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Principle of Genetics
นายแพทย ดร. ณตพล ศุภณัฐเศรษฐกุล
ภาควิชาพยาธิวิทยา และนิติเวชศาสตร
คณะแพทยศาสตร มหาวทิยาลัยนเรศวร
Email : [email protected]
http://www.uga.edu/srel/kidsdoscience/images/genetics-puppets.gifhttp://www.uwo.ca/biology/images/undergraduate/chromosome.jpg8 กรกฎาคม พ.ศ. 2554
Topics
The Role of Genetics in MedicineGenes and ChromosomesGenetic disorders
Single gene disordersMendelian inheritanceNon-mendelian inheritance
Chromosomal disordersPolygenic or multifactorial diseasesSomatic cell genetic disorders
Clinical geneticsGenetic screening testPrenatal diagnosis, newborn screeningGenetic counseling / ethicsGene therapy
Topics
The Role of Genetics in Medicine
First report in human genetics : Jewish report on hemophilia and gender transmissionIn 1865, Mendel published his workIn 1956, the correct chromosome number was reportedIn January 1959, the chromosomal abnormality associated with clinical disorders was ever reportedMapping of genes to chromosomes and specific chromosome region, abnormal gene functions
http://history.nih.gov/exhibits/nirenberg/images/photos/01_mendel_pu.jpg
http://www.scq.ubc.ca/wp-content/mendel.jpg
http://images.google.co.th/imgres?imgurl=http://www.virtualsciencefair.org/2004/mcgo4s0/public_html/t2/dwn_chromo.gif&imgrefurl=http://www.virtualsciencefair.org/2004/mcgo4s0/public_html/t2/dna.html&h=318&w=430&sz=29&hl=th&start=32&um=1&tbnid=4sRt4QRwm30RKM:&tbnh=93&tbnw=126&prev=/images%3Fq%3DDown%2Bsyndrome%26start%3D18%26ndsp%3D18%26um%3D1%26hl%3Dth%26sa%3DN
http://www.virtualsciencefair.org/2004/mcgo4s0/public_html/t2/dwn_chromo.gif
http://ghr.nlm.nih.gov/handbook/illustrations/chromosomallocation.jpgCystic Fibrosis Transmembrane Regulator, CTFR
The DNA sequence provided by the Human Genome Project (1988 – 2003)
3,095,784,273 base pairs with 32,020 genes
Approximately 3% of all pregnancies result in the birth of a child with a significant genetic disease or birth defect
Four major types of genetic disease:Single gene disorders Chromosomal disordersPolygenic or multifactorial diseasesSomatic cell genetic disorders
The Role of Genetics in Medicine
Genes and Chromosomes
Structure of DNACentral dogmaChromosomesGeneCell cycle and cell divisions :
mitosis meiosis
Mutation
Structure of DNA
http://academic.brooklyn.cuny.edu/biology/bio4fv/page/molecular%20biology/16-05-doublehelix.jpg
“Central Dogma”
DNA RNA Protein
TranslationTranscription
Replication
http://www.dnareplication.info/images/dnareplication.jpg
http://images2.clinicaltools.com/images/gene/mrnatext_highlight.jpg
Chromosomes
http://infohost.nmt.edu/~klathrop/DNA%20Coiling.jpg
Human Genome (chromosomes)
In Nucleus3.1 x 109 bp
In Mitochondria16,569 bp
Gene
Coding Sequences
(Exon)
Non coding Sequences
(Intron)
Non-gene (Extragenetic)
Repetitive DNA
Tandem repeats (satellite, minisatellite, microsatellite)
Interspersed repeats (SINES, LINES)
Non repetitive DNA
10% 90%
<10% >90% 50%50%
Cell cycle
http://www.cbp.pitt.edu/faculty/yong_wan/images/main_cell_cycle.jpg
http://ghs.gresham.k12.or.us/science/ps/sci/soph/cells/cycle/cycle.gif
http://tainano.com/Molecular%20Biology%20Glossary.files/image040.gifhttp://homepage.mac.com/enognog/cell%20cycle.jpg
Cell division
MitosisMeiosis and gametogenesisCrossing over
http://www.uhh.hawaii.edu/~ronald/392/Mitosis.JPG
http://www.mun.ca/biology/desmid/brian/BIOL2060/BIOL2060-20/2010.jpg
Mutationหมายถึงกระบวนการที่กอใหเกิดการเปลี่ยนแปลง
ทุกรูปแบบ ที่เกิดขึ้นกบัโมเลกุลของ DNA
“Wild type” and “mutant allele”Normal variation, polymorphism, inherited diseaseTypes of mutation
