The study of hereditary traits

Transcription

1 Hereditary traits The study of hereditary traits Traits determined by phenotypic expression of one or several genes, ± interaction with environment factors; The weight of hereditary factors in phenotype is greater than 50%. Classification: monogenic or polygenic; monofactorial or multifactorial; morphologic, physiologic, biochemical, psychic, compartmental. 2 Peculiarities of hereditary traits are genetically determined are produced prenatal; have a congenital manifestation; have a genealogic inheritance; have a familial distribution; are concordant in monozygotic tween; have a specific distribution in population; Associated with chromosomal abmormalities; can be associated with genetic markers Genetic determinism Environment factors Genetic factors Phenotypic expression during genotypeenvironment interaction: Synthesis of one protein (molecular expression) elementary trait Activity in cell / tissue (cellular expression) Normal / pathological trait at the level of organism fenotipic trait 4 2. Prenatal determination Genetic constitution of zygote is established during fecundation Differential gene expression Expression of normal genes Expression of pathological genes (amorphic alleles, cytotoxic genes, abnormal expression) Imprinting The determination of traits takes place in prenatal period, even if the trait will appear later 5 Deviation from prenatal genetic determination Prenatal influence and phenotypic modification of trait under environmental condition Amniotic constrictions may provoke amputations Drugs administrated during pregnancy may interfere with normal development of embryo Diseases suffered during pregnancy may induce abnormal non-genetical modifications Irradiation, chemical substances (including narcotics, alcohol) may induce abnormal phenotypes The stress during pregnacy Phenocopy - a phenotype that closely resembles a genetic disease state, but has arisen by a environmentally determined mechanism 6 1

2 3. Congenital manifestation Manifestation of hereditary traits in newborns BUT, there are several non-hereditary congenital traits and Hereditary traits which express in adults Deviations from congenital manifestation of hereditary traits There are a lot of characters which appear lately: These traits normally appear in childhood or in adults (abnormal number of teeth, baldness) Sex linked traits (sterility, amenorea) Adult s diseases (hypertension, diabetes, etc.) 7 8 Non-hereditary congenital manifestations Congenital manifestations Hemangiomas. These lesions can range from superficial "Port wine stains" (top) to complex, deep changes with great vascularity (bottom). Clubfoot deformity. These changes usually reflect intrauterine effects such as pressure or fetal positioning. "Split hand" deformity Postaxial polydactyly Fused digits (sindactyly) 9 10 Non-hereditary congenital manifestation The consequences of amniotic banding: the banding can be seen on left wrist one missing toe, two syndactyly toes and one toe bud a bilateral cleft lip and palate 4. Genealogic inheritance Trait's Inheritance from parents and its transmission to children It is possible to count the risk of disease for offspring

3 Healthy persons Monozygotic twins Affected persons Dizygotic twins Carrier woman Marriage / extramarital relation Consanguine marriage Deviations from genealogic inheritance Precocious death of affected persons (strong haemoglobinopathies, Duchenne/Backer myopathies); Sterility of affected persons (azoospermy, Moris syndrome); New mutations (de novo); Rare recessive diseases; Multifactorial diseases, including polygenic; Non-complete penetrance; Variable expresivity Non-hereditary genealogic inheritance Inheritance of some infectious diseases from mother to child: AIDS Syphilis Thoxoplasmosis Viral hepatitis B, C, D 5. Familial distribution High frequency of trait / disease in relatives of one family Familial aggregation (concentration) Is characteristic for dominant fullpenetrance and complete expresivity traits

4 Deviations from familial distribution Recessive traits Lethal traits Sterility de novo mutations Non-hereditary familial distribution Infectious diseases in family (tuberculosis, cholera, salmonellosis) Deficiency of some microelements (Iodine, flour) Similar feeding Deficiency of some indispensable substances (vitamins, amino acids, fatty acids) Concordance between monozygotic twins Concordance presence of same trait s variant in different individuals Discordance presence of different trait s variant in different individuals Monogenic, purely hereditary always are identical in monozygotic twins (100 % concordance) Non-hereditary and multifactorial traits may be discordant Monozygotic (identical) twins Result from the same zygote Have the same gender High concordance for monogenic, high-penetrance traits Variable concordance for multifactorial and incomplete penetrance traits Dizygotic (fraternal) twins Twin concordance data Result from different zygotes May have the same or different genders Variable concordance for monogenic and polygenic traits Trait Percent Concordance Monozygotic Dizygotic Hyperthyroidism Clubfoot Cleft lip ± palate Congenital hip dislocation Insulin-dependent diabetes Schizophrenia Pyloric stenosis 22 2 Coronary artery disease

5 H = Concordanc Hereditary coefficient (H) 100 e ( MZT ) Concordanc Concordanc edzt e ( DZT ) x100 A value which characterizes the role of hereditary factors in phenotype s formation Coefficient H has value 100% for purely hereditary traits (concordance in monozygotic twins is 100%) At H between % hereditary factors have a major role At H between 70-40% the trait has a genetic predisposition If H is lower then 40% - the trait is ecologic 7. Specific frequency in different populations Concentration of some genes / alleles specific ethnic or population groups Cystic fibrosis in Caucasians Sickle cell disease in populations of African origin PKU in Northern Europeans Gaucher disease in Jews Milk tolerance in northern ethnics High incidence of Plasmodium vivax malaria worldwide Hardy-Weinberg principle 1. In an ideally population the allele s frequency remain constant in time: p+q=1, where p frequency of dominant allele (A) q frequency of recessive allele (a) 2. In an ideally population the genotype s frequency remain constant in time: p 2 +2pq+q 2 =1, where p 2 frequency of dominant homozygous (AA) 2pq frequency of heterozygous (Aa) q 2 frequency of recessive homozygous (aa). 29 Characteristics of an ideal population It s numerous (over 1,5 thousand individuals); It s panmictic (random marriage); Absence of migration; Mutagenesis is constant; Absence of selection. 30 5

6 8. Presence of chromosomal abnormalities Cytogenetic method All chromosomal abnormalities induce changes in phenotype Chromosomal abnormalities may be divided in: Structural abberation Abnormal number of chromosomes (aneuploidies) Karyotyping metaphase and prometaphase chromosomes analysis; Molecular cytogenetic methods (FISH, mfish, SKY); Barr-body test - for of X chromosomes analysis; F-body test - for of Y chromosomes analysis Barr-body test Uniformly stained interphase chromosomes SKY method 9. Association with genetic markers A DNA sequence, which represents a normal gene linked to a pathological one; A microsattelite linked to a pathological gene; A restriction site. 35 Ex: Linked genes represent a haplotype (Rh - elliptocytosis); Direct DNA analysis shows the presence of mutation. 36 6

7 genotype D/D; 2 genotype I/D; 3 genotype I/I. METHODS USED IN HUMAN GENETICS Direct analysis of genetic material Molecular-genetic methods Cytogenetic method Analysis of primary product (protein) Biochemical method Genealogical inheritance analysis Genealogical method Establishing of genetic factor weight Twin method Establishing of genetic structure of population Population-statistical method