Category Archives: Genetics

A retro trio study

Nature News writes about a genetic study in Chinese families

The study also identified some new links. For example, mothers with higher levels of bile acid had shorter babies. Clifton says the analysis falls short of establishing causality but offers leads for further research.

I wonder about the title “The Born in Guangzhou Cohort Study enables generational genetic discoveries” which is more promotional than informational. I wonder also about the geopolitical statement as the map includes also Taiwan (with zero observations, as found also in a previous Cell paper). 

And well this is certainly not the first family study in China (see the halted research of Scott Weiss just before he went into vitamin lobbying).

It is also not any new information that mothers with higher levels of bile acid have shorter babies. Did neither interviewer nor interview partner ever hear of intrahepatic cholestasis during pregnancy that is leading to multiple adverse perinatal outcomes?
Cholestasis is leading to preterm birth, which is  leading to LBW (by an OR of 2) and also to shorter babies.  Without any preregistration and any replication study included, it is difficult to make any conclusion of “leads for further research”. The bile acid result may be a regional artifact if it is only found in one region – basically like in the farming studies.

Neither are numbers in this study as large as the Nature News piece wants us to believe,  I think that 332 trios is only an average study size.

 

Parallelized computer code and DNA transcription

At stackexchange there is a super interesting discussion on parallelized computer code and DNA transcription (which is different to the DNA-based molecular programming literature…)

IF : Transcriptional activator; when present a gene will be transcribed. In general there is no termination of events unless the signal is gone; the program ends only with the death of the cell. So the IF statement is always a part of a loop.

WHILE : Transcriptional repressor; gene will be transcribed until repressor is not present.

FUNCTION: There are no equivalents of function calls. All events happen is the same space and there is always a likelihood of interference. One can argue that organelles can act as a compartment that may have a function like properties but they are highly complex and are not just some kind of input-output devices.

GOTO is always dependent on a condition. This can happen in case of certain network connections such as feedforward loops and branched pathways. For example if there is a signalling pathway like this: A → B → C and there is another connection D → C then if somehow D is activated it will directly affect C, making A and B dispensable.

Of course these are completely different concepts. I fully agree with the further stackexchange discussion that

it is the underlying logic that is important and not the statement construct itself and these examples should not be taken as absolute analogies. It is also to be noted that DNA is just a set of instructions and not really a fully functional entity … However, even being just a code it is comparable to a HLL [high level language] code that has to be compiled to execute its functions. See this post too.

Please forget everything you read from Francis Collins about this.

Inheritance of facial characteristics

There is a fascinating story from Barcelona. Maybe I missed the NYT article last year but here it is: Cell Reports 40, 111257, August 23, 2022

Joshi et al. reported that look-alike pairs identified by facial recognition algorithms share genotypes but not DNA methylomes and microbiomes.

https://doi.org/10.1016/j.celrep.2022.111257

Based on an earlier study, Continue reading Inheritance of facial characteristics

Did the Neanderthal hominid suffer from asthma?

Maybe this is a largely irrelevant question –  basically as relevant as building a museum on top of some Neanderthal 1 bones – as we can never reliable predict a complex trait just by genetics and some broken bones.

Already Virchow was wrong  believing that the “Neanderthaler” was a modern human suffering from senility and malformations … Anyway, new research wants to answer this question:

Here we show that of the 51 asthma-associated loci that we surveyed, 39 carry variants that were derived in the Neanderthal lineage. The shared sequences suggest that some asthma variants may have originated from the Neanderthal genome after admixture and subsequent introgression into the Eurasian population. Of note, one variant, rs4742170, previously linked to asthma and childhood wheezing, was shown in a recent study to disrupt glucocorticoid receptor binding to a putative IL33 enhancer, and elevate enhancer activity of this key asthma gene.

