Genetic diseases

1
Genetic diseases

• human chromosomes- 23 pairs of homologous
  chromosomes
• first 22 pairs are called autosomes, the 23rd
  pair are the sex chromosomes
• normal somatic cells are diploid (46 chromosomes)
• normal gamete cells are haploid (23 chromosomes)

2
Karyotype

• is the orderly arrangement of metaphase
  chromosomes from the largest pair (chromosome
  one) to the smallest, and the last pair the sex
  chromosomes.

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Fig. 12Bc
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Fig. 12B
5
Fig. 12Bd
6
Use of karyotypes

• Diagnosis of polyplidy and aneuploidy conditions

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Polyplidy

• Polyplidy is when cells have multiple sets of
  chromosomes such as triploidy (3 sets), or
  tetraploidy (4 sets)
• Account for 10 of all known miscarriages

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Aneuploidy

• 2n1 and 2n-1 conditions for example
• results from nondisjunction during cell
  replication
• most often during meiosis

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Trisomy

• Trisomy is when there are three copies of one
  chromosome
• For example Kleinfelter's syndrome XXY (2n1)

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Fig. 12Bd2
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Monosomy

• A loss of a chromosome
• For example XO (Turner's syndrome) 2n-1
  conditions
• A loss of an autosome is usually lethal
• Generalization- a loss of genetic material
  (chromosome) is more serious than excess
  (chromosome duplication)

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Autosomal aneuploidy

• Live births- 13th, 18th, 21st
• Trisomy 16 is the most common trisomy among
  abortuses, not seen in live births

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Partial trisomy

• Extra portion of a chromosome is present in each
  cell
• Chromosomal mosaics some of the cells of the body
  have chromosome abnormalities and others do not
• Mosaics are formed by early mitotic nondisjunction

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Skill development

• Look at the provided karyotypes, determine sex,
  condition if any, number of chromosomes

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Down syndrome

• trisomy 21, translocations of 21st chromosome
• risk factors- mother- increase age
• father- exposure to toxic chemicals, radiation
  (age not a factor)
• risk- 1 in 1000 births

16
Down's syndrome

• mental retardation (20-50)
• males most often sterile, some female are fertile
• poor muscle tone, short stature, congenital heart
  disease
• increased susceptibility to leukemia and
  Alzheimer disease
• 75 of the fetuses spontaneous abort
• 20 of infants die before 10 years old

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Fig. 12.9
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sex chromosome aneuploidy

• 1 in 500 males
• 1 in 900 females

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triple X

• 1 in 1000 births
• some have infertility
• some have irregular menstrual cycles
• some have mental retardation (increases with each
  extra X)

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Turner's syndrome

• XO (2n-1)
• Short stature
• Sterile
• 15-20 of spontaneous abortions have Turner's
  syndrome and only 0.5 of the conceptions survive
  to term
• Treatment- female hormones

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Kleinfelter's syndrome

• XXY (2n1)
• infertile males

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abnormal chromosome structure
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Fig. 12.11
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deletions

• Loss of DNA- deletions short arm of chromosome 5
• cri du chat syndrome
• Low birth weight, severe mental retardation
• Microcephaly, heart defects

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Fig. 12.13a
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Fig. 12.13
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duplications

• not as serve

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Fig. 12.11c
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inversions

• position effect
• can cause loss of production control
• amounts, on/off controls are often affected

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Fig. 12.11d
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translocations

• reciprocal translocation
• robertsonian translocation
• long arms of two nonhomologous chromosomes fuse
  at the centromere forming a single chromosome
• examples documented 13, 14, 15, 21 and 22
• many of these have very small short arms

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Fig. 12.14a
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Fig. 12.14
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Chromosome terms

• short arm is the p portion above the centromere
• long arm is the q portion below the centromere

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Risk factors for aneuploidy

• persons with robertsonian translocations
  involving chromosome 21 will have multiple
  offspring with Down's syndrome

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Fragile sites

• example fragile X syndrome
• prevalence 11500 males, 1 in 2500 females
• male grandchild will be more affected than his
  grandfather
• 120 or more of CGG repeats leads to expression of
  the syndrome

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Fig. 12A
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Skill development

• construct a pedigree
• Analyze the pedigree for the following conditions
• Autosomal recessive diseases, autosomal dominant,
  X-linked disorders
• See problems and know symbols

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Characteristics to look for

• if the majority of individuals with the disease
  are males this is most likely a x linked disorder
• if both males and females get the disease and the
  disease or disorder skips some generations it
  most likely is autosomal recessive
• if both males and females get the disease or
  disorder, it does not skip generations, and there
  are large numbers of persons who come down with
  this condition it most likely is autosomal
  dominant

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Fig. 12.3
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Fig. 12.4
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Autosomal recessive disorders

• Examples-
• cystic fibrosis
• Tay-Sac disease
• Sickle cell anemia

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Fig. 11.10
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Characteristics of autosomal recessive disorders

• In order for an offspring to have disease or
  disorder both parents must be at least carriers
  for the condition
• Skips generations
• AA is normal, Aa is carrier, aa has disease

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Fig. 11.12
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Autosomal dominant diseases or disorders

• Examples of autosomal dominant disorders
• Achondroplasia
• Huntington's disease
• Hypercholesteremia
• Does not skip generations
• AA and Aa have disease, aa are normal

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Fig. 11.11
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Autosomal dominant

• If there is no prior history of disease in the
  family it is most likely due to a new mutation
• Another possibility is germline mosaicism- the
  parent would not have the disease but the germ
  cells contain the mutation

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Delayed age of onset

• Huntington's disease
• some forms of Alzheimer

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Fig. 11.13
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Penetrance

• percentage of individuals with a specific
  genotype who exhibit the phenotype

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expressivity

• extent of variation in phenotype associated with
  a particular genotype

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consanguinity

• closely related individuals who mate
• for example first cousin marriages
• inbreed- offspring of consanguineous mating
• consanguinity increases the risk for offspring
  with autosomal recessive disorders

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X linked inheritance

• females inherit these as autosomal recessive
  disorders
• males are hemizygous for genes on the X
  chromosome
• therefore a single mutated allele will cause
  males to inherit these diseases and disorders

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X inactivation

• Mary Lyon showed that somatic cells of normal
  females have one X chromosome inactivated (Barr
  bodies)
• Triple X females have 2 Barr bodies,
  Kleinfelter's syndrome males have one Barr
  bodies, Turner's syndrome females have no Barr
  bodies

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is it a male?

• Sometimes phenotypic male have an XX karyotypes
• Crossover has occurred involving the SRY gene
• this syndrome is similar to Kleinfelter's syndrome

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is it a female?

• sometimes phenotypic female have an XY karyotype
• crossover also causes this except this Y
  chromosome has lost the SRY gene
• not fertile, no ovaries

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Human Genome project and genome map

• 10,000 genes more than 9000 genetic diseases
• gene therapy has been done

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multifactorial inheritance

• Only 3 pairs of alleles can lead to 8x864
  phenotypes
• Distribution of phenotypes is a bell shaped curve
• Much more complicated- for example skin color is
  due to the interaction of at least 9 sets of
  genes
• Intelligence also is multifactorial

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Fig. 11.17
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Fig. 11.16
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Threshold model

• Clef lip, cleft palate, neural tube defects,

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Sex influenced traits and diseases

• baldness for example

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Table 12A