Chapter 1 : Genetics 101


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1 Chpter 1 : Genetics 101 Understnding the underlying concepts of humn genetics nd the role of genes, behvior, nd the environment will be importnt to ppropritely collecting nd pplying genetic informtion nd technologies during clinicl cre. This chpter provides some fundmentl informtion bout bsic genetic concepts including cell structure, the moleculr nd biochemicl bsis of disese, mjor types of genetic disese, lws of inheritnce, nd impct of genetic vrition.
2 6 Almost every humn trit nd disese hs genetic component, whether inherited or modifying the body s response to environmentl fctors such s toxins or behviorl fctors such s exercise. Understnding the underlying concepts of humn genetics nd the role of genes, behvior, nd the environment will be importnt in improving disese dignosis nd tretment. This section presents brod overview of bsic genetics concepts nd the moleculr nd biochemicl bsis of disese. 1.1 Cells, Genomes, DNA, nd Genes Cells re the fundmentl working units of every living system. All the instructions needed to direct their ctivities re contined within DNA (deoxyribonucleic cid) sequence. DNA from ll orgnisms is mde up of the sme chemicl units (bse pirs) bbrevited s A, T, C, nd G. The humn genome (totl composition of genetic mteril within cell) is pckged into lrger units known s chromosomes physiclly seprte molecules tht rnge in length from bout 50 million to 250 million bse pirs. Humn cells contin two sets of chromosomes, one set inherited from ech prent. Ech cell, except sperm nd eggs, contins 23 pirs of chromosomes 22 utosomes (numbered 1 through 22) nd one pir of sex chromosomes (XX or XY). Sperm nd eggs contin hlf s much genetic mteril (e.g., only one copy of ech chromosome). Understnding Genetics: A Guide for Ptients nd Helth Professionls Ech chromosome contins mny genes, the bsic physicl nd functionl units of heredity. Genes re specific sequences of bses tht encode instructions on how to mke proteins. The DNA sequence is the prticulr sidebyside rrngement of bses long the DNA strnd (e.g., ATTCCGGA). Ech gene hs unique DNA sequence. Genes comprise only bout 2% of the humn genome; the reminder consists of noncoding regions, whose functions my include providing chromosoml structurl integrity nd regulting where, when, nd in wht quntity proteins re mde. The humn genome is estimted to contin 20,00025,000 genes. Although ech cell contins full complement of DNA, cells use genes selectively. For exmple, the genes ctive in liver cell differ from genes ctive in brin cell since ech cell performs different functions nd therefore requires different proteins. Different genes cn lso be ctivted during development or in response to environmentl stimuli such s n infection or stress. 1.2 Mjor Types of Genetic Disese Mny, if not most, diseses hve their roots in genes. Genes through the proteins they encode determine how efficiently foods nd chemicls re metbolized, how effectively toxins re detoxified, nd how vigorously infections re trgeted. Genetic diseses cn be ctegorized into three mjor groups: singlegene, chromosoml, nd multifctoril.
