Lecture 13 - the human genome & DNA sequencing Flashcards
How does genetics affect our health throughout our lifespan?
embryonic - it is hard to obtain accurate numbers, but it is predicted that in the region of 50% of embryos have chromosomal defecrs
newborn babies - 5% of newborns suffer from a congenital disorder
- chromosomal
- mitochondrial disorder
- single gene
- complex (multi-factorial, genetic and environmental components)
What portion of diseases in later life have a genetic component in their aetiology (cause of disease)?
2 out of 3 diseases
What are prenatal chromosomal disorders?
- 85% clinically recognised conceptions terminate due to chromosomal abnormalities
- Predicted that up to 50% of conceptions terminate due to chromosomal abnormalities
What are live birth chromosomal disorder?
- 0.1% of live births display chromosomal abnormality
- aneuploidy (e.g. Down’s syndrome - Trisomy 21)
- chromosome translocations
Describe mitochondrial disorders
- each cell contains 100’s of mitochondria
- mitochondria has its own genome - 2-10 copies of a circular 16.6Kb genome
- Normally all copies of mDNA in a cell are the same (homoplasmic)
- in the case of a mutation in copy of mDNA a mixture of genomes arise (heteroplasmic)
- mutations within mDNA results in a number of mitochondrial disorders
- mitochondrial disorders do not follow Mendelian patterns of inheritance
- mitochondria are maternally inherited from cytoplasm of the egg
Where is mitochondria inherited from?
mitochondria is only inherited from the mother (from the cytoplasm of the egg)
Describe single gene disorders
- diseases alleles are a single gene
- follow a Mendelian inheritance pattern
- conditions are individually rare, but collectively common
- high penetrance (deterministic)
- tests are predictive
Describe complex diseases
- risk alleles are at multiple genes (polygenic)
- no simple pattern of inheritance, but runs in families
- conditions are common
- suggest a susceptibility, are not deterministic
- no reliable tests
- influenced by the environment
What is are the vital statistics of the human genome?
- 3.2Gb (3 x 10^9) base pairs
- Approximately 1.1% of the human genome is “coding” i.e. encodes proteins
- 20,500 proteins encoding genes
- As a comparison, Yeast - 6000 genes and Fly - 14,000 genes
is the remaining non-conserved - 90% of the human genome functional
What is much of the DNA content of a protein encoding gene?
non-coding sequences (introns)
Describe ENCODE - encyclopedia of DNA elements
- the Encyclopedia of DNA elements (ENCODE) consortium is an international research collaboration
- the goal of ENCODE is to build a comprehensive parts list of functional elements in the human genome
- this is achieved through a numerous genomic, functional & bioinformatics approaches
- this list includes elements that act at the protein and RNA levels and regulatory elements
Describe the process of sequencing the human genome
- draft of the human genome published 2001 following 15 years ($3 billion)
- 2 competing consortiums:
- International Human Genome Sequencing Consortium (IHGSC)
- Celera Genomics
Why was sequencing large genomes technically challenging?
- length of the genome
- generating enough clones to ensure complete coverage
- accuracy - sequencing must be repeated
- reassembling the genome from individual sequences (especially repetitive elements
- Sequence the whole euchromatic region (92%) minus the heterochromatic and repetitive regions
What is Next generation sequencing (NGS)?
- Novel sequencing technologies reduce the time and cost of sequencing
- Different approaches offered by different companies, but all are based upon sequencing a lot of small fragments of target DNA in contrast to Sanger sequencing
