Genes in Human Populations

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Genes in Human Populations

• Study of
• distribution and frequency of genes in
  populations
• reasons for different gene frequencies in
  different populations
• burden of genetic disease is related to
  frequency and severity of genetic disorders
• - to an individual and to the population as a
  whole.

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Hardy Weinberg Equilibrium

• States the relationships between the frequency of
  alleles at a locus, and the genotypes resulting
  from these alleles.
• assumes large population
• random mating
• no new mutations
• no immigration in or out.

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• (Hardy Weinberg equation p2
  2pq q2 1)
• If all alleles at a locus are either A or a,
• frequency of A in the population is p,
• frequency of a in the population is q
• then p q 1
• and, frequency of AA is p2
• aa is q2
• Aa is 2pq

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• (p2 2pq q2 1)
• Observed frequency of recessive disease in
  population is q2
  (eg, frequency of PKU 1/10,000)
• q2 1/10,000
• therefore q 1/100 (this is not the carrier
  frequency)
• Since p q 1
• p 1 q 1 1/100 99/100

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• Carrier frequency (2pq)
• 2pq 2 (99/100 x 1/100)
• 2(1 x 1/100)
• 2/100
• 1/50
• Probability that a couple will have a child with
  PKU (ie q2) is therefore
• 1/50 x 1/50 x ¼ 1/10,000

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Exceptions to Hardy Weinberg Assumptions

• Mutations may occur at different frequency in
  different populations
• Migration introduction / loss of alleles
• 3. Small population size
• - genetic isolate / founder effect
• 4. Non-random mating
• - consanguinity
• - assortative mating

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Changes in Allele Frequency

• Can be caused by
• mutation (source of genetic variation)
• selection (phenotypes differ in biological
  fitness)
• (deleterious mutations may be removed by early
  death / lack of reproduction)
• migration (movement in or out)

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Selection

• Zero fitness of AD mutations
• Early lethality
• Condition occurs only because of new mutations
• Appear sporadic rather than as AD pedigree
• eg. Thanatophoric dysplasia osteogenesis
  imperfecta, type 2.
• compare achondroplasia fitness of 0.20
  
• - frequency results from balance between loss
  by selection, and gain by new mutation

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Heterozygote Advantage

• Mutant allele has a high frequency despite
  reduced fitness in affected individuals.
• Heterozygote has increased fitness over both
  homozygous genotypes
• eg. Sickle cell anemia.

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• Sickle Cell Anemia in West Africa

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More influences on allele frequencies

• Effects of population size and non-random mating
• - contrary to Hardy Weinberg assumptions,
  humans have often lived in small populations,
  isolated from their neighbours

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Genetic Drift

• Fluctuation in allele frequency due to chance in
  a small population

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Founder Effect

• if an original member of a sub-population has a
  rare allele, it may become common in the
  sub-population (high carrier frequency),
  resulting in high frequency of rare disease
• eg. Huntingdon disease in Lake Maracaibo,
  Venezuela (AD)
• Rod-cone dystrophy or Bardet-Biedl syndrome
  in Nfld.
• Gyrate Atrophy in Finland
• Tyrosinemia in eastern Quebec 1/685 vs.
  1/100,000

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Non-random mating

• Assortative Mating
• Pakistani or Cypriot population in UK
• Ashkenazi Jewish population
• Deaf population or blind population

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Consanguinity/Inbreeding

• when an individuals parents have one or more
  common ancestors, identifiable from a pedigree
  (or archival records)
• - because of genetic isolate, cultural
  practice, assortative mating
• -Increased likelihood of q 2

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Clinical and Public Health Implications

• increased population-specific frequencies of
  genetic disorders
• eg Saguenay region of Quebec
• - increased frequency of tyrosinemia,
  hypercholesterolemia, Myotonic Dystrophy
• - dedicated treatment, screening, education for
  the public and health care providers