BLGY1232 Locating genes underlying human phenotypes
If the biochemical basis of the phenotype is known
This usually means we know which enzyme is defective and we know something
about the polypeptide sequence of the enzyme
The protein sequence can be used in a genome database search to identify the
gene sequence in the human genome allowing us to PCR-amplify the dene for
affect and unaffected individuals and identify any mutation in the affected
individuals and their families to see if they are also at risk
Haemoglobin in haemoglobinopathies, Hexosaminidase A in Tay-Sachs disease,
Apolipoprotein E in typeIII hyperlipidaemia, Cystic fibrosis etc.
If we don’t know the biochemical basis of a condition
We have to locate where the gene is in the genome, identify the correct coding
sequence and determine the nature of the mutation and its effect on the protein
encoded
2 statistical approaches can be used; analysis based on genetic linkage or
analysis based on allelic association both rely on genetic variation
(polymorphisms) between individuals
To locate the gene, we need to know where it lies in the genome in relation to
other known sequences that differ between individuals - We need to analyse
how it relates to other polymorphisms and the key point is that the variant
sequence should be maintained within a proportion of the population: it’s not
just a one-off mutation
Polymorphism = The existence of two or more variants (alleles, phenotypes, DNA
sequence variants, chromosome structural variations) at significant frequencies
in the population
Autozygosity mapping
Pedigree analysis in families with a high incidence of consanguineous marriage
Where parents are related, there is a higher frequency of autosomal recessive
inherited disorders
They are obviously homozygous or the causal mutation, but they will also likely
be homozygous for a large region of the chromosome around this
We can try and determine the genotypes of affected individuals and their family
members, to identify the genetic interval within which the disease gene lies; this
region will be homozygous in affected and heterozygous in unaffected family
members
Generally, any genetic variant allele that exists at or above a frequency of 1% of the
population is considered to be a polymorphism.
If the biochemical basis of the phenotype is known
This usually means we know which enzyme is defective and we know something
about the polypeptide sequence of the enzyme
The protein sequence can be used in a genome database search to identify the
gene sequence in the human genome allowing us to PCR-amplify the dene for
affect and unaffected individuals and identify any mutation in the affected
individuals and their families to see if they are also at risk
Haemoglobin in haemoglobinopathies, Hexosaminidase A in Tay-Sachs disease,
Apolipoprotein E in typeIII hyperlipidaemia, Cystic fibrosis etc.
If we don’t know the biochemical basis of a condition
We have to locate where the gene is in the genome, identify the correct coding
sequence and determine the nature of the mutation and its effect on the protein
encoded
2 statistical approaches can be used; analysis based on genetic linkage or
analysis based on allelic association both rely on genetic variation
(polymorphisms) between individuals
To locate the gene, we need to know where it lies in the genome in relation to
other known sequences that differ between individuals - We need to analyse
how it relates to other polymorphisms and the key point is that the variant
sequence should be maintained within a proportion of the population: it’s not
just a one-off mutation
Polymorphism = The existence of two or more variants (alleles, phenotypes, DNA
sequence variants, chromosome structural variations) at significant frequencies
in the population
Autozygosity mapping
Pedigree analysis in families with a high incidence of consanguineous marriage
Where parents are related, there is a higher frequency of autosomal recessive
inherited disorders
They are obviously homozygous or the causal mutation, but they will also likely
be homozygous for a large region of the chromosome around this
We can try and determine the genotypes of affected individuals and their family
members, to identify the genetic interval within which the disease gene lies; this
region will be homozygous in affected and heterozygous in unaffected family
members
Generally, any genetic variant allele that exists at or above a frequency of 1% of the
population is considered to be a polymorphism.