Sorry to say that there are now >3000 variants associated with asthma  including at least 354 coding variants while the authors used only 51 loci in their study derived from an outdated 2016 review. So we could already end up writing up a review here but  the paper continues with omissions and misunderstandings

most of the Neanderthal-derived SNPs we identified, including those near the lead variants for the asthma GWAS signals, are in non-coding regions of the gene

Unfortunately we need to be exact here – not just “near” some variants. The SNP rs4742170 that they showed from the EVA database had indeed the T allele in the Vindija Neanderthal

https://bioinf.eva.mpg.de/jbrowse/?loc=9%3A6242936..6242991&tracks=hg19_1000g%2Cvindija_hc_bam%2CAltai

but unfortunately when going then to dbSNP it is also found in the African genome.

https://www.ncbi.nlm.nih.gov/snp/?term=rs4742170

So the whole conclusion

Our findings here …  add asthma to the list of diseases that could be traced back to Neanderthals

is wrong.

Google Scholar ranking of my co-authors is completely useless

The title says it already while a new r-blogger post helped tremendously to analyze my own scholar account for the first time.

I always wondered how Google Scholar ranked my 474 earlier co-authors. Continue reading Google Scholar ranking of my co-authors is completely useless

sun + wind + allergy

New work by Harvard colleagues shows how sunshine hormone  D constrains inflammation by modulating the expression of key genes on chr17q. It builds on earlier collaborative work on the vitamin D receptor in 2004 (see their ref 5) as well on my annotation of IKZF3 (aka aiolos aka god of winds) in 2008  and again in 2022.

While our focus on allergy development was on vitamin D supplementation of newborns, the interest of Weiss et al. was on vitamin D deficiency in pregnancy.  Vitamin D deficiency may not be attributed to the rise of the asthma and allergy epidemic although this remains the never ending obsession of Weiss et al.

Nevertheless, also a wrong hypothesis may lead to new insights.  IKZF3 clearly is a key player where more recently heterozygous missense/LOF variants have been found in families with B-lymphopenia and EBV-associated lymphoma while the allergy proning effect is more in the 5-prime region.

The new study shows (again) that cholecalciferol suppresses the activation of the IL-2 pathway. But what is the net effect of artifical cholecalciferol exposure on naive T cells? Unfortunately the  new paper narrowly focuses on cytokine production in Th2 cells only and even misses the famous Cantorna review that clearly says

 Since 1983 it has been described that 1,25(OH)2D inhibited T cell proliferation and the secretion of select cytokines after mitogen stimulation. Moreover, 1,25(OH)2D directly inhibited IL-2 and IFN-γ transcription [,]. More recently 1,25(OH)2D has also been shown to inhibit IL-17 secretion by Th17 cells. The effects of 1,25(OH)2D on Th2 cells is more controversial with evidence that 1,25(OH)2D inhibits IL-4 transcriptionally as well as evidence that 1,25(OH)2D upregulates IL-4 in mouse and human T cells.

So  we need to rephrase the finding of an “immune protective effect of vitamin D in allergic lung inflammation” to an overall “immune suppressive effect of vitamin D” which is basic textbook knowledge. Unfortunately the early origin of allergy induction remains a mystery.

I never read the introduction of an article

I never read the introduction of an article, seldom the discussion section, but I always scan the methods and sometimes (if the methods warrant it) also the tables and figures. It seems that I am not alone here.

The survey indicated that individuals at different career stages valued different sections of scientific papers, and skill in reading the results section develops slowly over the course of an academic career.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189753

So why do we still write papers with an introduction that is longer than 1 sentence?

Parthenogenesis

When his mother Mary had been engaged to Joseph, but before they lived together, she was found to be with child from the Holy Spirit.
19: Her husband Joseph, being a righteous man and unwilling to expose her to public disgrace, planned to dismiss her quietly.
20: But just when he had resolved to do this, an angel of the Lord appeared to him in a dream and said, “Joseph, son of David, do not be afraid to take Mary as your wife, for the child conceived in her is from the Holy Spirit.

incredible? No.

https://www.nature.com/articles/d41586-023-02404-z

In the study above there are only 44 genes that were involved in parthenogenesis

This identified a polygenic system whereby increased expression of the mitotic protein kinase polo and decreased expression of a desaturase, Desat2, caused facultative parthenogenesis in the non-parthenogenetic species that was enhanced by increased expression of Myc.

