chromosomal abnormalities and inheritance of complex traits Flashcards
what are the four types of human genetic disease?
Single gene disorders
Genetic components of complex diseases
Chromosomal abnormalities
Mitochondrial diseases
what is aneuploidy, including three examples?
Aneuploidy - extra/lost chromosomes
Note - not the same as polyploidy which is no. of copies of whole genome, i.e. we are diploid organisms, bananas are triploid, wheat are hexaploid etc…
Examples:
Down Syndrome (trisomy 21)
Klinefelter syndrome (XYY)
Turner syndrome (X0)
name 5 sorts of changes that can occur to chromosome structure?
Deletions (a really big deletion visible on a microscope, e.g resulting in 5p deletion syndrome)
Duplications
Inversions - causes problems in meiosis for crossing over - swapping the wrong material
Reciprocal translocations (not same as substitutions)
Robertsonian translocations (can be a cause of down syndrome) long arms of two chromosomes come together, then the short arms of two also come together and are then often lost
what are some characteristics of down syndrome/trisomy 21?
growth failure
broad flat face
congenital heart disease
enlarged colon
abnormal pelvis
intestinal blockage
diminished muscle tone
many loops on the fingertips
what is trisomy 13?
Patau syndrome (trisomy 13)
Severe physical and mental abnormalities
Harelip
Small head
Rocker-bottom feet
Life expectancy of 130 days (though this is only an average, cases occur with patients surviving for years)
what is trisomy 18?
Edwards syndrome (trisomy 18)
Severe physical and mental abnormalities
‘faun-like’ ears
Small jaw
Narrow pelvis
Life expectancy – several weeks
give an exmaple of a sex chromosome disorder and its symptoms
Klinefelter syndrome (XXY)
sterile
tall
feminised physique
mildly impaired IQ
poor beard growth
small testes
breast development in 30% of cases
what are the four main causes of down syndrome?
95% of cases = nondisjunction , usually in maternal meiosis I
In rare families in which there is paternal nondisjunction, most of the errors occur in meiosis II
Robertsonian translocation. Chromosome 21 and 14 form a hybrid - not an entire extra copy of chromosome 21 but enough (4% cases)
Mosaics – nondisjunction at mitosis in early development of the embryo, so one cell has one copy of chromosome 21, the other has three. The trisomic cell survives and continues to develop, the monosomic one does not. The severity of down syndrome depends on when this nondisjunction occurs in development (earlier on = more cells affected) (1 % cases)
explain how NDJ in meiosis occurs at the first division
NDJ at meiosis one is more common in maternal cases, the homologous chromosomes from mum and dad (or nan and grandad if referring to the baby with down syndrome) are not separated, producing two gametes with no copy of chromosome 21, and two gametes with two copies of chromosome 21, but these copies are maternal and paternal/different alleles (important in diagnostics)
explain what happens when NDJ occurs in meiosis II
NDJ here is more common in the paternal line, at meiosis II
(inside dad) The homologous chromosome pairs from nan and grandad are separated in meiosis one
At the second division, one of the cells divides giving both copies of chromosome 21 to a single gamete (so this gamete has two identical copies of Chr 21/same alleles as they are from the same grandparent), so the other has no Chr 21
The other cell from meiosis one produces two normal gametes
how does Down Syndrome occur via Robertsonian translocation?
Chromosome 21, and another chromosome usually 14 (but not always), ‘translocate’, i.e. mix and match
where the long arm of 21 and 14 combine, and the short arms also combine. This results in a long chromosome carrying most of the genetic information from Chr 21 and Chr 14, and a short chromosome carrying few genes from Chr 21 and 14 - this short chromosome is usually lost in meiosis
We count the one long chromosome as a ‘full’ or viable copy of Chr 21 AND Chr 14 because it still contains most of the genetic information
this combined chromosome 14+21 can go down three possible routes
the route that results in trisomy 21 is when the normal Chr 21 is paired with the long chromosome made up of Chr 21 and 14’s long arms (so normally it should just be a regular Chr 14, but it counts as a copy of Chr 21 and a copy of Chr 14) so when a sperm brings along it’s single copy of Chr 21 the resulting zygote has three Chromosome 21s (albeit one of which is missing the short arm)
note - other route results in trisomy 14, and the other one results in normal gametes + balanced carriers
what is the maternal age effect?
The older the mother is at conception, the more likely the child is to have down syndrome
Possible explanation:
Oocytes are arrested at diplotene before birth
Meiosis only resumes at each menstrual period (so they’re waiting to undergo meiosis II).
This means that the chromosomes in the bivalent must remain properly associated for decades…
So there might be mechanism contributing to increased maternal nondisjunction with age (1 in 100 at 40)
why is the maternal age effect (DS) flawed?
most nondisjunction related to the effect of maternal age is due to nondisjunction at anaphase I, not anaphase II
***But not all of it! Still being researched
how would paternal down syndrome be diagnosed?
two of the copies of Chr 21, from dad, are identical (meiosis I was successful, its at meiosis II when the two sister chromatids are passed on together, so they’re identical)
if it were maternal, the three copies of Chr 21 would be different
what’s a continuous trait?
what’s a categorical trait?
