Transcript Autosomal Recessive Disorders

Principles of
Inheritance
GENETICS
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DNA
found in nucleus of each cell
composes chromosomes
chromosomes contain genes
genes-biological blueprints
dictate how we look, how our
body functions & may be
even how we behave
• traits are inherited
• passed down from
generations before us
• science of heredity-genetics
Genetics
• modern science of genetics-began
1860
• Gregor Mendel
• Father of Genetics
• helped lay down principles of
modern genetics
• Central European monk
• conducted experiments using
garden peas
• ideas were published in 1860's
• unrecognized until after his death
• not appreciated until early 1900s
• work applies to humans as well as
peas
• illustrates basic rules of
inheritance
Rules of Inheritance
• Mendel discovered
basic genetic
principles breeding
garden pea plant
• exercised strict
control over mating
of these plants
• studied seven
characteristics
• each with two
possible forms
Rules of Inheritance
• most important conclusion:
inherited variations are
transmitted to offspring as
discrete units
• until this time most assumed
characteristics of individual
organisms were blended from
generation to generation
• particulate theory
• Particles-now known as
genes
GENE
True Breeding Plants
• before beginning
Mendel worked with
his plants to ensure
he had true-breeding
plants
• produce offspring that
are identical to
parents
• purple flowers
purple offspring
Hybridization-CrossBreeding
• purple mom +
white dad
• hybridization
• or simply-cross
• offspring are
hybrids
Cross-Breeding
• true breeding parentsP generation
–for parental
• children-F1
generation
–f=filial-Latin for son
• when F1 plants are
matedoffspring-F2
generation
Mendel’s Experiments
• Mendel noticed that traits were
transmitted in predictable ways
from parents to offspring
• crossed different strains of
purebred plants & studied their
progeny
• at first worked with consequences
of crossing one trait at a time
• monohybrid cross
• would cross purple plant with
white plant & look at color of
offspring
• F1 generation-always purple
• Mendel wondered what had
happened to heritable factor for
white
Mendel’s Experiments
• when crossed F1
generations
• missing white factor
reappeared
• 75% of offspring had
purple flowers
• 25% had white
flowers
• 3:1 ratio
Mendel’s Experiments
• same pattern of
inheritance was found
for all characteristics
of pea plant
• in cross-pollinating
green pods-first
offspring generation
(f1) always had green
pods
• f2 generation
consistently had 3:1
ratio of green to
yellow
Mendel’s Conclusions
• white or yellow genes do not
disappear in f1 generation
• masked by purple or green
gene
• individuals inherit one unit
from each parent for each
trait
• specific trait may not show
up in an individual
• may be passed to next
generation
• from his results, Mendel
described four specific
hypotheses
Mendel’s Hypotheses
• there are alternative
forms of genes-alleles
• for each inherited
characteristic an
organism must have 2
genes
– one from each parent
• maybe-same or different
• two of same allelehomozygous
• two different allelesheterozygous
Mendel’s Hypotheses
• alleles represent genotype
• when alleles are differentallele
that determines appearance
(phenotype) is dominant
• other allele has no observable
effect on phenotype-recessive
• dominant genes-always
expressed
• need only one dominant gene to
have particular phenotype
• to have recessive characteristicmust carry two recessive genes
– unless gene is located on
sex chromosome
• customary to use capital letters
for dominant traits
• small letters for recessive ones
Genotype & Phenotype
• brown eye color is
dominant (B)
• blue (b) is recessive
• person with
genotype BB or Bb
would have brown
eyes
• person with
genotype bb would
have blue ones
Law of Segregation
• each f1 generation plant
inherits one allele from one
parent & one allele from
other
• when f1 plants mated,
each allele had equal
chance of being passed on
to offspring
• for any particular trait, pair
of alleles from each parent
separate
• only one allele passes from
each parent to offspring
• which allele in parent's pair
is inherited is-chance
Law of Segregation
• genes occur in pairs because
chromosomes occur in pairs
• during gamete productionmembers of each gene pair
separate so each gamete
contains one member of a pair
• during fertilization full number
of chromosomes is restored
• members of a gene or allele
pair are reunited
• segregation of alleles occurs
during process of gamete
formation-meiosis
Punnett Square
• used to illustrate basic
rules of inheritance
• shows alleles of mother
and alleles of father
• by simple multiplication
one can figure out
probability of obtaining
offspring with
characteristics of parents
Punnett Square
Examples
Example
• Brown eyed father-BB
• Blue eyes-mother-bb
• Recessive trait
Example
• father with red hair
• recessive trait
• has children with mother with
black hair
• dominant trait
• probability of having children
with red hair is
• ?
