Introduction to Human Genetics

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Introduction to Human Genetics

• Dr Pupak Derakhshandeh, PhD
• Ass Prof of Medical Science of Tehran University

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General Background

• single gene disorders
• diseases or traits phenotypes are largely
  determined of mutations at individual loci

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• chromosomal abnormalities
• diseases where the phenotypes physical changes
  in chromosomal structure - deletion, inversion,
  translocation, insertion, rings, etc
• chromosome number - trisomy or monosomy, or in
  chromosome origin - uniparental disomy

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• multifactorial traits
• diseases or variations phenotypes are strongly
  influenced mutant alleles at several loci

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• mitochondrial inheritance
• Diseases phenotypes are affected by mutations
  of mitochondrial DNA

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• diseases of unknown etiology
• "run in families"

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Mendelian traits, or single gene disorders

• autosomal recessive inheritance
• the locus on an autosomal chromosome
• both alleles mutant alleles to express the
  phenotype

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By effect on function

• Loss-of-function mutations
• Gain-of-function mutations
• Dominant negative mutations
• Lethal mutations

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Loss-of-function mutations

• Wild type alleles typically encode a product
  necessary for a specific biological function
• If a mutation occurs in that allele, the function
  for which it encodes is also lost
• The degree to which the function is lost can vary

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Loss-of-function mutations

• gene product having less or no function
• Phenotypes associated with such mutations are
  most often recessive
• to produce the wild type phenotype!
• Exceptions are when the organism is haploid
• or when the reduced dosage of a normal gene
  product is not enough for a normal phenotype
  (haploinsufficiency)

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Mendelian traits, or single gene disorders

• autosomal dominant inheritance
• the locus on an autosomal chromosome
• only one mutant allele for expression of the
  phenotype

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Loss-of-function mutations

• mutant allele will act as a dominant
• the wild type allele may not compensate for the
  loss-of-function allele
• the phenotype of the heterozygote will be equal
  to that of the loss-of-function mutant (as
  homozygot)
• to produce the mutant phenotype !

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Loss-of-function mutations

• Null allele
• When the allele has a complete loss of function
• it is often called an amorphic mutation
• Leaky mutations
• If some function may remain, but not at the level
  of the wild type allele
• The degree to which the function is lost can vary

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Gain-of-function mutations

• change the gene product such that it gains a new
  and abnormal function
• These mutations usually have dominant phenotypes
• Often called a neomorphic mutation
• A mutation in which dominance is caused by
  changing the specificity or expression pattern of
  a gene or gene product, rather than simply by
  reducing or eliminating the normal activity of
  that gene or gene product

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Gain-of-function mutations

• Although it would be expected that most mutations
  would lead to a loss of function
• it is possible that a new and important function
  could result from the mutation
• the mutation creates a new allele
• associated with a new function
• Genetically this will define the mutation as a
  dominant

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Mendelian traits, or single gene disorders

• X-linked recessive inheritance
• the locus on the X chromosome
• both alleles mutant alleles to express the
  phenotype in females

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Mendelian traits, or single gene disorders

• X-linked dominant inheritance
• the locus on the X chromosome
• only one mutant allele for expression of the
  phenotype in females

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Non Mendelian traitsgene disorders

• mitochondrial inheritance
• the locus the mitochondrial "chromosome"

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Mitosis

• cell division
• responsible for the development of the individual
  from the zygote
• somatic cells divide and maintain the same
  chromosomal complement
• each chromosome duplicates forming two chromatids
  
• connected to a single centromere

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centromeres

• the centromeres line up on the metaphase plate
• without the homologous pairing
• recombination found in meiosis
• exception for sister chromatid exchange of
  identical DNA information in mitosis
• centromere divides each chromatid becomes a
  daughter chromosome at anaphase of cell division
• two identical daughter cells with identical DNA
  complements

