Genes and Genetic Diseases Chapter 4 Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.

Genes and Genetic DiseasesGenes and Genetic Diseases

Chapter 4Chapter 4

Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.

2Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.

DefinitionsDefinitions

Genetics—the study of biologic heredityGenetics—the study of biologic heredity Gene—basic unit of heredityGene—basic unit of heredity

Genomics—the field of genetics concerned Genomics—the field of genetics concerned with the structural and functional studies of with the structural and functional studies of the genomethe genome Genome—DNA representing all of the genes for Genome—DNA representing all of the genes for

a given speciesa given species


DNADNA Pentose sugar (deoxyribose)Pentose sugar (deoxyribose) Phosphate molecule Phosphate molecule Four nitrogenous basesFour nitrogenous bases

Pyrimidines: cytosine and thyminePyrimidines: cytosine and thymine Purines: adenine and guaninePurines: adenine and guanine


Nitrogenous BasesNitrogenous Bases Nucleoproteins created from amino acidsNucleoproteins created from amino acids PurinesPurines

Adenine and guanineAdenine and guanine Double-ring structuresDouble-ring structures

PyrimidinesPyrimidines Cytosine and thymineCytosine and thymine Single-ring structuresSingle-ring structures


DNA StructureDNA Structure

Anti-parallel structureAnti-parallel structure Nucleotide pairingsNucleotide pairings

Adenine with thymineAdenine with thymine• 2 hydrogen bonds2 hydrogen bonds

Cytosine with guanineCytosine with guanine• 3 hydrogen bonds3 hydrogen bonds


DNA OrganizationDNA Organization

ChromosomeChromosome Temporary but consistent state of DNATemporary but consistent state of DNA Composed of two longitudinal sister chromatidsComposed of two longitudinal sister chromatids 1/10,000 as long as outstretched DNA1/10,000 as long as outstretched DNA

• 7.2 x 107.2 x 10-3-3 inches inches


DNA StructureDNA Structure

3 billion DNA base pairs per human cell3 billion DNA base pairs per human cell On average, humans vary on 3 million base pairsOn average, humans vary on 3 million base pairs

Human genome contains 20,000 to 25,000 Human genome contains 20,000 to 25,000 genesgenes


ProteinsProteins One or more polypeptidesOne or more polypeptides Composed of amino acidsComposed of amino acids

20 amino acids20 amino acids Directed by sequence of bases (codons)Directed by sequence of bases (codons)


DNA ReplicationDNA Replication Untwisting and unzipping of the DNA strandUntwisting and unzipping of the DNA strand

Single strand acts as a templateSingle strand acts as a template Complementary base pairing by DNA Complementary base pairing by DNA

polymerasepolymerase Adenine-thymine; cytosine-guanineAdenine-thymine; cytosine-guanine


TranscriptionTranscription RNA is synthesized from the DNA template RNA is synthesized from the DNA template

via RNA polymerasevia RNA polymerase Results in the formation of mRNAResults in the formation of mRNA mRNA moves out of the nucleus and into mRNA moves out of the nucleus and into

the cytoplasmthe cytoplasm Gene splicingGene splicing

Introns, extronsIntrons, extrons


TranscriptionTranscription


TranslationTranslation Process by which RNA directs the synthesis of Process by which RNA directs the synthesis of

a polypeptide via interaction with transfer RNAa polypeptide via interaction with transfer RNA Site of protein synthesis is the ribosomeSite of protein synthesis is the ribosome tRNA contains a sequence of nucleotides tRNA contains a sequence of nucleotides

(anticodon) complementary to the triad of (anticodon) complementary to the triad of nucleotides on the mRNA strand (codon)nucleotides on the mRNA strand (codon)

The ribosome moves along the mRNA The ribosome moves along the mRNA sequence to translate the amino acid sequence to translate the amino acid sequencesequence


TranslationTranslation


ChromosomesChromosomes Somatic cellsSomatic cells

Contain 46 chromosomes (23 pairs)Contain 46 chromosomes (23 pairs) Diploid cellsDiploid cells

GametesGametes Contain 23 chromosomesContain 23 chromosomes Haploid cells Haploid cells

• One member of each chromosome pairOne member of each chromosome pair MeiosisMeiosis

