Category Archives: Genetics

JACI – retractions overdue

JACI is the journal with the poorest experience  that I ever encountered as an author and  as a reviewer.  The editors never adequately responded to numerous errors in an earlier paper where I sent a long letter describing all details.

And it is a nightmare – even now with more than 100 corrigenda in this journal – as the editorial office  even modified correctly submitted images.  Yes, the JACI editor published also falsified data.

Only recently I also found another strange retraction note

The Publisher regrets that this article is an accidental duplication of an article that has already been published in J Allergy Clin Immunol

while the link of this retraction note goes to https://pubmed.ncbi.nlm.nih.gov/24892183 which is, however, a different paper.

It seem that the journal already lost the overview…

Why recent allergy congresses failed

Maybe allergy societies, journal editors and conference organizers never grasped the idea of unconferences

An academic conference is a traditional platform for researchers and professionals to network and learn about recent developments and trends in a particular academic field. Typically, the organizing committees and sponsors decide the main theme and sub-topics of the conference and select the presenters based on peer-reviewed papers. The selected speakers usually share their research with a large audience by means of presentations and posters. However, the most stimulating discussions generally take place over coffee breaks when attendees can interact with each other and discuss various topics, including their own research interests, in a more informal manner, while expanding their own professional networks. An emphasis on facilitating such informal/networking interactions is a central focus of “unconventional conferences”—or “unconferences.”

https://twitter.com/OdedRechavi/status/1522792505124790272 Continue reading Why recent allergy congresses failed

Longevity update

grg.org/WSRL/TableE.aspx has an update of our 2010 paper about longevity

https://grg.org/WSRL/TableE.aspx

and well, there is also an update on German centenarians

https://www.destatis.de/DE/Presse/Pressemitteilungen/Zahl-der-Woche/2022/PD22_28_p002.html

The Lancet and scientific integrity

We have learned in the past that the Lancet published editorials that clearly separated the journal from the publisher Elsevier

Reed Elsevier’s response is that the sale of military equipment is legal, government supported, and tightly regulated. However, The Lancet‘s collaborations in child survival and health-systems strengthening, for example, risk being tainted by Reed Elsevier’s promotion of the “selling process” of arms.

Of course you can’t sell weapons and distance yourself from selling weapons at the same time…

Hapmap

I find it increasingly difficult to get the haplotype structure of a given gene. While the are patches to the human genome at UCSC, this isn’t the same like good old hapmap.org by the HapMap consortium that has been retired back in 2016.

A recent computer security audit has revealed security flaws in the legacy HapMap site that require NCBI to take it down immediately. We regret the inconvenience, but we are required to do this. That said, NCBI was planning to decommission this site in the near future anyway (although not quite so suddenly), as the 1,000 genomes (1KG) project has established itself as a research standard for population genetics and genomics. NCBI has observed a decline in usage of the HapMap dataset and website with its available resources over the past five years and it has come to the end of its useful life.

It seems that also its successor, the 1000 genomes, will be retired during the next month. Unfortunately, the phasing server in Michigan does not allow any logon for whatever reason, UK biobank is too expensive so haplotypes basically vanished in the nirvana.

 

Medizinische Blickdiagnose

Es gab schon immer Lehrbücher der Blickdiagnose. Dazu gibt es auch schon länger AI basierte Programme, die automatisiert Röntgen-, CT- oder PET Bilder erkennen und Diagnosen zuordnen können. Aber ein neuer Beitrag in nature genetics zeigt eine neue faszinierende Methode der schwierigen Diagnose genetischer Syndrome per Bildanalyse. Nach längerer Vorbereitung wurden hier 17.560 Patienten mit 1.115 Krankheiten in einem Datensatz erfasst. Die Zuordnung sollte damit auch für weniger erfahrene Experten leichter möglich sein. Das alles erinnert mich an ein mehrtägiges Frauenradrennen, das ich einmal fotografiert habe. Mit den täglichen Bildern auf der Siegertribüne liess sich auch ganz ohne KI die Zyklusschwankungen erkennen, allerdings nicht bei allen Teilnehmerinnen (V.a. funktionelle Amenorrhoe)

What did Sequana really find at Tristan da Cunha?

