Fundamentals of human genetics. Human hereditary diseases. Methods of research of human heredity
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Transcript of Fundamentals of human genetics. Human hereditary diseases. Methods of research of human heredity
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Fundamentals of human genetics. Human hereditary
diseases. Methods of research of human heredity
Ass. Nedoshytko Khrystyna
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Genetic Terminology Genetic Terminology GenotypeGenotype- the alleles a - the alleles a person hasperson has
PhenotypePhenotype- the - the observable trait a person observable trait a person hashas
DominantDominant- Alleles affect - Alleles affect masks the other allele it masks the other allele it is paired withis paired with
RecessiveRecessive- Alleles affect - Alleles affect is masked by the other is masked by the other allele it is paired with.allele it is paired with.
HomozygousHomozygous- Pair of - Pair of alleles for a trait are alleles for a trait are identicalidenticalHeterozygousHeterozygous- Pair of - Pair of alleles for a trait are not alleles for a trait are not identicalidenticalHybridHybrid- Inherit non-- Inherit non-identical alleles for a traitidentical alleles for a trait
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A pair of homologous chromosomes, each in the unduplicated state (most often, one from a male parent and its partner from a female parent)
A gene locus (plural, loci), the location for a specific gene on a specific type of chromosome
A pair of alleles (each being a certain molecular form of a gene) at corresponding loci on a pair of homologous chromosomes
Three pairs of genes (at three loci on this pair of homologous chromosomes); same thing as three pairs of alleles
VISUAL REPRESENTATION
Pair of Chromosomes
Gene
Locus (loci)
Alleles
Heterozygous
Homozygous
Heterozygous
Homozygous
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Homologous ChromosomesHomologous ChromosomesHomologous Homologous autosomesautosomes are identical are identical in length, size, shape, and gene in length, size, shape, and gene sequencesequence
Sex chromosomes areSex chromosomes are nonidentical but nonidentical but still homologousstill homologous
Homologous chromosomes interact, Homologous chromosomes interact, then segregate from one another then segregate from one another during meiosisduring meiosis
DNA and proteinsarranged as cylindrical fiber
DNA
HistoneNucleosome
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Human KaryotypeHuman Karyotype
1 2 3 4 5 6 7 8 9 10 11 12
13 14 15 16 17 18 19 20 21 22 XX (or XY)
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Karyotype PreparationKaryotype PreparationCultured cells Cultured cells for 3 to 4 days in thefor 3 to 4 days in the presence ofpresence of phytohaemagglutininphytohaemagglutinin (mitogen)(mitogen) and and arrested at metaphasearrested at metaphase– This is when cells are most condensed and This is when cells are most condensed and
easiest to identify Arrested cells are broken easiest to identify Arrested cells are broken openopen
Metaphase chromosomes are fixed and Metaphase chromosomes are fixed and stained stained (how many copies of each chromosome (how many copies of each chromosome
in one cell?)in one cell?)
Chromosomes are photographed through Chromosomes are photographed through microscopemicroscope
Photograph of chromosomes is cut up and Photograph of chromosomes is cut up and arranged to form a karyotype diagramarranged to form a karyotype diagram
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Carrion Beetle(Phosphuga atrata)
Cotton Rat (Sigmodon hipsidus)
Pied Kingfisher (Ceryle rudis)
Karyotypes•The Alaskan king crab has 208 chromosomes.
•The fruit fly has 4.