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Mitosis

• Mutations during DNA replication in mitosis
• these mutations in somatic cell diseases, such
  as cancer
• most mitotic divisions/the fastest rate of
  growth
• before birth in the relatively protected
  environment of the uterus
• Most of us only increase 15 to 30 times our birth
  weight

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Meiosis (I)
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Meiosis (II)
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PEDIGREE CONSTRUCTION
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• AUTOSOMAL RECESSIVE INHERITANCE

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AUTOSOMAL RECESSIVE INHERITANCE

• affected individuals normal phenotypes
• one in ten thousand live births
• heterozygote frequency in the population one in
  fifty

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The Punnett Square for autosomal recessive
diseases with an affected child in the family

• Within the normal siblings of affected individual
  
• the probability of being a carrier is 2/3

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hallmarks of autosomal recessive inheritance

• Males and females equally likely to be
  affected
• the recurrence risk to the unborn sibling of an
  affected individual 1/4
• Parents of affected children may be related
• The rarer the trait in the general population,
  the more likely a consanguineous mating is
  involved

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Autosomal recessive inheritance

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rare autosomal recessive diseases

• individuals in the direct line of descent within
  the family carriers
• those individuals from outside the family are
  considered homozygous normal

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• AUTOSOMAL DOMINANT INHERITANCE

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Autosomal dominant diseases

• usually rare
• To produce a affected homozygote two affected
  heterozygotes would have to mate
• they would have only a 1/4 chance of having a
  normal offspring
• In the extremely rare instances
• where two affected individuals have mated the
  homozygous affected individuals
• usually are so severely affected they are not
  compatible with life

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Autosomal dominant diseases

• The mating of very closely related individuals
• two affected individuals to know each other,
  isnt forbidden in our society
• in most matings affected individuals
  heterozygotes
• the other partner will be homozygous normal

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Autosomal dominant diseases

• new mutations
• rare in nature
• every affected individual an affected biological
  parent
• Males and females
• an equally likely chance of inheriting the mutant
  allele
• The recurrence risk of each child of an affected
  parent
• 1/2
• Normal siblings of affected individuals
• do not transmit the trait to their offspring

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The defective product of the gene

• usually a structural protein, not an enzyme
• Structural proteins usually defective
• one of the allelic products is nonfunctional
• enzymes usually
• require both allelic products to be nonfunctional
  to produce a mutant phenotype

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The Punnett Square for autosomal recessive

• One gamete comes from each parent
• Two out of the four possible combinations
  affected
• two out of four normal

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AUTOSOMAL DOMINANT INHERITANCE
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AUTOSOMAL DOMINANT INHERITANCE

• Variable Expressivity
• Late Onset
• High Recurrent Mutation Rate
• Incomplete Penetrance

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VARIABLE EXPRESSIVITY (AD)

• One example Marfan syndrome
• autosomal dominant disease
• caused bya mutation in collagen formation
• It affects about 1/60,000 live births
• Symptoms of Marfan syndrome
• skeletal
• Optical
• cardiovascular abnormalities
• Skeletal abnormalities
• arachnodactyly (long fingers and toes)
• extreme lengthening of the long bones

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dislocation of the lens of the eye
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VARIABLE EXPRESSIVITY (AD) Marfan syndrome

• Optical abnormalities
• a dislocation of the lens of the eye
• Cardiovascular abnormalities
• responsible for the shorter life span of Marfan
  syndrome patients
• Each patient may express all of the symptoms, or
  only a few!
• That is variable expressivity
• Each patient with the mutant allele for Marfan
  syndrome
• expresses at least one of the symptoms

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VARIABLE EXPRESSIVITY (AD) Marfan syndrome

• Almost all are taller than average
• Almost all have long fingers
• Some may be very mildly affected and lead normal
  lives
• while others, more severely affected have a
  shorter life expectancy
• The disease
• recurrent mutations

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LATE ONSET (AD)

