Category Archives: Genetics

Single vitamin D bolus and HLA accessible chromatin

We have already recently seen that gene methylation in newborns can be changed by maternal vitamin D supplementation.
This is now confirmed in a single individual who was exposed to an oral bolus of 2000  μg of vitamin D3. Even within one day, effects could be observed.

Consistently accessible chromatin was detected at 5,205 genomic loci, the 853 most prominent of which a self-organizing map algorithm classified into early, delayed and non-responding genomic regions: 70 loci showed already after one day and 361 sites after two days significant (p < 0.0001) chromatin opening or closing. Interestingly, more than half of these genomic regions overlap with transcription start sites, but the change of chromatin accessibility at these sites has no direct effect on the transcriptome.

Early responses are described for SUN1 (funny in this context :-), FBF1 and WRAP73. Overall the genomic region around the human leukocyte antigen (HLA) cluster in chromosome 6 showed the highest normalized density of accessible chromatin explaining the immunosuppressive effect of sunshine.

The mutant says there is no God

There was an article already already some time ago “The Mutant Says in His Heart <There Is No God>: the Rejection of Collective Religiosity Centred Around the Worship of Moral Gods Is Associated with High Mutational Load”.

Industrialisation leads to relaxed selection and thus the accumulation of fitness-damaging genetic mutations. We argue that religion is a selected trait that would be highly sensitive to mutational load. We further argue that a specific form of religiousness was selected for in complex societies up until industrialisation based around the collective worship of moral gods. With the relaxation of selection, we predict the degeneration of this form of religion and diverse deviations from it. These deviations, however, would correlate with the same indicators because they would all be underpinned by mutational load. We test this hypothesis using two very different deviations: atheism and paranormal belief.

My first point is – where does the strange idea originate that only fools do not believe in God?

My first association from the bible was “The fool hath said in his heart, there is no God” (Ps 14:1) But there is  more: Job 12:7 but also Rom 3:11  (citing Ps 14) and maybe also Eph 4:18. On the other hand  (Mt 1,3) thinking is not a condition of belief – making the assertion of the psalm  more the exception the rule.

Which leads to the second strange point: Is there really a higher mutational load? No – it is just a speculation.

https://www.psychologytoday.com/us/blog/unique-everybody-else/201803/the-fool-says-in-his-heart-atheists-are-mutants

There’s an even bigger problem with Dutton et al.’s claims. Many studies show that atheists are more intelligent, on average, than religious believers … . Edward Dutton published a paper on this himself.

http://blogs.discovermagazine.com/neuroskeptic/2019/03/16/are-atheists-genetically-damaged/

Although Dutton et al. argue that atheism is an “aberration,” others have argued that atheism might be adaptive in certain environments. For example, atheism tends to be associated with certain individual characteristics such as preference for logical reasoning and scepticism over intuition, along with less sociality and higher individualism.

 

Compromised privacy

No One Is Safeguarding Your DNA

A person’s privacy can be compromised if a third or fourth cousin takes a home DNA test … The growing popularity of consumer DNA testing has helped law enforcement make arrests in decades-old crimes that would otherwise have remained cold cases. That may not be entirely good news for the rest of us, because using the technology to trace DNA to suspected criminals requires police to use a whole lot of other people’s genetic data, too. Like cell phone data a decade ago, it’s hard to say how all this information might be employed in the future. Imagine drug companies using it to target ads, life insurers using vast networks of relatedness to determine risk, or a scorned ex-lover employing the technique in some very 21st century stalking.

Yea, yea.

Fundamental and non fundamental objections of genome editing in humans

Braun, Schickl and Dabrock try to “map the underlying ethical arguments” (p6ff in “Moral Hazard” 2018) against human genome editing.

The various objections against germline genome editing can basically be divided into (1) fundamental (i.e. against the context of research and application) and (2) non fundamental (i.e. only against the context of application) arguments. The most prevalent fundamental arguments are (a) arguments of human dignity (b) arguments of naturalness and (c) slippery slope… The most common argument within the ethical (as well legal) debate on the use of genome editing techniques, like CRISPR technologies, is the safety argument as a non fundamental objection.

While I think the differentiation of fundamental vs non-fundamental is important for discriminating relevant from irrelevant arguments, the definitions are not fully clear. What is “context of research” – subject, object or objective? And what is “context of application” – the procedural conditions?

“Fundamental” may not be the best label as “fundamental” in German usually claims to be the  only right doctrine. Anyway, a fundamental argument will be an argument that cannot be easily overcome by a counter-argument as it is it is deeply grounded, heavy-weighted and basis for other conclusions.  A non-fundamental is just a non fundamental argument that can be rebutted immediately or in the foreseeable future.

