POM 16 - Introduction to medical genetics and mendelian inheritance Flashcards
what is RNA
single strand molecule that is transcribed from DNA and translated into proteins by ribosomes
what are the 4 categories of genetically determined diseases
single gene disorders
chromosomal disorders
multifactorial disorders
somatic cell disorders
what are mutations
permanent heritable change in the sequence of genomic DNA
change in DNA from its natural state which may be disease causing or benign normal variant
what is polymorphism
occurrence of 2+ alternative genotypes which each at a frequency greater than that which would be maintained by recurrent mutations alone
natural variations in genomic DNA sequence which have no obvious adverse effects on individual and occur with high frequency
why are polymorphisms important
evolutionary advantage to have variety
what are the 6 types of mutations
silent
missense
nonsense
frameshift
splice donor/acceptor
InDel
what is a silent mutation
single base change in protein coding part of DNA that does not result in an amino acid change
what is a missense mutation
single base change that does result in amino acid change but may not cause an abnormal phenotype
what is a nonsense mutation
single base change that changes an amino acid to a STOP codon and truncates the protein that is made
what is a frameshift mutation
insertion/deletion of bases in anything other than a multiple of 3 and changes the reading frame
what is a splice donor/acceptor mutation
alteration of sequences for accurate splicing of introns
what is an InDel mutation
a frame shift mutation
insertion/deletion of one or more bases - if its not a multiple of 3 bases then will shfit reading frame
what are the 2 strands of DNA called
RNA is a transcribed version that is complementary to what strand of DNA
sense and antisense strands
RNA is complementary to the sense strand - looks like the antisense strand of DNA
what eventually happens in a frameshift mutation
eventually introduces a stop codon by random chance in frameshift mutation
what is nonsense mediated decay
if peptide produced is going to be nonsense then the RNA encoding it is often broken down/decayed
what is a somatic genetic mutation and who can it affect
if a new mutation occurs in the non gamete forming cells
consequences of mutation are limited to the person in whom the changes occurred
what is a germline genetic mutation and who can it affect
new mutation occurs in cells that form gametes
change my be transmitted to and inherited by subsequent generations
how many pairs of chromosomes do humans have and which are sex chromosome
23 pairs
one pair of sex chromosomes and 22 pairs of autosomes
where do genes occupy
specific loci/positions on chromosomes
what does it mean to say genes are paired
one paternal one maternal
what are alleles
alternate forms of genes
what does homozygous and heterozygous mean
if the maternal and paternal alleles are identical = homozygous
if the maternal and paternal alleles differ = heterozygous
what are the 2 phenotypic consequences of mutations
gain of function mutations
loss of function mutations
what is a gain of function mutation
produces either increased amount/activity of the encoded protein/gene product
what is a loss of function mutation
produces either reduced amount/activity of the encoded protein/gene product
what is the degree of effect that a mutation will have on the phenotype of only one allele is affected
minimal effect as the other allele can still compensate and make the protein
what is a null allele
if no functional protein or any protein is produced/results from an allele
what is halpoinsufficiency and why might it occur
where one normal allele copy isn’t enough to compensate for the mutated allele
could occur if there is a critical balance between different proteins needed
what is a dominant negative effect
the abnormal protein interferes with the protein encoded by the remaining wild type allele
what is the proband in a pedigree chart
the individual we are focused on
what does dominant and recessive single gene disorders mean
dominant = phenotype of mutation if one allele has been changed by mutation
recessive = phenotype of mutation if both alleles have been changed by mutation
if a trait manifests in a heterozygote then is the trait dominant or recessive
dominant
what are the 3 types of mendelian patterns of inheritance
autosomal dominant
autosomal recessive
X linked recessive
what is the pattern of inheritance for autosomal dominant inheritance - in terms of parents and number of alleles affected
affected person usually has at least one affected parent
only need one of the 2 alleles changed in order to be experiencing the clinical phenotype - the wild type may not be enough for normal cellular function (haploinsufficiency)
what is an example of an autosomal dominant inheritance disease
achondroplasia
what is achondroplasia in terms of symptoms, inheritance pattern and what gene the mutations affect
autosomal dominant
shortening of proximal limbs, dwarfism via premature ossification of cartilage into bone
mutation in fibroblast growth factor receptor 3 (FGFR3) gene
apart from autosomal dominant inheritance how can someone have achondroplasia with two normal parents
spontaneous/de novo mutation in fathers germ cells
in achondroplasia cases due to spontaneous father germline mutation what pathways are affected due to FGFR3 mutation and how does this explain why achondroplasia risk increases with paternal age
increased activation of RAS/MAPK and PI3K/AKT pathways
signaling pathways which promote growth and survival of cells are turned on more by FGFR3 mutation so gradually germ cells are selected for better survival so with age you are more likely to fertilize eggs with these sperm
what is the pattern of inheritance for autosomal recessive inheritance - in terms of parents
affected people born to unaffected parents
parents are heterozygous asymptomatic carriers
when are autosomal recessive disorders expressed phenotypically
phenotype is only expressed in homozygous state - both alleles are mutant
what is an example of a autosomal recessive disorder
haemochromatosis
what is hereditary haemochromatosis
iron overload over time causes organ and tissue damage and iron deposition
what is the concept of locus heterogeneity
multiple genes mutations can lead to same disease
what is compound heterozygosity
heterozygous however have both alleles where coding proteins are non functional
what is lyonisation
random inactivation of part of one of the X chromosome in femal somatic cells
who does X linked recessive inheritance tend to affect in terms of clinical phenotype and what is the pattern of inheritance in terms of the parents
affects mainly males
usually unaffected parents
what are the 4 complications to basic mendelian pedigree patterns
pseudo-dominant pattern
variable penetrance
variable expressivity
new mutations/germline mosaicism
explain how pseudo-dominant pattern can complicate mendelian pedigree patterns
common recessive disorders can give pseudo dominant pattern
explain how variable penetrance can complicate mendelian pedigree patterns
failure of dominant condition to manifest
what does penetrance mean in genetics
whether a trait manifests/ is expressed
explain how variable expressivity can complicate mendelian pedigree patterns
when clinical phenotype varies between 2 individuals with same genotype even with the same mutation
what are the 2 types of genetic heterogeneity
allelic and locus
what is allelic heterogeneity
different mutations at the same locus (same gene)
what is locus heterogeneity
mutations at different loci
what chromosome is affected and how in down syndrome
trisomy 21
what causes down syndrome - 2 things
non disjunction during metaphase 1 = 2 paired chromosome copies are not separated properly
translocations = part of chromosome is put on another chromosome
describe the mechanisms of translocation
short arm of one chromosome exchanges with the long arm of another chromosome
creates large chromosome and a smaller fragment that often fails to segregate and is lost
what are multi-factoral genetic disorders
interaction of multiple genes sequences/polymorphisms/recent mutations with each other and the environment
how do somatic cell genetic disorders arise
arise in single cell then propagates - ie not in all body cells and not at all in germ cells
are somatic cell genetic disorders inheritable
no
