Tweet

Joni Coleman

30 Oct, 9 tweets, 3 min read

Elise Flynn will end the session, talking about "Transcription factor regulation of genetic variant effects across tissues and individuals" #ASHG20

Genetic variants associated with gene expression = eQTL #ASHG20

eQTLs can be context specific, whether in terms of effect size or the presence/absence of an effect. Know that eQTLs are enriched in TF binding sites. Suggests that modifications to TF binding are a major mechanism by which genetic variation regulates gene expression #ASHG20

TF availability can be a mechanism to explain context variability - minimal/maximal TF availability would mean no allele effect (no expression / saturation respectively) #ASHG20

Used GTEx to catalog TF regulating eQTLs and assess between-tissue variability. Use fine-mapping to ID ~1M eQTLs that could affect TF binding #ASHG20

Correlate eQTL effects with (relevant) TF expression levels in different tissues. ID ~400K TF-eQTL relationships at 5% FDR cross-tissue (1-10K relationships per TF). Is there a relationship between TF and eQTL between individuals in different tissues? #ASHG20

Yes - see 1000s of eQTL-TF relationships, and shared and tissue-specific relationships. [Need to review the paper, lots of findings that I'm not transcribing well, ironically] #ASHG20

E.g. PU.1 vs LIPA eQTL. Colocalises with CAD locus, LIPA has predicted role in CAD. Evidence for PU.1 regulation in multiple tissues. Locus shows complex transcriptional activity. Site-directed mutagenesis on 3 candidate variants shows transcriptional activity increases #ASHG20

Overall, ID 10K TF-eQTL interactions for 4K genes. Show tissue-specific and tissue-general effects. #ASHG20

• • •

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

This Thread may be Removed Anytime!

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

More from @Joni_Coleman

Joni Coleman

@Joni_Coleman

30 Oct

Finally, Margot Cousin presents on "Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome" #ASHG20

SHMT2 - encodes mitochondrial serine hydroxymethyltransferase 2. Key roles in amino acid metabolism and folic acid pathways, as well as mitochondrial respiration and protein translocation #ASHG20

Identified 4 individuals with biallelic SHMT2 variants. One individual has a variant disrupting a splice site. Other variants are missense on highly conserved residues, and are absent/extremely rare in gnoMAD. Variable dysmorphic features. Others incl. developmental delay #ASHG20

Read 8 tweets

Joni Coleman

@Joni_Coleman

30 Oct

Next up is Helen Miranda discussing "Increased p4EBP1 underlies ALS pathology associated to P56S mutant VAPB" #ASHG20

ALS is the most common adult-onset neurodegenerative disorder. 50% of patients do not survive beyond third year of diagnosis. Pathophysiology across upper and lower motor neurones. 90% of cases are sporadic in presentation. #ASHG20

Mutations in >25 genes have been associated in ALS. Focus on VAPB. Highly conserved gene that is ubiquitously expression. P56S mutation is the causative gene for ALS type 8 - mostly identified in Brazilian population, but has been identified globally. #ASHG20

Read 8 tweets

Joni Coleman

@Joni_Coleman

30 Oct

Next up is Victor Faundes, who will talk about Impaired eIF5A function causes a craniofacial-neurodevelopmental syndrome that is partially rescued in model systems by spermidine #ASHG20

EIF5A was identified as a candidate developmental disorder gene through WES. Used the DDD resource to identify a further 6 individuals with EIF5A variants, defined a novel syndrome of developmental delay and other features #ASHG20

EIF5A resolves ribosomal stalling caused by polyproline tracts. Aimed to understand how this is disrupted by the variants seen in patients. Haploinsufficiency is the most likely mechanism #ASHG20

Read 7 tweets

Joni Coleman

@Joni_Coleman

30 Oct

Slightly late into the fourth plenary: David Blair discussing "Common genetic variants associated with Mendelian disease severity revealed through cryptic phenotype analysis" #ASHG20

Cryptic phenotypes are phenotypes that underlie mendelian diseases, but which are not observed. For some, this will be a liability-threshold model (mendelian as extreme of normal range), but for others it will be a phenotypic outlier model (mendelian as truly separate) #ASHG20

Need models that differentiate between the models. May be morbidity-dependent genetic modifiers - e.g. may not see effects looking at the average of the population, but may see it at the extreme percentiles of severity #ASHG20

Read 7 tweets

Joni Coleman

@Joni_Coleman

30 Oct

Next is Xiaolei Zhang, discussing "Annotating high-impact 5'UTR variants with the UTRannotator"

The translation of upstream open reading frames can reduce the expression of genes considerably. Can have overlapping uORF, out of frame or in frame depending on where the stop coding of the uORF lies #ASHG20

uORF perturbing variants can be disease-causing. they are under strong negative selection and appear to cause disease through LoF of genes. #ASHG20

Read 7 tweets

Joni Coleman

@Joni_Coleman

30 Oct

Next is Bonnie Huang discussing "Inference of fitness effects of short tandem repeat polymorphisms improves functional categorisation" #ASHG20

STRS are DNA sequences with repeated 1-6 base pair motifs. About 1.6M in human genome. Repeat number differs between individuals #ASHG20

Discussing the logic underlying the SISTR method. Challenging to determine the pathogenicity of STR mutations. STRs harder to interpret than (coding) SNVs - adding extra amino acids has less clear an effect than removing or altering them #ASHG20

Read 11 tweets

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

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

Donate via Paypal Become our Patreon

Thank you for your support!