The Tristan study described before was leading to patent US6087485A. It describes

highly significant linkage in the genome scan (p=0.0001 for history of asthma and p=0.0009 for methacholine challenge) … at D11S907, a marker on the short arm of chromosome 11.

D11S907 or  AFM109YA1 is a microsatellite marker located at 11p13 in a gene known as EHF.  There should be 2 genes in close proximity of the marker: ASTH1I and ASTH1J.

ASTH1I and ASTH1J were detected by exon trapping. ASTH1I exons detected a 2.8 kb mRNA expressed at high levels in trachea and prostate, and at lower levels in lung and kidney …
ASTH1J exons detected a 6.0 kb mRNA expressed at high levels in the trachea, prostate and pancreas and at lower levels in colon, small intestine, lung and stomach.

The sequences of  table 2 in the patent are sufficient now to locate ASTH1I and ASTH1J. Continue reading What did Sequana really find at Tristan da Cunha?

25 years Transatlantic Airway Conference 1997 on asthma genetics in Key Biscayne

The conference series started in 1986 while the 12th conference was organized by Jeff Drazen with local support of Adam Wanner.

Sponsored by Boehringer Ingelheim, the participant list is the WHO is WHO in pulmonary genetics at that time: Bleecker, Meyers, Woolcock, Weiss, Burrows, Postma, Kauffmann, Dizier, LeSouef, Blumenthal, Banks-Schlegel, Slutsky, Zamel, Ober, Bousquet, Vercelli, Barnes, Adcock, Dahlen, Pauwels, Lewitt, Aron, Martinez, Cookson, Moffatt, Rosenwasser, Liggett, Rich, Papadopoulos, Levitt, Holgate, Elston, Morton and Marsh. Many of them do not live any more [1,2,3,4,5], some have made big careers [1,2], others have been fallen somewhat into disgrace [1,2,3]  and many already retired. Continue reading 25 years Transatlantic Airway Conference 1997 on asthma genetics in Key Biscayne

Lander landed

He basically killed one of my best papers by the Kruglyak-Lander rule of what is being “significant”. He started the stupid  CRISPR origin discussion. But now he steps down

President Biden’s top science adviser Eric Lander resigned on Monday after an investigation revealed he violated the White House‘s workplace policy by mistreating staff members

details at dailymail.co.uk

Lander ‘retaliated against staff for speaking out and asking questions by calling them names, disparaging them, embarrassing them in front of their peers, laughing at them, shunning them, taking away their duties, and replacing them or driving them out of the agency. Numerous women have been left in tears, traumatized, and feeling vulnerable and isolated,’ Wallace told the outlet.

Statnews has  a good commentary about “The fall of Eric Lander and the end of science’s “big ego’ era”

 It’s not quite “big science,” which isn’t going anywhere. Call it “big ego.” In science, “big ego” isn’t exactly a new phenomenon. But in recent decades it grew with the emergence of researchers who could both handle the kind of gloves-off debate that can mark academic discourse and marshal vast resources to make certain types of scientific discoveries, like mapping genomes.

What is needed is a confrontational approach

Google showed me today a long forgotten abstract. Although I am not an expert in schizophrenia we collaborated two decades ago on this particular chromosomal region.

What is even more remarkable is the challenging keynote of the Xth World Congress of Psychiatric Genetics in The Palais des Congre ́s Brussels, Belgium October 9 –13, 2002 by Irving Gottesman [+2016], the father of epigenetics in psychiatry. He wrote there

We cannot escape the history of our field and are constantly guided today by the accumulation of facts with either positive or negative valences from our past. But when did the clock start—with the domestication of animals, with Galton’s musings and amoral passion for data collection about individual differences in behavior, or with the initially objective scientizing of Mendelism applied to schizophrenia but ending with a Nazi-tainted albatross around the neck of psychiatric genetics. In regard to the long quest for the distal and genetic (partial) causes of mental diseases, the conclusion that both genetic and environmental factors, none yet known in detail, provide the distal causes of mental disorders—that statement is too general to be of use to making further progress. What is needed is a confrontational approach based on evidence collected from competing ‘schools of thought’, and then reconciliation before some kind of omniscient and impartial Science Court.