• Some autosomal dominant diseases
• do not express themselves until later in life
• the disease passed the mutant allele along to
  their offspring before they themselves know they
  are affected
• In some cases even grandchildren are born before
  the affected grandparent shows the first signs of
  the disease

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LATE ONSET (AD)

• Huntington disease (Huntington's Chorea)
• choreic movements expressed
• Progressive
• a good example of a late onset disease
• Age of onset varies from the teens to the late
  sixties
• with a mean age of onset between ages 35 and 45

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Huntington disease

• Nearly 100 of the individuals born with the
  defective allele will develop the disease by the
  time they are 70
• The disease progressive with death usually
  occurring between four and twenty-five years
  after the first symptoms develop

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Huntington disease (AD)

• At the gene level
• the expansion of an unstable trinucleotide
  repeat sequence
• CAG
• POLYGLUTAMINE DISEASES
• Somatic mutations expansion of trinucleotide
  repeat sequences
• in the coding region of the gene to produce a
  mutant allele

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Other diseases (AD)

• myotonic dystrophy
• an autosomal dominant disease
• expression is delayed
• expansion of unstable trinucleotide sequences
• CTG

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myotonic dystrophy

• unstable sequence lies in a non-translated region
  of the gene
• the size of the inherited expansion correlates to
  the age of onset
• or the severity of disease

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Repeats in non-coding sequences
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HIGH RECURRENT MUTATION RATE

• Achondroplasia
• the major causes of dwarfism
• Motor skills may not develop as quickly as their
  normal siblings
• but intelligence is not reduced
• about 1/10,000 live births

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Achondroplasia

• Almost 85 of the cases new mutations both
  parents have a normal phenotype
• The mutation rate for achondroplasia may be as
  much as 10 times the "normal" mutation rate in
  humans
• This high recurrent mutation is largely
  responsible for keeping the mutant gene in the
  population at its present rate

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INCOMPLETE PENETRANCE

• It should never be confused with variable
  expressivity
• variable expressivity
• the patient always expresses some of the symptoms
  of the disease
• and varies from very mildly affected to very
  severely affected
• incomplete penetrance
• the person either expresses the disease phenotype
  or he/she doesn't

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• Incomplete penetrance and variable expressivity
  are phenomena associated only with dominant
  inheritance, never with recessive inheritance

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INCOMPLETE PENETRANCE in a known autosomal
dominant disease
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• X-LINKED DOMINANT INHERITANCE

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X-LINKED DOMINANT INHERITANCE

• A single dose of the mutant allele will affect
  the phenotype of the female!
• A recessive X-linked gene
• requires two doses of the mutant allele to affect
  the female phenotype
• The trait is never passed from father to son

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X-LINKED DOMINANT INHERITANCE

• All daughters of an affected male and a normal
  female are affected (100)
• All sons of an affected male and a normal female
  are normal (100)
• Mating of affected females and normal males
  produce 1/2 the sons affected and 1/2 the
  daughters affected (50 50)
• Males are usually more severely affected than
  females
• The trait may be lethal in males

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X-LINKED DOMINANT INHERITANCE

• Males usually more severely affected than
  females
• in each affected female there is one normal
  allele producing a normal gene product
• and one mutant allele producing the
  non-functioning product
• while in each affected male there is only the
  mutant allele with its non-functioning product
  and the Y chromosome, no normal gene product at
  all

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X-LINKED DOMINANT INHERITANCE

• All daughters are affected (100) / All sons are
  normal (100)

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One example of an X-linked dominant
incontinentia pigmenti (IP)

• extremely rare
• The main features occur in the skin where a
  blistering rash occurs in the newborn period
• brown swirls
• a "marble cake-like" appearance on the skin
• the eyes
• central nervous system
• Teeth
• nails, and hair
• The severity varies from person to person

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incontinentia pigmenti
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key for determining X-L D/AD

• to look at the offspring of the mating of an
  affected male and a normal female
• If the affected male has an affected son
• then the disease is not X-linked

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What happens when males are so severely affected
that they can't reproduce?