• each child would carry a gene
for red hair
• this is the case if mother has
two dominant alleles in her
genotype
• what if we know that woman’s
mother had red hair
r
R
R
Rr
Rr
r
Rr
Rr
Dihybrid Cross
• Mendel next
crossed &
followed
inheritance of
two traits at
same time
• dihybird crosses
Dihydrid Crosses
• two characteristics Mendel
studied were seed shape
& color
• seeds were either green or
yellow & either wrinkled or
round
• knew round & yellow were
dominant
• wrinkled & green were
recessive
• wondered what would
happen in a dihybrid
cross
• mating GGWW pea with
ggww one
Principle of Independent
Assortment
• f1 generation yielded heterozygous
hybrids or RrYy
• phenotype was round & yellow
• when f1 generation was crossed found
distribution of one pair of alleles into
gametes did not influence distribution
of other pair
• genes controlling different traits are
inherited independently of one
another
• Principle of Independent
Assortment
• ratio was 9:3:3:1
• 9 yellow, round, 3 green, round, 3
yellow, wrinkled and one completely
recessive pea or green, wrinkled
Punnett Square
Test Crosses
• used to determine genotype of
specific specimens
• have a purple flowering pea plant
• want to know if pea plant has
purple flowers because it is
homozygous or heterozygous
• unknown plant is mated with
known plant
• cross purple-flowered unknown
with white-flowered plant
(completely recessive)
• if all offspring exhibited purple
flowersconclude unknown
parent is homozygous
• if offspring exhibited 1:1 ratio of
purple to white flowersconclude
unknown parent is heterozygous
Mendelian Pattern Inheritance
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genes coding for a particular trait are
located at particular positions on
chromosomes-loci
come in several forms-alleles
receive one allele from each parent
if identical-homozygous for a trait
if different-heterozygous
recessive traits are not expressed in
heterozygotes
for recessive alleles to be expressed,
one must have 2 copies
dominant traits can be expressed in
presence of another, different allele
dominant alleles prevent expression or
mask recessive alleles in
heterozygotes.
traits that are result of one set of genes
are single gene traits
transmission of single gene traits
follows Mendel’s patterns of
inheritance
Other Patterns of Inheritance
• over 4,500 human trains are
inherited according to simple
Mendelian principles
• there are exceptions to Mendel’s
rules
Incomplete dominance
• offspring is heterozygous
for a trait but phenotype
is intermediate between
phenotypes of
homozygous parents
• heterozygous
snapdragons of white &
red parents have pink
flowers
• sickle cell disorder
• homozygous individuals
have either normal blood
or sickle cell anemia
• heterozygous individuals
have sickle cell trait
Incomplete Dominance
Codominance
• phenotypes for both alleles at
a locus are expressed at
same time
• human ABO blood system
shows both simple Mendelian
inheritance & codominance
• A & B alleles are dominant to
O
• if have genotype AOblood
type is A
• if BOblood type is B
• however, neither A or B alleles
are dominant to one another
• codominant-both traits are
expressed
• person with allele for A & one
for B has blood type AB
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OO = Blood type O
AO = Blood type A
BO = Blood type B
AB = Blood type AB
AA = Blood type A
BB = Blood type B
Polygenetic Inheritance
• characteristics due to
multiple alleles
• many genes define a trait
• Height
• combination of genes for
height of face, size of
vertebrate & length of leg
bones
• skin color-due to
interactions between at
least 3 pairs of alleles
• continuous traits
• show gradations
• there is a series of
measurable intermediate
forms between 2 extremes
Sex-Linked Genes
• characteristics found
on X & Y chromosome
• inherited differently
• X linked, recessive
shows effect more in
males
• Recessive
– no corresponding
gene on Y
chromosome
– therefore trait will be
expressed
Chromosomes
• every nucleus in every
somatic or body cell
carries genetic blueprint for
who we are
• 46 chromosomes
• each paired with a like
chromosome
• 23 pairs
• 23 chromosomes came
from our mothers
• 23 from our fathers
Sex
Chromosomes
• exception found
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with sex
chromosomes
X& Y
chromosomes
other 22 pairs are
autosomes
sex chromosomes
determine gender
XX = girl & XY =
boy
Sex-Linked Traits
• sex linkage
– results from action of genes
present on sex chromosomes
• most located on X chromosome
• nearly all are recessive
• most X-linked genes have no
homologous loci on Y
chromosome
• baldness, color blindness &
hemophilia
• occur more in males than
females
• males receive only one allele of
a gene located on X
chromosome
• therefore even recessive alleles
will be expressed in males
• there is no dominant gene to
mask it
Inheritance of Sex-Linked Genes
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for sex linked traits-females are carriers
if have one recessive allele
affected when possess 2 recessive
alleles
affected fathers pass X-linked allele to
all daughters but not to sons
males receive X chromosomes only
from mothers
mothers can pass sex-linked alleles to
both sons & daughters
unaffected males do not carry defective
gene
carrier female has 50% chance of
producing affected son
50% chance of producing carrier
daughter
affected females are homozygous-rare
condition requires both carrier mom
and father with the condition
Genetic Disorders
• can be inherited as dominant or recessive traits by simple
Mendelian principles
• dominant disorders-inherited when one copy of dominant
allele is present
• recessive disorders require presence of two copies of
recessive gene
• disorders may be present at birth or become evident later
in life
• most inherited from parents
