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BLGY1232 > Human Genetics 1 > Flashcards

Human Genetics 1 Flashcards

1
Q

Who do human genetic disorders effect?

A

… affect at least 2% of all new born babies
… account for 50% of all childhood deafness, mental retardation and death
… affect 5% of the total population by the age of 25
… genetic variation also impacts on diseases in old age e.g. Alzheimer’s, osteoporosis and cancer

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2
Q

Classification of Human Genetic Disorders

A

1) single gene disorders
2) chromosome disorders
3) multifactorial disorders (the most common)

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3
Q

Locating the Genes / Variations Responsible for Human Phenotypes

A
  • segregation of hereditary traits studied in families
  • family trees drawn to determine mode of inheritance
  • statistical associations sought between genetic variation and hereditary traits to locate ‘disease alleles’ and genes responsible for other phenotypes
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4
Q

Autosomal Dominant Conditions

Examples

A

-Huntingdons
-myotonic dystrophy
-early onset Alzheimer’s
and >3160 others

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5
Q

Autosomal Dominant Conditions

Characteristics

A
  • affected person usually has one affected parent
  • can affect either sex
  • transmitted by either sex
  • a child of an affected x unaffected mating has a 50% chance of being affected
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6
Q

Penetrance

Definition

A

-the percentage of individuals with a particular genotype that express the phenotype expected of that genotype

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7
Q

Expressivity

Definition

A
  • the degree to which a trait is expressed

- variations in the expressed phenotype

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8
Q

What is an example of incomplete penetrance?

A

osteogenesis imperfect - brittle bone disease

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9
Q

Osteogenesis Imperfecta

A
  • caused by a mutation in collagen encoding genes
  • the mutations alter glycone by adding a bulkier side chain to the molecule which disrupts the tertiary structure
  • affects the ability of collagen to bind to mineral components of bone causing them to become brittle
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10
Q

What is an example of variable expressivity?

A

polydactyly

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11
Q

Polydactyly

A
  • a common condition seen in 1 in 500 births
  • variable expressivity can affect the number / size / appearance of digits
  • caused by mutations in a number of different genes
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12
Q

Autosomal Recessive Conditions

Examples

A

-cystic fibrosis
-beta-thalassaemia
-tay-sachs disease
and >3000 others

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13
Q

Autosomal Recessive Conditions

Characteristics

A
  • affected individuals usually born to unaffected parents (carriers)
  • carriers are asymptomatic
  • parental consanguinity increases incidence
  • affect either sex
  • 2 carriers have a 25% chance of having affected offspring
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14
Q

Cystic Fibrosis

Frequency

A
  • most common inherited disorder in the UK and in Caucasian European populations
  • 1/25 Europeans of Caucasian descent carry a defective CF allele
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15
Q

Cystic Fibrosis

Cause

A
  • loss of phenylalamine at position 508 in the cystic fibrosis transmembrane conductance regulator
  • a membrane located ATPase responsible for secretion of Cl- ions from cells
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16
Q

Cystic Fibrosis

Symptoms, Treatment and Prognosis

A
  • build up of viscous mucus affects breathing and provides a fertile site for bacterial infection
  • management by physiotherapy
  • gene therapy has been developed but the success rate is currently quite low
  • survival beyond age 35 is rare but improving
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17
Q

Beta - Thalassaemia

Cause

A
  • nonsense mutation in haemoglobin B (HBB) gene encoding beta-globin
  • results in reduced synthesis of haemoglobin
  • reduced oxygen carrying capacity of the blood
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18
Q

Beta - Thalassaemia

Malaria

A
  • beta-thalassaemia affects blood cells
  • upon interaction with malaria, blood cells in affected individuals disintegrate as they are relatively fragile
  • this means that sufferers have an enhanced resistance to malaria
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19
Q

