MEDICAL GENETICS

Lecture 1
Assoc Prof RUSU CRISTINA, MD PhD Medical Genetics Department University of Medicine and Pharmacy Iasi

GENETICS - SCIENCE OF HEREDITY AND VARIABILITY

1) 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's specific 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:

Nucleus contains 99% of cellular DNA; Mitochondria 1% of DNA; Ribosome (for protein synthesis reads the information
written in mRNA); Centriole move to the poles of the cell and determine joining of microtubules to form the division spindle;

Structures for the accomplishment of DNA roles:

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CENTRAL DOGMA OF GENETICS

GENE DNA segment that encodes genetic information (as a nucleotide sequence), that determines a trait; Information is TRANSCRIBED in mRNA and then TRANSLATED (decodified) as a specific aminoacid sequence a PROTEIN, that represents the basis for a specific TRAIT; Genetic information inheritance by DNA synthesis (semiconservative replication) and cell division.
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GENETICS - SCIENCE OF HEREDITY AND VARIABILITY

2) 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 individuals carrying new alleles from one population to another; Genetic recombination - produced in meiosis, assembles an existing array/ combination of different genes or chromosomes into new combinations;
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HUMAN GENETICS

Fundamental discipline studies the stucture, mechanisms and basic laws of heredity;
Clinical discipline studies human disorders produced by different mutations; Medico-social discipline genetic disorders represent a public 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 of patients 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 the diagnosis 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 one person 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; Genetic disorders manifest in many different organs; different symptoms at different ages; Psychological effects in both the patient and his family; Reproductive consequences of a genetic diagnosis.
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Consider the patient as a whole:

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 the individual (zygote embryo fetus newborn infant child adolescent adult old);
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BIOLOGIC INDIVIDUALITY (PHENOTYPE)

Every person is unique due to the individual combination of genetic and environmental factors; Phenotype: assembly of morphological, physiological and biochemical traits of an individual; 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 heredity
and 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 abnormal individual traits. Species traits are strictly genetic. Every species has an invariable and characteristic number of chromosomes. 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);
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Biochemical traits;
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INDICATION

TRAITS STUDIED

Blood transfusions Blood groups (ABO, Rh, MN, Xg et al) Prevention of newborn haemolytic Rh blood group disease Tissue typing for transplants HLA

Paternity testing Blood groups (ABO, Rh, MN, Xg, Hp), secretory Persons' identification in forensic status, taste sensitivity, dermatoglyphics medicine Gene localization on chromosomes ABO blood group, secretory status, HLA (by linkage studies) Differentiation of monozygotic MZT: Monogenic traits (blood groups, secretory (identical, MZT) and dizygotic status, taste sensitivity) 100% identical; (nonidentical, DZT) twins multifactorial traits 70-90% identical; DZT: different monogenic and multifactorial traits
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PURE HEREDITARY TRAITS

Abnormal individual traits:

Produced by mutations

Chromosomal e.g. Down syndrome, Monogenic e.g. hemophylia, Mitochondrial e.g. Leber optic atrophy;

Most of them are not influenced by the environment; Some genetic disorders could be influenced by the
environment e.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 different

phenotypes 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. different individuals will have different reactions to the same bacteria one of them could develop a severe infection, whereas the other could have only a mild one; Ecogenetics - study of genetically determined differences between individuals in their susceptibility to the action of environmental agents; Pharmacogenetics - study of genetically determined variations in responses to drugs in human (exaggerated response to drug with side effects, normal response or resistance to drug).
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GENOTYPE PHENOTYPE ENVIRONMENT RELATIONSHIP

G
E
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GENOTYPE PHENOTYPE 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 blood clotting IX G2; Recessive genes do not express everytime (only in homozygote, not in heterozygote); The same G different P; different mutations in the same gene determine different disorders; Phenocopies traits produced by the environment, similar to traits produced by heredity; e.g. microcephaly;
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ENVIRONMENT GENOTYPE RELATIONSHIP

Causal: E G (mutations); different agents from the environment produce different DNA abnormalities (mutations); Complex:

Different E the same G (different agents

could produce the same mutation); The same E different G (the same agent could produce different mutations)
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ENVIRONMENT PHENOTYPE RELATIONSHIP Causal: E P (agents from the environment could produce different clinical features);
Partial and complex:

Phenocopies; some traits produced by the environment

are very similar with traits produced by heredity; e.g. microcephaly;

Different E the same P; The same E different P; the same agent from the
environment acting in different moments of development produces different abnormalities.
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Thank you!

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