Lecture 3: Genetic basis of disease (2) Flashcards
a catalogue of inehrited clinical disorders established by
Victor McKusick in 1966.
current online version describes 3958 human disorders with Mendelian inheritance.
out of 3958 how many have been assigned to a specific gene. multiple genes
3645
Many chronic non-communicable human disease are caused by
multiple genes interacting both with each other and environmental factors
impossible to identify “the gene” in such situations, since many genes
are involved
e.g. of Many chronic non-communicable human diseases cause by multiple genes
Heart disease
Diabetes
Obesity
Cancer
Hypertension
Schizophrenia, autism & other neuropsychiatric disorders
Multiple Sclerosis
SNPs
Single nucleotide polymorphisms
- total of ~ 3x107 SNPs within the human genome
- SNPs are distributed randomly across the genome
~500,000 SNps distributed throughout the human genome provide
a detailed map of DNA sequence variation across the genome
How can SNPs be used to identify DNA sequences associated with
common diseases?
- Genome-wide analysis allows all of the SNP sequence variation to be
catalogued and compared from one person to the next - The SNPs present in each individual genome within a group of patients are
compared to the SNPs present in the genomes of healthy individuals
- a case versus control comparison
3. SNPs are identified that are more frequently found in patients (cases) than in healthy individuals (controls).
- Such high-scoring SNPs are thus associated with the disease and may play
potentially causative roles in the disease process. - These studies are called Genome Wide Association Studies (GWAS).
if out of two alleles within an SNP associated with a disease an allele is more frequent than the other then
the locus is associated with the disease.
Or if the 2 alleles are found in equal proportions in patients with this disease? If so then this
locus is not associated with the disease
GWAS
Genome Wide Association Studies
Genome Wide Association Studies can identify
Single Nucleotide
Polymorphisms (SNPs) that are associated with disease phenotypes
Genomic imprints are
structural modifications to specific regions of particular chromosomes that prevent the transcription of genes within such regions.
- inc. methylation of DNA sequences
imprinting of genes in mammals: Different imprints are introduced into the chromosomes of
sperm and eggs
The patterns of DNA methylation on the chromosomes of spermatozoa and eggs persist in the somatic tissues of the progeny that are formed at fertilisation
….but they are removed during germ line development within the embryo and re-applied in a pattern dependent on the sex of the embryo
Methylation of DNA on cytosine bases in CpG dinucleotides is a hallmark
of imprinted chromatin:
helps to switch genes off
in methylation of DNA on cytosine bases in CpG dinucleotides: cytosine becomes
cytosine –methylation–> 5-methylcytosine
Localised methylation of DNA occurs on a specific subset of genes during
oogenesis (Chromosome
From mother
maternal copy
-not expressed carries maternal imprint) & spermatogenesis (Chromosome
from father
paternal copy - not expressed carries paternal imprint)
oogenesis
is the production of an ovum
spermatogenesis
the process in which spermatozoa are produced from spermatogonial stem cells by way of mitosis and meiosis
Reciprocal genomic imprinting of UBE3A and SNORD116 complex
of genes on Human Chromosome 15 – in NORMAL somatic tissues
Human Chromosome 15 from mother
maternal copy:
-SNORD116 not expressed - IMPRINTED
-UBE3A Expressed
Human Chromosome 15 from father
paternal copy
-SNORD116 Expressed
-UBE3A not expressed (imprinted)
UBE3A carries a paternal imprint
SNORD116 carries a maternal imprint
MATERNAL / PATERNAL IMPRINTS ARE CREATED DURING
Gametogenesis.
Egg; SNORD116 not expressed, UBE3A expressed
Sperm: SNORD116 expressed, UBE3A not expressed.
Are then maintained in the somatic cells of an embryo
Imprint are erased in
EMBRYONIC PRECURSORS OF GERM CELLS
DURING EMBRYONIC DEVELOPMENT
MATERNAL / PATERNAL IMPRINTS ARE STABLE BUT
NOT PERMANENT
EPIGENETIC CHANGES:
RE-ESTABLISHED DURING SPERMATOGENESIS / OOGENESIS
DEPENDING ON SEX OF OFFSPRING
Since only one of the two alleles of an imprinted gene is transcribed in
somatic cells, heterozygosity for a mutation that inactivates the product
encoded by the transcribed copy may cause
disease
Prader-Willi Syndrome:
Low muscle tone, short stature, cognitive disability,
Chronic hunger, morbid obesity - caused by mutation of SNORD116 complex
Angelman Syndrome:
Cognitive disability, sleep disturbance, seizures, jerky
movements, frequent smiling - - caused by mutation of UBE3A
The genomic imprints and the impacts of syndromic mutations are
parent-of-origin specific
The human genome project revealed that
there is an enormous amount of
DNA sequence variation between individuals.
Some variation is associated with
human diseases and identifies
individual genes that contribute to polygenic disorders.
. Genetic defects in Imprinted Genomic Regions can cause parent-of-origin
specific syndromes in heterozygous individuals: when a loss-of-function mutation in the non-imprinted allele is combined with a wild-type imprinted allele, then neither allele produces wild-type gene product and the clinical phenotype results.
