Introduction To Basic Human Genetics - Gfmer.ch

Introduction to Basic HumanGeneticsProfessor Hanan HamamyDepartment of GeneticMedicine and DevelopmentGeneva University HospitalSwitzerlandTraining Course in Sexual andReproductive Health ResearchGeneva 2011

Module for community genetics educationalobjectives Knowledge of basic human genetics conceptsTraining in taking and recording a basic genetic family historyGuidelines on detecting possible genetic risks and where and when toreferTraining in the basic ethical principles and techniques of geneticcounselingTraining in preconception counselingTraining in prescreening counseling, how to detect at risk couples orindividuals and appropriate referralInformation on the advantages and disadvantages of consanguineousmarriagesInformation on common genetic disorders in the communityInformation on the existing specialist services and patient and familysupport organizationsInformation on genetic programs that would be introduced on thenational level

Contents Categories of genetic diseasesBirth defects( Congenital Disorders)Impact of genetic diseasesDNA and protein synthesisMutations

Spectrum of Human Disease Human diseases are caused by a multitude of genetic andenvironmental factors which are acting togetherIn certain conditions such as Down syndrome , geneticfactors predominate, while in tuberculosis for example,environmental factors predominateMost chronic non-communicable conditions such asschizophrenia and diabetes are caused by an interaction ofboth genetic and environmental factors

Categories of Genetic DiseasesSingle ndrialImprintingAcquired somaticabnormalitiese.g. cancer

Family history and construction of apedigree could point to the categoryof genetic disease in the family

Categories of Genetic Diseases Single gene or unifactorial or Mendeliandisorders: examples: thalassemias, sicklecell anemia, cystic fibrosis, albinismChromosomal disorders such as Downsyndrome , Turner syndromeMultifactorial disorders : both genetic andenvironmental factors play a role in causingthe disease such as diabetes, asthma andschizophrenia

Birth defects (Congenital Disorders) According to the World Health Organization,the term congenital disorder includes anymorphological, functional and biochemicalmolecular defects that may develop in theembryo and fetus from conception until birth,whether detected at birth or later.This term is synonymous with the term birthdefect used in the United States of America

Underlying causes of birth nmentalfactors in uteroUnknown

Classification of Congenital Disorders(Birth Defects)Congenitalabnormality (CA),or malformationDisability(e.g. mentalsubnormality)(e.g. congenital heartdefect)Fetal disease(e.g. fetaltoxoplasmosis)Geneticdisease(e.g. hic)

Impact of genetic diseases Of all neonates, 2-3% have at least one major congenitalabnormality, at least 50% of which are caused exclusively orpartially by genetic factors.chromosome abnormalities occur in about 0.5% in neonatessingle-gene disorders occur in about 1% of in neonatesA chromosome abnormality is present in 40-50% of allrecognized first-trimester pregnancy loss. Approximately 1in 6 of all pregnancies results in spontaneous miscarriage,thus around 5-7% of all recognized conceptions arechromosomally abnormal.

Impact of genetic diseases Genetic disorders account for 50% of all childhoodblindness, 50% of all childhood deafness and 50% of allcases of severe learning difficulty.Approximately 1% of all malignancy is caused by single-geneinheritance, and between 5% and 10% of common cancerssuch as breast, colon and ovary have a strong hereditarycomponent.Taking into account common diseases as diabetes andhypertension ( multifactorial disorders) , it has beenestimated that over 50% of the older adult population willhave a genetically determined medical problem.

Prevalent disordersThe 4 most serious and prevalent geneticand congenital disorders are: Hemoglobin disorders ( thalassemia andsickle cell anemia) and G6PD deficiency Down syndrome Neural tube defects Congenital heart defects

DNA DNA molecule is composed oftwo chains of nucleotidesarranged in a double helix.The backbone of each chain isformed by phosphodiesterbonds between the 3' and 5'carbons of adjacent sugars,the two chains being heldtogether by hydrogen bondsbetween the nitrogenousbases ( adenine, guanine,cytosine and thymine )The arrangement of thebases in the DNA moleculeshows specific pairing of thebase pairs: guanine (G) in onechain always pairs withcytosine (C) in the other chainand adenine (A) always pairswith thymine (T).

Chromosome structureThe packaging of DNA intochromosomes involves severalorders of DNA coiling and folding.There is the primary coiling ofthe DNA double helix, thesecondary coiling around sphericalhistone 'beads', forming what arecalled nucleosomes. There is atertiary coiling of thenucleosomes to form thechromatin fibres

DNA Replication During nuclear division the two strandsof the DNA double helix separatethrough the action of the enzyme DNAhelicase, each DNA strand directingthe synthesis of a complementary DNAstrand through specific base pairing,resulting in two daughter DNA duplexesthat are identical to the original parentmolecule. The process of DNAreplication is termed semiconservative,as only one strand of each resultantdaughter molecule is a newlysynthesized strand.

