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

• Genotype- the alleles a person has
• Phenotype- the observable trait a person has
• Dominant- Alleles affect masks the other allele
  it is paired with
• Recessive- Alleles affect is masked by the other
  allele it is paired with.

• Homozygous- Pair of alleles for a trait are
  identical
• Heterozygous- Pair of alleles for a trait are not
  identical
• Hybrid- Inherit non-identical alleles for a trait

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VISUAL REPRESENTATION Pair of Chromosomes Gene Lo
cus (loci) Alleles Heterozygous Homozygous
A pair of homologous chromosomes, each in the
unduplicated state (most often, one from a male
parent and its partner from a female parent)
Heterozygous
Homozygous
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
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Homologous Chromosomes

• Homologous autosomes are identical in length,
  size, shape, and gene sequence
• Sex chromosomes are nonidentical but still
  homologous
• Homologous chromosomes interact, then segregate
  from one another during meiosis

DNA
DNA and proteins arranged as cylindrical fiber
Nucleosome
Histone
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Human 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 Preparation

• Cultured cells for 3 to 4 days in the presence of
  phytohaemagglutinin (mitogen) and arrested at
  metaphase
• This is when cells are most condensed and easiest
  to identify Arrested cells are broken open
• Metaphase chromosomes are fixed and stained (how
  many copies of each chromosome in one cell?)
• Chromosomes are photographed through microscope
• Photograph of chromosomes is cut up and arranged
  to form a karyotype diagram

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• Karyotypes
• The Alaskan king crab has 208 chromosomes.
• The fruit fly has 4.
• Number has nothing to do with complexity of the
  organism

Cotton Rat (Sigmodon hipsidus)
Pied Kingfisher (Ceryle rudis)
Carrion Beetle (Phosphuga atrata)
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Prenatal Diagnosis

• Amniocentesis (1-2)
• Amniotic fluid removed
• Chorionic villus sampling (0.3)
• Cells from the chorion (surrounds ammnion)
• Fetoscopy (2-10)
• Direct visualization, removal of blood from
  umbilical vein

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Prenatal diagnosis
www.visembryo.com/baby/hp.html
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Amniocentesis
Removal of about 20 ml of amniotic fluid
containing suspended cells that were sloughed off
from the fetus Performed during weeks 15-17 of
pregnancy
A few biochemical analyses with some of the
amniotic fluid
Centrifugation
Quick determination of fetal sex and analysis of
purified DNA
Fetal cells
Biochemical analysis for the presence of alleles
that cause many different metabolic disorders
Growth for weeks in culture medium
Fig. 11.19, p. 186
Karyotype analysis
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Sex Chromosomes

• Discovered in late 1800s
• Mammals, fruit flies
• XX is female, XY is male
• Human X and Y chromosomes function as homologues
  during meiosis
• (In some organisms XX is male, XY female but for
  this class XX is female and XY is male, no tricky
  stuff)

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Sex Determination
eggs
sperm
Female germ cell
Male germ cell
sex chromosome combinations possible in new
individual
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The Sex Chromosomes

• The Y Chromosome
• Fewer than two dozen genes identified
• One is the master gene for male sex determination
  
• SRY gene (Sex-determining region of Y)
• SRY present, testes form
• SRY absent, ovaries form

• The X Chromosome
• Carries more than 2,300 genes
• Most genes deal with nonsexual traits
• Genes on X chromosome can be expressed in both
  males and females

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Pedigree

• Chart that shows genetic connections among
  individuals
• Standardized symbols
• Knowledge of probability and Mendelian patterns
  used to suggest basis of a trait
• Conclusions most accurate when drawn from large
  number of pedigrees

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• The individual who needs genetical medical
  consultation is called the proband O,
• Proband tells to doctor medical history about his
  disorder and any other affected persons in the
  family. If this disorder (disease) is
  inheritance, we can draw family trees.

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Pedigree symbols
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• Children marked under horizontal line from left
  to right, in order of birth.
• Members of the same generation are placed on the
  same horizontal level. Roman numbers are used for
  each generation and Arabic numerals are used to
  indicate each individual within a generation.