•Number has nothing to do with complexity of the organism
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Prenatal DiagnosisPrenatal Diagnosis
Amniocentesis (1-2%)Amniocentesis (1-2%)– Amniotic fluid removedAmniotic fluid removed
Chorionic villus sampling (0.3%)Chorionic villus sampling (0.3%)– Cells from the chorion (surrounds Cells from the chorion (surrounds
ammnion)ammnion)
Fetoscopy (2-10%)Fetoscopy (2-10%)– Direct visualization, removal of blood Direct visualization, removal of blood
from umbilical veinfrom umbilical vein
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www.visembryo.com/baby/hp.html
Preimplantationgenetic diagnosis
Chorion villisampling
cordocentesis
amniocentesis
Prenatal diagnosis
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Fig. 11.19, p. 186Karyotype analysis
Fetal cells
Centrifugation
Growth for weeks in culture medium
Removal of about 20 ml of amniotic fluid containing suspended cells that were sloughed off from the
fetus Performed during weeks 15-17 of Performed during weeks 15-17 of
pregnancypregnancyA few biochemical
analyses with some of the amniotic fluid
Quick determination of fetal sex and analysis of purified
DNA
Biochemical analysis for the presence of alleles that cause
many different metabolic disorders
AmniocentesisAmniocentesis
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Sex ChromosomesSex Chromosomes
Discovered in late 1800sDiscovered in late 1800s
Mammals, fruit fliesMammals, fruit flies
– XX is female, XY is maleXX is female, XY is male
Human X and Y chromosomes function Human X and Y chromosomes function
as homologues during meiosisas homologues during meiosis
((In some organisms XX is male, XY female but for this In some organisms XX is male, XY female but for this
class XX is female and XY is male, no tricky stuff)class XX is female and XY is male, no tricky stuff)
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Sex Determination Sex Determination
XX
XY
XX
XY
X X
Y
X
sex chromosome combinations possible in new individual
Y
X
sperm
X
X
eggs
Female germ cell Male germ cell
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The Sex ChromosomesThe Sex ChromosomesThe Y ChromosomeThe Y Chromosome
Fewer than two dozen Fewer than two dozen genes identifiedgenes identifiedOne is the master gene One is the master gene for male sex for male sex determination determination – SRY gene (Sex-SRY gene (Sex-
determining region of determining region of Y)Y)
SRY present, testes formSRY present, testes formSRY absent, ovaries SRY absent, ovaries formform
The X ChromosomeThe X ChromosomeCarries more than 2,300 Carries more than 2,300 genesgenes
Most genes deal with Most genes deal with nonsexual traitsnonsexual traits
Genes on X Genes on X chromosome can be chromosome can be expressed in both expressed in both males and femalesmales and females
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Pedigree Pedigree
Chart that shows genetic connections Chart that shows genetic connections
among individualsamong individuals
Standardized symbolsStandardized symbols
Knowledge of probability and Mendelian Knowledge of probability and Mendelian
patterns used to suggest basis of a traitpatterns used to suggest basis of a trait
Conclusions most accurate when drawn Conclusions most accurate when drawn
from large number of pedigreesfrom large number of pedigrees
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The individual who needs genetical medical The individual who needs genetical medical consultation is called the consultation is called the probandproband O, O,
Proband tells to doctor medical history Proband tells to doctor medical history about his disorder and any other affected about his disorder and any other affected persons in the family. If this disorder persons in the family. If this disorder (disease) is inheritance, we can draw family (disease) is inheritance, we can draw family trees.trees.
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Pedigree symbolsPedigree symbols
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Children marked under horizontal line Children marked under horizontal line from left to right, in order of birth.from left to right, in order of birth.
Members of the same generation are Members of the same generation are placed on the same horizontal level. placed on the same horizontal level. Roman numbersRoman numbers are used for each are used for each generation and generation and Arabic numeralsArabic numerals are are used to indicate each individual within used to indicate each individual within a generation.a generation.
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Pedigree for PolydactlyPedigree for Polydactly
I
II
III
IV
V
*Gene not expressed in this carrier.