Formation of haploid cells from diploid cellsFormation of haploid cells from diploid cells


Chromosome StructureChromosome Structure

Short armShort arm ““p”—petitp”—petit

Long armLong arm ““q”q”

CentromereCentromere RegionRegion of attachment of sister chromatidsof attachment of sister chromatids

TelomereTelomere Region containing multiple base pairsRegion containing multiple base pairs Shorten with each cell divisionShorten with each cell division


ChromosomesChromosomes

Diploid (2n) number in humans is 46Diploid (2n) number in humans is 46 Somatic cells contain the diploid number of Somatic cells contain the diploid number of

chromosomes (retained during mitosis)chromosomes (retained during mitosis) Gametes contain the haploid number of Gametes contain the haploid number of

chromosomes (occurs through meiosis)chromosomes (occurs through meiosis)


ChromosomesChromosomes AutosomesAutosomes

The first 22 of the 23 pairs of chromosomes in The first 22 of the 23 pairs of chromosomes in males and femalesmales and females

The two members are virtually identical and thus The two members are virtually identical and thus said to be homologoussaid to be homologous

Sex chromosomesSex chromosomes Remaining pair of chromosomesRemaining pair of chromosomes In females, it is a homologous pair (XX)In females, it is a homologous pair (XX) In males, it is a nonhomologous pair (XY)In males, it is a nonhomologous pair (XY)


KaryotypeKaryotype Ordered display of chromosomesOrdered display of chromosomes


MutationMutation

Any inherited alteration of genetic materialAny inherited alteration of genetic material Chromosome aberrationsChromosome aberrations Base pair substitutionBase pair substitution

• One base pair is substituted for another; may result in change One base pair is substituted for another; may result in change in amino acid sequencein amino acid sequence

• Silent substitutionSilent substitution Does not result in an amino acid changeDoes not result in an amino acid change RNA codons GUU, GUC, GUA, GUG all code for the amino acid RNA codons GUU, GUC, GUA, GUG all code for the amino acid

valinevaline


MutationsMutations

Mutations in somatic cells are not Mutations in somatic cells are not transmitted to offspringtransmitted to offspring

Mutations in gametes are transmitted to Mutations in gametes are transmitted to offspringoffspring

Point mutationPoint mutation A single nucleotide base-pair change in DNAA single nucleotide base-pair change in DNA

Rates of spontaneous mutationRates of spontaneous mutation Varies per geneVaries per gene 1010-4-4 to 10 to 10-7-7 per gene per generation per gene per generation


MutagenMutagen Agent known to increase the frequency of Agent known to increase the frequency of

mutationsmutations RadiationRadiation ChemicalsChemicals


Silent MutationSilent Mutation

A DNA sequence change that does not A DNA sequence change that does not change the amino acid sequence of a change the amino acid sequence of a genegene


Missense MutationMissense Mutation

A type of mutation that results in a single A type of mutation that results in a single amino acid change in the translated gene amino acid change in the translated gene productproduct


Nonsense MutationNonsense Mutation

A type of mutation in which an mRNA stop A type of mutation in which an mRNA stop codon is:codon is: Produced, resulting in premature termination of Produced, resulting in premature termination of

the protein sequence the protein sequence oror Removed, resulting in an elongated protein Removed, resulting in an elongated protein

sequencesequence


Nonsense MutationNonsense Mutation Premature termination of the protein Premature termination of the protein

sequencesequence

Elongation of the protein sequenceElongation of the protein sequence

THE FAT CAT ATE THE RATTHE FAT CAT ATE THE RAT

THE FAT CAT ATETHE FAT CAT ATE

THE FAT CAT ATE THE RATTHE FAT CAT ATE THE RAT

THE FAT CAT ATE THE RAT AND THE HAT AND THE MATTHE FAT CAT ATE THE RAT AND THE HAT AND THE MAT


Frameshift MutationFrameshift Mutation

An alteration of DNA in which an addition An alteration of DNA in which an addition or deletion of a base pair occursor deletion of a base pair occurs

Results in a change in the entire “reading Results in a change in the entire “reading frame” frame”