The classification of fundamental by Braun, Schickl and Dabrock is even problematic as well. “Naturalness” is not a fundamental argument as it is nearly impossible to define a “natural” human genome. IMHO “slippery slope” is also not a logical argument at all – having more fear mongering elements than a  strict consequentialist logic.

I would therefore like to split any fundamental objections by the disciplines where they originate: (a)  philosophical/theological anthropology (b) biology and (c) sociology.

FUNDAMENTAL OBJECTION
-- anthropology
  .. human dignity
  .. missing embryonal consent
  .. genetic heteronomy
-- biology
  .. off target risks / safety
  .. unknown genetic background effects
  .. unknown next generation effects
  .. dissolution of species boundaries
-- sociology
  .. missing societal consensus
  .. new naturalism
  .. new eugenics
  .. new racism
NON FUNDAMENTAL OBJECTION
  .. medical necessity
  .. ethics vote
  .. no pre-tests
  .. no trial exit strategy
  .. conflicts of interest
  .. consent without alternatives
  .. and all Krimsky rules

Safety could of course could be a fundamental argument as set out by Nüsslein Vollhard: we can not 100% predict from one cell the fate from another cell.

Maybe this very first classification of arguments could be a further step into a more rational ethical discussion.

Braun, Schickl and Dabrock write on the same page that “the potentiality argument … which is considered to be the strongest argument for absolute embryo protection, is increasingly criticized by ethicists” citing Schöne-Seifert et al 2013 and  themselves as Schickl et al 2014. Their argument: we can reprogram now adult cells, the potentiality is therefore not a unique property of the human embryo, the embryo therefore has not any unique value, the embryo does not need protection.
I ask – instead of REVOKING potentiality of the human embryo why not EXPANDING potentiality to reprogrammed stem cells?
I have also doubts that a “reprogrammed” stem cell will ever have the unique potentiality of an embryo in situ for 3 reasons:
1. a stem cell is not a de novo creation but just a replication.
2. a stem cell will never replicate the complicated epigenetic pattern of an embryonic cell (which is a unique part of the embryonic identity, putting the Schickl argument in a row of genetic exceptionalism arguments).
3. lastly there is never ever maternal support of a stem cell, ignoring the complex biological support chain of human embryos.

And of course potentiality cannot be denied from a biological standpoint. It can be even exactly quantified: One of three fertilized eggs will develop into a human.

(TBC)

Abwehr des Bio-Terrorismus

Nature hat einen interessanten Beitrag, wie in Zukunft der Bioterrorismus abgewehrt werden soll: Alle Sequenzen, die an die Oligo Fabrik gehen, sollen routinemassig vorher gescreent werden, für was sie codieren. Das wird eine extrem komplexe Aufgabe für die Bioinformatik sein. Wenig Aussicht auf Erfolg hat der Vorschlag allerdings, wenn Biokampfstoffe staatlich gefördert werden.

What makes an allele dominant on the molecular level?

This was a question, I have been asked yesterday.

Although dominance is the property an allele, dominance is not”regulated” on the genomic level but a function of the resulting protein. According to the largely citied Wilkie paper there are numerous mechanisms

  • reduced gene dosage expression or protein activity
  • increased gene dosage
  • ectopic or temporally altered mRNA expression
  • increased or constitutive protein activity
  • dominant negative effects
  • altered structural proteins
  • toxic protein alterations
  • new protein functions

In lay terms also explained at biology.stackexchange

… the dominant allele encodes a protein that can perform its function. For example, the dominant allele for the CFTR gene encodes a channel that can let chloride into and out of the cells. The recessive allele, on the other hand encodes a protein that cannot do its job correctly (this also called a loss-of-function mutation). So if you inherit a functional copy from one parent and a non-functional copy from the other parent, you will still have one copy of the protein that can do its job. Only if you get a nonfunctional copy from both parents will you have a recessive condition called cystic fibrosis.

IVF eine Zeitbombe?

Nachdem es also doch so viele IVFs in Deutschland gibt (12.000 IVF bei 785.000 Geburten im Jahr ), wäre es doch mal interessant, was es an Spätwirkungen für die IVF Kinder gibt, sobald sie das niedrige Geburtsgewicht und angeborene Defekte überlebt haben.

S. 22 Jahrbuch Deutsches IVF Register 2018

Aus zwei Gründen ist die Frage allerdings nicht ganz leicht zu beantworten. Erstens gibt es bisher keine IVF Kinder, die älter als 40 Jahre sind und damit gibt es auch keine Erfahrung mit den typischen Krankheiten ab 60 Jahre.

Und zweitens gibt es diverse Krankheiten der Eltern, die überhaupt erst zur IVF geführt haben, aber nicht der IVF selbst angelastet werden können. Zudem sind IVF Mütter deutlich älter als im Durchschnitt, was selbst schon ein Krankheitsrisiko für die Kinder bedeutet.

