polymorphisms and mutations

polymorphisms

• a genetic variant present in the population in a frequency

• the stable co exsitence of more than one variant (allele) of a gene in a population

• a non pathogenicc genetic variant (irrespecive of frequency- clinical genetics definition)

single nucleotide polymorphisms

• what does each represent

• where is it found

• what does it act as

• most common

• each snp represents a difference in a single nucelotid

• occur normally throughout a perosns DNA , 1 in 1000 nucleotides

• might be unique to a person or common populations

• found in DNA between genes and act as markes to locate disease associated genes

• snps within a gene or in a regulatory region near a gene may play a more direct role in disease by affecting a genes function

hereditary mutation-

• happened in the prev generations and were transmitted down through the germline

• must be present in sperm or egg for this to cuur

aquired mutation

• changes which occur during the lifetime of the individual

• if only present in the somatic cells these will not be passed on.

point mutations

• substitution of a single base pair of DNA

• missense or nonsense

• conservtive or non

• insertion or deletion of 1bp are not considered point

what are synonmous changes and where does this usually occur

when a base change occurs in a codon without altering the amino acid

usually happens in the 3rd base of hte codon.

what are non synonymous changes?

• if a base change occurs at site 1 or 2 this usually changes the amino acid the codon codes for

• non silent changes

missense mutation and 2 types

• change a codon - causing a change in aa

• conservative if the amino acid sub has similar biochemical properties so little to no effect on protein structure or function

• non conservative- diffeent buichemcial properties so major effect on prtein strcture or funciton

• properties include positive, negative, non polar, hydrophobic side chains. special cases include cysteine, selenocysteine, glycine, proline

hyperkalemic periodic paralysis

• what type

• what does it affect

• where is it descended from- type of mutation

• what is it responsible for

• hereditary autosomal dominant

• affects horses under stress

• undergo a paralytic attack affecting most skeletal muscles

• most descended from a single stud (spontaneous germline mutation)

• sdeclared the HYPP status of quarter horses

• partly responsible for the enhanced muscular tone of this animal

• trait was highly desirable for breeder

HYPP how does it work

• what is it

• what substitution and where

• what does this cause

• is a sodium channelopathy

• single nucleotide change causes phenylalanine to leucine subsitution in a domain of a transmembrane ion channel

• prevents complete inactivation of the Na-K channel

• channel becomes leaky allowing potassium to escape while Na enters continually enhancing muscle tone

• after stressful exercise elevation of extracellular potassium escaping through channels that are working normally. persistent inward sodium current int he aberrant channels

• complete depolarisation of the membrane- loss of electrical excitabilith and onset of a paralytic attack

what do nonsense mutation create

truncated protein due to premature stop

citrullinemia

• what breed is affected

• what type of mutation and which enzyme is affected

• which mutation and which aa is afected

• what does this lead to

• rare genetic disorder in holstein freisians

• nonsense mutation causes premature stop codon in arginosuccinate synthetase ASS enzyme

• C-T mutation converting arginine 86 to stop

• urea cycle is arrested- build up of circulating ammonia

• neurological and locomotor fefects - ataxia, blindness, aimless wandering and death

• treatment rarely successful- euthanasia

nonsense mediated decay

• what does the initial transcript contain

• when the introns are spliced out of mrna what proteins remain

• normally what does the ribosome do

• where are normal stop codons located

• what happens in nonsense mediated decay

• initial transcript contains exons and introns

• introns spliced out of mRNA- proteins known as exon junction complexes remain where exons spliced together

• normally ribosome moves along mRNA displacing EJCs untl it hits stop codon at the end of the open reading frame

• nromal stop codons are always downstream of the last EJC

• if a mutaiton creates a new premature termination codon that stops translation before ribosome reaches the last EJC then NMD is activated: mrna is degratded and little to no protein is produced

examples of nonsense mediated decay

• which species is affected

• symptoms

• signs of a carrier

• what is affected

• crooked tail syndrome in belgian blue cattle

• recessive disorder showing musuclar hypertrophy

• scolioiss and tail deviations

• carriers have increased muscle mass

• mRNA levels reduced in carrier and affected as mutatn mrna with ptc degraded by nmd

• reduction in mrc2 prteons indiseased and carrier animals as mrna degraded by nmd

mutations in non coding regulatory regions

• where

• what does this lead to the disruption of

• mutations in which location affect translation, and how does this happen

• mutations in the promoter sequence or enhancer regions can affec gene expression- disrupt the binding of transcription factors required to turn genes on or off

• Mutations in 5’UTR or 3’UTR of mRNAs can affect translation.

• - destabilise mrna causing it to be degraded before translation can occur

• prevent the binding of factors whihc promote/repress translation of mRNA into protein

molecular basis of musculature in texel sheep

what is aneuploidy

chromosome consittution with one or more chromosomes extra or missing from a euploid set

Estimated that ~50% pregnancies are lost before implantation

Most due to chromosome number/structure abnormalities

Trisomy 21 – viable (Down’s syndrome)

Trisomy 13, 18 – most die < 1month after birth

Sex chromosome aneuploidies tolerated

XXY   – Klinefelter Syndrome

XYY(n)   – XXY Syndrome

XO   - Turner Syndrome (only 1 X chromosome)

Not always whole chromosomes – parts can break off and get reattached to other chromosomes

copy number variation

differences between individuals in regions of chromosomes 1-100kb in length

INDEL

• what does it caused by

insertion and deletion

polymorphimsm between individuals caused by insertion or deletion of regions of chromosomes

insertions are often caused by 2 classes of transposable elements- DNA elements whihc can copy themselves and insert into other areas in the genome

SINE and LINE

• how many base paired long and how many copies per genome

• what can insertion of these into coding or regulatory sequences of a gene cause

Short interspersed nuclear elements - <500bp long (10⁶ copies/genome)

Long interspersed nuclear elements - >5000bp long (10⁵ copies/genome)

Insertion of these into the coding or regulatory sequences of a gene can cause insertional mutagenesis if the insertion disrupts gene expression or protein function.

types