COVID19 and type 1 diabetes

There were some diabetes experts at my former work place who opposed against doing COVID19 studies even sending us  epidemiologists into home office while leaving a large study in Munich to the police,  BMW and medical students

Funnily enough, they even warned about any COVID19 research in Cell magazine

… widespread redeployment of world-class expertise from other areas into the current acute phase of COVID-19 research can lead to substantial loss of focus. A longer-term diversion of resources runs the risk of stifling much-needed new basic research and technological breakthroughs that have the potential to revolutionize biomedicine. … A refocus on COVID-19 research activities is likely to engender adverse effects on society’s clear and urgent need for sustained research into major diseases, which will continue to afflict humankind and remain leading causes of death and disability well beyond the end of the acute COVID-19 challenge.

So we had plenty of time to see studies coming up that loss of focus COVID19 is now even inducing  their major disease – early onset of diabetes. The story now goes on to a JAMA metaanalysis and a Nature commentary that confirms the diabetes association in 42 studies including 102 984 youths and showing a

higher incidence rate during the first year of the pandemic compared with the prepandemic period (incidence rate ratio [IRR], 1.14; 95% CI, 1.08-1.21). There was an increased incidence of diabetes during months 13 to 24 of the pandemic compared with the prepandemic period (IRR, 1.27; 95% CI, 1.18-1.37).

The accompanying commentary makes a direct damage of SARS-CoV-2 to  pancreatic cells in children unlikely while the most

probable explanation is that the immune system’s attack on the pancreas is triggered by a COVID-19 infection, which happens with other infections as well, like enteroviruses and hepatitis B.

I can agree on that while my question now: Do  genes play a major role?

Most genetic research of COVID-19 went into disease severity while there was a paper last week describing disease protection by HLA-B*15:01.  As summarized in Science this study of blood donors infected by seasonal coronaviruses showed that

T cells from the subjects with HLA-B*15:01 also reacted aggressively to a fragment of the spike protein from two of the seasonal coronaviruses. This fragment is almost identical to the snippet of SARS-CoV-2’s spike protein that the researchers had tested. The results suggest that when people with the HLA-B variant came down with colds caused by seasonal coronaviruses, they obtained a degree of immunity against similar coronaviruses, including SARS-CoV-2.

For type 1 diabetes  an association with  HLA DR/DQ has been described not only be us but also by many other groups before.

This association is however with class II, not class I as found now in COVID-19. Nevertheless there could be some linkage disequilibrium between class I and II variants although I could not find the B*15 allele in an earlier paper.

Or is the T1D/COVID119 association just by co- or cross activation of the immune system?

Before any expensive profiling of antibodies it may be worthwhile to go for some association testing eg HLA-B*15:01 in T1D as there are known complex transcriptional regulatory circuits in the HLA locus.

Research strategies should never be dogmatic…

An update on the asthma exome

Here is a quick update on some genes of my recent asthma exome paper coming now from the 1 M  exome paper published yesterday as a preprint.

loss of function variants IL1RL1. https://rgc-mcps.regeneron.com/gene/IL1RL1, 12 May 2023

Also ClinVar shows that the IL33 receptor is not “essential” making anti IL33 receptor antibodies like etokimab, itepekimab, tozorakimab a safe therapy although not being effective in any LOF mutation carrier.

The most interesting thing in the preprint is in supplemental table 2 with the s-het values for 16,704 genes. From that table  I have selected  my favorite target  IL33 receptor together with TLR1, ALOX15, GSDMA, IL13 and IKZF3 ( BTNL2 could not be found in the list).

asthma exome  https://rgc-mcps.regeneron.com/gene/IL1RL1, 12 May 2023

IKZF3 would be dangerous to be touched (see my 2008 commentary) while in the 2022 exome paper I  also found  only protective variants in the 5′-UTR but not any LOF variant   – probably as IKZF3 is the only essential gene in the list.

So what’s next? I am still thinking how to reduce my exome set to the causal variants as half of the mutations are probably LD artefacts. And well, it would be super interesting to examine now two extreme inbred populations for their mutation spectrum,  loosing either asthma variants by healthy (Amish) or diseased founders (Tristan da Cunha). Unfortunately there is little hope that this will happen – current science is built more on competition than collaboration.

