Lecture 1 Med Gen

8/3/2019 Lecture 1 Med Gen

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MEDICAL GENETICSLecture 1

Assoc Prof RUSU CRISTINA, MD PhD

Medical Genetics Department

University of Medicine and Pharmacy Iasi


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GENETICS - SCIENCE OF

HEREDITY AND VARIABILITY1) HEREDITY - individual's property to pass his personal

traits and those of species to his offspring;

DNA is the molecular support of heredity;

DNA has 3 main roles:

holds the hereditary (genetic) information for all individual'sspecific traits;

expresses hereditary information via specific protein synthesis; transmits hereditary information in the succession of cells/

individual generations


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GENETIC APPARATUS

Structures that contain DNA:

Nucleuscontains 99% of cellular DNA; Mitochondria1% of DNA;

Structures for the accomplishment of DNA roles:

Ribosome (for protein synthesisreads the informationwritten in mRNA);

Centriolemove to the poles of the cell and determinejoining of microtubules to form the division spindle;


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GENEDNA segmentthat encodes geneticinformation (as anucleotide sequence), that

determines a trait;

Information isTRANSCRIBED inmRNA and thenTRANSLATED

(decodified) as a specificaminoacid sequenceaPROTEIN, that representsthe basis for a specificTRAIT;

Genetic informationinheritanceby DNAsynthesis (semi-conservative replication)and cell division.

CENTRAL DOGMA OF GENETICS


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GENETICS - SCIENCE OF

HEREDITY AND VARIABILITY2) VARIABILITY - phenomena that determine genetic

differences between individuals within a population/between different populations ;

Variability has 3 main sources: Mutations - any change in the genetic material giving rise to

different cells/ individuals;

Gene flow - exchange of genes by migration of individualscarrying new alleles from one population to another;

Genetic recombination - produced in meiosis, assembles anexisting array/ combination of different genes or chromosomesinto new combinations;


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HUMAN GENETICS

Fundamental disciplinestudies the stucture,mechanisms and basic laws of heredity;

Clinical disciplinestudies human disorders produced bydifferent mutations;

Medico-social disciplinegenetic disorders represent apublic health problem:

Frequent- > 5% newborn infants; Expensive; Could be prevented; Rarely have specific treatment;


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HUMAN GENETICS - FIELDS

Medical Genetics: study of the hereditary nature of human disease.

Clinical Genetics: deals with the care, diagnosis and counselling ofpatients with congenital malformations or genetic disorders;

Dysmorphology: study of abnormalities of morphologic development;

Population Genetics: study of genetic variation in human populations;

Developmental genetics: study of the genetic control of development;

Cytogenetics: study of chromosomes;

Molecular Genetics: clinical application of molecular biology to thediagnosis and treatment of different disorders;

Genomics: study of the genome, its organization and functions.


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THINKING GENETICALLY

Etiologic approach to disease: identify the cause;

The family as the unit of concern: the diagnosis of oneperson has implications for other members of the family

risk to develop the disorder/ have affected children; relatives have to take care of the affected persons in the family;

Consider the patient as a whole:

Genetic disorders manifest in many different organs; differentsymptoms at different ages;

Psychological effects in both the patient and his family; Reproductive consequences of a genetic diagnosis.


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GENETIC INDIVIDUALITY (GENOTYPE)

Every individual has an unique genetic information;

Genotype: genetic information included in the

nucleus of somatic cells;

Produced by fertilization;

Determines ontogenetic development of theindividual (zygoteembryofetusnewborn

infantchildadolescentadultold);


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BIOLOGIC INDIVIDUALITY (PHENOTYPE)

Every person is unique due to the individualcombination of genetic and environmental factors;

Phenotype: assembly of morphological,physiological and biochemical traits of anindividual;

Expressed as: Different vulnerability; Variable expression of the disorder in different individuals; Different reaction when treated;


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DETERMINISM OF PHENOTYPIC TRAITS

The contribution of heredity and environment in the

determinism of different traits is variable;

Three types of features can be differentiated:

(1) pure hereditary traits ("genetic traits");

(2) traits determined by the interaction between heredityand environment ("multifactorial traits");

(3) pure ecological traits ("nongenetic traits")Her (1) (2) (3) Env


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1) PURE HEREDITARY TRAITS Determined exclusively (100%) by the normal or

abnormal genetic structure of the individual.