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Pedigree for Polydactly
male
female

1
2
3
4
5
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Autosomal Recessive Inheritance Patterns

• If parents are both heterozygous, child will have
  a 25 chance of being affected

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Galactosemia

• Caused by autosomal recessive allele
• Gene specifies a mutant enzyme in the pathway
  that breaks down lactose

enzyme 1
enzyme 2
enzyme 3
GALACTOSE-1- PHOSOPHATE
GALACTOSE-1- PHOSOPHATE
LACTOSE
GALACTOSE
glucose
intermediate in glycolysis
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Autosomal Dominant Inheritance

• Trait typically appears in every generation

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Huntington Disorder

• Autosomal dominant allele
• Causes involuntary movements, nervous system
  deterioration, death
• Symptoms dont usually show up until person is
  past age 30
• People often pass allele on before they know they
  have it

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Genetics Problem

• A woman (hh) with normal nerve physiology has a
  child with a man (Hh) who will develop Huntington
  Disease
• What is the chance that the child will have
  Huntington Disease?

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Sex-Linked Genes

• Is there a special pattern of inheritance for
  genes located on the X chromosome or the Y
  chromosome?
• Because these chromosomes determine sex, genes
  located on them are said to be sex-linked genes
• Many sex-linked genes are found on the X
  chromosome
• More than 100 sex-linked genetic disorders have
  now been mapped to the X chromosome
• The human Y chromosome is much smaller than the X
  chromosome and appears to contain only a few
  genes

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X-Linked Recessive Inheritance

• Males show disorder more than females
• Son cannot inherit disorder from his father

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A typical X-linked recessive pedigree
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X Linked Recessive Inheritance

• Trait is much more common in males than females
• An affected man passes the gene to all of his
  daughters
• A son of a carrier mother has a 50 chance of
  inheriting the trait
• Male-to-male transmission never occurs
• Carrier females are usually asymptomatic, but
  some may express the condition with variable
  severity because of Lyonization, or
  X-inactivation.

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X-Chromosome Inactivation

• Females have two X chromosomes, but males have
  only one
• If just one X chromosome is enough for cells in
  males, how does the cell adjust to the extra X
  chromosome in female cells?
• The answer was discovered by the British
  geneticist Mary Lyon
• In female cells, one X chromosome is randomly
  switched off
• That turned-off chromosome forms a dense region
  in the nucleus known as a Barr body
• Barr bodies are generally not found in males
  because their single X chromosome is still active

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Barr body
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X linked recessive, normal father, carrier mother
carrier daughter 1 normal daughter 1 affected
son 1 normal son
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X linked recessive, affected father

• 2 carrier daughters
• 2 normal sons
• Never any Male-to-
• Male transmission!

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Examples of X-Linked Traits

• Color blindness
• Inability to distinguish among some of all colors
• Hemophilia
• Blood-clotting disorder
• 1/7,000 males has allele for hemophilia A
• Was common in European royal families

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Royal Hemophilia Pedigree
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Duchenne Muscular Dystrophy 

• Duchenne muscular dystrophy is a sex-linked
  disorder that results in the progressive
  weakening and loss of skeletal muscle
• In the United States, one out of every 3000 males
  is born with this condition
• Duchenne muscular dystrophy is caused by a
  defective version of the gene that codes for a
  muscle protein
• Researchers in many laboratories are trying to
  find a way to treat or cure this disorder,
  possibly by inserting a normal allele into the
  muscle cells of Duchenne muscular dystrophy
  patients

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Distribution of Mendelian disorders

• 68 Autosomal dominant
• 26 Autosomal recessive
• 6 X-linked recessive

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• In a sex-influenced trait, an allele is dominant
  in one sex but recessive in the other.
• Hormonal differences can cause this difference in
  expression.
• For example, a gene for hair growth pattern has
  two alleles, one that produces hair all over the
  head and another that causes pattern baldness.
  The baldness allele is dominant (A) in males but
  recessive (a) in females, which is why more men
  than women are bald. A heterozygous male (Aa) is
  bald, but a heterozygous female is not. The
  genotype of a bald women is aa.

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More Sex-Linked Recessive Inheritance
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.
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 y
X X
X y
y Ear Hair
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Thank you for attention !