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SUMMARY:External Seminar Leopold Parts "Expanding\, minimizing\, and rando
 mizing the human genome"
DTSTART:20261127T100000Z
DTEND:20261127T110000Z
DTSTAMP:20261111T234200Z
UID:indico-event-510@indico.i2bc.paris-saclay.fr
DESCRIPTION:Speaker: Leopold Parts - Wellcome Sanger Institute\, UK\nTitle
 : Expanding\, minimizing\, and randomizing the human genome\nAbstract: The
  human genome reference sequence is a quarter century old\, and the ongoin
 g challenge is to interpret the variation in it. While predicting structur
 es and mutation effects for protein coding genes is making rapid strides\,
  there remains a gap in our understanding of the remaining 99% that is non
 -coding. This gap is due to the number of nucleotides to measure in an ass
 ay\, and the rarity of signals outside exons. I will talk about three proj
 ects to address this gap. First\, we used a chromosome transfer strain wit
 h extensive genomic characterization to discover how 200Mb of evolutionari
 ly distant sequence function in a human cell. These data also allowed us t
 o probe the limits of current AI approaches - where do the huge models suc
 ceed and fail in predicting the output of a chromosome in a cell? Second\,
  we attempted to generate qualitatively novel types of data at scale to ad
 dress the gaps in models’ abilities to account for distal gene regulatio
 n. To do so\, we created randomized regulatory regions by inserting recomb
 inase sites around enhancer elements\, and induced rearrangements with the
  recombinase. We applied our approach to dissect a distal super-enhancer o
 f the OTX2 gene\, generating over 100 alternative regulatory configuration
 s in a single experiment\, and establishing how they drive gene expression
  and chromatin accessibility as well as the individual contributions of it
 s elements to this activity. Third\, we used paired prime editing in poole
 d screens to delete multiple kilobases of sequence in a massively parallel
  way. We discovered hundreds of non-coding regions with fitness effects\, 
 and validated deletions with impact as well as tolerated ones in regions w
 ith functional annotations. Together\, these approaches can scale to shed 
 light on the non-coding genome dispensability\, resolve many human gene re
 gulatory landscapes\, and clarify the limitations of the current predictab
 ility of genome function\, ultimately paving the way to writing desired fu
 nctions directly into DNA at scale.Invited by Daan Noordermeer\n\nhttps://
 indico.i2bc.paris-saclay.fr/event/510/
LOCATION:B26-N2-000 (I2BC CNRS Gif)
URL:https://indico.i2bc.paris-saclay.fr/event/510/
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