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How many live births have some kind of genetic disorder?

- approx 8% (but estimates vary) have some sort recognisable before adulthood


Are genetic diseases rare?

- individually rare but collectively common


What are most genetic disorders caused by?

- single gene mutation (= single gene disorders = SGD)


What major birth defects are there?

- chromosomal
- mitochondrial
- complex (multifactorial)


How common are complex diseases?

- before we die 2/3 will suffer from one


What are complex diseases?

- genetic component in etiology
- susceptibility caused by alleles at 100s-1000s lico and v heavily mod by env (interaction between genes and env)


Do freqs of SGDs vary, whats an eg.?

- yes, vary in diff pops
- eg. CF v common (1 in 500) in N. Europe, but rare everywhere else


What are some eg.s of common complex disorders?

- rheumatoid arthritis, epilepsy, MS, type I/II diabetes
- psychiatric disorders --> alzheimer's, schizophrenia, autism
- congenital defects --> cleft lip and palate, pyloric stenosis


What is the missing heritability problem?

- amount of genetic variability identified through GWAS etc. doesn't account for variation of heritability disorders


Where are SGDs catalogued?

- OMIM (online mendelian inheritance in man)


How many SGDs are there?

- ≈5000 disorders affection ≈3400 genes (so mutations in some genes responsible for more than 1 disorder)
- total no. documented = ≈7400
- ≈20,000 human genes


How common are chromosomal disorders prenatally?

- ≈8% clinically recognisable conceptions terminate due to chromosomal abnormalities
- but may be 50% of all conceptions (but most terminate before know pregnant)


How common are chromosomal disorders in live births, and what types are there?

- 0.1%
- aneuploidies --> Down's syndrome (trisomy 21), Edwards syndrome (trisomy 18)
- translations


How significant is the mito genome?

- 16kb, so much smaller than nuclear DNA, but sig amount by weight


What do mito disorders cause?

- multi system failures --> basal ganglia (causing ataxia), heart, endocrine system, sight and hearing, skeletal muscle


When does maternal inheritance and what does this cause?

- if mother heteroplasmic
- variable phenotype in siblings
- progressive onset
- diff degrees of severity in diff organs


What might accum of mtDNA (and therefore O free radicals) be involved in?

- ageing


Why bother identifying variants responsible for SGD?

- stopping repeated medical tests which may be invasive and distressing --> not needed as know diagnosis
- introd approp treatment and stop inapprop treatment (eg. for epilepsy usually have to try series of medication till find what works, but if know mutation, know treatment)
- psychological benefits to affected and family
- scientific knowledge


What are the difficulties w/ diagnosing rare diseases?

- genetic heterogeneity in medically well characterised disorders (sometimes over 50 genes) --> so diseases can be caused by mutations in many genes
- atypical disease presentation
- novel variant in known gene


What are some eg.s of diseases that genetically heterogenous?

- polydactyly
- retinitis pigmentosa
- lipid metabolism


What other problems is there w/ identifying alleles responsible or rare diseases (apart from w/ diagnosis)?

- if novel disorder but suspected SGD
- or documented disorder w/ unknown genetic basis


How has identifying genes assoc w/ disorders progressed?

- originally mapping
- now WES/WGS
- downward trend of genes identified in recent years


What are WES and WGS?

- WES = whole exome sequencing
- WGS = whole genome sequencing


Why is WES used and not WGS?

- SGD so far all in coding seq
- cheaper
- fewer variants to analyse (coding seq under selective pressure so less variation, unlike intergenic seq)


Where are complex disease variants usually found in genome?

- nearly all outside coding seq, in intergenic seq
- prob affect expression of coding seq


If each individual shows approx 20,000 variants after WES, then how can we identify causative variant of a SGD?

- predicted effect on protein function --> exclude any that don't affect coding seq (ie. silent/replacement), look at whether AA changes are conservative (if not, bigger effect, eg. hydrophobic for hydrophilic)
- disease allele will be rare, look at pop databases --> if recessive have to look for homozygous variant, doesn't have to be same mutation as long as affects same gene
- same allele in unrelated indivs w/ same disorder --> if unaffecteds too can rule out
- expert appraisal of biological relevance to disorder phenotype --> recapitulation in model system/organism and look at seq conservation
- databases of pathogenic variants (think genes not alleles)


What types of mutation can lead to loss of function, and how can loss of function be predicted/assessed?

- likely to lead to loss of function --> by frameshift, protein terminating variant (PTV), splice sites, exon deletions
- function prediction, eg. polar substitution in TM domain
- seq conservation
assessed by computer programmes, eg. SIFT, Polyphenz


When can usually loss of function mutations not be harmful and why?

- frameshift and PTV if near end of ORF don't have much effect


What was ExAC?

- exome aggregation consortium
- 60,000 exomes and identifies v rare alleles
- looks at pop freq to identify which alleles are v rare and which pot harmful alleles occur freq in apparently healthy indivs
- the size of the database is key


What has ExAC now been succeeded by?

- gnomAD --> 123,000 WES an 15,000 WGS
- multiple other databases now exist