Zumindestens von der Theorie her, ist die IVF jedenfalls nicht ganz ungefährlich für den Embryo, man braucht Hormone und ein künstliches Medium, was vor allem die Methylierungsstatus der Embryos beeinflusst (dazu gibt es mehrere Studien, die wichtigste von 2015). Eigenartigerweise gibt es aber nur wenig klinische Literatur zu dem Thema und Null Information am Deutschen IVF Register. Das Register schreibt mir am 31.12.

Auswertungen zu Spätfolgen gehören bisher nicht zu den Standardauswertungen des Deutschen IVF-Registers (D·I·R).

und setzt sich damit dem Vorwurf aus, mit dem Register primär PR zu betreiben.

Die fehlenden Studienbasis fiel auch vor kurzem auch dem Independent auf.
Das   letzte medizinische  IVF Review  ist leider schon etwas angejahrt. Beschriebene Risiken sind vor allem Depression im frühen Erwachsenenalter, Alkoholismus, erhöhter Bluthochdruck, erhöhter Nüchternzucker, erhöhter BMI, vorzeitige Knochenalterung sowie Schilddrüsenerkrankungen.  Hypertonie hört sich harmlos an,  wird  aber als ein Symptom einer vorzeitigen Gefäßalterung gewertet.

 

Eigentlich müsste es regelmässige Kontrolluntersuchungen nach IVF geben, am besten im Rahmen klinischer Studien.  Nicht umsonst wird auch die Richtlinie der assistierte Reproduktion gerade komplett neu verfasst, da die alte nicht mehr brauchbar war.

Could the correction of a deleterious mutation be a disadvantage?

When working on a forthcoming talk about the ethics of correcting gene defects, I asked myself: Are there any empirical examples where the correction of a so called “deleterious” mutation may be a disadvantage? Or in other words: Are there any beneficial side-effects of otherwise deleterious mutations?

(Don’t answer this with the joke that the Y chromosome is a X with a large deletion :-)

Yes, there are some examples of heterozygote advantage

  • HBB-p.E6V leads to sickle cell anemia and malaria resistance
  • CFTR Delta F508 leads to CF and protects against tuberculosis

Maybe I am not asking if there are beneficial/deleterious mutations in a single gene – the question here is more about distant / cis-regulating elements.  And there seems to be a thesis that

deleterious mutations have long been thought to be unimportant, however this view overlooks the pivotal role of epistasis. The unique experiments presented here give new insights into the historical and highly contingent nature of evolution. While evolution frequently finds a well adapted solution in the long-term, evolving populations will frequently climb suboptimal peaks initially. Deleterious mutations become useful because they aide evolution in reconciling short-term and long-term adaptation.

the thesis made it also into a PNAS paper

It might seem obvious that deleterious mutations must impede evolution. However, a later mutation may interact with a deleterious predecessor, facilitating otherwise inaccessible adaptations. … We studied digital organisms—computer programs that replicate and evolve—to compare adaptation in populations where deleterious mutations were disallowed with unrestricted controls. Control populations achieved higher fitness values because some deleterious mutations acted as stepping stones across otherwise impassable fitness valleys. Deleterious mutations can thus sometimes play a constructive role in adaptive evolution.

Looks like humans shouldn’t interfere with their own evolution as long as the rules are not known… The PNAS paper above has been cited many times, it will take some time to scan these for more empirical examples.

Weight Loss Advice

23andme is again in the headlines

Consumer DNA-testing giant 23andMe Inc. plans to add new wellness offerings it hopes will help its customers shed a few pounds, but some genetics experts say the jury is still out on the science behind the products.
On Tuesday, the Mountain View, California-based company announced a partnership with Lark Health, an artificial-intelligence coaching service that delivers personalized advice for weight loss and diabetes prevention via an app. Lark will allow customers to incorporate weight-related genetic data from 23andMe into its service.

We don’t need artifical intelligence for that, just a simple BMI table

Underweight Below 18.5
Normal 18.5–24.9
Overweight 25.0–29.9
Obesity 30.0 and Above

According to NIH recommendations people who are considered obese (BMI >30) or those who are overweight (BMI of 25-29.9) and have two or more risk factors, it is recommended to lose weight. Even a small weight loss of 5 to 10 percent of your current weight will help lower your disease risk. Point. No need to send your money to 23andme, just give it to a charity now. 23andme has already enough money for selling private data of some other boobies.