Consequences of MutationsConsequences of Mutations

Gain of function Gain of function Associated with Associated with

dominant disordersdominant disorders Production of new Production of new

protein productprotein product Overexpression of a Overexpression of a

protein productprotein product Inappropriate Inappropriate

expression of a expression of a protein productprotein product

Loss of functionLoss of function Associated with Associated with

recessive disordersrecessive disorders Loss of 50% of the Loss of 50% of the

protein productprotein product• May or may not be May or may not be

adequate for normal adequate for normal functionfunction


Chromosome AbnormalitiesChromosome Abnormalities Euploid cellsEuploid cells

Cells that have a multiple of the normal number Cells that have a multiple of the normal number of chromosomes of chromosomes

Haploid and diploid cells are euploid forms Haploid and diploid cells are euploid forms When a euploid cell has more than the When a euploid cell has more than the

diploid number, it is called a polyploid cell diploid number, it is called a polyploid cell Triploidy: a zygote having three copies of each Triploidy: a zygote having three copies of each

chromosome (69)chromosome (69) Tetraploidy: four copies of each (92 total)Tetraploidy: four copies of each (92 total)

Triploid and tetraploid fetuses don’t surviveTriploid and tetraploid fetuses don’t survive


Chromosome AbnormalitiesChromosome Abnormalities Disjunction Disjunction

Normal separation of chromosomes during cell Normal separation of chromosomes during cell division division

NondisjunctionNondisjunction Usually the cause of aneuploidyUsually the cause of aneuploidy Failure of homologous chromosomes or sister Failure of homologous chromosomes or sister

chromatids to separate normally during meiosis chromatids to separate normally during meiosis or mitosisor mitosis


NondisjunctionNondisjunction


Chromosome AbnormalitiesChromosome Abnormalities AneuploidyAneuploidy

A somatic cell that does not contain a multiple of A somatic cell that does not contain a multiple of 23 chromosomes23 chromosomes

A cell containing three copies of one A cell containing three copies of one chromosome is trisomic (trisomychromosome is trisomic (trisomy))

Monosomy is the presence of only one copy of Monosomy is the presence of only one copy of any chromosomeany chromosome

Monosomy is often fatal, but infants can survive Monosomy is often fatal, but infants can survive with trisomy of certain chromosomes with trisomy of certain chromosomes • ““It is better to have extra than less”It is better to have extra than less”


Chromosomal DisordersChromosomal Disorders

Leading cause of mental retardation and Leading cause of mental retardation and miscarriagemiscarriage

Incidence of chromosomal abnormalitiesIncidence of chromosomal abnormalities 1/12 conceptions1/12 conceptions Approximately 95% of conceptions with Approximately 95% of conceptions with

chromosome disorders result in miscarriagechromosome disorders result in miscarriage 50% of first-trimester miscarriages associated with a 50% of first-trimester miscarriages associated with a

major chromosomal abnormalitymajor chromosomal abnormality 1/150 live births with a major diagnosable 1/150 live births with a major diagnosable

chromosomal abnormalitychromosomal abnormality


Autosomal AneuploidyAutosomal Aneuploidy

Down syndromeDown syndrome Best-known example of aneuploidyBest-known example of aneuploidy

• Trisomy 21 (47, XX or 47, XY karyotype)Trisomy 21 (47, XX or 47, XY karyotype)

1:800 live births1:800 live births Mentally retarded, low nasal bridge, epicanthal Mentally retarded, low nasal bridge, epicanthal

folds, protruding tongue, poor muscle tonefolds, protruding tongue, poor muscle tone Risk increases with maternal ageRisk increases with maternal age Increased risk of congenital heart disease, Increased risk of congenital heart disease,

gastrointestinal disease, and leukemiagastrointestinal disease, and leukemia


Down SyndromeDown Syndrome


Other Autosomal AneuploidiesOther Autosomal Aneuploidies

Trisomy 13 and 18Trisomy 13 and 18 More severe clinical manifestations than trisomy More severe clinical manifestations than trisomy

2121 Death in early infancy is commonDeath in early infancy is common


Autosomal AneuploidyAutosomal Aneuploidy Partial trisomyPartial trisomy

Only an extra portion of a chromosome is Only an extra portion of a chromosome is present in each cellpresent in each cell

