Sudbery (Human genetics) Flashcards
How was the human genome seq?
- HGO large intl consortium
- 1st mapped –> genetic maps, physical maps, clone maps, then seq
What were the 1000 genomes and ENCODE projects?
- seq whole genome of 1000 w/ ethnically diverse backgrounds, gave map of human diversity
- database of common mutations in healthy people
- human ancestry –> out of Africa, humans and neanderthals have common ancestor, both left Africa and some interbreeding, so non-Africans carry 2-3% neanderthal DNA
What are the characteristics of the human genome? (size, protein coding, conservation)
- 3x10^9 bp
- 1.1% encodes protein
- 20,500 protein coding genes
- 8% conserved w/ other animals = functional, eg. regulatory
- 50% repetitive DNA
Is the 90% non-conserved seq in human genome functional?
- biochemists say yes –> ENCODE projects
- geneticists say no
How is the human genome complex?
- DNA highly compacted into increasing successive levels of coiling
- active gene has transcribing region, promoter and regulatory region (can be far away)
What are coding regions (exons) separated by in human genome?
- introns
- spliced out in mRNA
Why are no 2 genomes identical?
- 15 mil common SNPs (single nucleotide polymorphisms)
- any individuals exome will contain 20,000 variants to standard seq
What are the characteristics of single gene disorders?
- simple Mendelian inheritance
- individually rare, but collectively common
- high penetrance but variable expressivity
- predictive tests available
- usually alter coding region
What are the characteristics of complex diseases and phenotypic traits?
- familial but no simple inheritance pattern
- relatives of affected have increased risk
- common
- influenced by env
- no reliable tests, susceptibility not deterministic
- risk alleles at many polygenes, usually non-coding, presumably regulatory regions
- multifactorial and polygenic
Why are genetic diseases more common in children of cousin marriages?
- everyone carries many recessive mutations
- most hetero mutations rare for any 1 allele, so chances of both parents carrying same allele low
- in cousins, for each allele hetero in grandparent, chance of homozygosity in each child for each allele =1/64
What does consanguineous mean?
- parents biologically related
What is haploinsufficiency and in what kind of inheritance is it found?
- need 2 copies to make enough protein
- autosomal dominant
What did the whole exome seq (WES) pipeline involve?
- seq exome 20,000 variants
- filter out common variant
- find gene inactivating mutations (change sense to nonsense codon)
- pedigree specific strategies (eg. if looking for recessive mutation in both copies, likely to be diff mutation in biologically unrelated parents)
- if same gene affected in unrelated cases then plausible biological mechanisms
- recapitulate in animal model/in vitro culture (give same mutations to see if effect same)
How has the way in which genes are identified changed?
- only mapping until 2009
- now WES/WGS more common and more genes identified
Case study of consanguineous autosomal recessive disorder - symptoms
- proband = 16yr old girl
- complex symptoms shared w/ 8 consanguineous relatives
- suggestive of 3 complex neurotransmitter disorders: dopamine, serotonin and epinephrine
- neurotransmitter levels normal
- dopamine breakdown products elevated in urine
- treatment to increase dopamine caused immediate worsening of condition