Genes and environment

An interesting interview 1999 at Edge reloaded: Children don’t do things half way: children don’t compromise with Judith Rich Harris

How the parents rear the child has no long-term effects on the child’s personality, intelligence, or mental health. […] The trouble is, the evidence is ambiguous. It’s clear that children resemble their biological parents; what isn’t clear is why. Is it the environment the parents provided, or is it the genes they provided? Just knowing there’s a correlation isn’t enough—we have to tease apart the effects of the genes from the effects of the home environment. One way to do it is by looking at adopted kids. And what we find is that the correlation disappears. The adopted child reared in a let’s-read-a book-together home ends up no smarter, on the average, than the one reared in a don’t-bother-me-I’m-watching-TV home. […] In fact, for personality (which is what I’m mainly interested in), only about half the variation from one person to another can be attributed to the genes. More precisely, about half the reliable variance in measured personality characteristics—the variance that remains after measurement error is subtracted—can be attributed to differences in genes. […] They still haven’t acknowledged the fact that whatever genetic predispositions the children have, there’s a good chance the parents have them too. […] In study after study, was that the environment shared by two kids reared in the same home could account for no more than 5 percent of the variance in personality characteristics. […] Well, the way children behave outside their parents’ home is certainly more lasting, because that’s where they’re going to spend their adult lives. […] the impetus comes from the child doing the conforming, not from the group. Tailoring your behavior to that of the other members of your group is something that people of all ages do automatically, usually without even realizing that they’re doing it.

Paternal mitochondrial inheritance

So far I thought this is not happening in humans, but a  PNAS paper published this month shows it may be even a genetic trait as the authors found biparental mtDNA inheritance in 17 members in three multi-generation families.
There are around 50-75 mitochondria in a single sperm which appears to be a quite low number (∼0.1%) relative to the number maternal mitochondria.
This unexpected paternal origin of mtDNA raises questions how exactly paternal mtDNA can escape its normal fate of being eliminated from the embryo. Are paternal mitos just being diluted and there is much more (micro-)heteroplasmy than currently known?
I don’t know why the authors didn’t do formal linkage analysis. And I also don’t know if their conclusion is correct “that occasional paternal transmission events seem to have left no detectable mark on the human genetic record” not citing an 1996 PNAS paper

In the majority of mammals—including humans—the midpiece mitochondria can be identified in the embryo even though their ultimate fate is unknown. The “missing mitochondria” story seems to have survived—and proliferated—unchallenged in a time of contention between hypotheses of human origins, because it supports the “African Eve” model of recent radiation of Homo sapiens out of Africa.

In the age of single cell sequencing it may no more be adequate to believe in maternal inheritance alone.

CRISPR CAS Babies: Doubt on the Sanger sequences

Using the new inDelphi (Nature 2018) prediction we can examine the gRNA guided cut used for the CRISPR Baby experiment. The results are somewhat unexpected

Maybe it is difficult to extrapolate from mouse to human embryonic stem cells but one observed event is not even listed here.

The results marked with a star have been observed

The -15 genotype has a probability of less than 0.05%. For +1 genotype the probability is 0.09% and for the -4 deletion it is 3.74%.

Looking therefore again at the Hong Kong slides of He Jiankui, I am getting doubts if the chromatogram  of embryo 2  is correct interpreted even if we admit that the labels of embryo 1 and 2 have been switched..

Color enhanced + sharpened version Hong Kong slide. Unfortunately the chromatograms do not expand to the left also.

Embryo 2 does not show a clean  sequence at all and certainly not a -4/+1 genotype as indicated everywhere “ATTTTCCATACAG-ATTCAATTCTGGACTAAAATAAATACCT” isn’t even a human sequence at all.

Gene Editing

Die Entwicklung des Gene Editing ist schwer nachvollziehbar ohne detaillierte Kenntnisse der Enzymchemie. Das neueste LJ 12/18 hat ziemlich versteckt auf S.44 eine exzellente Beschreibung von BE1 (mutiertes dCas9 mit APOBEC1-Cytidin-Deaminase, Einzellstrang R Loop),  BE2 (Uracil-Glycosylase-Inhibitor), BE3 (dCas9 mit Nick), HF-BE3 (high fidelity), BE4-GAM, BE4max, bis zum ABE 7th generation…

Das Basen-Editing tüftelten David Ruchien Liu und seine Mitarbeiter vom Broad-Institut in Cambridge, USA, aus. Sie kombinierten CRISPR-Cas-Komponenten mit Bestandteilen der mRNA-Editiersysteme, die sowohl Pro- wie auch Eukaryoten benutzen. Liu fasste die Methode in einer Presseerklärung so zusammen: „Wir haben programmierbare molekulare Maschinen entwickelt, die an einer von uns aus- gewählten Stelle im Genom eine Base austauschen, ohne dabei einen Doppelstrangbruch in die DNA einzufügen.“

Was noch fehlt?  Die bisherigen BE können bisher nur  Pyrimidine C -> T und T -> C, oder Purine A -> G und  G -> A Transitionen. Das Problem sind Transversionen von  Purinbase nach Pyrimidinbase oder umgekehrt also  T -> A oder C->G, denn dafür gibt es keine Enzyme.