Chromosome mosaicsChromosome mosaics Trisomies occurring only in some cells of the Trisomies occurring only in some cells of the

body body


Sex Chromosome AneuploidySex Chromosome Aneuploidy One of the most common is trisomy X. This is One of the most common is trisomy X. This is

a female that has three X chromosomes. a female that has three X chromosomes. Termed “metafemale”Termed “metafemale”

Symptoms are variable: sterility, menstrual Symptoms are variable: sterility, menstrual irregularity, and/or mental retardationirregularity, and/or mental retardation

Symptoms worsen with each additional XSymptoms worsen with each additional X


Sex Chromosome AneuploidySex Chromosome Aneuploidy Turner syndromeTurner syndrome

Females with only one X chromosomeFemales with only one X chromosome CharacteristicsCharacteristics

• Absence of ovaries (sterile)Absence of ovaries (sterile)• Short stature (~ 4Short stature (~ 4''77""))• Webbing of the neckWebbing of the neck• EdemaEdema• Underdeveloped breasts; wide nipples Underdeveloped breasts; wide nipples • High number of aborted fetusesHigh number of aborted fetuses• X is usually inherited from motherX is usually inherited from mother


Turner SyndromeTurner Syndrome


Sex Chromosome AneuploidySex Chromosome Aneuploidy Klinefelter syndromeKlinefelter syndrome

Individuals with at least two Xs and one Y Individuals with at least two Xs and one Y chromosomechromosome

CharacteristicsCharacteristics• Male appearanceMale appearance• Develop female-like breastsDevelop female-like breasts• Small testesSmall testes• Sparse body hairSparse body hair• Long limbsLong limbs

Some individuals can be XXXY and XXXXY. Some individuals can be XXXY and XXXXY. The abnormalities will increase with each X.The abnormalities will increase with each X.


Klinefelter SyndromeKlinefelter Syndrome


Alterations in Chromosome Alterations in Chromosome StructureStructure

DeletionDeletion Loss of a sequence of DNA from a chromosomeLoss of a sequence of DNA from a chromosome

InversionInversion Chromosomal rearrangement in which a segment of a Chromosomal rearrangement in which a segment of a

chromosome is reversed end to endchromosome is reversed end to end



TranslocationTranslocation Transfer of one chromosome segment to anotherTransfer of one chromosome segment to another

Ring chromosomeRing chromosome Structurally abnormal chromosome in which the Structurally abnormal chromosome in which the

telomere of each chromosome arm has been telomere of each chromosome arm has been deleted and the broken arms have joineddeleted and the broken arms have joined



Chromosome breakageChromosome breakage If a chromosome break does occur, physiologic If a chromosome break does occur, physiologic

mechanisms usually repair the break, but the mechanisms usually repair the break, but the breaks often heal in a way that alters the structure breaks often heal in a way that alters the structure of the chromosomeof the chromosome

Agents of chromosome breakageAgents of chromosome breakage• Ionizing radiation, chemicals, and virusesIonizing radiation, chemicals, and viruses



Breakage or loss of DNABreakage or loss of DNA Cri du chat syndromeCri du chat syndrome

““Cry of the cat”Cry of the cat” Deletion of short arm of chromosome 5 (5p-)Deletion of short arm of chromosome 5 (5p-) Low birth weight, metal retardation, and Low birth weight, metal retardation, and

microcephalymicrocephaly



Infant with cri du Infant with cri du chat (5p deletion) chat (5p deletion) syndromesyndrome



DuplicationDuplication A repeated gene or gene sequenceA repeated gene or gene sequence Rare occurrenceRare occurrence Less serious consequences because better to Less serious consequences because better to

have more genetic material than less (deletion)have more genetic material than less (deletion) Duplication in the same region as cri du chat Duplication in the same region as cri du chat

causes mental retardation but no physical causes mental retardation but no physical abnormalitiesabnormalities



InversionsInversions Two breaks on a chromosomeTwo breaks on a chromosome Reversal of the gene orderReversal of the gene order Usually occurs from a breakage that gets reversed Usually occurs from a breakage that gets reversed

during reattachmentduring reattachment• ABCDEFG may become ABABCDEFG may become ABEDCEDCFGFG



