Kaitlin Samocha Profile picture
Apr 26 4 tweets 2 min read Twitter logo Read on Twitter
Gosia Borowiak #GRD23: The field figured out how to make progenitor cells in culture, but trying to get homogenous populations of human beta cells was a challenge.

Time an endocrine progenitor is formed matters in likelihood of developing into a alpha vs beta cell.
Gosia Borowiak #GRD23: Digging into the microenvironment that influence human endocrine development. Found that WNT5A is necessary and sufficient for beta cell in vitro induction.

nature.com/articles/s4146…
Gosia Borowiak #GRD23: Re-emphasizes a point from yesterday: need to have a "factory" to be able to make large amounts of high quality cells if you want to do disease modelling / testing.

Figured out a way to allow serial expansion of these cells [MMP2, I believe].
Gosia Borowiak #GRD23: Deep dive into the stem cells of a patient with a PDX1 risk variant (-18 C>T). Patient cell lines did not make as many pancreatic cells. Find systematic differences in amino acid concentrations, and that the variant alters NF-Y binding to the PDX1 promoter.

• • •

Missing some Tweet in this thread? You can try to force a refresh
 

Keep Current with Kaitlin Samocha

Kaitlin Samocha Profile picture

Stay in touch and get notified when new unrolls are available from this author!

Read all threads

This Thread may be Removed Anytime!

PDF

Twitter may remove this content at anytime! Save it as PDF for later use!

Try unrolling a thread yourself!

how to unroll video
  1. Follow @ThreadReaderApp to mention us!

  2. From a Twitter thread mention us with a keyword "unroll"
@threadreaderapp unroll

Practice here first or read more on our help page!

More from @ksamocha

Apr 26
Rob Taylor #GRD23 on multi-omic approaches to dissect mitochondrial pathology.

Clinical mitochondrial diseases collectively have a prevalence of ~1 in 4000 and have functional, molecular, clinical, and prognostic heterogeneity.
Rob Taylor #GRD23: Some of this complexity comes from the fact that cells have many copies of the mitochondrial genome. Pathogenic variants can either be homoplasmic (in all copies) or heteroplasmic (in some copies).
Rob Taylor #GRD23: High throughput sequencing has helped identify pathogenic variants + new disease genes.

A few examples shown, including POLRMT, UQCRH, etc.
Read 6 tweets
Apr 26
Kristine Bilgrav Saether #GRD23: Transposable elements jump through the genome via RNA intermediates. They make up ~50% of the genome. Multiple versions, some of which are autonomous (LINE) and some are non-autonomous (SVA).
Kristine Bilgrav Saether #GRD23: Can use methods like MELT (👍 @DrGeneUK), xTEA, etc for short reads. For long reads, look at split reads so they wrote a new one called TELLR.

Studying 1KG and SweGen samples.
Kristine Bilgrav Saether #GRD23: TELLR finds split reads and insertions, then uses DBSCAN to cluster, minmap2 --> TE calls.

Long reads also give methylation information, which is useful since TE activity is controlled via epigenetics.
Read 4 tweets
Apr 26
Kaiyue Ma #GRD23: Mutations in alpha-dystroglycan can lead to dystroglycanopathies.

Developing SMuRF (saturation mutagenesis-reinforced functional assays) to test variants in alpha-DG glycosylation enzymes like FKRP.
Kaiyue Ma #GRD23: SMuRF scores have the expected distributions for variant type (e.g. synonymous look neutral, nonsense functional). Missense mutations in the catalytic domain tend to be more disruptive (vs those in stem). Good correlation of score with ClinVar classifications.
Kaiyue Ma #GRD23: SMuRF, EVE, and REVEL all do well in AUC analysis of computational predictors. REVEL is the best, but high correlation between SMuRF scores and REVEL. Improvements to SMuRF underway.
Read 4 tweets
Apr 26
Danny Miller (@danrdanny) #GRD23: Starts with his take home points
- long-read sequencing will fundamentally change clinical genetic testing
- will reduce barriers to accessing comprehensive testing
- this will happen even if the cost of generating other types of data falls to $0
.@danrdanny #GRD23: Traditional genetic workup (mircoarray -> panel -> exome) is diagnostic in <50% of cases.

Pitches that we can use long-read sequencing as a single test that could then be analyzed in different ways (SV -> repeat expansion -> genome, etc).
.@danrdanny #GRD23: Long-reads are 1kb+ in length. Read accuracy varies (90-99%) and the cost is $500-$3k.

Long-read sequencing finds 2x as many structural variants as short reads. See:
cell.com/ajhg/pdfExtend…
Read 8 tweets
Apr 25
Now on is David Liu (@davidrliu) walking through programmable nucleases. >200 patients have been treated with therapies enabled by CRISPR nucleases thus far #GRD23
.@davidrliu #GRD23: While nucleases are good for gene disruption, they aren't great for gene correction.

Developed base editing and prime editing to address this gap and have editors now that can address all single nucleotide base changes.
.@davidrliu #GRD23: Have been able to show both ex vivo and in vivo base editing. Example of in vivo base editing for progeria in mice:
nature.com/articles/s4158…

Untreated mice live ~7.5months, but the ABE-treated mice live much longer.
Read 6 tweets
Apr 25
Hannah Verdin #GRD23: Over the last few years, just started carrier screening in Belgium via BeGECS (Belgian Genetic Expanded Carrier Screening). 400 couples have been studied to date.

Recruited pre-conception, but couples have to pay 1.5keuros.
Hannah Verdin #GRD23: Couple report is generated to inform of an increased couple risk. Also generate individual reports to provide information about specific high impact variants.
Hannah Verdin #GRD23: ~6.6% of couples had an increased couple risk for an autosomal recessive disorder. 1.3% had increased couple risk for X-linked disorders.
Read 4 tweets

Did Thread Reader help you today?

Support us! We are indie developers!


This site is made by just two indie developers on a laptop doing marketing, support and development! Read more about the story.

Become a Premium Member ($3/month or $30/year) and get exclusive features!

Become Premium

Don't want to be a Premium member but still want to support us?

Make a small donation by buying us coffee ($5) or help with server cost ($10)

Donate via Paypal

Or Donate anonymously using crypto!

Ethereum

0xfe58350B80634f60Fa6Dc149a72b4DFbc17D341E copy

Bitcoin

3ATGMxNzCUFzxpMCHL5sWSt4DVtS8UqXpi copy

Thank you for your support!

Follow Us on Twitter!

:(