I couldn’t agree more. What is needed is a confrontational approach based on evidence collected from competing ‘schools of thought’, and then reconciliation before some kind of omniscient and impartial Science Court.

Censored IL33 research

the AMGEN website …

Back to the roots

Rewriting a local Python notebook now to Colabs (as I don’t have an eGPU and therefore also no CUDA support in macOS) I am now again restricted by a daily timeout…

This reminds me so much back to 1989/1990 when we programmed SAS on an IBM mainframe under VM/CMS.  I usually went there early in the morning just to reserve my disk space :-)  In the evening it was all gone just like Colabs nowadays…

 

Computermuseum: SAS files of https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1793604/
***                                                                             
* Auswertung des genetischen Einflusses...;                                                            
cms fi data disk dummy dummy e;                                                 
data a; set data.ges_crit(keep=                                        
asthma frage  f1ekzem f33heu f36ekzem);                                                       
***

BTW without an expensive GPU I had to use our HPC now. Will try a Jetson Nano or Google Coral in the near future as this seems to be more energy friendly.

How atopic dermatitis is linked to vitamin D and how IL33 splice variants associate to eosinophil numbers

(first published 12 Dec2020 and revised 10Dec2021)

We had a major discussion right before our 2010 paper where I argued that rare variants should have been included into our asthma/allergy/dermatitis GWAS. Ten years after there is now a nice paper using massive exome sequencing that finally includes them.

It seems that the respiratory tract isn’t so much influenced by rare gene variants but that there is a strong effect in  the immune system.

And there is another interesting fact.

…Surveying the contribution of rare variants to the genetic architecture of human disease through exome sequencing of 177,882 UK Biobank participants …if we look at the …. European population who are carriers of a filaggrin (FLG) PTV, we find those carriers have significantly higher risk for well-known associations, such as dermatitis  … and asthma … Concomitant increases in vitamin D levels suggest … increased sensitivity to ultraviolet B radiation.

So far, I have only assumed an asthma/allergy priming effect of oral vitamin D in the newborn gut. This paper now argues for an increased vitamin D sensitivity also in the skin of  FLG dermatitis patients which is interesting given the largely contradictory data of serum vitamin D and atopic dermatitis. Maybe dermatologists should focus their research more on skin and local vitamin D turnover?

 

-II-

 

The most prominent IL33 variant carried by over 2,300 people is splice acceptor 9-6250473-G-C followed by 600+ individuals with splice donor 9-6250600-G-T.

There are not too many carriers of this variant by the sheer amount of 177,882 participants. We nevertheless know already something about the seven IL33 splice variants since 2012.

Novel Splice Variants of IL-33: Differential Expression in Normal and Transformed Cells Journal of Investigative Dermatology (2012) 132, 2661–2664; doi:10.1038/jid.2012.180

with updates  in  2016

Gordon, Alternative splicing of interleukin-33 and type 2 inflammation in asthma, PNAS 2016

as well as in 2017

Fig 3A Smith et al. A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma, PLoS Genetics 2017 – describes the splice site as NM_001199640:exon7:c.487-1G>C or rs146597587-C

 

So I did a sequence match to compare the new finding with these older publications.

own sequence match exon7 using data from dbSNP, UCSC GoldenPath and Uniprot – reference is hg19

 

Indeed, the 2017 paper already described rs146597587 which is probably identical to the splice acceptor 9-6250473-G-C in Astra UK Phewas (genome positions do not match – I used hg19 while I don’t know the Astra reference) . Astra says also c.613-1G>C while rs146597587 is just upfront of my codon 205 (3*205=615) whatever that means.

The Astra UK Phewas at least confirms the Iceland paper above

rs146597587-C associates with lower eosinophil counts (ß= -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids.

So it is basically a rediscovery meaning that we reached saturation.