.cervix and pernicious anaemia – A.
• Among OCP users, thorombotic episode risk is higher in A group
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Erythroblastosis foetalis
• Foetus(Rh+) and Mother(Rh-):
• Foetal red cells cross placenta and act as foreign antigen.
• 2 types of Rh antibodies are produced: - the "strong" or saline antibodies and
- the "weak" or albumin antibodies.
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Erythroblastosis foetalis
• The smaller antibodies enter foetal circulation.
• Foetus is killed in utero if severe resulting miscarriage.
• If damage is less severe, then jaundice, anaemia and oedema occurs.
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Sickle cell Anaemia
• An Autosomal recessive disorder leading to chronic haemolytic anaemia due to abnormal RBC.
• Homozygous individuals of this disease suffer from acute anaemia and in most cases die before puberty.
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Sickle cell Anaemia
• The disease is prevalent among blacks, specially in certain parts of Africa.
• Association with Malaria prevalence.
• The hb S gene is carried in 8 % of American blacks, and one birth out of 400 in American blacks will produce a child with sickle cell anaemia.
• In India, there is high incidence in certain regions.
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Sickle cell Anaemia
• Prenatal diagnosis is now available for couples at risk of producing a child with sickle cell anaemia.
• DNA from foetal cells can be directly examined for sickle cells.
• Genetic counselling should be made available to such couples
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Thalassemia
• Hereditary disorders characterized by reduction in synthesis of globin chain.
• Hypochromic microcytic anaemia due to defective haemoglobinization.
• Alpha thalassemia is primarily due to gene deletion
• Beta thalassemia are usually caused by point mutations
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Thalassemia
• Signs develop after 6 months?
• Prenatal diagnosis for couples at risk .
• Asian couples with thallesemia will lead to hydrops foetalis in infant.
• More common in Mediterranean areas.
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Haemophilia
• Hereditary bleeding disorder affecting 15-20 of every 100,000 males born.
• Estimated 420,000 people with haemophilia worldwide.
• The disorder affects males, and is carried by females.
• The disorder concerns the absence, decrease or deficient function of blood coagulating factor.
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Haemophilia
• In severe cases it most commonly occurs in the large joints of the limbs.
• Therapy with plasma derivatives has reduced mortality in developed countries.
• The main causes of death have stemmed from infections as the side-effects of treatment, including AIDS and liver disease secondary to hepatitis
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Cystic fibrosis
• The gene defect in the cystic fibrosis was identified in 1989.
• Autosomal Recessive affecting the respiratory and gastrointestinal tracts and the sweat glands.
• Incidence ranges from 2.5 to 5 per 10,000 live births in most European populations.
• The condition is less common in blacks, and rare in Orientals.
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Cystic fibrosis
• If treated promptly the life expectancy would be around 30 to 40 yrs.
• The gene defect in the cystic fibrosis was identified in 1989.
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Phenylketonuria
• Autosomal recessive disorder.
• Due to deficiency of liver enzyme phenylalanine hydroxylase which converts phenylalanine to tyrosine.
• Incidence rate is about 1 in 10,000 males.
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Phenylketonuria
• It accumulates in blood and produce toxic effect on the brain lead to mental retardation.
• Testing of bottle-fed infants should be done no sooner than 48 hours after the first successful formula feeding.
• Breast-fed babies, however, are tested at 7 days, since breast milk often has little protein content before the 5th day .
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Multifactorial disorder
• The mode of inheritance of multifactorial disorders is complex.
• The influence of smoking, diet, obesity and lack of exercise on ischaemic heart disease.
• Campbell (1965) stressed that some genetic factors are effective only under certain environmental conditions.
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Role of genetic predisposition in common disorder
• Cancer :10-25% of cases of cancer of the breast or colon.
• Coronary heart disease:• High blood pressure and high blood cholesterol
levels, are also genetically influenced.
• Diabetes :• Non- insulin dependent form of the diabetes have
strong familial tendency.
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DNA Technology
• The synthesis of DNA probes.
• Permits further analysis of DNA by the examination of unknown sequences.
• New diagnostic techniques: • Restriction enzymes that cut DNA consistently only at
specific sequences.• PCR for amplifying known DNA sequences.
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DNA Technology
• DNA sequencing methods.
• In vitro methods for examining the protein product of gene sequences with unknown functions.
• New cytogenetic techniques such as fluorescence in situ hybridization (FISH), which permits direct visualization of the relationship of genes to one another in the nucleus of the living cell.