Genes It is estimated that there areapproximately 20,000-25,000 genes in thenuclear genomeThese unique single-copy genes in humansrepresent less than 2% of the genomeThere are 37 mitochondrial genes in thecytoplasm that are only inherited from themother

Structure of a gene The gene is formed of a DNA segment of codingregions called exons and non-coding regions calledintrons. The sequence of bases in the exonsdetermine the sequence of aminoacids and hencethe protein structure

Protein synthesis:involves two processes, transcription andtranslation Transcription: information is passed fromthe DNA to mRNA ( messenger RNA)Translation: Occurs in the ribosomes inthe cytoplasm where the information ispassed from mRNA to construct a chain ofaminoacids

Transcription The information istransferred from DNA inthe nucleus to messengerRNA (mRNA) in thecytoplasm. Each base inmRNA is complementary tothe corresponding base inDNA template strand (inRNA , uracil (U) replaces theplace of thymine tocomplement adenine )

RNA splicing Process by whichnon-codingsequences of basepairs (introns) areremoved from theinitial mRNA so thatonly exons (thecoding sequences) ofa gene to form thefinal messenger RNA(mRNA.)

Translation It is the transmission ofgenetic information frommRNA to protein.mRNA is transported fromnucleus to cytoplasm whereit is associated with theribosomes.Each tRNA specific for anaminoacid has a specifictrinucleotide sequencecalled anticodoncomplementary to themRNA codon

Transfer RNA and codon Twenty different amino acids arefound in proteins and, as DNA iscomposed of four differentnitrogenous bases, then obviously asingle base cannot specify one aminoacid. If two bases were to specify oneamino acid, there would be only 16possible combinations. If, however,three bases specified one amino acidthen the possible number ofcombinations of the four bases wouldbe 64. The triplet of nucleotide basesin the mRNA that codes for aparticular amino acid is called a codon.There is a specific tRNA for eachamino acid that has 3 series of 3 basescalled anticodons that arecomplementary to the e bases (codon)on mRNA

Transfer RNA and codon

Gene Mutations A mutation is defined as a change in the geneticmaterial. Mutations can arise through exposure tomutagenic agents, or spontaneously througherrors in DNA replication and repair.Somatic mutations may cause adult-onset diseasesuch as cancer but cannot be transmitted tooffspring. A mutation in gonadal tissue or agamete can be transmitted to future generations

Types of DNA mutations Substitution: replacement of a singlenucleotide by anotherDeletion: loss of one or more nucleotidesInsertion: addition of one or morenucleotidesExpansion of trinucleotide repeatsequences

Effects of mutations on the protein Silent mutation ( synonymous): replacement of asingle nucleotide by another but with no change inthe amino acidMissense (non synonymous) replacement of asingle nucleotide by another with change in theamino acidNonsense: (non synonymous) replacement of asingle nucleotide by another which leads to achange from a cdon for an amino acid to a stopcodon and truncation of the polypeptide chainFrameshift

Factors implicated in mutagenesis Ionizing radiation includes electromagnetic wavesof very short wavelength (X-rays and γ rays), andhigh-energy particles (α particles, β particles andneutrons).Chemical mutagens : In humans, chemicalmutagenesis may be more important than radiationin producing genetic damage. Experiments haveshown that certain chemicals, such as mustard gas,formaldehyde, benzene, some basic dyes and foodadditives, are mutagenic in animals.Defective DNA repair: The occurrence ofmutations in DNA, if left unrepaired, would haveserious consequences for both the individual andsubsequent generations.

Cell CycleThe cell passes through2 stages:1. Mitosis cell division2. Interphase: dividedinto G1, S and G2 G1 is the period forprotein synthesis S is the period forDNA replication

Chromosomes can only be visualised under themicroscope during mitosis( 46,XX in female and 46,XY in male)Metaphase plate(chromosomes of one cell asseen under the microscope )Karyotype (chromosomesarranged in a special way

Chromosome types

X and Y chromosomes

Conclusions When a baby is suspected to have acongenital disorder, it is important todifferentiate between single gene,chromosomal and multifactorial disordersbecause the methods of investigationsdiffer and the risk of recurrence in futurepregnancies differs as will be discussedlater

Introduction to Basic Human Genetics Professor Hanan Hamamy Department of Genetic Medicine and Development Geneva University Hospital Switzerland Training Course in Sexual and Reproductive Health Research Geneva 2011 . Module for c