Yachna Jain

[Kuljeet @genbiolab]

14/n b) Beyond the established view that the genomic rearrangements have potential role in speciation by creating reproductive barriers, our observations highlight their significant role in the evolution of lineage-specific traits.

[Kuljeet @genbiolab]

13/n Why a genome order that has predisposed us to disease is selected in the evolution then? That’s because the copy number variations of functionally heterogenous gene-clusters may lead to lethality due to compromised multiple pathways.

[Kuljeet @genbiolab]

12/n Take home lessons: a) The linear clustering of functionally related genes may have conferred certain advantages as documented widely, though at the cost of increased susceptibility to disorders associated with copy number variations of functionally homogenous cluster.

[Kuljeet @genbiolab]

11/n Therefore, the 3p21.31 split is acquired independently in hystrico- and sciuromorphs and the breakpoints are also different in the two clades. This is analogous to biological replicates of an evolutionary experiment and imply the convergent evolution of 3p21.31 split.

[Kuljeet @genbiolab]

10/n Why our observations are not fluke? First of all, the 3p21.31 split is confirmed in multiple hystrico- /sciuromorphs. Secondly, the hystrico and sciuromorphs are not phylogenetic neighbours. In fact, sciuromorphs are more closer to myomorphs.

[Kuljeet @genbiolab]

9/n ii) Many genes near the break-points were associated with the traits that were diverged in hystrico-/sciuromorphs, suggesting the possibility of adaptive significance of the 3p21.31 split.

[Kuljeet @genbiolab]

8/n and relative shortage of competitors and predators of rodents in habitats like South America. This implied that the constraints on bodymass were relieved in ancestral hystrico/-sciuromorphs. As a result, the 3p21.31 cluster was allowed to split;

[Kuljeet @genbiolab]

6/n This may nullify the pro-tumorigenic impact through co-deletions or co-amplifications of genes with opposite effects; c) The split also caused the significant expression divergence of the genes near the break-points likely through chromosomal position effects.

[Kuljeet @genbiolab]

5/n This has several important consequences: a) the hyrtico/-sciuromorphs escape the co-deletion/co-silencing of all TSGs of 3p21.31 in cis and, therefore, are less susceptibile to cancer; b) the split TSG clusters gain proximity to cassettes of proto-oncogenes from elsewhere.

[Kuljeet @genbiolab]

4/n Interestingly, 3p21.31 is split and interspersed by long genomic inserts in rodents of hystricomorpha (naked mole rat, capybara etc.) and of sciuromorpha (squirrels, marmots etc.) suborders, while remaining syntenic in myomorpha (mouse, rat etc), and in all other mammals.

[Kuljeet @genbiolab]

3/n The clustering of 3p21.31 was specifically acquired in the common ancestor of placental mammals. The teleost, reptiles, and marsupials do not exhibit the clustering.

[Kuljeet @genbiolab]

2/n The synteny of 3p21.31 cluster is evolutionarily and functionally constrained in most mammals owing to genes associated with terrestrial adaptation of mammals, like bodymass limitation through negative regulation of growth, response to UV etc.

[Kuljeet @genbiolab]

The key points:
1/n Dense clustering of tumor suppressor genes (TSGs) at 3p21.31 locus predisposes mammals to several types of cancers through co-deletion or co-silencing of >20 TSGs in cis.

[Kuljeet @genbiolab]

Why some rodents, like naked mole rat and capybara, are resistant to cancer? In the following study we discovered a link between genome organization and cancer resistance. 🧵👇for detail. @Anjoom_ @KeerthivasanRC @yachna89 @Nature_NPJ

[Kuljeet @genbiolab]

7/n Why the evolutionarily constrained 3p21.31 cluster got split in hystrico/sciuromorphs? i) The rate of bodymass evolution of hystrico/sciuromorphs were significantly higher during Eocene, an epoch marked by mammalian radiation, emergence of more open habitat,

[Gene Regulation @generegulation]

Pluralistic and stochastic gene regulation: examples, models and consistent theory
https://t.co/eqB8JEKwWO #TFbinding #ENCODE