Base substitution => silent mutation, missense, nonsenseInsertion => frameshift mutationDeletion => frameshift mutationChromosomal abnormality
http://www.layevangelism.com/bastxbk/images/mutation.jpg
http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=112100&screenWidth=1280&screenHeight=800
Genetic disorders
Single gene disordersMendelian inheritanceNon-Mendelian inheritance
Chromosomal disordersPolygenic or multifactorial disordersSomatic cell genetic disorders
I. Single gene disorders
TerminologyMechanism of mutationFunctional effects of mutation on proteinMendelian inheritance of single gene disorders
TerminologyGenotype = genetic constitution of an individualPhenotype = observed characteristicHomozygote = identical alleles at a given locusHeterozygote = two different alleles at a given locusAutosomes = any chromosomes other than sex
chromosomesAutosomal inheritance = involve any chromosomes
other than sex chromosomesPedigree charts = to illustrate the inheritance
http://naturalsciences.sdsu.edu/ta/classes/lab2.4/trait.jpg
TerminologyLocus = position of DNA sequences, or gene on a chromosomeAllele = possible alternative form of a given geneDNA polymorphism = the occurrence in a population of two or more alternative genotypesGene pool = the study of frequency of total alleles on a given locusPopulation genetics = the study of the genetic composition of populations
http://www.geneticsandhealth.com/wp-content/allele.jpg
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/Chromo7.gif
Gene loci
http://www.genome.gov/Pages/Hyperion/DIR/VIP/Glossary/Illustration/Images/autosome.gif
http://www.geneticsandhealth.com/wp-content/pedigree%20image_1.gif
http://www.geneticsandhealth.com/wp-content/pedigree%20image_2.gif
http://www.migeneticsconnection.org/genomics/Family%20History/pedigreeSymbols.jpg
Introduction
Single gene disorders are caused by individual mutant genes
There are approximately 11,000 single gene disorders, affecting 1% of the populations
Follow Mendelian patterns of inheritanceAutosomal dominant inheritance (AD)Autosomal recessive inheritance (AR)X-linked recessive inheritanceX-linked dominant inheritanceY-linked (Holandic) inheritance
Mandelian Inheritance
Autosomal dominant inheritanceAutosomal recessive inheritanceX-linked recessive inheritanceX-linked dominant inheritanceY-linked (Holandic) inheritance
A “dominant phenotype” is one that is expressed in heterozygotes, whereas a “recessive trait” is expressed only in homozygotes
If the expression of each allele can be detected in the presence of the other, the two alleles are termed “co-dominant”
http://www.uic.edu/classes/bms/bms655/gfx/pedigree1.gif
Autosomal Dominant
Phenotypically expressed in homozygotes and heterozygotes for that geneThere is vertical inheritance (affected child usually has an affected parent)Unaffected family members usually have unaffected partners, and they produce normal childrenAffected family members, usually have unaffected partners, and they produce a 1:1 ratio of normal and affected childrenUsually both sexes are equally affected, and they are equally likely to pass on the disease
http://www.sciencemuseum.org.uk/on-line/genes/images/1-3-5-1-4-2-1-1-1-3-0.jpg
http://www.moondragon.org/obgyn/graphics/achondroplasiacomparison.jpg
http://www.commonwealthadoption.org/images/johnston.jpg
Achondroplasia
http://www.nhlbi.nih.gov/health/dci/images/Marfan_lowres.gif
http://www.homoeopathiker.de/homoeopathik/syphilis/bilder/marfan3.jpg
Marfan syndrome
Examples