Beta - Thalassaemia

Frequency

A
  • the recessive allele is most prevalent in Mediterranean and Middle Eastern populations
  • this is in areas where malaria is more prevalent as this gives a selective advantage to carriers of the disease allele
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20
Q

Sickle Cell Anaemia

Cause

A
  • mutation in the haemoglobin B (HBB) gene encoding beta-globin
  • point mutation resulting in the change of an amino acid from glutamic acid to valine
  • effects folding preventing correct binding with oxygen
  • also gives red blood cells a characteristic sickle shape
21
Q

Sickle Cell Anaemia

Malaria

A
  • heterozygous individuals (carriers) are resistant to malaria
  • sickle trait is incompletely recessive so heterozygotes will have a small number of sickled red blood cells which malaria cannot infect
22
Q

X-Linked Recessive Conditions

Examples

A

-haemophilia
-ducheme muscular dystrophy
-fragile X syndrome
-red green colour blindness
and >1100 others

23
Q

X-Linked Recessive Conditions

Characteristics

A
  • mainly affect males as they only have one copy of the X chromosome
  • affected males are usually born to unaffected parents
  • females always affected if father is affected and mother is at least a carrier
  • females can also be affected by non random X inactivation
  • no male to male transmission as males pass on their X chromosome to their daughter and their Y chromosome to their sons
24
Q

X-Linked Dominant Conditions

Examples

A

-X linked vitamin D resistant rickets
-CMTX
and ~500 others

25
Q

X-Linked Dominant Conditions

Characteristics

A
  • can affect either sex but females more than males
  • females are more often mildly and more variably affected than males
  • the child of an affected female has a 50% chance pf being affected regardless of sex
  • for an unaffected male, all of his daughters will definitely be affected
26
Q

Mitochondrially Inherited Conditions

Examples

A
  • Leigh’s disease
  • leber optic distrophy
  • kearns-sayre syndrome
  • MELAS
  • MERF
27
Q

Mitochondrially Inherited Conditions

Characteristics

A
  • affected individuals born only to affected females
  • all offspring of affected females are affected to some degree
  • affected males cannot pass on the condition
  • this is because the zygote gets its mitochondria from the egg
28
Q

Leigh’s Disease

A
  • neurological syndrome
  • usually results in early infant mortality
  • symptoms: ataxia, neurodegeneration, lactic acidosis
  • progressive death of brain cells eventually leads to death
  • several causes which might be autosomal recessive, X-linked recessive ot mitochondrial inheritance
29
Q

Triparental IVF

A
  • two possible procedures
    i) obtain zygote from father and affected mother, transplant zygote nucleus into enucleated donor egg from healthy donor female
    ii) transplant nucleus of affected mother’s egg cell into enucleated egg of healthy donor female, then fertilise the ‘recombinant’ egg
30
Q

First Question Asked When Trying to Determine the Sequence of a Phenotype

A

-is the biochemical basis of the phenotype known?

31
Q

Finding the Sequence of a Phenotype

Biochemical Basis of Phenotype Known

A
  • protein sequence can be used in a genome database search
  • identify the gene sequence in the human genome
  • PCR amplify the gene from the affected and unaffected individuals
  • identify any mutations in the affected individual and their family
32
Q

Finding the Sequence of a Phenotype

Biochemical Basis of Phenotype Unknown

A
  • have to locate gene in genome, identify the correct coding sequence, determine the nature of the mutation
  • there are two statistical approaches which can be used to achieve this:
    i) analysis based on genetic linkage
    ii) analysis based on allelic association
  • both methods rely on genetic variation (polymorphism) between individuals
33
Q

Autozygosity Mapping

A
  • pedigree analysis in families with a high incidence of consanguineous marriage
  • offspring homozygous for the causal mutation are also likely to be homozygous for a large region of DNA either side of the mutation as well
  • by comparing the genomes off individuals with the disorder you can identify the disease interval, the smallest section of chromosome required for the disorder
  • this means that the causal mutation is somewhere in that genetic interval
  • the genetic interval in which the causal mutation lies will be homozygous in affected individuals and heterozygous in unaffected family members
34
Q