TranslocationsTranslocations The interchanging of material between The interchanging of material between

nonhomologous chromosomes nonhomologous chromosomes Translocation occurs when two chromosomes Translocation occurs when two chromosomes

break and the segments are rejoined in an break and the segments are rejoined in an abnormal arrangementabnormal arrangement



Fragile sitesFragile sites Fragile sites are areas on chromosomes that Fragile sites are areas on chromosomes that

develop distinctive breaks or gaps when cells are develop distinctive breaks or gaps when cells are culturedcultured

No apparent relationship to diseaseNo apparent relationship to disease



Fragile X syndromeFragile X syndrome Site on the long arm of the X chromosomeSite on the long arm of the X chromosome Associated with mental retardation; second in Associated with mental retardation; second in

occurrence to Down syndromeoccurrence to Down syndrome Higher incidence in males because they have only Higher incidence in males because they have only

one X chromosomeone X chromosome


GeneticsGenetics Gregor MendelGregor Mendel

Austrian monkAustrian monk Garden pea experimentsGarden pea experiments Mendelian traitsMendelian traits


GenesGenes

Basic units of heredityBasic units of heredity Sequences of chromosomal DNA coding for Sequences of chromosomal DNA coding for

the production of a functional productthe production of a functional product Templates for mRNA that code for specific Templates for mRNA that code for specific

proteinsproteins All genes are contained in each cell of the All genes are contained in each cell of the

bodybody


GenesGenes

Locus: location occupied by a gene on a Locus: location occupied by a gene on a chromosomechromosome

Allele: alternate version of a gene at a locusAllele: alternate version of a gene at a locus Each individual possesses two alleles for each Each individual possesses two alleles for each

genegene Homozygous: possessing identical alleles of a Homozygous: possessing identical alleles of a

given genegiven gene Heterozygous: possessing two different alleles of Heterozygous: possessing two different alleles of

a given genea given gene PolymorphismPolymorphism

Locus that has two or more alleles that occur with Locus that has two or more alleles that occur with appreciable frequencyappreciable frequency


GeneticsGenetics

HomozygousHomozygous Loci on a pair of chromosomes have identical allelesLoci on a pair of chromosomes have identical alleles ExampleExample

• O blood type (OO)O blood type (OO)

HeterozygousHeterozygous Loci on a pair of chromosomes have different allelesLoci on a pair of chromosomes have different alleles Example Example

• AB blood type (A and B alleles on pair of loci)AB blood type (A and B alleles on pair of loci)


GeneticsGenetics Genotype (“what they have”)Genotype (“what they have”)

The genetic makeup of an organismThe genetic makeup of an organism Phenotype (“what they demonstrate”)Phenotype (“what they demonstrate”)

The observable, detectable, or outward appearance The observable, detectable, or outward appearance of the genetics of an organismof the genetics of an organism

Example Example A person with the A blood type could be AA or AO. A person with the A blood type could be AA or AO.

A is the phenotype; AA or AO is the genotype.A is the phenotype; AA or AO is the genotype.


GeneticsGenetics

If two alleles are found together, the allele that If two alleles are found together, the allele that is observable is dominant, and the one whose is observable is dominant, and the one whose effects are hidden is recessiveeffects are hidden is recessive

In genetics, the dominant allele is represented In genetics, the dominant allele is represented by a capital letter, and the recessive by a by a capital letter, and the recessive by a lowercase letterlowercase letter

Alleles can be codominantAlleles can be codominant


GeneticsGenetics

CarrierCarrier A carrier is one that has a disease gene but is A carrier is one that has a disease gene but is

phenotypically normalphenotypically normal For a person to demonstrate a recessive disease, For a person to demonstrate a recessive disease,

the pair of recessive genes must be inheritedthe pair of recessive genes must be inherited ExampleExample

• Ss = sickle cell anemia carrierSs = sickle cell anemia carrier

• ss = demonstrates sickle cell diseasess = demonstrates sickle cell disease


PedigreesPedigrees

Used to study specific genetic disorders within Used to study specific genetic disorders within familiesfamilies