Skeletal: Marfan syndrome, Achondroplasia, Osteogenesis imperfectaNervous system: Huntington disease, NeurofibromatosisUrinary: Polycystic kidney diseaseGastrointestinal: Familial polyposis coliHematopoietic: Von Willebrand diseaseMetabolic: Familial hypercholesterolemia, Acute intermittent porphyria
http://www.uic.edu/classes/bms/bms655/lesson5.html
Autosomal Recessive
Expressed only in homozygotes, otherwise can be traitThere is horizontal inheritance (normal parents often have more than one affected child)Affected individuals have phenotypically normal parentsAffected individuals usually have unaffected partners and all their children will be carriers
If a carrier has an unaffected partner, there is a 50% chance of the children being carriersOnly mating between heterozygotes (carrier) will produce affected individuals, with an expected frequency of 1 in 4There is an association with consanguinity due to sharing of genes in families (rare recessive genetic disorders are more likely to arise through consanguinity)Both sexes are equally affected and equally likely to pass the mutation to the next generation
http://upload.wikimedia.org/wikipedia/commons/thumb/3/3e/Autorecessive.svg/300px-Autorecessive.svg.png
http://healthnet.md.chula.ac.th/text/forum1/thalassemia2/picture/thalassemia.jpg
http://home.kku.ac.th/acamed/kanchana/p7.jpg
http://www.microscopyu.com/galleries/pathology/images/sicklecell/sicklecellanemia40x02small.jpg
http://www.irondisorders.org/News/SickleCell.jpg
Example
Metabolic: Cystic fibrosis, Phenylketonuria, Hemochromatosis, Glycogen storage disease, Galactosemia, HomocystinuriaHematopoietic: Thalassemia, Sickle cell diseaseEndocrine: Congenital adrenal hyperplasiaNervous: Friedreich ataxia
X-linked Dominant
Rare, and difficult to distinguish from AD except that affected males have normal sons, but all daughters are affected
Example : X-linked hypophosphatemic rickets, Rett syndrome
http://www.uic.edu/classes/bms/bms655/gfx/pedigree5.gif
http://www.uic.edu/classes/bms/bms655/lesson7.html#RECESSIVE
X-linked Recessive
Many more males than females show the recessive phenotypeThe disease is transmitted by a carrier female, who is usually asymptomaticIf a mother is a carrier, her son have a 50% chance of being affected and her daughters a 50% chance of being carriersAn affected male will usually have no affected offspring, but all his daughters will be carriers and, in turn, 50% of their sons will be affectedNo sons of the affected male will inherit the gene (there is no male-to-male transmission)
Females do not tend to show X-linked recessive disease. However, woman can be affected in the following condition :
If she is the daughter of an affected male (XdY) and a carrier female (XdX)If there is X chromosome-autosome translocationIf 45,X (Turner syndrome) is presentIf greater proportion of normal X chromosomes are inactivated
http://www.neurologyarticles.com/sitebuilder/images/Scan10106-176x315.jpg
Gower’s sign
http://medicalimages.allrefer.com/large/x-linked-recessive-genetic-defects.jpg
Duchenne muscular dystrophy
Example
Musculoskeletal: Duchenne muscular dystrophy, Becker muscular dystrophyBlood: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, Hemophilia A and BMetabolic: Diabetes insipidus, Lesch-Nyhan syndromeNervous: Fragile-X syndromeImmune: Agammaglobulinemia
Y-linked (Holandic)
http://cas.bellarmine.edu/tietjen/HumanBioogy/Finished%20Images/gen17.gifhttp://cas.bellarmine.edu/tietjen/HumanBioogy/bills_developmental_abnormalities.htm
II. Chromosomal Abnormalities
TerminologyIntroductionNumerical Chromosome abn.Structural chromosome abn.Chromosome instability synd.