• 15-20% are result of new mutations
– molecular alterations in genetic material, arising during fetal
development
• disorders are classified according to location of defective
gene-autosomal or sex & mode of transmissiondominant or recessive
Autosomal Genetic Disorders
• each human has 22 pairs of
homologous autosomal
chromosomes
• 1 set of sex chromosomes
– females-homozygous-XX
– males-heterozygous-XY
• more than 10,000 single gene
disorders have been
catalogued
• autosomal disorders are
found in 1 in 500 individuals
in general population
• affect males & females
equally
Autosomal Recessive & Dominant
Disorders
• autosomal recessive
disorders
– require 2 recessive genes
for particular problem
• autosomal dominant
disorders
– require individual has at
least one dominant allele
• for autosomal dominant
disorders at least one parent
must be affected
• for autosomal recessive
disorders parents may or
may not have the disorder
• parents without disorder are
called carriers
Autosomal Dominant Disorders
• few in number
• close to 4,400 known
• dominant genes often
code for functional or
structural proteins
– typically affect body
structures such as
skin, bone, and teeth
• everyone bearing gene is
affected
• Huntington's disease
– causes slow
progressive
deterioration of brain
& eventually death
Paternal gametes
D
d
d
Dd
dd
Dd
dd
Maternal
gametes
d
D = mutant gene
d = normal gene
2 dd: 2 Dd
Autosomal Dominant Disorders
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expressed in those who have one
altered copy of a gene
parent has 1 in 2 chance of passing
altered gene to offspring with each
pregnancy
risk remains constant no matter
how many affected or unaffected
children are born
follows predictable patterns of
inheritance
males & females-equally affected
affected individual has an affected
parent
unaffected individuals do not
transmit disorder
offspring of affected person mating
with a normal mate has 50% change
of inheriting disorder
rare mating of 2 individuals each
with one copy of defective gene has
a 75% chance of producing an
affected offspring
Autosomal Dominant Diseases
• Brachydactyly
– short fingers & toes
• familial hypercholesterolemia,
• familial polycystic disease
• one type of Alzheimer's disease
• hereditary colon cancer
• Achondroplasia
– dwarfism in which homozygous condition
is lethal at embryo stage
Autosomal Recessive Disorders
• due to recessive allele
• manifested only in
homozygous genotype
• person having
heterozygous genotype-Aa
is a carrier
• estimated-each carry 5-10
recessive lethal genes
• most never experienced
because have another
chromosome with good
copy of gene from other
parent
• recessive defective genes
when present in only one
copy do not affect owner
Autosomal Recessive Disorders
• males & females-equally
affected
• disorder-not apparent in
parents or relatives
• if individual is affectedboth parents must be
carriers
• mating of 2 carriers
produces 25% chance of
producing offspring with
disorder
• 50% of offspring will be a
carrier for the disorder
Autosomal Recessive Disorders
• recessive
conditions that
affect humans
include
• cystic fibrosis
• Tay-Sachs
disease
• beta thalassemia
• phenylketonuria
• albinism
Albinism
• group of inherited
conditions in which there is
little or no pigment in eyes,
skin, and hair
• individuals have inherited
two altered copies of a
gene that does not work
correctly
• does not allow body to
make usual amount of
melanin
• result of lack of
tyrosinase
• enzyme that catalyzes
formation of melanin from
tyrosine
Cystic Fibrosis
• most frequent &
common single
gene disorder
• 5% of white
Americans carry
defective gene
• 1 in 25 persons of
European ancestry
are carriers
Sex Linked Genetic Disorders
• more males than
women affected
• need to acquire
only one
recessive trait
from mother
• due to gene on
X chromosome
Sex linked Disorders
Hemophilia
Diagnosis
• ability to diagnosis improved over last few years
• ability to detect exceeds ability to treat
• many children with recessive disorders are born to parents
who are normal
• possible to do carrier testing to determine whether or not
someone is a carrier for a particular recessive gene
• by determining whether individual is a carrier risks for
passing gene to an offspring can be assessed
• carrier testing may be considered by individuals who have
family history and/or are members of an ethnic group
known to be at increased risk for a disorder
• Genetic counseling is often recommended prior to carrier
testing
Fetal Testing
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techniques are available to test fetus prior to
birth
Ultra sound
non invasive
uses sound waves to produce image of fetus
used to determine gestational age, fetal position
& placenta location
cannot detect biochemical or chromosomal
abnormalities.
Amniocentesis
invasion
needle inserted into abdomen or vaginafluid
is obtainedskin cells of fetus are cultured &
harvested & analyzed for abnormal levels of
certain substances
karyotype can be performed on harvested
cells indicating chromosomes present
only certain disorders can be detected this way
may not provide information until late in
pregnancy
Amniocentesis
Fetal Testing
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Chorionic Villus Sampling
tissue removed from chorion
– outer membrane of fetal sac
can do as early as 8 weeks of gestation
cells do not need to be cultured
Blood tests
conducted on mother
15 to 20 week of pregnancy
Alpha fetoprotein (AFP) in mother’s blood
may indicate neural tube defects
Embryoscopy
– direct visualization
can be used to detect abnormalities & to
treat them
can be conducted as early as 1st trimester
scope is inserted into uterus
often used to diagnose structural
abnormalities
may be used to treat disorders with gene
or stem cell therapy