mendelian inheritance of human disease Flashcards
what are the 5 types of mutation?
- Base change causing amino acid change (missense)
- Base change causing premature stop
- Insertion or deletion of bases “in frame”
- Insertion or deletion of bases out of frame
- Mutations affecting promotors or splicing
what are 3 mendelian inheritance mutations which cause disease?
- Autosomal dominant - passed on through generations
- Autosomal recessive - passed on through gen but not necessarily expressed
- X-linked
- Mitochondrial
packaging of DNA:
what is a chromosome?
what is a gene?
what is a locus?
what is an allele?
- chromosome = linear DNA molecule
- gene = length of DNA which encodes a particular protein
- locus = genes are arranged along the chromosome in a linear order, with each gene in a precise location
- allele = alternative forms of a gene, varying in each individual
- each chromosome bears only a single allele at a given locus
how man chromosomes does a human have?
- Human = 46 chromosomes = 2x23 homologous pairs
- in females = 2x22 and XX
- in male = 2x22 pairs and XY
what is a genetic disease?
what are 5 examples of changes in DNA sequences?
Genetic disease - a disease caused by changes in the DNA sequences (genes)
- chromosome aneuploidies (extra or missing chromosome)
- more subtle chromosome abnormality (deletion/moving of locus)
- extra piece of chromosome
- missing piece of chromosome
- change in gene sequence:
- insertion/deletion of bases/change of single base
where and when can mutations occur?
mutations can occur anywhere and could change information flow and cause a deleterious effect:
- DNA is the whole genetic information
- Transcription - converting DNA to mRNA
- Translation - converting mRNA into proteins
mutations and their effects:
what do promoter and splice site sequence changes effect?
- Promotor and splice site sequence changes:
- Stops transcription or causes abnormal splicing
mutations and their effects:
what do base changes which cause an amino acid change (missense) cause?
- Base change causing an amino acid change: (missense)
- Causes change in protein sequence
- Not every base change causes disease (not all deleterious)
- This may or may not reduce protein function
- Some missense mutations make a protein work faster (advantageous)
- base change causing a premature stop codon
mutations and their effects:
what can the insertion or deletion of bases cause?
- Insertion or deletion of bases:
- remember that 3 base pairs encode 1 amino acid
- Mutations may be “in-frame” or “out of frame”
what is a trinucleotide repeat expansion?
the replication of a trinucleotide
what is mendelian inheritance?
what is non-mendelian inheritance?
Mendelian Inheritance: a change in a single gene, sufficient to cause clinical disease, is inherited in a fashion predicted by Mendel’s laws
everything else including common “multifactorial” disease e.g. cancer
what are the symbols and meanings for a pedigree drawing?
what is the percentage of shared genes within first degree relatives?
- offspring is 50% unless identical twins, then 100% of genetics are shared
what is the percentage of shared genes within second degree relatives (cousins)
25% percentage of shared genes
what is the percentage of shared genes within third degree relatives?
12.5% of genes shared
describe autosomal dominant inheritance
- only 1 faulty copy of gene to cause disease
-if the mutation on the allele is autosomal dominant, then the disease is seen in all generations
- there is a 50% risk of offspring being affected if a parent is affected
- the disease severity can be variable, as some individuals with a mutation may not show disease
- male and females are equally likely to be affected
- example: Marfan’s syndrome, mutations in Fibrillin 1 (FBN1)
what is allelic heterogeneity?
different mutations in the same gene can cause the same disease (allelic heterogeneity)
- seen in Marfan’s syndrome
what is locus heterogeneity?
the same disease (phenotype) might be caused by mutations in one of several genes (locus heterogeneity)
seen in:
hereditary Haemorrhagic Telangiectasia (HHT1)
- caused by a point mutation in Endoglin Gene on chromosome 9
hereditary Haemorrhagic Telangiectasia (HHT2)
- caused by different mutation of different gene
however different mutations, the same phenotype (disease) is seen
describe autosomal recessive inheritance
- 2 faulty copies of a gene is needed to cause disease
- often only one generation affected
- 1 in 4 risk of an affected child if parent’s carriers
-
increased likelihood in consanguineous families (inbred)example: sickle cell anaemia
- single cell base pair change within the coding sequence of the relevant gene and changes one amino acid that produces the disease if you inherit 2 mutated version
GAG=glutamate
GTG=valine
describe X linked inheritance
- the affected gene (gene fault) is on the X chromosome
X-linked recessive
-a female carries a mutation but will not show major features of disease
- for a female carrier:
- half of the male children of carrier will be affected
- half of the female children will be carriers
- for an affected male
- all of the male children will be normal (no male to male transmission)
- all of female children will be carriers
X-linked dominant
- a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.
what does the X chromosome contain? give two examples of x linked conditions
what does the Y chromosome contain?
X chromosome:
- lots of genes of present
- x linked conditions: dystrophin or haemophillia
Y chromosome:
- not many genes present
- contains SRy gene which is male determination
complications to basic pedigree patterns:
define nonpenetrance
define variable expression
nonpenetrance: failure of a genotype to manifest
variable expression: different family members may show different features of a disorder
- both seen more often in dominant conditions
- these features can be due to influence of other genes and environment, as well as chance
what do the DNA base pairs within mitochondria code for?
why is this DNA inherited exclusively maternally?
they mainly code for genes which are mainly involved in mitochondrial function which produce mainly mitochondrial specific proteins (genes for mitochondrial metabolic pathways and ribosomal RNAs)
inherited almost exclusively maternally since majority of mitochondria is within the eggs before fertilisation