3 Chpter 1 : Genetics Thousnds of diseses re known to be cused by chnges in the DNA sequence of single genes. A gene cn be chnged (mutted) in mny wys resulting in n ltered protein product tht is unble to perform its function. The most common gene muttion involves chnge in single bse in the DNA misspelling. Other muttions include the loss (deletion) or gin (dupliction or insertion) of single or multiple bses. The ltered protein product my still retin some function but t reduced cpcity. In other cses, the protein my be totlly disbled by the muttion or gin n entirely new but dmging function. The outcome of prticulr muttion depends not only on how it lters protein s function but lso on how vitl tht prticulr protein is to survivl. Imge Credit: U.S. Deprtment of Energy Humn Genome Progrm, In ddition, genetic diseses cn be cused by lrger chnges in chromosomes. Chromosoml bnormlities my be either numericl or structurl. The most common type of chromosoml bnormlity is known s neuploidy, n bnorml chromosome number due to n extr or missing chromosome. A norml kryotype (complete chromosome set) contins 46 chromosomes including n XX (femle) or XY (mle) sex chromosome pir. Structurl chromosoml bnormlities include deletions, duplictions, insertions, inversions, or trnsloctions of chromosome segment. [See Appendix H for more informtion bout Chromosoml Abnormlities.] Multifctoril diseses re cused by combintion of genetic, behviorl nd environmentl fctors. The underlying etiology of multifctoril diseses is complex nd heterogeneous. Exmples of these conditions include neurl tube defects, dibetes, nd hert disese. While multifctoril diseses cn recur in fmilies, some muttions cn be cquired throughout n individul s lifetime such s in cncer. All genes work in the context of environment nd behvior, both t the cellulr nd globl perspectives. Altertions in behvior or the environment, such s diet, exercise, exposure to toxic gents, or medictions cn ll hve influences on trits tht re t lest in prt geneticlly determined. 1.3 Lws of Inheritnce The bsic lws of inheritnce re importnt in order to understnd ptterns of disese trnsmission [See Appendix B for more informtion bout Clssicl Mendelin Genetics (Ptterns of Inheritnce).] Singlegene diseses re usully inherited in one of severl ptterns depending on the loction of the gene (i.e., chromosomes 122 or X nd Y) nd whether one or two norml copies of the gene re needed for norml protein ctivity. There re five bsic modes of inheritnce for singlegene diseses: utosoml dominnt, utosoml recessive, Xlinked dominnt, Xlinked recessive, nd mitochondril.
4 8 Genetic diseses cused by chromosoml bnormlities re generlly not inherited, but usully occur s rndom events during the formtion of reproductive cells. Below re smple pedigree of ech type of inheritnce pttern nd overview of fmily history ptterns: Affected Unffected A A A Understnding Genetics: A Guide for Ptients nd Helth Professionls Autosoml Dominnt Individuls crrying one mutted copy of gene in ech cell will be ffected by the disese Ech ffected person usully hs one ffected prent Tends to occur in every genertion of n ffected fmily Xlinked Dominnt Femles re more frequently ffected thn mles Fthers cnnot pss Xlinked trits to their sons (no mletomle trnsmission) Autosoml Recessive Affected individuls must crry two mutted copies of gene Prents of ffected individul re usully unffected nd ech crry single copy of the mutted gene (known s crriers) Not typiclly seen in every genertion. Xlinked Recessive Mitochondril Mles re more frequently ffected thn femles Fmilies with n Xlinked recessive disorder often hve ffected mles, but rrely ffected femles, in ech genertion Both prents of n ffected dughter must be crriers Only mother must be crrier of ffected son (fthers cnnot pss Xlinked trits to theirs) Only femles cn pss on mitochondril conditions to their children (mternl inheritnce) Both mles nd femles cn be ffected Cn pper in every genertion of fmily
5 Chpter 1 : Genetics Genetic Vrition All individuls re 99.9 percent the sme with respect to their DNA sequence. Differences in the sequence of DNA mong individuls re clled genetic vrition. Genetic vrition explins some of the differences mong people, such s physicl trits nd lso whether person hs higher or lower risk for certin diseses. Genetic vrition is referred to s muttions or polymorphisms. While muttions re generlly ssocited with disese nd reltively rre, polymorphisms re more frequent nd their clinicl significnce not s strightforwrd. Single nucleotide polymorphisms (SNPs) re DNA sequence vritions tht occur when single nucleotide is ltered. SNPs occur every 100 to 300 bses long the 3billionbse humn genome. A single individul my crry millions of SNPs. While some genetic vrition my cuse or modify risk to disese, others my result in neutrl phenotype or result in no detectble phenotype. For exmple, genetic vrints in single gene ccount for the different blood types A, B, AB, nd O. Understnding the clinicl significnce of genetic vrition is complicted process due to the limited knowledge of which genes re involved in disese or condition, nd the multiple genegene nd genebehviorenvironment interctions likely to be involved in complex, chronic diseses. New technologies re enbling fster nd more ccurte detection of genetic vrints in hundreds or thousnds of genes in single experiment. Selected References Deprtment of Energy, Humn Genome Project Eduction Resources. Avilble t Ntionl Librry of Medicine, Genetics Home Reference Your Guide to Understnding Genetic Conditions. Avilble t Online Mendelin Inheritnce in Mn. Avilble t
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