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DNA Technology
• Comparison between the DNA sequences of different genes and species.
• Insertion of coding DNA sequences into animal embryos to create transgenic animals, including animal models of human diseases.
• Insertion of missing DNA sequences into individuals with genetically determined disorders, or the excision of harmful sequences (gene therapy).
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Gene therapy
• Gene therapy is the introduction of a gene sequence into a cell with the aim of modifying the cell's behaviour in a clinically relevant fashion.
• The gene may be introduced using a virus (usually a retrovirus or adenovirus) or by means of lipid or receptor targeting.
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The Human genome project
• The Human Genome Project is an attempt to systematize the research on mapping and isolating human genes that is already in progress in many countries, in order to create a single linear map of the human genome.
• Agencies with a role in coordinating human genome data include UNESCO, the Genome Data Base, HUGO, the National Institute of Health/Department of Energy (USA), the Medical Research Council (UK), Genethon (France) and the European Union.
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The human genome diversity project
• As part of the work of HUGO, the Human Genome Diversity Project is aimed at increasing understanding of human evolution.
• The major objective is to define the genetic relationships between human populations and interpret them in Terms of natural selection, genetic drift, migration, etc.
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Population genetics
• Population genetics has been defined as the study of precise genetic composition of population and various factors determining the incidence of inherited traits in them.
• Population genetics was founded by Hardy in England and Weinberg in Germany in 1908.
• The Hardy-Weinberg law states that "the relative frequencies of each gene allele tends to remain constant from generation to generation" in the absence of forces that change the gene frequencies.
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Factors which influences the gene frequency
• Mutation : – Heterozygotes of sickle cell trait were found to be
resistant to falciparum malaria.
– Each gene has its own characteristic mutation rate from 104 to 106 per generation.
– During the past 30 years, mutation rates have probably risen owing to increased use of X-rays and chemical mutagens.
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Factors which influences the gene frequency
• Natural selection:– Darwin proposed the theory of natural selection
or survival of the fittest to explain evolution.
– Natural selection is the process whereby harmful genes are eliminated from the gene pool and genes favourable to an individual tend to be preserved and passed on to the offspring.
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Factors which influences the gene frequency
• Population movements: – Population movements will lead to changes in the
distribution of genes.
– Breeding structure:– Mating's tend to occur selectively as assortative
mating within various status and family relationships.
– Public health measures are thus decreasing the selection rates and increasing the genetic burden.
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Preventive and social measures
• Health promotional method• Eugenics – Negative eugenics– Positive eugenics
• Euthenics• Genetic counselling– Prospective genetic counselling– Retrospective genetic counselling
Preventive and social measures
• Other genetic preventive measures– Consanguineous marriage– Late marriage
• Specific protection– Detection of genetic carriers– Prenatal diagnosis– Screening of newborn– Recording preclinical cases
• Early diagnosis & treatment• Rehabilitation
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Health promotional method
• Eugenics:• Galton proposed the term eugenics for the science
which aims to improve the genetic endowment of human population.
• Negative eugenics:• Hitler sought to improve the German race by killing
the weak and defective; this was negative eugenics.
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Health promotional method
• Positive eugenics :• It seeks to improve the genetic composition of the population by
encouraging the carriers of desirable genotypes to assume the burden of parenthood.
• Disadvantage – (i) The majority of socially valuable traits - like intelligence and
positive character features, though partially determined biologically are not inherited in such a simple way as, say blood groups.
– (ii) we cannot determine which gene we transmit to our children.
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Euthenics • The solution of improving the human race does
not lie in contrasting heredity and environment, but rather in the mutual interaction of heredity and environmental factors.
• This environmental manipulation is called euthenics and has considerable broader prospects for success.
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Genetic Counselling• Prospective genetic counselling : – heterozygous marriage can be prevented or reduced, the
prospects of giving birth to affected children will diminish.
• Retrospective genetic counselling– Most genetic counselling is at present retrospective, i.e., the
hereditary disorder has already occurred within the family.
– The methods which could be suggested under retrospective genetic counselling are : (i) contraception (ii) pregnancy termination and (iii) sterilization depending upon the attitudes and cultural environment of the couples involved .
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Other Genetic preventive Measures
• Consanguineous marriages :– Increased risk in the offspring of traits controlled by
recessive genes, and those determined by polygenes. Ex: albinism, alkaptonuria, phenylketonuria
• Late marriages : – "Trisomy 21" incidence in a mother at age 20 is only
1 : 3000; by the age 40, it is 1:40.