 

Legends of science – photo #51

It is one of the most famous photos taken by Raimond Gosling (1926-2015), a former student of Wilkins and Franklin, who

is largely forgotten when the story of DNA is told. To mark the anniversary of his paperclip-inspired contribution, Nature has interviewed him. You can hear the results at go.nature.com/lizfik … In this interview, a humble Gosling fondly recalls that Franklin’s response to Crick and Watson’s model of the double helix was gracious and sanguine: “She didn’t use the word ‘scooped’. What she actually said was, ‘We all stand on each other’s shoulders’.”

The contribution of Rosalind Franklin has been always controversially discussed with “here, little Raimond, put this round the collimator”. Continue reading Legends of science – photo #51

Any proof for hygiene hypothesis by lockdown babies?

It is an interesting question – does social distancing influence later allergy ? Lawler et al. in November 2021

http://www.doi.org/10.1111/pai.13591

report the impact of COVID‐19 lockdown in 365 Irish babies at 6 months of age enrolled in the CORAL study. These were a subset of 3773 infants born in two participating major maternity hospitals in Dublin between March and May 2020. Unfortunately only 10% of children participated, so families were self-selected.  Allergic rhinitis was common in both mothers (36%) and fathers (30%) which is higher than reported by Allergy Ireland (26%) and explained by the authors that parental allergy is “higher than the general population, which may have contributed to parental desire to enrol in this study.”

A follow-up in March 2022 in 344 children consecutively shows higher food allergy (4.7% vs 3.5%, NS) when compared to an earlier cohort (BASELINE 2008). Atopic dermatitis increased of 15.5% in the BASELINE study to 25.3% in CORAL (no P reported) which is not unexpected given the interest of parents in an allergy study.

Maybe a short questionnaire at 2026 school entry would be informative than the current study? Nevertheless the authors needed now to analyze their stool samples sitting in the shelves. This is the content of  the March 2023 preprint that has just been published. There may be an association of some bacteria with atopic dermatitis but in the end it is a useless result as the strongest risk factors for atopic dermatitis – parental history and/or FLG mutations – are missing from the presented models

At the end we can safely assume that the 2020 lockdown did not have any influence on allergy prevalence in Ireland.

Arguments against germline therapy

from Tina Rulli “Reproductive CRISPR does not cure disease” in bioethics 2019.

Consider an analogy. Imagine Bill has the following options:
6. Take SICK pill. Bill gets sick.
7. Take SICK pill, then take ANTIDOTE. Bill prevents sickness and remains healthy.
8. Do nothing. Bill stays healthy.
Now imagine that prior to this decision, ANTIDOTE is taken off the market so that it is unavailable to Bill. The unavailability of ANTIDOTE does not mean that Bill gets sick. For Bill has the option to simply not take the sick pill. Bill could just stay healthy (option 8). Offering ANTIDOTE is only morally urgent if it is inevitable that Bill will get sick, i.e., if Bill is forced to take the SICK pill (option 6).

Top 5 talks of the 3rd International Summit on Human Genome Editing

The final statement came by email this morning statement-from-the-organising-committee-of-the-third-international-summit-on-human-genome-editing

Remarkable progress has been made in somatic human genome editing, demonstrating it can cure once incurable diseases. To realise its full therapeutic potential, research is needed to expand the range of diseases it can treat, and to better understand risks and unintended effects. The extremely high costs of current somatic gene therapies are unsustainable. A global commitment to affordable, equitable access to these treatments is urgently needed. Heritable human genome editing remains unacceptable at this time.

And well, my subjective selection of  the best talks is also here (unfortunately the video quality is poor and there is no way to timestamp the URL, so you have to recall the time marks below).

As always masterful moderation by Robin Lovell-Badge including the fire alarm ;-) My top 5 talks are

  1. Chinese legislation whitewashed at 1:03:10
  2. David Liu excellent overview at 1:25:14
  3. Filippa Lentzos with a super nice talk on hopes and fears at 2:53:25
  4. Tue Kiran Musunuru with another excellent overview at  2:18:54
  5. Rising star Tina Rulli at 1:28:29

(Jennifer Doudna 4:25:17 was a bit disappointing when talking about my research field involving asthma and microbiome.
The two father mouse of Katsuhiko Hayashi that gained wider attention [Guardian, Nature, …] is found at  3:14:02.