http://images.wikio.com/images/p/51ca/the-world-s-worst-genetic-mutation-in-a-dog.jpg
TerminologyKaryotype = the chromosome constitution of an individual, normal human karyotype is 46,XY (male) and 46,XX (female)Polyploidy = the number of hapoloid chromosome sets is greater than two (2n), triploidy, tetraploidyAneuploidy = chromosome number is not an exact multiple of haploid number, monosomies, trisomiesTrisomy = three representatives of a given chromosome, trisomy 21 in Down dyndromeMonosomy = one member of a chromosome pair is missing, Turner syndrome (45,X)Translocation = the transfer of one segment of a chromosome to another
http://www.asklenore.info/miscarriage/bick/images/fig3.jpg
http://www.ucl.ac.uk/~ucbhjow/bmsi/lec7_images/47_xx_21.gif
http://www.myoops.org/cocw/tufts/courses/20/content/D293242/C293223.jpg
http://www.nature.com/onc/journal/v24/n33/images/1208711f1.jpg
Spectral Karyotyping (SKY) Analysis
IntroductionMaybe numerical or structuralNomenclatureNumerical disorders : [47, XY,+21],
[45,X]Structural disorders :
[46,XY,t(14;21)(q11,p10)], [46,XY,dup(5) (q20-q30)], [46,XY,del(15)(q11-q13)], (break point, margin, or region)
Numerical Chromosome Abnormalities
Concern : Extra single chromosome, Missing single chromosome, Extra haploid sets
MechanismsPolyploidyTrisomiesMonosomies
Polyploidy
Fertilization by two spermA diploid sperm due to failure in meiosisA diploid ovum due to failure in meiosis
TrisomiesFailure of separation (nondisjunction) of homologous chromosomes at meiosis I Failure of separation of chromatids in meiosis IIAdvancing maternal age is associated with increased incidence of trisomy
Monosomies
Result from nondisjunctionFrom “anaphase lag” = delay in movement of one chromosome to reach the pole of the cell before the nuclear membrane reforms during anaphase
http://www.anselm.edu/homepage/jpitocch/genbio/nondisjunction.JPG
ExamplesAutosomal disorders :
Trisomy 21 (Down syndrome)Trisomy 18 (Edwards syndrome)Trisomy 13 (Patau syndrome)
Sex chromosome disorders : Klinefelter syndrome (47,XXY)Turner syndrome (45,X)
XXX = female with an extra X chromosomeXYY = male with an extra Y chromosomeXX male = Y sequences are transferred to the X chromosome, look like male with Klinefelter syndrome
http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=108200&screenWidth=1280&screenHeight=800
Down’s syndrome
CVS : Endocardial cushion defect (Atrioventricular septal defect) most commonGI : increase risk of Hirschprung’s diseases(intestinal stenosis)Down’s syndrome faciesSimian creaseGap between 1st and 2nd toes
http://upload.wikimedia.org/wikipedia/commons/c/c3/Trisomy21_graph.jpg
http://cas.bellarmine.edu/tietjen/HumanBioogy/Finished%20Images/gen30.gif
Trisomy-13Patau syndromeTrisomy DPolydactyly, CL/CP
http://cas.bellarmine.edu/tietjen/HumanBioogy/bills_developmental_abnormalities.htm
Trisomy -18Edwards syndromeTrisomy E
http://cas.bellarmine.edu/tietjen/HumanBioogy/bills_developmental_abnormalities.htm
http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=109400&screenWidth=1280&screenHeight=800
http://cas.bellarmine.edu/tietjen/HumanBioogy/bills_developmental_abnormalities.htm
http://www.biology.iupui.edu/biocourses/n100/images/XYYMale.gif
http://modculture.typepad.com/photos/uncategorized/2007/03/14/xyy.jpg
The XYY Man is Spider Scott (Stephen Yardley), a burglar with an extra "Y" chromosome - which makes him predisposed towards crime. So when he's tapped up fresh out of prison by British intelligence to do a big job for a big price, he goes for it - which leads to a chain of events that threaten his life - and indeed other people's lives.It's one of those 70s plots that involves various secret agents from several different countries - South Africa, Rhodesia (it still existed) and China in particular.