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Specific protection
• Patients undergoing X-ray examination should be protected against unnecessary exposure of the gonads to radiation.
• X-ray examination of the pregnant uterus to determine the presence of twins or the lie of the foetus is to be strongly deprecated.
• Rh haemolytic disease of the newborn which is a genetically determined immunological disorder is preventable by immunization by anti- D globulin
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Early diagnosis and treatment
• Detection of genetic carriers :– The female carriers of Duchenne type of muscular
dystrophy, an X-linked disorder, can now be detected by elevated levels of serum creatine kinase in 80 per cent of carriers.
– Crarriers can be recognized with a high degree of certainty e.g.. acatalasia); in some only a proportion of carriers can be detected (e.g., haemophilia, PKU, galactosaemia).
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Amniocentesis
• Done as early as 14th week of pregnancy.
• The diagnosis of chromosomal anomalies is made by culture and Kryotyping of fetal cells from amniotic fluid, and of metabolic defects by biochemical analysis.
• A mother aged 35 years or more (because of high risk of Down's syndrome with advanced maternal age).
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Amniocentesis
• Patients who have had a child with Down's syndrome or other chromosomal anomalies.
• Parents who are known to have chromosomal translocation.
• Parents who have had a child with a metabolic defect -detectable by amniocentesis. When determination of the sex is warranted, given a family history of a sex-linked genetic disease e.g., certain muscular dystrophies.
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Prenatal diagnosis
Indications for prenatal diagnosisIndications Methods Advanced maternal age, previous child with chromosome aberration, intrauterine growth delay
Cytogenetics ( amniocentesis, chorionoc villus sampling)
Biochemical disorder Protein essay, DNA diagnosis
Congenital anomaly Sonography, foetoscopyScreening for neural tube defects & trisomy Maternal serum alpha
feto protein & chronic gonadatropin
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Screening of newborn infants
• Screening tests for the early diagnosis -sex chromosome abnormalities, congenital dislocation of hip, PKU, congenital hypothyroidism, sickle cell disease, cystic fibrosis, Duchenne muscular dystrophy, congenital adrenal hyperplasia, G6PD deficiency etc.
• Biochemical screening of newborn infants was first used for PKU in 1966.
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Screening of newborn infants
• Heel-prick blood samples are usually collected at 5-10 days after birth. Screening of newborns for congenital hypothyroidism is carried out in most developed countries.
• Sickle-cell disease can be detected by haemoglobin electrophoresis using Guthrie blood spots.
• Neonatal screening for cystic fibrosis is based on the measurement of immunoreactive trypsin in Guthrie blood spots.
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Recognizing pre-clinical cases
• Heterozygotes for phenylketonuria can be detected by a phenylalanine tolerance test.
• A simple urine examination for sugar after morning breakfast is good enough to detect diabetics.
• Examination of sibs and close relatives of diabetics by a glucose tolerance test will often reveal preclinical cases of acholuric jaundice.
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Recognizing pre-clinical cases
• A raised serum uric acid should arouse suspicion of gout.
• Sickle cell trait can be uncovered by subjecting the red cells to reduced oxygen tension.
• Thalassaemia minor can be detected by studying the blood picture.
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Established genetic population- screening services
Type of service Conditions Preventive or screening action
Primary Rhesus haemolytic Post-partum use of Anti-D
prevention disease globulin
Congenital rubella Immunization of girls
Congenital Addition of folic acid to the malformations maternal diet (may prevent
neural tube defects) Control of maternal diabetes; Avoidance of mutagens andteratogens such as alcohol,certain drugs and possibly
tobaccoAntenatal Congenital Ultrasound foetal anomaly scan,
screening malformations maternal serum alpha-fetoprotein estimation
Chromosomal Noting maternal age and abnormalities maternal serum factor levels Checking family history
Inherited disease Carrier screening for haemoglobinopathies, Tay-Sachs disease
Neonatal Congenital Examination of the newborn for
screening malformations early treatment (e.g., of congenital dislocation of the hip)
Phenylketonuria, Biochemical tests for early congenital treatment hypothyroidism, sickle-cell disease
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Rehabilitation
• With many genetic or partially genetic conditions causing physical or mental disability, much can be done for the patient and for his family in helping him to lead a better and more useful life.
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• Thank you