Classified as: species traits, normal and abnormalindividual traits.

Species traits are strictly genetic. Every species

has an invariable and characteristic number ofchromosomes. It determines a reproductive barrier

between species.


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PURE HEREDITARY TRAITS Normal individual traits:

Produced by a pair of allelic genes (monogenic traits);

Inherited according to Mendels laws; Polymorphic (many variants in the population);

ABO, Rh blood groups; Seric groups (haptoglobins, transferins); Enzyme groups; Tisular groups (HLA);

Biochemical traits;


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INDICATION TRAITS STUDIED

Blood transfusions

Prevention of newborn haemolytic

disease

Blood groups (ABO, Rh, MN, Xg et al)

Rhblood group

Tissue typing for transplants HLA

Paternity testing

Persons' identification in forensic

medicine

Blood groups (ABO, Rh, MN, Xg, Hp), secretory

status, taste sensitivity, dermatoglyphics

Gene localization on chromosomes

(by linkage studies)

ABO blood group, secretory status, HLA

Differentiation of monozygotic

(identical, MZT) and dizygotic

(nonidentical, DZT) twins

MZT: Monogenic traits (blood groups, secretory

status, taste sensitivity) 100% identical;

multifactorial traits 70-90% identical;

DZT: different monogenic and multifactorial traits


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PURE HEREDITARY TRAITS Abnormal individual traits:

Produced by mutations Chromosomale.g. Down syndrome,

Monogenice.g. hemophylia, Mitochondriale.g. Leber optic atrophy;

Most of them are not influenced by the environment;

Some genetic disorders could be influenced by theenvironmente.g. phenyl-ketonuria (PKU);


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2) MULTIFACTORIAL TRAITS Produced by heredity + environment;

Normal individual traits:

E.g. height, weight, blood pressure, intelligence; Heredity (the genotype) determines: A part of the feature (heritability);

The upper limit for the development of the feature;

The same genotype (identical twins) produces differentphenotypes in different environments;


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MULTIFACTORIAL TRAITS Abnormal individual traits:

Multifactorial disorders - E.g. Isolated birth defects: neural tube defects, heart defects, hip

dislocation; Common disorders of adulthood: HTA, obesity, diabetes; Disorders produced by somatic mutations: cancer;

Heredity determines genetic predisposition

(vulnerability for a certain disorder); The environment has the key role:

Good environment healthy; Bad environment sick;


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3) PURE ECOLOGICAL TRAITS Produced by environment only;

E.g.: burns, poisonings, infections, trauma etc;

Look like pure ecological, but, in fact, the clinical picture could be

modified by the genetic structure of the individual; E.g. differentindividuals will have different reactions to the same bacteriaone ofthem could develop a severe infection, whereas the other could haveonly a mild one;

Ecogenetics - study of genetically determined differences betweenindividuals in their susceptibility to the action of environmental agents;

Pharmacogenetics - study of genetically determined variations inresponses to drugs in human (exaggerated response to drug with sideeffects, normal response or resistance to drug).


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GENOTYPEPHENOTYPE

ENVIRONMENT RELATIONSHIP

G P

E


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GENOTYPEPHENOTYPE

RELATIONSHIP

Causal: G P;

Partial and complex: Different G the same P; e.g. hemophylia A and B; G1 lack

of clotting factor VIII no blood clotting lack of bloodclotting IX G2;

Recessive genes do not express everytime (only in homozygote,not in heterozygote);

The same G different P; different mutations in the same genedetermine different disorders; Phenocopiestraits produced by the environment, similar to traits

produced by heredity; e.g. microcephaly;


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ENVIRONMENTGENOTYPE

RELATIONSHIP

Causal: E G (mutations); differentagents from the environment produce

different DNA abnormalities (mutations); Complex:

Different E the same G (different agentscould produce the same mutation);

The same E different G (the same agent couldproduce different mutations)


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ENVIRONMENTPHENOTYPE

RELATIONSHIP

Causal: E P (agents from the environmentcould produce different clinical features);

Partial and complex: Phenocopies; some traits produced by the environmentare very similar with traits produced by heredity; e.g.microcephaly;

Different E the same P; The same E different P; the same agent from theenvironment acting in different moments of developmentproduces different abnormalities.


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Thank you!

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Lecture 1 Med Gen