L4 - Polygeneic and somatic disorders Flashcards
what are polygenic disorders caused by
envirnoment and genetics
= monogenic disorders just caused by a singl gene so has little effect from environment
define epistasis
interactions of different non-allele genes
= expression of gene 1 relies on expression of gene 2
what is genetic heterogeneity
prescence of multiple genetic factors that contribute to a single phenotype
= can be different pathways to achieve this
give 3 charecteristics of polygenic or ‘complex/multifactorial’ disorders
multiple genes involved
inheritance is unclear
genetic and envirnmental influence
define liability
all the contribting factors for a disease
= population on a model shows a normal distriibution
Above a threshold disease develops
genetic factprs shift the cirve increasung or decreasing chance of developing disease
define heritability
proportion/percentage of the ‘risk’ to obtain a disease being due to genetic factors
what can be used to analyse heritability
twin studies
= due to being gentically identical a disease in one and not the other would be due to environmental factors
why are there problems with genetic analysis of polygenic disorders - 3 reasons
- genetic heterogeneity:
several suscptibility genes with varying levels of effects
= difficult to pinpoint which gene/mutation is cause
= disrupts linkage analysis
- not all succetible indiviudals are affected:
just because sombody has the mutation doesnt mean they express the phenotype
= Brac1 exqmple with breast cancer
- phenocopy:
disease is just due to environmental factors
name 2 methods for identifying genes in polygenic disorders
- Linkagae analysis:
works best with families and is MUCH LESS effective. ompared to when doing monogenic disorders
= sib-apir analysis is used
- Asociation studies:
GWAS –> use statistical tests to find markers/differences/SNPs
define and explain sib-pair analysis
Non-paramentric form of linkage analysis
siblingings share 50% of their DNA on average
by comparing siblings that both have a disease/trait we can identify regions that they share more often than expected by chance
what are candidate genes
genes that are assumed to be responsbile for a trait based on prior knowledge of function,loci ect
what is a genome-wide association study (GWAS)
studies that scan the entire genome of many individuals to find genetic markers associated with particular diseases or traits
= identify genetic variants (usually single-nucleotide polymorphisms (SNPs) that are associated with specific traits or diseases
describe the method of GWAS in gene identification for polygenic disorders
- candidates are split into those affected (cases) and inaffected (controls)
- analyze millions of SNPs across the genome using genotyping arrays.
- Each SNP is tested to see whether its frequency differs significantly between the case and control groups.
= Finds SNPs that are significantly more common in people with the disorder
= threshold value in place to see if due to chance or not
limitations of genome-wide asociation studies
- Correlation not causation:
identifies asociations = this does not necasarily mean that gene is responsbile - large sample required to detect small variations
- different ethnic populations are not differentiated
define the linkagae disequilibrium
specific combinations of alleles or genetic markers are found together more than expected by chance
= genetic material inherited together
= scientists use this to only tag SOME SNPs not all
= can then infer based on the tagged SNPs the ones around it as they are inherited together/LD
Following GWAS and gettimg some ‘hits’ what should be done
Fine mapping:
Narrow down the region around the hit to identify the most likely causal variant
= Use statistical tools or sequencing data to distinguish between the SNPs in LD
define ‘quantitative trait’ and ‘quantitaive trait loci’
QT:
a measurable ‘continous’ phenotype/trait that
QTL:
location of the genes that cause this measurable trait
= found tghrough mapping/statistical analysis
define what ‘mapping’ actually is
Process of identifying the locations of genes or other genetic markers on chromosomes
genetic mapping = inheritance through generations due to recombination events –> linkage analysis or GWAS
physical mapping = physical location of genes or markers on a chromosome –> uses methods like FISH
define what expression QTLs are (eQTL)
variations in the expression of a gene rather than the actual gene itself
= QTLS identify a gene is responsible
= eQTLs identify how much they are responsible due to differences in gene expression
how could expresiion eQTLs affect transcriptional,post transcriptional and post translational modifications
- changes in regulatory elelements = more transcription, methylation due to more CPG islands
- affect expression of splicing proteins
- affect protein stucture - inactive or alterred post-tran modifications
give an example of height in humans of how SNPs/eQTLs can affect transcription,post tramnscription and post translational regulation
A QTL for height might affect the transcription of a growth factor gene, making it more or less active (transcriptional regulation).
That same QTL might alter the stability of the mRNA produced by the gene, affecting how much protein is made (post-transcriptional regulation).
The QTL could influence the modification of the protein produced, such as phosphorylation or glycosylation, which could affect its activity in growth pathways (post-translational regulation).
name 2 polygenic disorders
Schizophrenia
Type 1 diabetes
what type of disease is type 1 diabetes
polygeneic disorder
autoimmune insulin-dependnat disease
early onset
= 6p21 codes for MHC/HLA molecules = defect causes immune cells to attack beta cells in pancreas
= where insulin is produced
name 2 ways that type 1 diabtetes loci were identified
Non-parametric linkagae analysis - sib-pair
Genome-wide assiciation studies with SNPs
