4/29/16

BMS 525, Spring, HW#31

Spencer Thomas

Structural Variation in the Human Genome and its role in Disease.

Structural variation of the genome can arise at the level of SNPs, CNVs,
macroscale chromatin structure, and even genome wide disruptions. One fairly well
characterized structural variation in cancer is broadly classified as chromosomal
instability (CIN) which is characterized by widespread microsatellite aberrations as well
as indels in genes, creating CNV for oncogenes and tumor suppressor genes. In the
case of sporadically acquired cancers, including some colorectal cancer and the most
common breast carcinoma (invasive ductal carcinoma (IDC)), loss of regulatory DNA
repair pathways and genomic maintenance systems results in a so-called mutator
phenotype that is associated with lack of DNA repair competence and, in general,
cellular maintenance pathways. These mutator phenotype facilitate acquisition of SNPs
and CNVS that alter WT alleles, and can promote microsatellite instability (MIN).
MIN is associated with mutations in numerous other genes, which contribute to
progression of colon and IDC, occurring in ~15% of colon cancers and results from
dysfunction of the mismatch repair (MMR) system mutagenesis or DNMT
hypermethylation of certain promoters (MLH1). These inherited (A) n or (CA)n thus
promote tumorigenesis through generating mutations in target genes that possess
coding microsatellite repeats in important mitogen and apoptosis-regulating pathways,
such as the TGF- pathway (TGFBR2) and intrinsic-apoptotic pathways (BAX).
Incidentally, these microsatellites cause replication slippage which even upon
recognition, will not result in cellular senescence and potentiating cellular genomic
aberrations, aka MIN. Although, dysregulation of cell maintenance pathways contributes
to the overall chromosomal instability (CIN), the accumulation of microsatellite repeats
results in local and widespread topographical changes in the chromosomes.
Macroscopically, the folding and general arrangement of chromosomes harboring
mutations may further affect the spatial regulation and chromosomal organization at the
10 nm, 30 nm, and 300 nm level.
Although MIN causes alterations at the transcriptional level, perturbation of
replication and origin selection. Accumulation of microsatellites results in physical
blockade of replication and origins by gaining macrosatellite rich loops, but disruption of
DDR checkpoints and mitosis checkpoints has also been observed with the mutations
and amplifications been observed in key genes
Additionally, these MIN and at the holistic level can result in inadvertent activation
of homologous repair pathways as well as retrotransposons. One key translocation
documented in subsets in both CRC and IDC is when highly active promoters (IgG)
translocate to sites of proto-oncogenes (RAF/MEK/ERK/MAPK), which facilitates
proliferation and general CIN. Similarly, alterations in the MMR and DDR pathways in
association with MIN facilitated unequal crossovers between palindromic oriented
repeats on homologous chromosomes can result in reciprocal duplications concomitant
to deletions. Mispairing between inverted near-palindromic repeats can result in
inversion of intervening sequences that may result in the production of new genes or,
more importantly, key inadvertent intra-chromosomal loops, which is a catalyst for
chromosomal wide CIN. Consequently, these duplications, inversions, and deletions
frequently mediate polymorphic sequence rearrangement via non-allelic homologous
recombination, and disperse changes in copy numbers.

4/29/16

BMS 525, Spring, HW#31

Spencer Thomas