*
malefemale
1 2 3 4 5
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Autosomal Recessive Autosomal Recessive Inheritance PatternsInheritance Patterns
If parents are If parents are
both both
heterozygous, heterozygous,
child will have a child will have a
25% chance of 25% chance of
being affected being affected
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GalactosemiaGalactosemia
Caused by autosomal recessive alleleCaused by autosomal recessive allele
Gene specifies a mutant enzyme in the Gene specifies a mutant enzyme in the pathway that breaks down lactosepathway that breaks down lactose
LACTOSE GALACTOSEGALACTOSE-1-PHOSOPHATE
GALACTOSE-1-PHOSOPHATE
enzyme 1 enzyme 2 enzyme 3
+glucose intermediate
in glycolysis
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Autosomal Autosomal Dominant InheritanceDominant Inheritance
Trait typically Trait typically appears in appears in every every generationgeneration
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Huntington DisorderHuntington Disorder
Autosomal dominant alleleAutosomal dominant allele
Causes involuntary movements, Causes involuntary movements, nervous system deterioration, deathnervous system deterioration, death
Symptoms don’t usually show up until Symptoms don’t usually show up until person is past age 30person is past age 30
People often pass allele on before they People often pass allele on before they know they have itknow they have it
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Genetics ProblemGenetics Problem
A woman (hh) with normal nerve A woman (hh) with normal nerve physiology has a child with a man physiology has a child with a man (Hh) who will develop Huntington (Hh) who will develop Huntington DiseaseDisease
What is the chance that the child What is the chance that the child will have Huntington Disease?will have Huntington Disease?
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Sex-Linked GenesSex-Linked GenesIs there a special pattern of inheritance for Is there a special pattern of inheritance for genes located on the X chromosome or the genes located on the X chromosome or the Y chromosome? Y chromosome? Because these chromosomes determine sex, Because these chromosomes determine sex, genes located on them are said to be genes located on them are said to be sex-sex-linked geneslinked genesMany sex-linked genes are found on the X Many sex-linked genes are found on the X chromosomechromosomeMore than More than 100 sex-linked genetic disorders 100 sex-linked genetic disorders have now been mapped to the X chromosomehave now been mapped to the X chromosomeThe human Y chromosome is much smaller The human Y chromosome is much smaller than the X chromosome and appears to contain than the X chromosome and appears to contain only a few genes only a few genes
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X-Linked Recessive X-Linked Recessive InheritanceInheritance
Males show Males show disorder more disorder more than femalesthan females
Son cannot Son cannot inherit disorder inherit disorder from his fatherfrom his father
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A typical X-linked recessive A typical X-linked recessive pedigreepedigree
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X Linked Recessive InheritanceX Linked Recessive Inheritance
Trait is much more common in males than femalesTrait is much more common in males than females
An affected man passes the gene to all of his An affected man passes the gene to all of his daughtersdaughters
A son of a carrier mother has a 50 % chance of A son of a carrier mother has a 50 % chance of inheriting the traitinheriting the trait
Male-to-male transmission Male-to-male transmission nevernever occurs occurs
Carrier females are usually asymptomatic, but some Carrier females are usually asymptomatic, but some may express the condition with variable severity may express the condition with variable severity because of Lyonization, or X-inactivation.because of Lyonization, or X-inactivation.
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X-Chromosome InactivationX-Chromosome Inactivation
Females have two X chromosomes, but males have Females have two X chromosomes, but males have only oneonly oneIf just one X chromosome is enough for cells in males, If just one X chromosome is enough for cells in males, how does the cell “adjust” to the extra X chromosome in how does the cell “adjust” to the extra X chromosome in female cells?female cells?The answer was discovered by the British geneticist The answer was discovered by the British geneticist Mary LyonMary LyonIn female cells, one X chromosome is randomly switched In female cells, one X chromosome is randomly switched offoff– That turned-off chromosome forms a dense region in the That turned-off chromosome forms a dense region in the
nucleus known as a nucleus known as a Barr bodyBarr body– Barr bodies are generally not found in males because their Barr bodies are generally not found in males because their
single X chromosome is still activesingle X chromosome is still active
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Barr bodyBarr body
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X linked recessive, normal X linked recessive, normal father, carrier motherfather, carrier mother
carrier daughter
1 normal daughter
1 affected son
1 normal son
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X linked recessive, affected X linked recessive, affected fatherfather
2 carrier daughters2 carrier daughters
2 normal sons: 2 normal sons:
Never any Male-to-Never any Male-to-
Male transmission!Male transmission!