• This is not uncommon in X-linked dominant
  diseases
• There are no affected males
• to test for X-linked dominant inheritance to see
  if the produce all affected daughters and no
  affected sons !!!

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What happens when males are so severely affected
that they can't reproduce?

• Next pedigree shows the effects of such a disease
  in a family
• There are no affected males
• only affected females, in the population!

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X-linked dominant inheritance (severe)
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• X-LINKED RECESSIVE INHERITANCE

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X-LINKED RECESSIVE INHERITANCE

• They are, in general, rare
• Hemophilia (A/B)
• Duchenne muscular dystrophy
• Becker muscular dystrophy
• Lesch-Nyhan syndrome

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X-LINKED RECESSIVE INHERITANCE

• More common traits
• glucose-6-phosphate dehydrogenase deficience
• color blindness

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A rare X-linked recessive disease
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The hallmarks of X-linked recessive inheritance

• the disease is never passed from father to son
• Males are much more likely to be affected than
  females
• If affected males cannot reproduce, only males
  will be affected
• All affected males in a family are related
  through their mothers
• Trait or disease is typically passed from an
  affected
• grandfather, through his carrier daughters, to
  half of his grandsons

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X-linked recessive inheritance
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• SEX LIMITED INHERITANCE

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SEX LIMITED INHERITANCE

• In some X-linked recessive diseases, such as
  Duchenne muscular dystrophy
• expression of the disease phenotype is limited
  exclusively to males
• In some X-linked dominant traits, such as
  incontinentia pigmenti
• expression is limited to females
• males do not survive to term
• There are autosomal diseases that are limited to
  expression in only one sex
• Precocious puberty / beard growth are factors
  expressed only in males
• The hereditary form of prolapsed uterus is
  expressed only in females

DMD incontinentia pigmenti
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• MITOCHONDRIAL INHERITANCE

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MITOCHONDRIAL INHERITANCE

• A few human diseases
• to be associated with mitochondrial inheritance
• Leber optic atrophy a disease of mitochondrial
  DNA
• The ovum, originating in the female
• 100,000 copies of mitochondrial DNA
• the sperm, originating in the male
• has fewer than 100 copies, and these are probably
  lost at fertilization
• Virtually all of ones mitochondria come from his,
  or her, mother
• Affected fathers produce no affected offspring
• while the offspring of affected mothers are
  affected

The DNA of mitochondria contains about ten
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Mitochondrial inheritance pattern
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• IMPRINTING

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IMPRINTING

• 1/10,000 and 1/30,000 live births
• for some genes the origin of the gene may be
  important
• For some loci
• the gene inherited from the father
• acts differently from the gene inherited from the
  mother
• even though they may have the same DNA

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Prader-Willi syndrome

• About 75 of patients with Prader-Willi syndrome
  
• a small deletion of the long arm of chromosome
  15
• this deletion is on the paternal chromosome (the
  father's genes are missing)

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Prader-Willi syndrome
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Angelman syndrome

• When this deletion is on the maternal chromosome
  (the mother's genes are missing) Angelman
  syndrome results

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Angelman syndrome
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uniparental disomy

• The two diseases have very different clinical
  symptoms
• a rare chromosomal event in which both
  chromosomes come from a single parent (mother or
  father)
• both chromosomes 15 are derived from the mother
  Prader-Willi syndrome
• When both chromosomes 15 are derived from the
  father Angelman syndrome

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normal development an individual

• inherit one copy of this chromosomal region from
  his or her father and one from his or her mother
• Several other regions show uniparental disomy
  without this effect on the phenotype!
• Small deletions usually affect the phenotype but
  they produce the same phenotype whether of
  maternal or paternal origin
• Imprinting represents an exception to Mendel's
  laws and remains an important area of research

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