Structural Chromosome Abnormalities
Result from breakage and limitations of DNA repair systems
MechanismsTranslocationInversionDuplicationDeletion and ring chromosomeIsochromosome
http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=107050&screenWidth=1280&screenHeight=800
http://www.nature.com/ejhg/journal/v11/n10/images/5201047f1.jpg
ExamplesPrader-Willi syndrome and Angelman syndrome : deletion on 15q11-13
Prader-Willi : inheritance of the deletion from the fatherAngelman : inheritance of the deletion from the mother
Cri du chat syndrome (cat-like cry) : Deletion of the region on 5p15.2 or the whole short arm of chromosome 5
http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=112800&screenWidth=1280&screenHeight=800
http://atlasgeneticsoncology.org/Deep/Images/GenomImprintFig6.jpghttp://www.blackwellpublishing.com/korfgenetics/jpg/300_96dpi/Fig6-30.jpg
ExamplesPrader-Willi syndrome and Angelman syndrome : deletion on 15q11-13
Prader-Willi : inheritance of the deletion from the fatherAngelman : inheritance of the deletion from the mother
Cri du chat syndrome (cat-like cry) : Deletion of the region on 5p15.2 or the whole short arm of chromosome 5
http://cas.bellarmine.edu/tietjen/HumanBioogy/Finished%20Images/gen30.gif
mental retardation, low birth weight, low set ears, cat-like cry
III. Multifactorial Disorders
TerminologyMultifactorial disordersThreshold model of multifactorial disordersExamples of multifactorial disorders
Terminology
Polygenic inheritance : the inheritance of traits that are influenced by many genes at different loci
Multifactorial disorder : disorder in which both environmental and genetic factors are important
Multifactorial Inheritance
Normal human characteristics : Blood pressure, height, finger ridges, and intelligence
Congenital malformations : neural tube defects, cleft lip and palate, and congenital heart disease
Common disorders of adult life : DM, Hypertension, peptic ulcer, and schizophrenia
Heritability and Environmental factors
Heritability : percentage denoting that the genetic contribution of a given disease
If heritability is high, there is a high correlation in relatives
Environmental factors : can be manipulated to reduce an individual’s susceptibility below than the threshold
Threshold model for Multifactorial disorders
http://www.uic.edu/classes/bms/bms655/gfx/figure18.gif(Tendency)
Example
Diabetes mellitus, type I (Insulin-dependent)Essential hypertension (62% heritability)Atherosclerosis (65% heritability)Peptic ulcer (37% heritability)Schizophrenia (85% heritability)Asthma (80% heritability)Alzheimer disease
The age of expression of the major types of genetic disease
Clinical genetics
Genetic testingPrenatal diagnosis, newborn screeningGenetic counseling / ethicsGene therapy
Genetic Testing for Carrier Detection
To identify asymptomatic heterozygotes for AR traits, or AD disorders that have limited penetrance or late onset
Confined to small ethnic populations in which there is an anomalously high incidence of a particular disease
Examples : Thalassemia, Cystic fibrosis, ADPKD, Cascade screening
Prenatal diagnosis
To assure of having unaffected children when the risk of having an affected child is unacceptably high
NOT equivalent to the assurance of having normal children, It does not address all possible birth defects
Noninvasive techniques : ultrasonography, maternal serum screening
Invasive technique : amniocentesis, chorionic villus sampling, cordocentesis
DNA analysis (PCR, Southern blot), Cytogenetic analysis
http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/1062.jpg
http://www.pennhealth.com/health_info/pregnancy/graphics/images/en/19177.jpghttp://www.pennhealth.com/health_info/pregnancy/graphics/images/en/19175.jpg
Cordocentesis
http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/19163.jpghttp://www.pennhealth.com/health_info/pregnancy/graphics/images/en/19166.jpg
Chorionic villi sampling
Newborn screening
To identify treatable genetic disorders such as phenylketonuria, galactosemia, maple syrup urine disease, and congenital adrenal hyperplasia in newborn infants
Dietary management is usually an early intervention to eliminate clinical symptoms that would otherwise lead to severe disability, mental impairment, or dealth
Prevalence, severity of a condition, availability, effectiveness of a treatment, and cost will determine which disorder will be screened
http://www.health.state.mn.us/divs/fh/mcshn/ncfu/images/pkupath.gif
http://www.qctimes.com/content/articles/2005/07/22/features/health/doc42e079564f5f3070410001_thumb.jpg
Inborn error of metabolism- PKU, galactosemia
Hormonal abnormality- congenital hypothyroidism- congenital adrenal hyperplasia
Genetic Counseling / Ethics
Indications for genetic counselingInformation conveyed in genetic counselingThe process of genetic counseling
http://www.gen.vcu.edu/images/counseling.jpg