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Examples of X-Linked TraitsExamples of X-Linked Traits
Color blindnessColor blindness– Inability to distinguish among some of all Inability to distinguish among some of all
colorscolors
HemophiliaHemophilia– Blood-clotting disorderBlood-clotting disorder
– 1/7,000 males has allele for hemophilia A1/7,000 males has allele for hemophilia A
– Was common in European royal familiesWas common in European royal families
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Royal Hemophilia PedigreeRoyal Hemophilia Pedigree
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Duchenne Muscular Dystrophy Duchenne Muscular Dystrophy
Duchenne muscular dystrophy is a sex-linked disorder Duchenne muscular dystrophy is a sex-linked disorder that results in the that results in the progressive weakening and loss of progressive weakening and loss of skeletal muscleskeletal muscleIn the United States, one out of every 3000 males is In the United States, one out of every 3000 males is born with this conditionborn with this conditionDuchenne muscular dystrophy is caused by a Duchenne muscular dystrophy is caused by a defective version of the gene that codes for a muscle defective version of the gene that codes for a muscle proteinproteinResearchers in many laboratories are trying to find a Researchers in many laboratories are trying to find a way to treat or cure this disorder, possibly by way to treat or cure this disorder, possibly by inserting a normal allele into the muscle cells of inserting a normal allele into the muscle cells of Duchenne muscular dystrophy patients Duchenne muscular dystrophy patients
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Distribution of Mendelian disordersDistribution of Mendelian disorders
68 % Autosomal dominant68 % Autosomal dominant
26 % Autosomal recessive26 % Autosomal recessive
6 % X-linked recessive6 % X-linked recessive
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In a In a sex-influenced traitsex-influenced trait, an allele is dominant , an allele is dominant in one sex but recessive in the other. in one sex but recessive in the other. Hormonal differences can cause this Hormonal differences can cause this difference in expression. difference in expression.
For example, a For example, a gene for hair growthgene for hair growth pattern has pattern has two alleles, one that produces hair all over two alleles, one that produces hair all over the head and another that causes pattern the head and another that causes pattern baldness. The baldness. The baldness allelebaldness allele is dominant ( is dominant (AA) ) in males but recessive (in males but recessive (aa) in females, which ) in females, which is why more men than women are bald. A is why more men than women are bald. A heterozygous male (heterozygous male (AaAa) is bald, but a ) is bald, but a heterozygous female is not. The genotype of heterozygous female is not. The genotype of a bald women is a bald women is aaaa..
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Male-pattern baldnessMale-pattern baldness
More Sex-Linked Recessive InheritanceMore Sex-Linked Recessive Inheritance
By age 50, nearly 60% of all men will experience some male pattern baldness. By age 50, nearly 60% of all men will experience some male pattern baldness.
35 million Americans experience some degree of hair loss,resulting in $900 million dollars a year being spent in efforts to grow it back.
35 million Americans experience some degree of hair loss,resulting in $900 million dollars a year being spent in efforts to grow it back.
Rogaine: only 5% actually grow hair, 20-30% will have no effect, Rogaine: only 5% actually grow hair, 20-30% will have no effect,
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X-Linked Dominant inheritance:
1) a trait affects mostly females;
2) if the affected female is heterozygous, she will pass the trait to a half of her offspring (male and female);
3) an affected male passes the trait to his daughters.
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Enamel hypoplasia (hereditary defect that cause holes and cracks to appear around the crowns of the teeth)
is sex-linked dominant trait.
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Y-Linked inheritance:
1) a trait affects only males;
2) father passes a trait to all sons.
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Hairy pinnae (hairy ears) – Y-linked trait
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Y-linked Ear-Hair
X X
X X
X y
X y
X
X y
X
y = Ear Hairy = Ear Hair
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Thank you for attention !