203.341!

Module 3!
Genome Evolution:
Patterns and Mechanisms!
Austen Ganley, 2015

203.341!
Genome Variation!
Lectures 19-20!

Austen Ganley, September 28th, 2015

The Genome •  “The complete genetic material of an organism”! •  “All of the hereditary material possessed by an organism”! •  “The entire genetic complement of an organism”! •  “The total genetic makeup of an organism”! .

influenzae)! First eukaryote (S.virus)! First bacterium (H.1977:! 1995:! 1996:! 2001:! 2016?:! First genome (φX174 . cerevisiae)! Human genome! $1000 human genome! .

Chromosome structure •  In most eukaryotes. the genome is organised into several chromosomes! •  The basic structure of chromosomes is broadly similar for most species! .

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What’s in the genome? .

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copy number variations. fuelled obviously by mutation! •  Basically. structural changes (insertions. translocations). and chromosomal changes (aneuploidy. deletions. we can divide the mutations into substitutions. fusion.Mutation •  Genomes are undergoing continuous change. fission)! •  Should be aware of the general mechanisms by which substitutions occur (and what they are)! •  Will deal with transposon mutations in week 12! . small indels. duplications.Genome Dynamics . inversions.

Don’t forget somatic mutations: not heritable.. but still important!! .Problem with multicellularity.

duplications. but most homologous recombination is a DSB repair mechanism! .Structural Changes •  Most structural changes (insertions. deletions. translocations) result from double strand break (DSB) repair! •  You know recombination from meiotic recombination. inversions. copy number variations.

repair of DSBs is essential! •  How do they do this? There are two main pathways:! –  Non-homologous end-joining! –  Homologous recombination! 0.9% of cells .DSB Repair •  DSBs in the DNA are always occurring! •  Cell cannot grow if not repaired: checkpoint arrest because of DNA damage!! •  Thus.

Non-homologous end joining (NHEJ) •  Simple way to repair DSBs: find the two ends and join them back together! •  Ends are recognised by the Ku70 and Ku80 protein complex! •  These recruit other enzymes that trim the broken ends and ligate them together! •  NHEJ is the dominant pathway in mammalian cells! .

Homologous recombination •  Homologous recombination can repair DSBs without losing genetic information! •  Occurs using the other sister chromatid as the template (meiotic recombination is a special exception). If so. when in the cell cycle must repair occur?! .

Classical DSB repair model •  First step is resection of the ends: this is the degradation from the 5’ end of one strand of DNA! •  Single-stranded DNA ends find a homologous target to invade. forming a D-loop! •  The 3’ ends can act as primers for DNA synthesis! •  This forms double-Holliday junction structures: Holliday junctions are cross over structures between two DNA molecules! •  Once all the degraded DNA has been re-synthesised and ligated. the structure is resolved! .

this can result in:! –  Insertion/deletion! –  Duplication/copy number variation! –  Inversion! –  Translocation! •  Homologous recombination is less prone to this.Structural Changes Redux •  Both homologous recombination and NHEJ can join the wrong things up! •  Depending on what is joined and how. except for repeat sequences! .

Recombination and duplication .

Recombination and inversion .

Segmental Duplications •  Usually defined as at least 1kb and at 90% sequence identity! .

including aneuploidy (resulting from nondisjunction)! •  HeLa is a cancer cell line isolated from an AfricanAmerican woman.Aneuploidy •  Cancer is characterised by genome instability. in the 1950s! . Henrietta Lacks.

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