Continuous - human height for example - any value is possible
These typically have complex inheritance - multiple genes + environment determining outcome
Categorical - includes single gene disorders like CF - you have it or you don’t
Can involve multiple genetic and environmental factors - e.g. diabetes (have it or you don’t - kind of)
in this case there is a threshold trait - accumulation of risk factors end up reaching a threshold at which point you ‘have the disease’
***Complex inheritance pattern (for these threshold traits)
are continuous and categorical traits mutually exclusive?
A categorical trait may involve an underlying continuous trait, e.g. blood glucose in diabetes surpasses a certain threshold
what is quantitative genetics?
studies the inheritance of traits that show complex inheritance patterns resulting from a mix of genetic and environmental factors
May cover continuous or categorical traits
Any biological phenomenon for which variation exists may show complex inheritance and can be studied as a complex trait
statistics - what values do you need to know when studying complex inheritance?
The mean - of group/sample/population that could potentially interbreed
Variance - degree to which trait of individuals deviates from the population mean
Standard deviation = sq. root of variance - preferred because it has the same unit as the mean and is therefore more understandable in context
Normal distribution
Correlation and regression
what causes normal curves of traits in populations?
variation can be due to genetic or environmental factors
A combination of these factors is what causes ‘normal curves’ of traits in populations
explain the equation used for quantifying gene-environment interactions
For any quantitative trait:
X = _X + g + e
X = value for trait in question
_X = population mean
g = deviation from mean due to genetics
e = deviation from the mean due to environmental variation
OR
Vx = Vg + Ve
This is another way of looking at gene-environment interactions - by quantifying the variances caused by genetics vs environment
Phenotypic variation = genetic variation + environmental variation
in terms of the two equations used to quantify gene-environment interactions, what is a good idea when studying a trait?
You want to make either g (deviation from mean due to genetics) or e (due to environment) equal to zero, so you can study the other one
Clones or inbred lines, for example, would mean g = 0
Selfing - is simply crossing an organism with itself - C. elegans and yeast can do this, other organisms like mice aren’t and are inbred instead
what is broad sense heritability?
why is it important?
Broad sense heritability = how much of variation seen is due to genetics, how much is the environment?
Why we care -
Knowing the cause = more targeted and effective treatment
If, for a disease, you discover environment is the issue, you can recommend a lifestyle change
If it’s genetic, you can research potential medicines
equation for heritability?
H2 = Vg / Hx
Heritability = the degree of variation in a phenotype within a population that is due to the genetic variation
Broad sense heritability = variation due to genetics over all of the variation
If broad sense heritability = 0, all variation must be due to environmental factors
So in inbred lines, H2 = 0
what a three things you can do to get around the stats challenges of modelling complex disease?
- Huge numbers - to lessen effects of hugely varying life choices and environments
- Case controlled studies - healthy vs patient group compared to identify effects of the disease in question. Not as powerful as large-scale studies but they are less expensive
- Pooling samples - combining patient data from multiple studies
when studying complex traits, genetics vs environment etc… its important not to?
DOUBLE DIP
Very important to use different data sets - at the 95% level, 5 % of the time there will appear to be a significant difference when THERE IS NOT - if you are using this same data set over and over again for multiple diseases you increase your chances of getting a false positive
how are twin studies used to look at complex inheritance?
You observe correlation between monozygotic and dizygotic twins, to see how much variation is due to environment (only option in identical twins), and compare to dizygotic twins
Monozygotic twins share 100% same genes, so any variation must be due to environment.
if The 90% of monoz. are the same, and around 60% for dizygotic twins (who share 50% genes), you can assume there is a strong genetic component,
If there was no genetic component at all, you would expect both twins to
Be equally similar (the only factor influencing variation would be environmental)
what is the first indication in a twin study that a disease has a strong genetic component?
A higher percentage of disease incidence in both identical twins is the first indication of a genetic component.
however - percentages lower than 100% in identical twins indicate that DNA alone does not determine susceptibility to disease, other factors must be involved
For twins with schizophrenia, 50% identical twins share the disease, while only about 10-15% of fraternal twins do.
This difference is evidence for a strong genetic component in susceptibility to schizophrenia
twins environments become more different as they age. How can this be useful tor researchers?
If one twin gets a disease while the other doesn’t, it is likely due to an environmental factor, which researchers can try to identify
If both twins get a disease despite different environments, researchers can look for similar genetic components that are likely to have contributions change
what evidence showed how twins’ environments change as they age?
Young twins still have very similar epigenomes, but older twins can have hugely different epigenomes
The more different the twins’ environment, the more different their epigenome
does everyone like twin studies?
prof. Wendy Johnson, a psychologist, believes genetics and environment cannot be untangled, they are not independent (which is what all the stats relies on)