Genetic Polymorphism

Definition

A
  • existence of two or more variants at significant frequency in the population
  • any DNA sequence variant present at a frequency of >1% in the population
  • any non-pathogenic variation
35
Q

Uses of Genetic Polymorphisms in Human Genetics

A

-polymorphic regions of DNA that segregate with the target allele can be used to track the inheritance of certain alleles through a family tree

36
Q

Genetic Markers

RFLPs

A
  • restriction fragment length polymorphisms
  • can be used to identify genotypes if it associated with a disease allele
  • not convenient to use
  • detection of RFLPs requires southern blot using a cloned probe, a relatively slow and laborious process
37
Q

Genetic Markers

SSRs

A
  • simple sequence repeats
  • sequence length variants at defined positions in the genome resulting from DNA replication errors
  • easily detected by PCR
  • used for genetic fingerprinting
  • but only about 10^5 exist in a genome
38
Q

Genetic Markers

SNPs

A
  • single nucleotide polymorphisms (snips)
  • very common, 1 every 100-300 bp in the human genome
  • easily detected by PCR
  • identified in whole genome sequencing so we know what the sequences of DNA to either side of them are making it easy to design primers
  • use a gene specific primer which binds to the sequence before the SNP
  • use allele specific primer which include the SNP so can be used to distinguish between different alleles
  • competitive PCR between gene specific and allele specific primers is the basis of a number of medium-through put genotyping assays that can score the allelic status of thousands of different SNP loci simultaneously in large numbers of individuals
39
Q

Analysis Based on Genetic Linkage

A
  • ideally requires large multi-generational families (OR many small families considered collectively)
  • known mode of inheritance
  • useful for single gene disorders
40
Q

What do linkage and association studies rely on?

A

-co-segregation of alleles and phenotype

41
Q

Co-segregation - Parental Genotype AaBb

2 genes on different chromosomes

A
  • independent assortment in meiosis
  • 25% of getting each combination
  • cannot detect any genetic linkage
42
Q

Co-segregation - Parental Genotype AaBb

2 genes far apart on the same chromosome

A
  • recombination is frequent enough for loci to assort independently
  • 25% chance of getting each combination
  • cannot detect any genetic linkage
43
Q

Co-segregation - Parental Genotype AaBb

2 genes close together on the same chromosome

A
  • close linkage between loci
  • cosegregation of linked alleles
  • most of the time you get parental combinations
  • but very rarely you get recombinants
44
Q

Close Linkage Between Polymorphic and Disease Locus

A
  • if the polymorphic locus is sufficiently closely linked to an autosomal dominant disease gene, we can score the presence of a particular allele at the polymorphic locus as a predictor of affected status
  • variation at the polymorphic locus is NOT responsible for the disease phenotype, but is LINKED to the genotype that is responsible for the phenotype
45
Q

Haplotype Analysis

A
  • by increasing the number of markers tested you have a better chance of defining the chromosomal region carrying the affected gene
  • alleles at linked loci distinguish maternal and paternal chromosomal regions
  • haplotypes consisting of co-segregating alleles are common because recombination is infrequent and not entirely random
46
Q

Is recombination random?

A
  • no
  • there are locations on a chromosome where recombination is supressed e.g. at the centromere
  • and regions where recombination is frequent, recombination hot spots
47
Q

Linkage Disequilibirum

A
  • loci between which there is very little recombination, causing allelic co-segregation, are said to be in linkage disequilibrium
  • linkage disequilibrium describes a measure of the ‘correlation of co-segregation’
  • it can be calculated as a correlation coefficient which decreases as distance between loci increases
48
Q

Co-segregation and Recombination

A

-cosegregation and recombination can be used to locate chromosomal regions where genes of interest must lie

BLGY1232 (19 decks)

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