Indications for Genetic Counseling
Known or suspected hereditary disease in a patient or familyBirth defectsMental retardationAdvanced maternal ageFamily history of early onset cancerRecurrent pregnancy lossTeratogen exposureConsanguinity
Information Conveyed in Genetic Counseling
The magnitude of the risk of occurrence or recurrence
The impact of the disease on the patient and the family
The possibility of modification of either the impact or the risk
Anticipated future development
The process of genetic counseling
Establishing the diagnosis (most important)
Presenting the risk in context
Discussing options, communication, and support
Other considerations
Ethical Considerations in Genetic Counseling
Consanguinity and incestDisputed paternityConfidentiality and conflicts of interestRespect for AutonomyBeneficence and Nonmaleficence (do no harm)Privacy and confidentialityJustice and Equity
Examples of ethical issues
The mating of the first-degree relativesTesting for identification of biologic fatherPrenatal diagnosis for determination of fetal sex, or congenital birth defectsHigh risk experimental therapy in a gravely ill infantLoss of health insurance, or job because of a genetic predisposition
Gene therapyThe treatment of a disease by addition, insertion, or replacement of a normal gene or genes
Two possible strategies :Germ-line gene therapySomatic cell therapy
Requirements :The gene involved should be cloned and characterizedThe specific tissue to be targeted should be accessible and identifiedA safe and efficient vector system for the gene should be definedThe scientific rationale for the gene therapy approach should besound and the perceived risks commensurate with the potential benefits
Germ-line Gene Therapy
Genetic changes would be introduced into every cell type, including the germ line
Can be passed from generation to generation
Considered unethical
Somatic Cell Gene Therapy
The genetic modifications are targeted specifically to the diseased tissue
Germ cells would continue to carry the mutant forms of the disease gene
http://fig.cox.miami.edu/Faculty/Dana/germinalsomatic.jpg
Gene therapyThe treatment of a disease by addition, insertion, or replacement of a normal gene or genes
Two possible strategies :Germ-line gene therapySomatic cell therapy
Requirements :The gene involved should be cloned and characterizedThe specific tissue to be targeted should be accessible and identifiedA safe and efficient vector system for the gene should be definedThe scientific rationale for the gene therapy approach should besound and the perceived risks commensurate with the potential benefits
http://openlearn.open.ac.uk/file.php/2430/SK195_5_001i.jpg
Vector system
The vector system is the means by which DNA is delivered to the target cells
Two main types of vector systemPhysical (nonviral) vector systems : LiposomesViral vectors
Integrate into the genome : retroviral, lentiviral, adeno-associated virus (AAV)Maintained as an episome : adenovirus
http://www.acceleratingfuture.com/michael/blog/images/Gene_therapy.jpg
http://openlearn.open.ac.uk/file.php/2430/SK195_5_002i.jpg
Therapeutic strategies
Selecting which genes to transfer and into what types of target cells
Two general approaches to deliver gene therapy vector to the patient
Ex vivo gene therapyIn vivo gene therapy
The most obvious and direct strategy is the treatment of a recessive genetic deficiency with the replacement of the missing DNA sequence
http://www.biochem.arizona.edu/classes/bioc471/pages/Lecture25/Lecture25.html
http://www.biochem.arizona.edu/classes/bioc471/pages/Lecture25/Lecture25.html
Diseases which can potentially be treated by gene therapy
Disorder Defect
Hypercholesterolemia LDL receptor abnormalities
Hemophilia Factor VIII (A), Factor IX (B) deficiency
Emphysema Alpha-1 antitrypsin deficiency
Cystic fibrosis CTFR mutations
Phenylketonuria Phenylalanine hydroxylase deficiency
Muscular dystrophy Dystrophin mutations
Thalassemia Alpha- and beta- globin gene mutations
Cancer Protooncogene and tumor suppressor gene mutations
Referencesคัมภิรานนท, อมรา., “พันธุศาสตรมนุษย (Human Genetics), พิมพครั้งที่ 2.” เท็กซ แอนด เจอรนัล พับลิเคชั่น, กรุงเทพมหานคร, 2546.บุญแสง, วิชัย., และคณะ., “ลายพิมพดีเอ็นเอ..จากสารพันธุกรรมสูเทคโนโลยีพิสูจนบุคคล, พิมพครั้งที่ 2.” สํานักงานพัฒนาวิทยาศาสตร และเทคโนโลยีแหงชาติ, ปทุมธานี, 2545.Gelehrter, T.D., Collins, F.S., Ginsburg, D., “Principles of Medical Genetics, 2nd edition.”Williams & Wilkins, Maryland, 1998.Lamb, N.E., “Crash course : Cell Biology and Genetics.” Mosby-Elsevier, Inc., Philadelphia, 2007.Kumar, V., et al., “Robbins and Cotran Pathologic Basis of Disease, 7th edition.” Elsevier Inc., Philadelphia, 2005.Rimoin, D. L., editors, et al., “Emery and Rimoin’s Principles and Practice of Medical Genetics, 4th edition.” Churchill Livingstone, London, 2002, volume 1.