Begins with the probandBegins with the proband


PedigreesPedigrees


Single-Gene DisordersSingle-Gene Disorders

Recurrence riskRecurrence risk The probability that parents of a child with a genetic The probability that parents of a child with a genetic

disease will have yet another child with the same disease will have yet another child with the same diseasedisease

Recurrence risk of an autosomal dominant traitRecurrence risk of an autosomal dominant trait• When one parent is affected by an autosomal dominant When one parent is affected by an autosomal dominant

disease and the other is normal, the occurrence and disease and the other is normal, the occurrence and recurrence risks for each child are one halfrecurrence risks for each child are one half



Autosomal dominant disorderAutosomal dominant disorder Abnormal allele is dominant, normal allele is Abnormal allele is dominant, normal allele is

recessive, and the genes exist on a pair of recessive, and the genes exist on a pair of autosomesautosomes


Autosomal Dominant DisordersAutosomal Dominant Disorders Characteristics of autosomal dominant Characteristics of autosomal dominant

disordersdisorders Condition is expressed equally in males and Condition is expressed equally in males and

femalesfemales Approximately half of children of an affected Approximately half of children of an affected

heterozygous individual will express the heterozygous individual will express the conditioncondition• Homozygous affected individuals are rareHomozygous affected individuals are rare

No generational skippingNo generational skipping


Gene MappingGene Mapping



Autosomal dominant traitsAutosomal dominant traits



Autosomal dominant trait pedigreeAutosomal dominant trait pedigree


PenetrancePenetrance

The percentage of individuals with a specific The percentage of individuals with a specific genotype who also express the expected genotype who also express the expected phenotypephenotype Incomplete penetranceIncomplete penetrance

• Individual who has the gene for a disease but does not Individual who has the gene for a disease but does not express the disease express the disease

• Retinoblastoma (eye tumor in children) demonstrates Retinoblastoma (eye tumor in children) demonstrates incomplete penetrance (90%)incomplete penetrance (90%)


ExpressivityExpressivity

Expressivity is the variation in a phenotype Expressivity is the variation in a phenotype associated with a particular genotypeassociated with a particular genotype

This can be caused by modifier genesThis can be caused by modifier genes Examples:Examples:

von Recklinghausen diseasevon Recklinghausen disease• Autosomal dominantAutosomal dominant

• Long arm of chromosome 17Long arm of chromosome 17

• Disease varies from dark spots on the skin to malignant Disease varies from dark spots on the skin to malignant neurofibromas, scoliosis, gliomas, neuromas, etc.neurofibromas, scoliosis, gliomas, neuromas, etc.


ExpressivityExpressivity



Autosomal recessive disorderAutosomal recessive disorder Abnormal allele is recessive and a person must be Abnormal allele is recessive and a person must be

homozygous for the abnormal trait to express the homozygous for the abnormal trait to express the diseasedisease

The trait usually appears in the children, not the The trait usually appears in the children, not the parents, and it affects the genders equally because parents, and it affects the genders equally because it is present on a pair of autosomesit is present on a pair of autosomes



Autosomal recessive disorder recurrence riskAutosomal recessive disorder recurrence risk Recurrence risk of an autosomal dominant traitRecurrence risk of an autosomal dominant trait

• When two parents are carriers of an autosomal recessive When two parents are carriers of an autosomal recessive disease, the occurrence and recurrence risks for each disease, the occurrence and recurrence risks for each child are 25%child are 25%


Autosomal Recessive DisorderAutosomal Recessive Disorder


Autosomal Recessive DisordersAutosomal Recessive Disorders

CharacteristicsCharacteristics Condition expressed equally in males and femalesCondition expressed equally in males and females Affected individuals most often the offspring of Affected individuals most often the offspring of

asymptomatic heterozygous carrier parentsasymptomatic heterozygous carrier parents• Approximately 1/4 of offspring will be affected; 1/2 will be Approximately 1/4 of offspring will be affected; 1/2 will be

asymptomatic carriers; and 1/4 will be unaffectedasymptomatic carriers; and 1/4 will be unaffected• Individuals must be homozygous for the condition to be Individuals must be homozygous for the condition to be

expressedexpressed Generational skipping may be presentGenerational skipping may be present Consanguinity may be presentConsanguinity may be present


ConsanguinityConsanguinity

Mating of two related individualsMating of two related individuals Dramatically increases the recurrence risk of Dramatically increases the recurrence risk of

recessive disordersrecessive disorders


Sex-Linked DisordersSex-Linked Disorders

Disorders involve X and Y chromosomesDisorders involve X and Y chromosomes X-linked disorders usually expressed by males X-linked disorders usually expressed by males

because females have another X chromosome to because females have another X chromosome to mask the abnormal allelemask the abnormal allele Most are recessiveMost are recessive

Y-linked disorders uncommon because Y Y-linked disorders uncommon because Y chromosome contains relatively few geneschromosome contains relatively few genes Father-son transmission presentFather-son transmission present No father-daughter transmission No father-daughter transmission


X-Linked Recessive DisordersX-Linked Recessive Disorders

CharacteristicsCharacteristics Males most commonly affectedMales most commonly affected

• Affected males cannot transmit the genes to sons, but Affected males cannot transmit the genes to sons, but they can to all daughtersthey can to all daughters

Unaffected carrier femalesUnaffected carrier females• Sons of female carriers have a 50% risk of being Sons of female carriers have a 50% risk of being

affectedaffected

Pedigree analysisPedigree analysis• Generational skipping often presentGenerational skipping often present

• No father-to-son transmissionNo father-to-son transmission



A.A. Outcomes for offspring of an Outcomes for offspring of an unaffected father and a unaffected father and a heterozygous unaffected carrier heterozygous unaffected carrier mother (most common scenario)mother (most common scenario)

B.B. Outcomes for offspring of an Outcomes for offspring of an affected father and a homozygous affected father and a homozygous unaffected motherunaffected mother

C.C. Outcomes for offspring of an Outcomes for offspring of an affected father and a heterozygous affected father and a heterozygous unaffected carrier mother unaffected carrier mother



HemophiliaHemophilia Bleeding disorders resulting from a congenital Bleeding disorders resulting from a congenital

deficiency of coagulation factorsdeficiency of coagulation factors• Hemophilia A: factor VIII deficiencyHemophilia A: factor VIII deficiency

20.6/100,000 male births in U.S.20.6/100,000 male births in U.S.

• Hemophilia B: factor IX deficiencyHemophilia B: factor IX deficiency 5.3/100,000 male births in U.S.5.3/100,000 male births in U.S.

Mutations associated with factor VIII deficiency:Mutations associated with factor VIII deficiency:• Large deletions or insertions, frameshift and splice Large deletions or insertions, frameshift and splice

junction changes, and nonsense and missense junction changes, and nonsense and missense mutationsmutations

• Mutations vary across families but tend to be similar Mutations vary across families but tend to be similar within familieswithin families


Multifactorial InheritanceMultifactorial Inheritance

Characteristics of multifactorial disordersCharacteristics of multifactorial disorders Result from hereditary and environmental Result from hereditary and environmental

factorsfactors Hereditary component is polygenicHereditary component is polygenic

• Individual involved genes follow mendelian principlesIndividual involved genes follow mendelian principles• Many genes act together to influence the expressed Many genes act together to influence the expressed

traittrait



Concordance and discordanceConcordance and discordance ConcordanceConcordance

• Expression of the disease in two related family Expression of the disease in two related family membersmembers

DiscordanceDiscordance• Expression of the disease in one family member but Expression of the disease in one family member but

not a secondnot a second



Twin studies and concordanceTwin studies and concordance Genetic conditionsGenetic conditions

• Monozygotic (MZ) twins: 100% concordanceMonozygotic (MZ) twins: 100% concordance• Dizygotic (DZ) twins: less than 100% and similar to Dizygotic (DZ) twins: less than 100% and similar to

that among other siblingsthat among other siblings Environmental conditionsEnvironmental conditions

• Equal concordance rates among MZ and DZ twinsEqual concordance rates among MZ and DZ twins Multifactorial conditionsMultifactorial conditions

• MZ twins with greater concordance than DZ twins, but MZ twins with greater concordance than DZ twins, but rates are not 100%rates are not 100%

Adoption studiesAdoption studies Gene-environment-lifestyle interactionGene-environment-lifestyle interaction

Genes and Genetic Diseases Chapter 4 Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.

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